Histone deacetylase inhibitors and compositions and methods of use thereof

Abstract

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

Claims

1. A method for treating a patient suffering from a condition or disorder mediated by at least one histone deacetylase, wherein the condition or disorder is cancer, amyotrophic lateral sclerosis (ALS), diabetes, a cardiovascular condition, epilepsy, depression, viral infection, or fungal infection, and wherein the method comprises administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, ##STR00098## wherein: each of the dashed lines indicate a single or double bond, provided that the ring contains one or two double bonds that are non-adjacent; R.sup.1 is C(O)NH(OH) or N(OH)C(O)R.sup.5, wherein R.sup.5 is hydrogen, lower alkyl or lower haloalkyl; R.sup.2 is aryl, heteroaryl, or heterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile; and R.sup.3 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, CONR.sub.bR.sub.c, alkyl, alkyl substituted with NR.sub.bR.sub.c, cycloalkyl, haloalkyl, hydroxyl, alkoxy, alkoxy substituted with NR.sub.bR.sub.c, aryl, heteroaryl, and nitrile; for each occurrence, R.sup.4 is independently selected from halo, lower alkyl, lower haloalkyl, and hydroxyl; x and y are independently selected from 1, 2, and 3, provided that the sum of x+y is 4, n is 0, 1, 2 or 3; R.sub.b is hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or heteroaryl; and R.sub.c is hydrogen or C.sub.1-C.sub.4 alkyl; or R.sub.b and R.sub.c, and the nitrogen to which they are attached, form a heterocycloalkyl group; and where for R.sub.b and R.sub.c, each C.sub.1-C.sub.6 alkyl, aryl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted with one or more substituents independently selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, aryl, heteroaryl, aryl-C.sub.1-C.sub.4 alkyl-, heteroaryl-C.sub.1-C.sub.4 alkyl-, C.sub.1-C.sub.4 haloalkyl-, OC.sub.1-C.sub.4 alkyl, OC.sub.1-C.sub.4 alkylphenyl, C.sub.1-C.sub.4 alkyl-OH, C.sub.1-C.sub.4 alkyl-OC.sub.1-C.sub.4 alkyl, OC.sub.1-C.sub.4 haloalkyl, halo, OH, NH.sub.2, C.sub.1-C.sub.4 alkyl-NH.sub.2, N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), NH(C.sub.1-C.sub.4 alkyl), N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkylphenyl), NH(C.sub.1-C.sub.4 alkylphenyl), cyano, nitro, oxo (as a substituent for heteroaryl), CO.sub.2H, C(O)OC.sub.1-C.sub.4 alkyl, CON(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), CONH(C.sub.1-C.sub.4 alkyl), CONH.sub.2, NHC(O)(C.sub.1-C.sub.4 alkyl), NHC(O)(phenyl), N(C.sub.1-C.sub.4 alkyl)C(O)(C.sub.1-C.sub.4 alkyl), N(C.sub.1-C.sub.4 alkyl)C(O)(phenyl), C(O)C.sub.1-C.sub.4 alkyl, C(O)C.sub.1-C.sub.4 phenyl, C(O)C.sub.1-C.sub.4 haloalkyl, OC(O)C.sub.1-C.sub.4 alkyl, SO.sub.2(C.sub.1-C.sub.4 alkyl), SO.sub.2(phenyl), SO.sub.2(C.sub.1-C.sub.4 haloalkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-C.sub.4 alkyl), SO.sub.2NH(phenyl), NHSO.sub.2(C.sub.1-C.sub.4 alkyl), NHSO.sub.2(phenyl), and NHSO.sub.2(C.sub.1-C.sub.4 haloalkyl).

2. The method of claim 1, wherein the compound of Formula I is a compound of Formula II, Formula III, or Formula IV: ##STR00099## or a pharmaceutically acceptable salt thereof.

3. The method of claim 1, wherein the compound of Formula I is a compound of Formula XI, Formula XII, or Formula XIII: ##STR00100## or a pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein R.sup.1 is C(O)NH(OH).

5. The method of claim 1, wherein R.sup.1 is N(OH)C(O)R.sup.5.

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

7. The method of claim 1, wherein R.sup.2 is heteroaryl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, and haloalkyl.

8. The method of claim 1, wherein R.sup.3 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

9. A method for treating a patient suffering from a condition or disorder mediated by at least one histone deacetylase, wherein the condition or disorder is cancer, amyotrophic lateral sclerosis (ALS), diabetes, a cardiovascular condition, epilepsy, depression, viral infection, or fungal infection, wherein the method comprises administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from: (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopent-2-enecarboxamide; (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(o-tolyl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(o-tolyl)cyclopent-2-enecarboxamide; (R)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide; (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrazin-2-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrazin-2-yl)cyclopent-2-enecarboxamide; (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxamide; (S)-3-(5-chloropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(quinoxalin-6-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrimidin-5-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(5-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxamide; (S)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-3-(2-cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)quinoxalin-6-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(imidazo[1,2-a]pyridin-7-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(3-methylbenzo[d]isoxazol-5-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide; (S)-3-(2-cyclopropylpyrimidin-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(6-methylpyridin-3-yl)cyclopent-2-enecarboxamide; (S)-3-(5-chloro-6-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)cyclopent-2-enecarboxamide; (S)-3-(benzo[d]isothiazol-7-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; N-hydroxy-1-phenylcyclopent-3-enecarboxamide; 1-(2-fluorophenyl)-N-hydroxycyclopent-3-enecarboxamide; (S)-3-cyclopropyl-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-N-hydroxy-1,3-diphenylcyclopent-2-enecarboxamide; (R)-N-hydroxy-1,3-diphenylcyclopent-2-enecarboxamide; (S)-3-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclopent-2-enecarboxamide; (S)-3-(5-chloro-2-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyridin-3-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxamide; (S)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-3-(benzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-3-(benzo[b]thiophen-2-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3,4-difluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxamide; 4-(5-fluoropyridin-3-yl)-N-hydroxy-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxamide; 3-fluoro-4-(5-fluoropyridin-3-yl)-N-hydroxy-2-methyl-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxamide; and 3-fluoro-N-hydroxy-2-methyl-4-(quinoxalin-6-yl)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxamide.

10. A method for treating a patient suffering from a neurodegenerative condition, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, ##STR00101## wherein: each of the dashed lines indicate a single or double bond, provided that the ring contains one or two double bonds that are non-adjacent; R.sup.1 is C(O)NH(OH) or N(OH)C(O)R.sup.5, wherein R.sup.5 is hydrogen, lower alkyl or lower haloalkyl; R.sup.2 is aryl, heteroaryl, or heterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile; and R.sup.3 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, CONR.sub.bR.sub.c, alkyl, alkyl substituted with NR.sub.bR.sub.c, cycloalkyl, haloalkyl, hydroxyl, alkoxy, alkoxy substituted with NR.sub.bR.sub.c, aryl, heteroaryl, and nitrile; for each occurrence, R.sup.4 is independently selected from halo, lower alkyl, lower haloalkyl, and hydroxyl; x and y are independently selected from 1, 2, and 3, provided that the sum of x+y is 4, n is 0, 1, 2 or 3; R.sub.b is hydrogen, C.sub.1-C.sub.6 alkyl, aryl, or heteroaryl; and R.sub.c is hydrogen or C.sub.1-C.sub.4 alkyl; or R.sub.b and R.sub.c, and the nitrogen to which they are attached, form a heterocycloalkyl group; and where for R.sub.b and R.sub.c, each C.sub.1-C.sub.6 alkyl, aryl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted with one or more substituents independently selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, aryl, heteroaryl, aryl-C.sub.1-C.sub.4 alkyl-, heteroaryl-C.sub.1-C.sub.4 alkyl-, C.sub.1-C.sub.4 haloalkyl-, OC.sub.1-C.sub.4 alkyl, OC.sub.1-C.sub.4 alkylphenyl, C.sub.1-C.sub.4 alkyl-OH, C.sub.1-C.sub.4 alkyl-OC.sub.1-C.sub.4 alkyl, OC.sub.1-C.sub.4 haloalkyl, halo, OH, NH.sub.2, C.sub.1-C.sub.4 alkyl-NH.sub.2, N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), NH(C.sub.1-C.sub.4 alkyl), N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkylphenyl), NH(C.sub.1-C.sub.4 alkylphenyl), cyano, nitro, oxo (as a substituent for heteroaryl), CO.sub.2H, C(O)OC.sub.1-C.sub.4 alkyl, CON(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), CONH(C.sub.1-C.sub.4 alkyl), CONH.sub.2, NHC(O)(C.sub.1-C.sub.4 alkyl), NHC(O)(phenyl), N(C.sub.1-C.sub.4 alkyl)C(O)(C.sub.1-C.sub.4 alkyl), N(C.sub.1-C.sub.4 alkyl)C(O)(phenyl), C(O)C.sub.1-C.sub.4 alkyl, C(O)C.sub.1-C.sub.4 phenyl, C(O)C.sub.1-C.sub.4 haloalkyl, OC(O)C.sub.1-C.sub.4 alkyl, SO.sub.2(C.sub.1-C.sub.4 alkyl), SO.sub.2(phenyl), SO.sub.2(C.sub.1-C.sub.4 haloalkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-C.sub.4 alkyl), SO.sub.2NH(phenyl), NHSO.sub.2(C.sub.1-C.sub.4 alkyl), NHSO.sub.2(phenyl), and NHSO.sub.2(C.sub.1-C.sub.4 haloalkyl), and the neurodegenerative condition is Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NIID), Dentatorubral pallidolusyian atrophy (DRPLA), Friedreich's ataxia, Rubenstein-Taubi Syndrome, a polyglutamine disease; spinocerebellar ataxia 1 (SCA 1), spinocerebellar ataxia 7 (SCA 7), seizures, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis, dyskinesis, familial tremor, Gilles de la Tourette syndrome, diffuse Lewy body disease, progressive supranuclear palsy, Pick's disease, primary lateral sclerosis, progressive neural muscular atrophy, spinal muscular atrophy, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, Shy-Drager syndrome, Kennedy's disease, protein-aggregation-related neurodegeneration, Machado-Joseph's disease, spongiform encephalopathy, prion-related disease, multiple sclerosis (MS), progressive supranuclear palsy (Steel-Richardson-Olszewski disease), Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, cerebellar degeneration, motor neuron disease, Werdnig-Hoffman disease, Wohlfart-Kugelberg-Welander disease, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, retinitis pigmentosa, Leber's disease, progressive systemic sclerosis, dermatomyositis, or mixed connective tissue disease.

11. The method of claim 10, wherein the compound of Formula I is a compound of Formula II, Formula III, or Formula IV: ##STR00102## or a pharmaceutically acceptable salt thereof.

12. The method of claim 10, wherein the compound of Formula I is a compound of Formula XI, Formula XII, or Formula XIII: ##STR00103## or a pharmaceutically acceptable salt thereof.

13. The method of claim 10, wherein R.sup.1 is C(O)NH(OH).

14. The method of claim 10, wherein R.sup.1 is N(OH)C(O)R.sup.5.

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

16. The method of claim 10, wherein R.sup.2 is heteroaryl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, and haloalkyl.

17. The method of claim 10, wherein R.sup.3 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

18. A method for treating a patient suffering from a neurodegenerative condition selected from Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NIID), Dentatorubral pallidolusyian atrophy (DRPLA), Friedreich's ataxia, Rubenstein-Taubi Syndrome, a polyglutamine disease; spinocerebellar ataxia 1 (SCA 1), spinocerebellar ataxia 7 (SCA 7), seizures, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia, spasmodic torticollis, dyskinesis, familial tremor, Gilles de la Tourette syndrome, diffuse Lewy body disease, progressive supranuclear palsy, Pick's disease, primary lateral sclerosis, progressive neural muscular atrophy, spinal muscular atrophy, hypertrophic interstitial polyneuropathy, retinitis pigmentosa, hereditary optic atrophy, hereditary spastic paraplegia, Shy-Drager syndrome, Kennedy's disease, protein-aggregation-related neurodegeneration, Machado-Joseph's disease, spongiform encephalopathy, prion-related disease, multiple sclerosis (MS), progressive supranuclear palsy (Steel-Richardson-Olszewski disease), Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, cerebellar degeneration, motor neuron disease, Werdnig-Hoffman disease, Wohlfart-Kugelberg-Welander disease, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, retinitis pigmentosa, Leber's disease, progressive systemic sclerosis, dermatomyositis, and mixed connective tissue disease; wherein the method comprises administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from: (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopent-2-enecarboxamide; (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(o-tolyl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(o-tolyl)cyclopent-2-enecarboxamide; (R)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide; (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrazin-2-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrazin-2-yl)cyclopent-2-enecarboxamide; (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxamide; (S)-3-(5-chloropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(quinoxalin-6-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrimidin-5-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(5-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxamide; (S)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-3-(2-cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)quinoxalin-6-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(imidazo[1,2-a]pyridin-7-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(3-methylbenzo[d]isoxazol-5-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide; (S)-3-(2-cyclopropylpyrimidin-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(6-methylpyridin-3-yl)cyclopent-2-enecarboxamide; (S)-3-(5-chloro-6-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)cyclopent-2-enecarboxamide; (S)-3-(benzo[d]isothiazol-7-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; N-hydroxy-1-phenylcyclopent-3-enecarboxamide; 1-(2-fluorophenyl)-N-hydroxycyclopent-3-enecarboxamide; (S)-3-cyclopropyl-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-N-hydroxy-1,3-diphenylcyclopent-2-enecarboxamide; (R)-N-hydroxy-1,3-diphenylcyclopent-2-enecarboxamide; (S)-3-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclopent-2-enecarboxamide; (S)-3-(5-chloro-2-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyridin-3-yl)cyclopent-2-enecarboxamide; (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxamide; (S)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-3-(benzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-3-(benzo[b]thiophen-2-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide; (S)-1-(3,4-difluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxamide; 4-(5-fluoropyridin-3-yl)-N-hydroxy-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxamide; 3-fluoro-4-(5-fluoropyridin-3-yl)-N-hydroxy-2-methyl-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxamide; and 3-fluoro-N-hydroxy-2-methyl-4-(quinoxalin-6-yl)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxamide.

Description

EXAMPLES

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

Abbreviations

(2) aq.: Aqueous DCM: Dichloromethane DCE: Dichloroethane DIPEA: Diisopropylethylamine DME: Dimethoxyethane DMF: Dimethylformamide DMSO: Dimethylsulfoxide ee: Enantiomeric excess ES+: Electrospray Positive Ionization ES: Electrospray Negative Ionization Et.sub.2O: Diethyl ether EtOAc: Ethyl acetate h: Hour HPLC: High Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry LiHMDS: Lithium bis(trimethylsilyl)amide M: Mass MeCN: Acetonitrile MeOH: Methanol NaHMDS Sodium bis(trimethylsilyl)amide NMP: N-Methyl pyrrolidinone o-tolyl: 2-Methylphenyl Pd/C: Palladium on carbon Pd.sub.2(dba).sub.3: Tris(dibenzylideneacetone)dipalladium(O) Pd(dppf)Cl.sub.2: [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM Pd(PPh.sub.3).sub.4: Tetrakis(triphenylphosphine)palladium(O) RT: Retention time r.t.: Room temperature sat.: Saturated TFFH: Tetramethylfluoroformamidinium hexafluorophosphate THF: Tetrahydrofuran TM: Target material Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
Analytical Conditions

(3) TABLE-US-00001 Analytical Condition Method Description 10 cm_ESI_Formic_MeCN, 1 Solvents: Acetonitrile (far UV grade) 10 cm_ESCI_Formic_MeCN 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) 15 cm_Formic_Ascentis_HPLC_MeCN 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: Supelco, Ascentis Express C18 or Hichrom Halo C18, 2.7 m C18, 150 4.6 mm. Flow Rate: 1 mL/min Gradient: A: Water/formic B: MeCN/formic Time A % B % 0.00 96 4 3.00 96 4 9.00 0 100 13.6 0 100 13.7 96 4 15 96 4 Typical Injections 2-7 L (concentration~0.2-1 mg/mL) 10 cm_Formic_ACE- 3 Solvents: Acetonitrile (far UV grade) with AR_HPLC_CH3CN, 0.1% (v/v) formic acid. Water 10 cm_Formic_ACE 3 C18 (high purity via PureLab Ultra unit) with AR_HPLC_CH3CN 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 acid B: MeCN/formic acid 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

(4) Compounds were named with the aid of the CambridgeSoft Chemistry Cartridge (v. 12.0.3.1212) software.

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

Preparation of Intermediates

Preparation of Intermediate 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-oxocyclopentane-carboxylate

(6) Method 1

(7) ##STR00007##

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

(8) (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 ethyl acetate and left to stand at 20 C. for 16 h. Precipitated solids were filtered and washed with cold Et.sub.2O/iso-hexane (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 (diethyl ether to EtOAc)this gives a close running impurity which can be easily separated at the next step.] R.sub.f=0.2 (66% EtOAc/iso-hexane); MS (ES+) consistent with target (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

(9) 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 iso-hexane to 50% EtOAc in iso-hexane) gave the title compound as a colorless glass (42.0 g, 93%). R.sub.f=0.55 (66% EtOAc/iso-hexane); MS (ES+) consistent with target (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

(10) 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. aq. 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 iso-hexane to 10% EtOAc in iso-hexane) gave the title compound as a colorless oil which darkens upon standing (30.0 g, 80%). R.sub.f=0.80 (60% EtOAc/iso-hexane); MS (ES+) consistent with target (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: (3S)-methyl 1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate

(11) 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 (1M 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 iso-hexane to 33% EtOAc in iso-hexane) 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/iso-hexane); MS (ES+) consistent with target (M+H).sup.+.

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

(12) 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 CH.sub.2Cl.sub.2 (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 iso-hexane to 40% EtOAc in iso-hexane) 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/iso-hexane); MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR (ppm) (CDCl.sub.3): 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/iso-hexane); MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR (ppm) (CDCl.sub.3): 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 1)

(13) To a solution of (1S,3S)-methyl 1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (1.60 g, 6.5 mmol) in anhydrous dichloromethane (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 CH.sub.2Cl.sub.2 (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 iso-hexane to 20% EtOAc in iso-hexane) to give the title compound as a colorless solid (1.42 g, 84%). R.sub.f=0.25 (33% EtOAc/iso-hexane); .sup.1H NMR (ppm) (CDCl.sub.3): 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 Intermediate 2: (R)-methyl 1-(3-fluoro-2-methylphenyl)-3-oxocyclopentane-carboxylate

(14) Method 2

(15) ##STR00008##

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

(16) 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 N-bromosuccinimide (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 iso-hexane to 10% EtOAc in iso-hexane) to give the title compound as a colorless oil (1.5 g, 35%). .sup.1H NMR (ppm) (CDCl.sub.3): 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

(17) 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 iso-hexane to 20% EtOAc in iso-hexane) gave the title compound as a white crystalline solid (2.06 g, 96%). .sup.1H NMR (ppm) (CDCl.sub.3): 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

(18) 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 HCl.sub.(aq) (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 iso-hexane to 5% EtOAc in iso-hexane) gave the title compound as a white crystalline solid (890 mg, 75%). .sup.1H NMR (ppm) (CDCl.sub.3): 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, 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

(19) 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 iso-hexane to 30% EtOAc in iso-hexane) gave the title compound as a white crystalline solid (766 mg, 75% [95% based on recovered starting material]). .sup.1H NMR (ppm) (CDCl.sub.3): 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)

(20) To a solution of (1S,3R)-methyl-1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (766 mg, 3.04 mmol) in anhydrous dichloromethane (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 CH.sub.2Cl.sub.2 (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 iso-hexane to 20% EtOAc in iso-hexane) to give the title compound as a colorless solid (656 mg, 86%). .sup.1H NMR (ppm) (CDCl.sub.3): 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).

Step 6: Recrystallization of Intermediate 2

(21) Intermediate 2 (1.8 g, Chiral HPLC: (Chiralpak IC 10/90 IPA/MeOH (50/50/0.1% formic acid)/heptane, 1.0 mL/min) 97.4% ee) was dissolved in minimum hot heptane and the solution allowed to cool. Crystals formed and the supernatant was decanted using a pipette. The process was repeated. The solid crystals were dried in vacuo to give the title compound (1.5 g). Chiral HPLC (Chiralpak IC 10/90 IPA/MeOH (50/50/0.1% formic acid)/heptane, 1.0 mL/min)>99.5% ee).

Preparation of Intermediate 3: ()-methyl 1-(3-fluoro-2-methylphenyl)-3-oxocyclopentane Carboxylate

(22) Prepared from ()-butane-1,2,4-triol following the procedures described in Method 1 for the preparation of Intermediate 1 but omitting the DBU mediated lactonization step (step 5). LCMS (ES+) 251 (M+H).sup.+, RT 3.80 min (Analytical method 1); .sup.1H NMR (ppm) (CDCl.sub.3): 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).

Preparation of Intermediate 4: (S)-methyl 1-phenyl-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate

(23) ##STR00009##

(R)-1,4-Dibromobutan-2-yl 2-phenyl Acetate

(24) To a stirred solution of (R)-1,4-dibromobutan-2-ol (2.70 g, 11.6 mmol), prepared following step 1 of Method 2 using (R)-butane-1,2,4-triol in place of (S)-butane-1,2,4-triol, in DCM (50 mL) was added phenylacetic acid (1.44 g, 10.6 mmol), dicyclohexylcarbodiimide (2.18 g, 10.6 mmol) and DMAP (20 mg, catalytic) and the mixture stirred at r.t for 17 h. The white solid was filtered 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 (3.95 g, >99%).

(1R,4S)-4-Phenyl-2-oxabicyclo[2.2.1]heptan-3-one

(25) To a stirred solution of (R)-1,4-dibromobutan-2-yl 2-phenyl acetate (3.54 g, 10.1 mmol) in 1,4-dioxane (150 mL) at r.t. was added LiHMDS (24 mL, 1 M in THF, 24 mmol) at a rate of 1 mL/min. After complete addition, the mixture was stirred for 1 h and quenched with 1 M HCl.sub.(aq) (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, 0-30% EtOAc in iso-hexane) gave the title compound as a white crystalline solid (1.01 g, 53%).

(1S,3R)-Methyl 3-hydroxy-1-phenylcyclopentanecarboxylate

(26) To a stirred solution of (1R,4S)-4-phenyl-2-oxabicyclo[2.2.1]heptan-3-one (1.01 g, 5.37 mmol) in MeOH (25 mL) was added 4 M HCl in dioxane (6 mL). The mixture was stirred at r.t for 17 h and then concentrated. Purification by flash silica chromatography (gradient elution, 0-35% EtOAc in iso-hexane) gave the title compound as a white crystalline solid (699 mg, 59%).

(S)-Methyl 3-oxo-1-phenylcyclopentanecarboxylate

(27) To a solution of (1S,3R)-methyl 3-hydroxy-1-phenylcyclopentanecarboxylate (699 mg, 3.18 mmol) in dichloromethane (20 mL) was added Dess-Martin Periodinane (1.62 g, 3.81 mol). The reaction mixture was stirred at r.t. for 3 h. Reaction mixture was quenched with a mixture of 10% Na.sub.2S.sub.2O.sub.3 and sat. aq. NaHCO.sub.3 solution (1:1, 50 mL) and then rapidly stirred for 30 minutes. Organic layers were extracted with further CH.sub.2Cl.sub.2 (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, 0-20% EtOAc in iso-hexane) to give the title compound as a colorless solid (656 mg, 86%).

(S)-Methyl 1-phenyl-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (Intermediate 4)

(28) (S)-Methyl 3-oxo-1-phenylcyclopentanecarboxylate (630 mg, 2.89 mmol) and THF (25 mL) were combined under a nitrogen atmosphere and cooled with an ice bath. NaHMDS (1 M in THF) (5.2 mL, 5.2 mmol) was added dropwise followed after 20 minutes by N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.59 g, 4.05 mmol). Reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Reaction mixture was then diluted with CH.sub.2Cl.sub.2, washed with water, evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a clear oil (590 mg, 58%).

Preparation of Examples

(29) General Synthetic Methods

(30) ##STR00010##
Method A (Vinyl Triflate Formation)

(31) To a solution of methyl 1-(3-fluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate (1.30 g, 5.20 mmol) in anhydrous THF (10 mL) was added drop-wise NaHMDS (1 M in THF, 5.80 mL, 5.80 mmol) at 0 C. The reaction mixture was stirred at 0 C. for 1 h. After this time N-phenylbistriflimide (2.23 g, 6.24 mmol) was added portionwise with 2 h additional stirring. The reaction mixture was quenched via addition of sat. NH.sub.4Cl (5 mL) with rapid stirring for 10 min. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). Organic layers were extracted, washed with brine (50 mL), then dried, filtered using a phase separation cartridge and concentrated to give a yellow oil.

(32) Comins' reagent (N,N-bis(trifluoromethylsulfonyl)-5-chloro-2-pyridylamine) may also be used in this method, in place of N-phenylbistriflimide.

(33) Method B (Suzuki Coupling)

(34) To a solution of methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.5 g, 1.31 mmol) in 1,2 dimethoxyethane (8 mL) was added boronic acid (1.31 mmol), potassium carbonate (0.362 g, 2.62 mmol) and water (4 mL). The reaction mixture was heated to 60 C. after which time a colorless solution formed. [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.06 g, 0.07 mmol) was added and the reaction mixture was heated to 80 C. under N.sub.2 for 2 h. After this time the reaction mixture was cooled to r.t. and filtered through Celite, washing with EtOAc (310 mL). Combined organics were extracted with water (15 mL) then brine (20 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated.

(35) Method B (ii) (Suzuki Coupling)

(36) To a solution of methyl-1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.2 g, 0.5 mmol) in 1,2 dimethoxyethane (8 mL) was added bis(pinacolato)diboron (0.15 g, 0.6 mmol), potassium acetate (0.060 g, 0.6 mmol), [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.03 g, 0.02 mmol) and water (2 mL). The reaction mixture was heated to 80 C. under N.sub.2 for 2 h. After this time the reaction mixture was cooled to r.t. and aryl bromide (0.57 mmol), potassium carbonate (0.036 g, 1.31 mmol) and tetrakis(triphenylphosphine)palladium(O) (0.03 g, 0.026 mmol) were added and the reaction mixture heated to 110 C. under N.sub.2 for 2 h. Reaction mixture was cooled to rt and filtered through Celite, washing with EtOAc (310 mL). Combined organics were extracted with water (15 mL) then brine (20 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated.

(37) Method B (iii) (Suzuki Coupling)

(38) To a solution of methyl-1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.3 g, 0.78 mmol) in 1,4 dioxane (8 mL) was added bis(pinacolato)diboron (0.298 g, 1.17 mmol), potassium acetate (0.154 g, 1.56 mmol), tris(dibenzylideneacetone) dipalladium(O), (0.215 g, 0.24 mmol) and S-Phos (0.038 g, 0.094 mmol). The reaction mixture was heated to 80 C. under N.sub.2 for 2 h. After this time the reaction mixture was cooled to r.t. and aryl bromide (0.86 mmol), cesium carbonate (0.51 g, 1.57 mmol) and palladium tetrakis(triphenylphosphine) (0.045 g, 0.039 mmol) were added and the reaction mixture heated to 110 C. under N.sub.2 for 1 h. Reaction mixture was cooled to r.t. and filtered through Celite, washing with EtOAc (310 mL). Combined organics were extracted with water (15 mL) then brine (20 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated.

(39) Method C (Ester Hydrolysis)

(40) To a solution of Suzuki product in methanol (7 mL) was added 15% w/v sodium hydroxide solution (3 mL). The reaction mixture was capped and heated at 60 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 (40 mL) and 1M aqueous HCl (20 mL). Organic layers were extracted, washed with brine (40 mL), dried, filtered (phase separation cartridge) and concentrated.

(41) Method C (ii) (Ester Hydrolysis)

(42) To a solution of ester (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.

(43) Method D (Hydroxamic Acid Formation)

(44) To a solution of carboxylic acid (0.08 g, 0.27 mmol), triethylamine (0.08 g, 115 L, 0.81 mmol) in anhydrous DMF (3 mL) was added tetramethylfluoroformamidinium hexafluorophosphate (0.09 g, 0.35 mmol) at 0 C. The reaction mixture was stirred at this temperature for 15 min, then O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.05 g, 0.41 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 (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.

(45) Where single enantiomers have been obtained from separation of racemic mixtures the (R) and (S) configuration has been assigned based on comparison to samples prepared from pure (R) or (S) intermediates or by the biochemical potency of single enantiomers.

Example 1: (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopent-2-enecarboxamide

(46) ##STR00011##

Step 1: (R)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate

(47) Following Method A from Intermediate 2 (1.30 g, 5.20 mmol). The residue was purified by flash silica column chromatography (gradient elution iso-hexane to 30% EtOAc in iso-hexane) to give the title compound as a colorless semi-solid (2.23 g, 112% by weight; contains residual PhN(Tf).sub.2). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (R)-methyl 1-(3-fluoro-2-methylphenyl)-3-phenylcyclopent-2-enecarboxylate

(48) Following Method B from (R)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.5 g, 1.31 mmol) and phenylboronic acid (0.16 g, 1.31 mmol). The crude product was purified by flash silica column chromatography (gradient elution iso-hexane to 25% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.23 g, 82%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (R)-1-(3-fluoro-2-methylphenyl)-3-phenylcyclopent-2-enecarboxylic Acid

(49) Following Method C from (R)-methyl 1-(3-fluoro-2-methylphenyl)-3-phenylcyclopent-2-ene-carboxylate (0.23 g) and used without further purification (0.194 g, 92%). MS (ES+) consistent with target (M+H).sup.+.

Step 4: (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopent-2-enecarboxamide

(50) Following Method D from (R)-1-(3-fluoro-2-methylphenyl)-3-phenylcyclopent-2-enecarboxylic acid (0.08 g, 0.27 mmol) and purified by preparative HPLC to give the title compound as a cream solid (44 mg, 52%). LCMS (ES+) 312 (M+H).sup.+, RT 3.89 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.12 (1H, s), 8.73 (1H, s), 7.58 (2H, d, J=1.6 Hz), 7.54-7.28 (3H, m), 7.18 (2H, q, J=1.6 Hz), 7.14 (1H, t, J=1.6 Hz), 6.49 (1H, s), 3.31-3.23 (1H, m), 2.90-2.84 (1H, m), 2.75-2.69 (1H, m), 2.14 (3H, d, J=2.4 Hz), 1.88-1.81 (1H, m).

Example 2: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopent-2-enecarboxamide

(51) ##STR00012##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate

(52) Following Method A from Intermediate 1 (1.50 g, 6.00 mmol). The residue was purified by flash silica column chromatography (gradient elution iso-hexane to 30% EtOAc in iso-hexane) to give the title compound as a colorless oil (1.73 g, 75%). MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR (ppm) (CDCl.sub.3): 7.14 (1H, q, J=1.6 Hz), 6.97 (2H, dd, J=1.6 Hz), 5.96 (1H, s), 3.69 (3H, s), 3.62-3.30 (1H, m), 2.88-2.84 (1H, m), 2.69-2.64 (1H, m), 2.08 (3H, d, J=2.4 Hz), 2.02-1.95 (1H, m).

Step 2: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-phenylcyclopent-2-enecarboxylate

(53) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.2 g, 0.52 mmol) and phenylboronic acid. The crude product was purified by flash silica column chromatography (gradient elution iso-hexane to 25% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.112 g, 70%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-3-phenylcyclopent-2-enecarboxylic Acid

(54) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-phenylcyclopent-2-ene-carboxylate (0.112 g, 0.36 mmol) and used without further purification (0.1 g, 94%). MS (ES+) consistent with target (M+H).sup.+.

Step 4: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopent-2-enecarboxamide

(55) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-phenylcyclopent-2-enecarboxylic acid (0.08 g, 0.27 mmol) and purified by preparative HPLC to give the title compound as a cream solid (0.02 g, 24%). LCMS (ES+) 312 (M+H).sup.+, RT 3.98 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.12 (1H, s), 8.74 (1H, s), 7.58 (2H, d, J=1.6 Hz), 7.54-7.28 (3H, m), 7.18 (2H, q, J=1.6 Hz), 7.14 (1H, t, J=1.6 Hz), 6.49 (1H, s), 3.31-3.23 (1H, m), 2.90-2.84 (1H, m), 2.75-2.69 (1H, m), 2.14 (3H, d, J=2.4 Hz), 1.88-1.81 (1H, m).

Example 3: (R)-1-(3-fluoro-2-methyl-phenyl)-N-hydroxy-3-(o-tolyl)cyclopent-2-ene-1-carboxamide

Example 4: (S)-1-(3-fluoro-2-methyl-phenyl)-N-hydroxy-3-(o-tolyl)cyclopent-2-ene-1-carboxamide

(56) ##STR00013##

Step 1: ()-methyl 1-(3-fluoro-2-methyl-phenyl)-3-(o-tolyl)cyclopent-2-ene-1-carboxylate

(57) Prepared from ()-methyl 1-(3-fluoro-2-methyl-phenyl)-3-(trifluoromethylsulfonyloxy)cyclopent-2-ene-1-carboxylate and 2-methylphenyl boronic acid following Method B to give the title compound as a clear oil. MS (ES+) consistent with (MCO.sub.2Me).sup.+.

Step 2: ()-1-(3-fluoro-2-methyl-phenyl)-3-(o-tolyl)cyclopent-2-ene-1-carboxylic Acid

(58) Prepared from ()-methyl 1-(3-fluoro-2-methyl-phenyl)-3-(o-tolyl)cyclopent-2-ene-1-carboxylate following Method C to give the title compound as a tan oil. MS (ES+) consistent with target (M+H).sup.+.

Step 3: (R)-1-(3-fluoro-2-methyl-phenyl)-N-hydroxy-3-(o-tolyl)cyclopent-2-ene-1-carboxamide and (S)-1-(3-fluoro-2-methyl-phenyl)-N-hydroxy-3-(o-tolyl)cyclopent-2-ene-1-carboxamide

(59) Following Method D from ()-1-(3-fluoro-2-methyl-phenyl)-3-(o-tolyl)cyclopent-2-ene-1-carboxylic acid followed by preparative HPLC then separation by chiral HPLC to give the title compounds as off white solids; enantiomer 1 (R) (15 mg, 100% ee) (Chiralpak IC 10/90 IPA/MeOH (50/50/0.1% formic acid)/heptane, 5.0 mL/min), 1000 psi); RT 7.4 min (Chiralpak IC 10/90 IPA/MeOH (50/50/0.1% formic acid)/heptane, 1.0 mL/min); LCMS (ES+) 326 (M+H).sup.+, RT 4.14 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.07 (1H, s), 8.73 (1H, s), 7.27-7.16 (6H, m), 7.09-7.04 (1H, m), 6.08 (1H, s), 3.32-3.25 (1H, m), 2.91-2.83 (1H, m), 2.68-2.61 (1H, m), 2.41 (3H, s), 2.14 (3H, d, J=2.5 Hz), 1.83-1.76 (1H, m).

(60) Enantiomer 2 (S) (15 mg, 100% ee) (Chiralpak IC 10/90 IPA/MeOH (50/50/0.1% formic acid)/heptane, 5.0 mL/min), 1000 psi); RT 8.5 mins (Chiralpak IC 10/90 IPA/MeOH (50/50/0.1% formic acid)/heptane, 1.0 mL/min); LCMS (ES+) 326 (M+H).sup.+, RT 4.15 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.07 (1H, s), 8.73 (1H, s), 7.27-7.16 (6H, m), 7.09-7.04 (1H, m), 6.08 (1H, s), 3.32-3.25 (1H, m), 2.91-2.83 (1H, m), 2.68-2.61 (1H, m), 2.41 (3H, s), 2.14 (3H, d, J=2.5 Hz), 1.83-1.76 (1H, m).

Example 5: (R)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide

Example 6: (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide

(61) From Intermediate 3:

(62) ##STR00014##

Step 1: ()-methyl 1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoropyridin-3-yl)cyclopent-2-ene-1-carboxylate

(63) A suspension of ()-methyl 1-(3-fluoro-2-methyl-phenyl)-3-(trifluoromethylsulfonyloxy)cyclopent-2-ene-1-carboxylate (prepared using Method A from Intermediate 3, 1.01 g, 2.64 mmol), 3-fluoropyridine-5-boronic acid (376 mg, 2.67 mmol), Pd(PPh.sub.3).sub.4 (153 mg, 0.13 mmol) and CsF (597 mg, 3.93 mmol in 4:1 v/v DME:MeOH (8.7 mL) was stirred at 120 C. for 1 h under microwave irradiation. The mixture was concentrated onto silica and purified by silica column chromatography (gradient elution, 0-100% EtOAc in iso-hexane) to yield the title compound as a white powder (760 mg, 87%). MS (ES+) consistent with target (M+H).sup.+.

Step 2: ()-1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoropyridin-3-yl)cyclopent-2-ene-1-carboxylic Acid

(64) From ()-methyl 1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoropyridin-3-yl)cyclopent-2-ene-1-carboxylate (760 mg, 2.31 mmol) using Method C. After cooling to room temperature the mixture was concentrated to dryness and partitioned between water (20 mL) and EtOAc (20 mL). The mixture was acidified to pH 6 with acetic acid before separating the two phases. The aqueous phase was extracted with EtOAc (20 mL); the combined organic extracts were dried (Na.sub.2SO.sub.4) and concentrated. Purification by flash silica column chromatography (gradient elution CH.sub.2Cl.sub.2 to 10% MeOH in CH.sub.2Cl.sub.2) yielded the title compound as shiny white prisms (503 mg, 69%).

Step 3: ()-1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoropyridin-3-yl)-N-tetrahydropyran-2-yloxy-cyclopent-2-ene-1-carboxamide

(65) A stirred solution of ()-1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoro-3-pyridyl)cyclopent-2-ene-1-carboxylic acid (104 mg, 0.33 mmol) in DMF (2.3 mL) at 20 C. was treated with Et.sub.3N (0.13 mL, 0.93 mmol) and TFFH (106 mg, 0.40 mmol). The mixture was stirred for 15 min before addition of O-(tetrahydropyranyl)hydroxylamine (45.2 mg, 0.39 mmol), after which stirring was continued for 19 h. The reaction was poured into water (50 mL) and extracted with EtOAc (325 mL). The combined organic extracts were washed with water (325 mL) and brine (25 mL), dried (Na.sub.2SO.sub.4) and concentrated. Purification by flash silica column chromatography (gradient elution iso-hexane to 100% EtOAc in iso-hexane) yielded the title compound as a colorless oil (81 mg, 59%). MS (ES+) consistent with target (M+H).sup.+.

Step 4: (R)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide and (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide

(66) A solution of ()-1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoropyridin-3-yl)-N-tetrahydropyran-2-yloxy-cyclopent-2-ene-1-carboxamide (81 mg, 0.20 mmol) in 2:1 v/v THF:water (8.6 mL) at 20 C. was treated with PTSA monohydrate (26.5 mg, 0.14 mmol). The mixture was stirred in a sealed tube at 50 C. for 6 h. After cooling to room temperature, MP-carbonate beads (227 mg) were added and the mixture stirred for 50 min. The mixture was filtered to remove solids, washing with EtOAc (55 mL). The filtrate was concentrated and purified by preparative HPLC to give the racemic product as a white solid (35 mg, 54%). Preparative chiral purification gave the title compounds as white solids: (R) enantiomer (14 mg, 22% yield, 100% ee); (Chiralpak IA 40/60 EtOH (0.1% formic acid)/heptane, 5.0 mL/min), 1400 psi); RT 13.15 min (Chiralpak IA 40/60 EtOH (0.1% formic acid)/heptane, 1.0 mL/min); LCMS (ES+) 331 (M+H).sup.+, RT 3.32 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.21 (1H, s), 8.82 (1H, s), 8.70 (1H, apparent t, J=1.6 Hz), 8.55 (1H, d, J=2.6 Hz), 7.97 (1H, ddd, J=8.8, 4.0, 3.3 Hz), 7.24-7.19 (2H, m), 7.13-7.06 (1H, m), 6.78 (1H, s), 3.30-3.23 (1H, m), 2.99-2.90 (1H, m), 2.83-2.70 (1H, m), 2.17 (3H, d, J=2.5 Hz), 1.94 (1H, ddd, J=13.1, 9.1, 6.1 Hz);

(67) (S) enantiomer (13 mg, 20% yield, 100% ee); (Chiralpak IA 40/60 EtOH (0.1% formic acid)/heptane, 5.0 mL/min), 1400 psi); RT 9.46 min (Chiralpak IA 40/60 EtOH (0.1% formic acid)/heptane, 1.0 mL/min); LCMS (ES+) 331 (M+H).sup.+, RT 3.32 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.21 (1H, s), 8.82 (1H, s), 8.70 (1H, apparent t, J=1.6 Hz), 8.55 (1H, d, J=2.6 Hz), 7.97 (1H, ddd, J=8.8, 4.0, 3.3 Hz), 7.24-7.19 (2H, m), 7.13-7.06 (1H, m), 6.78 (1H, s), 3.30-3.23 (1H, m), 2.99-2.90 (1H, m), 2.83-2.70 (1H, m), 2.17 (3H, d, J=2.5 Hz), 1.94 (1H, ddd, J=13.1, 9.1, 6.1 Hz).

Example 5: (R)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide

(68) From Intermediate 2:

(69) ##STR00015##

Step 1: (R)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)cyclopent-2-enecarboxylate

(70) Following Method B from (R)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.4 g, 1.05 mmol) and 3-fluoropyridine-5-boronic acid. The crude product was purified by flash silica column chromatography (gradient elution, 0-33% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.23 g, 65%). MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR (ppm) (CDCl.sub.3): 8.61 (1H, t, J=1.7 Hz), 8.41 (1H, d, J=2.7 Hz), 7.53-7.47 (1H, m), 7.17-7.09 (1H, m), 7.07-6.92 (2H, m), 6.45 (1H, t, J=1.9 Hz), 3.70 (3H, s), 3.37 (1H, ddd, J=13.3, 8.8, 4.3 Hz), 3.08-2.97 (1H, m), 2.83 (1H, dddd, J=16.1, 9.3, 4.5, 1.9 Hz), 2.14 (3H, d, J=2.5 Hz), 2.06 (1H, ddd, J=13.2, 9.3, 6.0 Hz).

Step 2: (R)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)cyclopent-2-enecarboxylic Acid

(71) Following Method C from (R)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)cyclopent-2-enecarboxylic acid (0.20 g) and used without further purification (0.196 g, 97%). MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR (ppm) (DMSO-d.sub.6): 12.66 (1H, s), 8.68 (1H, s), 8.48 (1H, d, J=2.7 Hz), 8.01 (1H, d, J=10.5 Hz), 7.18-7.10 (2H, m), 7.05-6.98 (1H, m), 6.80 (1H, s), 3.14 (1H, ddd, J=13.0, 8.9, 4.5 Hz), 2.99-2.88 (1H, m), 2.80-2.70 (1H, m), 2.12 (3H, d, J=2.5 Hz), 1.90 (1H, ddd, J=13.0, 9.3, 5.9 Hz).

Step 3: (R)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide

(72) Following Method D from (R)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)cyclopent-2-enecarboxylic acid (0.18 g, 0.57 mmol) and purified by preparative HPLC (130 mg, 69%). LCMS (ES+) 331 (M+H).sup.+; RT 3.41 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.21 (1H, s), 8.82 (1H, s), 8.70 (1H, apparent t, J=1.6 Hz), 8.55 (1H, d, J=2.6 Hz), 7.97 (1H, ddd, J=8.8, 4.0, 3.3 Hz), 7.24-7.19 (2H, m), 7.13-7.06 (1H, m), 6.78 (1H, s), 3.30-3.23 (1H, m), 2.99-2.90 (1H, m), 2.83-2.70 (1H, m), 2.17 (3H, d, J=2.5 Hz), 1.94 (1H, ddd, J=13.1, 9.1, 6.1 Hz).

Example 7: (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrazin-2-yl)cyclopent-2-ene carboxamide

Example 8: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrazin-2-yl)cyclopent-2-ene carboxamide

(73) ##STR00016##

Step 1: ()-methyl 1-(3-fluoro-2-methylphenyl)-3-(pyrazin-2-yl)cyclopent-2-ene-1-carboxylate

(74) Following Method B (ii) from ()-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl) sulfonyl) oxy) cyclopent-2-enecarboxylate (0.1 g, 0.26 mmol) and 2-bromopyrazine. The crude product was purified by flash silica column chromatography (gradient elution iso-hexane to 25% EtOAc in iso-hexane) to give the title compound as a pale yellow oil (55 mg, 72%). MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR (ppm) (CDCl.sub.3): 8.77 (1H, s), 8.58 (1H, d, J=1.6 Hz), 8.48 (1H, d, J=1.6 Hz), 7.14-7.06 (2H, m), 6.97 (1H, t, J=2.6 Hz), 6.87 (1H, s), 3.71 (3H, s), 3.40-3.36 (1H, m), 3.12-3.09 (1H, m), 2.98-2.94 (1H, m), 2.15 (3H, d, J=2.4 Hz), 2.12-2.06 (1H, m).

Step 2: ()-1-(3-fluoro-2-methylphenyl)-3-(pyrazin-2-yl)cyclopent-2-ene-carboxylic Acid

(75) Following Method C from ()-methyl 1-(3-fluoro-2-methylphenyl)-3-(pyrazin-2-yl)cyclopent-2-ene-1-carboxylate (0.055 g, 0.18 mmol) and used without further purification (0.049 g, 94%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrazin-2-yl)cyclopent-2-enecarboxamide and (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrazin-2-yl)cyclopent-2-enecarboxamide

(76) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(pyrazin-2-yl)cyclopent-2-enecarboxylic acid (0.1 g, 0.33 mmol) and purified by preparative HPLC to give the racemic product as a cream solid (43 mg, 35%). Preparative chiral purification gave the title compounds as white solids; (S) enantiomer (12 mg, 20%, >99.5% ee) (Chiralpak IA 50/50 IPA/MeOH (0.1% formic acid)/heptane, 5.0 mL/min), r.t., 1400 psi); LCMS (ES+) 331 (M+H).sup.+, RT 3.03 min (Analytical method 1); RT 18.0 min, (Chiralpak IA 40/60 EtOH (0.1% formic acid)/heptane, 1.0 mL/min, r.t.); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.22 (1H, s), 8.92 (1H, s), 8.78 (1H, s), 8.65 (1H, d, J=1.6 Hz), 8.55 (1H, d, J=1.6 Hz), 7.19-7.04 (3H, m), 7.02 (1H, s), 3.30-3.26 (1H, m), 2.97-2.91 (1H, m), 2.84-2.82 (1H, m), 2.14 (3H, d, J=2.4 Hz), 1.94-1.87 (1H, m).

(77) (R) enantiomer (11.5 mg, 19%, >99.5% ee) (Chiralpak IA 50/50 IPA/MeOH (0.1% formic acid)/heptane, 5.0 mL/min), r.t., 1400 psi). LCMS (ES+) 331 (M+H).sup.+, RT 3.03 min (Analytical method 1); RT 11.8 min (Chiralpak IA 40/60 EtOH (0.1% formic acid)/heptane, 1.0 mL/min); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.22 (1H, s), 8.92 (1H, s), 8.78 (1H, s), 8.65 (1H, d, J=1.6 Hz), 8.55 (1H, d, J=1.6 Hz), 7.19-7.04 (3H, m), 7.02 (1H, s), 3.30-3.26 (1H, m), 2.97-2.91 (1H, m), 2.84-2.82 (1H, m), 2.14 (3H, d, J=2.4 Hz), 1.94-1.87 (1H, m).

Example 9: (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxamide

(78) ##STR00017##

Step 1: (R)-methyl 1-(3-fluoro-2-methylphenyl)-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxylate

(79) Following Method B from (R)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.5 g, 1.31 mmol). The crude product was purified by flash silica column chromatography (gradient elution, 0-50% EtOAc in iso-hexane) to give the title compound as a brown oil (0.14 g, 33%); MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR (ppm) (CDCl.sub.3): 8.76 (2H, s), 7.16-7.09 (1H, m), 7.06-6.91 (2H, m), 6.46-6.40 (1H, m), 3.71 (3H, s), 3.37 (1H, ddd, J=13.3, 8.8, 4.4 Hz), 3.07-2.96 (1H, m), 2.83 (1H, dddd, J=16.1, 9.3, 4.4, 1.9 Hz), 2.76 (3H, s), 2.14 (3H, d, J=2.5 Hz), 2.10-1.99 (1H, m).

Step 2: (R)-1-(3-fluoro-2-methylphenyl)-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxylic Acid

(80) Following Method C from (R)-methyl 1-(3-fluoro-2-methylphenyl)-3-(2-methylpyrimidin-5-yl) cyclopent-2-enecarboxylate (0.14 g) and used without further purification (0.12 g, 90%); MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR (ppm) (DMSO-d.sub.6): 12.70 (1H, s), 8.94 (2H, s), 7.20-7.11 (2H, m), 7.08-7.02 (1H, m), 6.79 (1H, s), 3.16 (1H, ddd, J=13.23, 8.77, 4.30 Hz), 2.98-2.87 (1H, m), 2.81-2.71 (1H, m), 2.61 (3H, s), 2.13 (3H, d, J=2.46 Hz), 1.95-1.85 (1H, m).

Step 3: (R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxamide

(81) Following Method D from (R)-1-(3-fluoro-2-methylphenyl)-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxylic acid (0.12 g, 0.38 mmol) and purified by preparative HPLC (41 mg, 37%); LCMS (ES+) 328 (M+H).sup.+, RT 3.03 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.17 (1H, s), 8.89 (2H, s), 8.78 (1H, s), 7.19-7.05 (3H, m), 6.70 (1H, s), 3.31-3.26 (1H, m), 2.91-2.87 (1H, m), 2.78-2.72 (1H, m), 2.64 (3H, s), 2.14 (3H, d, J=2.4 Hz), 1.93-1.86 (1H, m).

Example 10: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxamide

(82) ##STR00018##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(2-methylpyrimidin-5-yl)cyclopent-2-ene Carboxylate

(83) Following Method B (ii) from (S)-methyl-1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.2 g, 0.5 mmol). Crude material was purified by flash silica column chromatography (gradient elution iso-hexane to 100% EtOAc in iso-hexane) to yield the title compound as a pale yellow oil (0.108 g, 63%). MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR (ppm) (CDCl.sub.3): 8.62 (2H, s), 7.14-6.97 (3H, m), 6.76 (1H, s), 3.71 (3H, s), 3.40-3.36 (1H, m), 3.12-3.09 (1H, m), 2.98-2.94 (1H, m), 2.68 (3H, s) 2.15 (3H, d, J=2.4 Hz), 2.12-2.06 (1H, m).

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxylic Acid

(84) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(2-methylpyrimidin-5-yl)cyclopent-2-ene-carboxylate (0.108 g, 0.33 mmol) and used without further purification (0.074 g, 72%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyrimidin-5-yl)cyclopent-2-ene Carboxamide

(85) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(2-methylpyrimidin-5-yl)cyclopent-2-enecarboxylic acid (0.074 g, 0.24 mmol) and purified by preparative HPLC to give the title compound as a cream solid (0.02 g, 28%). LCMS (ES+) 328 (M+H).sup.+, RT 2.93 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.17 (1H, s), 8.89 (2H, s), 8.78 (1H, s), 7.19-7.05 (3H, m), 6.70 (1H, s), 3.31-3.26 (1H, m), 2.91-2.87 (1H, m), 2.78-2.72 (1H, m), 2.64 (3H, s), 2.14 (3H, d, J=2.4 Hz), 1.93-1.86 (1H, m).

Example 11: (S)-3-(5-chloropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(86) ##STR00019##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-chloropyridin-3-yl)cyclopent-2-enecarboxylate

(87) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (700 mg, 1.83 mmol) and 3-chloropyridine-5-boronic acid utilizing CsF, DME, MeOH and palladium tetrakis(triphenylphosphine) at 120 C. The crude product was purified by flash column chromatography to give the title compound as a clear gum (354 mg, 56%). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(5-chloropyridin-3-yl)cyclopent-2-enecarboxylic Acid

(88) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-chloropyridin-3-yl)cyclopent-2-enecarboxylate (350 mg) and used without further purification (332 mg, 100%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-3-(5-chloropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(89) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(5-chloropyridin-3-yl)cyclopent-2-enecarboxylic acid (332 mg, 1 mmol) and purified by preparative HPLC to give the title compound as a white solid (144 mg, 42%). LCMS (ES+) 347/349 (M+H).sup.+; RT 3.47 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.17 (1H, s), 8.78 (1H, s), 8.74 (1H, d, J=2 Hz), 8.56 (1H, d, J=2.4 Hz), 8.13 (1H, t, J=2 Hz), 7.20-7.17 (2H, m), 7.09-7.05 (1H, m), 6.76 (1H, s), 3.35-3.20 (1H, m), 2.95-2.88 (1H, m), 2.79-2.72 (1H, m), 2.14 (3H, d, J=2.4 Hz), 1.95-1.88 (1H, m).

Example 12: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(quinoxalin-6-yl)cyclopent-2-enecarboxamide

(90) ##STR00020##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(quinoxalin-6-yl)cyclopent-2-enecarboxylate

(91) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (330 mg, 0.86 mmol) and quinoxaline-5-boronic acid utilizing CsF, DME, MeOH and palladium tetrakis(triphenylphosphine) at 120 C. The crude product was purified by flash column chromatography to give the title compound as a clear gum (299 mg, 96%). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(quinoxalin-6-yl)cyclopent-2-enecarboxylic Acid

(92) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(quinoxalin-6-yl)cyclopent-2-enecarboxylate (290 mg) and used without further purification (201 mg MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(quinoxalin-6-yl)cyclopent-2-enecarboxamide

(93) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(quinoxalin-6-yl)cyclopent-2-enecarboxylic acid (200 mg, 0.57 mmol) and purified by preparative HPLC to give the title compound as a tan solid (109 mg, 53%). LCMS (ES+) 364 (M+H).sup.+; RT 3.41 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.21 (1H, s), 8.97 (1H, d, J=1.6 Hz), 8.93 (1H, d, J=2 Hz), 8.80 (1H, s), 8.22 (1H, dd, J=8.8, 1.6 Hz), 8.11 (1H, d, J=8.8 Hz), 8.05 (1H, d, J=1.6 Hz), 7.25-7.15 (2H, m), 7.11-7.06 (1H, m), 6.86 (1H, s), 3.35-3.25 (1H, m), 3.08-3.01 (1H, m), 2.94-2.89 (1H, m), 2.17 (3H, d, J=2.4 Hz), 1.99-1.92 (1H, m).

Example 13: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)cyclopent-2-enecarboxamide

(94) ##STR00021##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)pyridin-4-yl)cyclopent-2-enecarboxylate

(95) Following Method B from (S) methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (310 mg, 0.81 mmol) and 2-trifluoromethyl-pyridine-4-boronic acid utilizing CsF, DME, MeOH and palladium tetrakis(triphenylphosphine) at 120 C. The crude product was purified by flash column chromatography to give the title compound as a clear gum (194 mg, 63%).

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)pyridin-4-yl)cyclopent-2-enecarboxylic Acid

(96) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)pyridin-4-yl)cyclopent-2-enecarboxylate (190 mg) and used without further purification (141 mg, 77%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)cyclopent-2-enecarboxamide

(97) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)pyridin-4-yl)cyclopent-2-enecarboxylic acid (141 mg, 0.39 mmol) and purified by preparative HPLC to give the title compound as a tan solid (35 mg, 24%). LCMS (ES+) 381 (M+H).sup.+; RT 10.5 min (Analytical method 3); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.20 (1H, s), 8.82 (1H, s), 8.77 (1H, d, J=5.2 Hz), 8.15 (1H, s), 7.80 (1H, d, J=5.2 Hz), 7.20-7.04 (4H, m), 3.35-3.20 (1H, m), 2.97-2.92 (1H, m), 2.83-2.76 (1H, m), 2.15 (3H, d, J=2.4 Hz), 2.09-1.93 (1H, m).

Example 14: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrimidin-5-yl)cyclopent-2-enecarboxamide

(98) ##STR00022##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(pyrimidin-5-yl)cyclopent-2-enecarboxylate

(99) Following Method B from (S) methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (380 mg, 1 mmol) and pyrimidine-5-boronic acid utilizing CsF, DME, MeOH and palladium tetrakis (triphenylphosphine) at 120 C. The crude product was purified by flash column chromatography to give the title compound as a clear gum (327 mg, 100%). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(pyrimidin-5-yl)cyclopent-2-enecarboxylic Acid

(100) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(pyrimidin-5-yl)cyclopent-2-enecarboxylate (320 mg) and used without further purification (296 mg, 97%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrimidin-5-yl)cyclopent-2-enecarboxamide

(101) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(pyrimidin-5-yl)cyclopent-2-enecarboxylic acid (262 mg, 0.88 mmol) and purified by preparative HPLC to give the title compound as a tan solid (144 mg, 52%). LCMS (ES+) 314 (M+H).sup.+; RT 3.02 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.19 (1H, s), 9.15 (1H, s), 9.03 (2H, s), 8.78 (1H, s), 7.21-7.17 (2H, m), 7.15-7.04 (1H, m), 6.86 (1H, s), 3.35-3.21 (1H, m), 2.97-2.90 (1H, m), 2.81-2.74 (1H, m), 2.14 (3H, d, J=2 Hz), 2.09-1.93 (1H, m).

Example 15: (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)-N-hydroxycyclopent-2-enecarboxamide

(102) ##STR00023##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)cyclopent-2-enecarboxylate

(103) Following Method B (iii) from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.3 g, 0.78 mmol). The crude product was purified by flash column chromatography to yield the title compound as a pale yellow gum (217 mg, 84%). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)cyclopent-2-enecarboxylic Acid

(104) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)cyclopent-2-enecarboxylate (217 mg) and used without further purification (187 mg, 72%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)-N-hydroxycyclopent-2-enecarboxamide

(105) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)cyclopent-2-enecarboxylic acid (187 mg, 0.59 mmol) and purified by preparative HPLC to give the title compound as an off white solid (89 mg, 45%). LCMS (ES+) 331 (M+H).sup.+; RT 3.53 min (Analytical method 1). .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.16 (1H, s), 8.73 (1H, s), 8.57 (1H, d, J=2.9 Hz), 7.77-7.64 (2H, m), 7.22-7.00 (3H, m), 6.79 (1H, s), 3.29-3.22 (1H, m), 2.93-2.82 (1H, m), 2.80-2.70 (1H, m), 2.12 (3H, d, J=2.4 Hz), 1.90-1.79 (1H, m).

Example 16: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxamide

(106) ##STR00024##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxylate

(107) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.25 g, 0.65 mmol), (6-(trifluoromethyl)pyridin-3-yl)boronic acid utilizing CsF, DME, MeOH and palladium tetrakis(triphenylphosphine) under microwave conditions at 120 C. for 1 h. The crude product was triturated with diethyl ether to give the title compound as an orange solid (274 mg). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxylic Acid

(108) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxylate (274 mg) and used without further purification (193 mg, 80% over two steps). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxamide

(109) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxylic acid (193 mg, 0.53 mmol) and purified by recrystallization from DCM to give the title compound as an off white solid (91 mg, 45%). LCMS (ES+) 381 (M+H).sup.+; RT 10.7 min (Analytical method 3). .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.19 (1H, s), 8.98 (1H, s), 8.78 (1H, s), 8.19 (1H, d, J=8.2 Hz), 7.90 (1H, d, J=8.2 Hz), 7.22-7.11 (2H, m), 7.12-7.02 (1H, m), 6.82 (1H, s), 3.25 (1H, ddd, J=13.2, 8.8, 4.4 Hz), 2.98-2.87 (1H, m), 2.82-2.73 (1H, m), 2.13 (3H, d, J=2.5 Hz), 1.97-1.86 (1H, m).

Example 17: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(5-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxamide

(110) ##STR00025##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxylate

(111) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.25 g, 0.65 mmol) and (5-(trifluoromethyl)pyridin-3-yl)boronic acid utilizing CsF, DME, MeOH and palladium tetrakis(triphenylphosphine) under microwave conditions at 120 C. for 1 h. The crude product (340 mg) was used without further purification in the next step. MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxylic Acid

(112) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxylate (340 mg) and used without further purification (262 mg, 92% over two steps). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(5-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxamide

(113) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)cyclopent-2-enecarboxylic acid (193 mg, 0.53 mmol) and purified by recrystallization from DCM to give the title compound as an off white solid (91 mg, 45%). LCMS (ES+) 381 (M+H).sup.+; RT 10.4 min (Analytical method 3); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.17 (1H, s), 9.07 (1H, s), 8.91 (1H, s), 8.79 (1H, s), 8.37 (1H, s), 7.24-7.14 (2H, m), 7.12-7.04 (1H, m), 6.88 (1H, s), 3.29-3.19 (1H, m), 3.04-2.92 (1H, m), 2.87-2.77 (1H, m), 2.16 (3H, d, J=2.5 Hz), 2.01-1.90 (1H, m).

Example 18: (S)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(114) ##STR00026##

Step 1: 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

(115) A 100 mL round bottom flask was charged with 4-pyrazoleboronic acid pinacol ester (1.0 g, 5.15 mmol), 18-crown-6 (0.27 g, 1.03 mmol) and anhydrous acetonitrile (25 mL). The reagents were stirred until a colorless solution formed then sodium chlorodifluoroacetate (0.94 g, 6.18 mmol) was added and the reaction mixture heated to reflux for 18 h. After this time the reaction mixture was cooled to r.t. and the precipitated solid removed by filtration through celite, washing with EtOAc (320 mL). Combined organics were filtered through a hydrophobic frit and condensed to give a pale yellow oil. The crude product was purified by flash silica column chromatography (gradient elution iso-hexane to 33% EtOAc in iso-hexane) to give the title compound as a colorless solid (1.06 g, 84%). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-methyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(116) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.15 g, 0.40 mmol) and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.10 g, 0.41 mmol). The crude product was purified by flash silica column chromatography (gradient elution iso-hexane to 33% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.12 g, 77%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic Acid

(117) Following Method C (ii) from (S)-methyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (0.05 g, 0.14 mmol) to give a colorless residue which crystallized on standing (0.43 g, 89%). MS (ES+) consistent with target (M+H).sup.+.

Step 4: (S)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(118) Following Method D from (S)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic acid (0.04 g, 0.12 mmol) and purified by preparative HPLC (22 mg, 52%). LCMS (ES+) 352 (M+H).sup.+; RT 3.57 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.17 (1H, s), 8.78 (1H, s), 8.42 (1H, s), 8.15 (1H, s), 7.85 (1H, t, J=59.2 Hz), 7.23-7.07 (3H, m), 6.33 (1H, s), 3.27-3.20 (1H, m), 2.84-2.78 (1H, m), 2.68-2.59 (1H, m), 2.16 (3H, d, J=2.4 Hz), 1.88-1.83 (1H, m).

Example 19: (S)-3-(2-cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(119) ##STR00027##

Step 1: 3-bromo-2-cyclopropyl-5-fluoropyridine

(120) To a solution of 3-bromo-2-chloro-5-fluoropyridine (760 mg, 3.62 mmol) in THF (3 mL) was added a solution of cyclopropylzinc bromide in THF (0.5 M, 8 mL, 4 mmol) and Pd(PPh.sub.3).sub.4 (125 mg) and the reaction mixture was stirred at 20 C. overnight. Additional cyclopropylzinc bromide (0.5 M, 4 mL, 2 mmol) and Pd(PPh.sub.3).sub.4 (65 mg) was needed to consume all starting material. The reaction mixture was stirred at 20 C. for an additional 6 h, then it 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. Purification by flash column chromatography (SNAP column 25 g, iso-hexane-EtOAc: 0-25%) gave the title compound as a yellow oil (401 mg, 51%).

Step 2: (S)-methyl-3-(2-cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(121) Following Method B (iii) from (S)-methyl-1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.54 g, 1.4 mmol) and 3-bromo-2-cyclopropyl-5-fluoropyrimidine (0.40 g, 1.86 mmol). The crude product was purified by flash column chromatography to give the title compound as pale yellow oil (301 mg, 58%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-3-(2-cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic Acid

(122) Following Method C from (S)-methyl-3-(2-cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (300 mg, 0.81 mmol). The crude product (250 mg) was used without further purification. MS (ES+) consistent with target (M+H).sup.+.

Step 4: (S)-3-(2-cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(123) Following Method D from (S)-3-(2-cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic acid (250 mg, 0.70 mmol) and purified by preparative HPLC to give the title compound as a white solid (62 mg, 24%). LCMS (ES+) 371 (M+H).sup.+; RT 10.6 min (Analytical method 3); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.07 (1H, s), 8.65 (1H, d, J=1.5 Hz), 8.31 (1H, d, J=2.7 Hz), 7.34 (1H, dd, J=10.3, 2.8 Hz), 7.16-6.95 (3H, m), 6.51 (1H, s), 3.18 (1H, m), 2.98-2.88 (1H, m), 2.78-2.69 (1H, m), 2.12-2.05 (4H, m), 1.71 (1H, m), 1.03-0.97 (2H, m), 0.82-0.71 (2H, m).

Example 20: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)quinoxalin-6-yl)cyclopent-2-enecarboxamide

(124) ##STR00028##

Step 1: (S)-methyl-1-(3-fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)quinoxalin-6-yl)cyclopent-2-enecarboxylate

(125) Following Method B (iii) from (S)-methyl-1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.65 g, 1.7 mmol) and a mixture of 7 & 6-bromo-2-(trifluoromethyl)quinoxaline (0.53 g, 1.88 mmol). The crude product was purified by flash column chromatography to give the title compound as pale yellow oil (230 mg, 57%). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)quinoxalin-6-yl)cyclopent-2-enecarboxylic Acid

(126) Following Method C from (S)-methyl-1-(3-fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)quinoxalin-6-yl)cyclopent-2-enecarboxylate (230 mg, 0.53 mmol) and used without further purification (210 mg). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)quinoxalin-6-yl)cyclopent-2-enecarboxamide

(127) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)quinoxalin-6-yl)cyclopent-2-enecarboxylic acid (210 mg, 0.51 mmol) and purified by preparative HPLC to give the title compound as an off-white solid (60 mg, 28%). LCMS (ES+) 432 (M+H).sup.+; RT 4.23 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.28 (1H, s), 9.46 (1H, s), 8.85 (1H, s), 8.49 (1H, d, J=9.0 Hz), 8.31 (1H, d, J=8.9 Hz), 8.25 (1H, s), 7.28-7.22 (2H, m), 7.16-7.09 (1H, m), 7.01 (1H, s), 3.41-3.32 (1H obscured by water), 3.15-3.02 (1H, m), 3.01-2.88 (1H, m), 2.22 (3H, s), 2.06-1.96 (1H, m).

Example 21: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(imidazo[1,2-a]pyridin-7-yl)cyclopent-2-enecarboxamide

(128) ##STR00029##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(imidazo[1,2-a]pyridin-7-yl)cyclopent-2-enecarboxylate

(129) Following Method B (iii) from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.3 g, 0.78 mmol) and 7-bromoimidazo[1,2-a]pyridine (0.169 g, 0.86 mmol). The crude product was purified by flash column chromatography to give the title compound as a pale yellow gum (157 mg, 57%). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(imidazo[1,2-a]pyridin-7-yl)cyclopent-2-enecarboxylic Acid

(130) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(imidazo[1,2-a]pyridin-7-yl)cyclopent-2-enecarboxylate (217 mg). The crude product was obtained as an off white solid (156 mg) and used without further purification. MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(imidazo[1,2-a]pyridin-7-yl)cyclopent-2-enecarboxamide

(131) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(imidazo[1,2-a]pyridin-7-yl)cyclopent-2-enecarboxylic acid (156 mg, 0.46 mmol) and purified by preparative HPLC to give the title compound as an off white solid (52 mg, 31%). LCMS (ES+) 352 (M+H).sup.+; RT 2.39 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.16 (1H, s), 8.78 (1H, s), 8.52 (1H, d, J=7.1 Hz), 7.95 (1H, s), 7.58 (1H, d, J=1.2 Hz), 7.49 (1H, s), 7.28-7.14 (3H, m), 7.10-7.02 (1H, m), 6.65 (1H, s), 3.29-3.22 (1H, m), 2.97-2.86 (1H, m), 2.83-2.73 (1H, m), 2.15 (3H, d, J=2.5 Hz), 1.94-1.84 (1H, m).

Example 22: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(3-methylbenzo[d]isoxazol-5-yl)cyclopent-2-enecarboxamide

(132) ##STR00030##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(3-methylbenzo[d]isoxazol-5-yl)cyclopent-2-ene Carboxylate

(133) Following Method B from (S)-methyl-1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.15 g, 0.40 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole (0.11 g, 0.42 mmol). The crude product was purified by flash silica column chromatography (gradient elution iso-hexane to 20% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.12 g, 82%). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(3-methylbenzo[d]isoxazol-5-yl)cyclopent-2-enecarboxylic Acid

(134) Following Method C (ii) from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(3-methylbenzo[d]isoxazol-5-yl)cyclopent-2-enecarboxylate (0.12 g, 0.33 mmol) to give a colorless solid (0.09 g, 81%). MS (ES.sup.+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(3-methylbenzo[d]isoxazol-5-yl)cyclopent-2-enecarboxamide

(135) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(3-methylbenzo[d]isoxazol-5-yl)cyclopent-2-enecarboxylic acid (0.09 g, 0.26 mmol) and purified by preparative HPLC to give the title compound as a white solid (0.06 g, 63%). LCMS (ES+) 367 (M+H).sup.+; RT 3.82 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.14 (1H, s), 8.75 (1H, s), 7.95 (1H, s), 7.89 (1H, dd, J=8.8, 1.7 Hz), 7.69 (1H, d, J=8.8 Hz), 7.18-7.14 (2H, m), 7.08-7.01 (1H, m), 6.54 (1H, s), 3.30-3.22 (1H, m), 2.97-2.87 (1H, m), 2.82-2.72 (1H, m), 2.57 (3H, s), 2.13 (3H, d, J=2.4 Hz), 1.87 (1H, ddd, J=13.0, 9.1, 6.1 Hz).

Example 23: (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide

(136) ##STR00031##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)cyclopent-2-enecarboxylate

(137) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (500 mg, 1.31 mmol) and 2-methoxy-3-fluoropyridine-5-boronic acid utilizing CsF, DME, MeOH and palladium tetrakis(triphenylphosphine) at 120 C. The crude product was purified by flash column chromatography to give the title compound as a clear gum (385 mg, 82%). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)cyclopent-2-enecarboxylic Acid

(138) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)cyclopent-2-enecarboxylate (190 mg) and used without further purification (149 mg). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)-N-hydroxycyclopent-2-enecarboxamide

(139) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)cyclopent-2-enecarboxylic acid (148 mg, 0.43 mmol) and purified by preparative HPLC to give the title compound as a white solid (76 mg, 49%). LCMS (ES+) 361 (M+H).sup.+; RT 3.75 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.17 (1H, s), 8.79 (1H, s), 8.15 (1H, d, J=1.6 Hz), 8.03 (1H, dd, J=1.6 Hz, J=11.6 Hz), 7.22-7.18 (2H, m), 7.15-7.05 (1H, m), 6.57 (1H, s), 4.02 (3H, s), 3.35-3.25 (1H, m), 2.95-2.85 (1H, m), 2.80-2.65 (1H, m), 2.18 (3H, d, J=2.4 Hz), 1.99-1.92 (1H, m).

Example 24: (S)-3-(2-cyclopropylpyrimidin-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(140) ##STR00032##

Step 1: (S)-methyl 3-(2-cyclopropylpyrimidin-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(141) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (300 mg, 0.79 mmol) and 2-cyclopropylpyrimidine-5-boronic acid utilizing CsF, DME, MeOH and palladium tetrakis(triphenylphosphine) at 120 C. The crude product was purified by flash column chromatography to give the title compound as a clear oil (191 mg, 69%). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-3-(2-cyclopropylpyrimidin-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic Acid

(142) Following Method C from (S)-methyl 3-(2-cyclopropylpyrimidin-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (190 mg) and used without further purification (160 mg). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-3-(2-cyclopropylpyrimidin-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(143) Following Method D from (S)-3-(2-cyclopropylpyrimidin-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic acid (154 mg, 0.46 mmol) and purified by preparative HPLC to give the title compound as a white solid (93 mg, 58%). LCMS (ES+) 354 (M+H).sup.+; RT 3.51 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.16 (1H, s), 8.82 (2H, s), 8.77 (1H, s), 7.18-7.14 (2H, m), 7.08-7.05 (1H, m), 6.65 (1H, s), 3.30-3.20 (1H, m), 2.95-2.85 (1H, m), 2.80-2.65 (1H, m), 2.27-2.19 (1H, m), 2.20 (3H, d, J=2.3 Hz), 1.95-1.85 (1H, m), 1.1-0.98 (4H, m).

Example 25: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(6-methylpyridin-3-yl)cyclopent-2-enecarboxamide

Example 26: (S)-3-(5-chloro-6-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(144) ##STR00033##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(6-methylpyridin-3-yl)cyclopent-2-enecarboxylate and (S)-methyl 3-(5-chloro-6-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(145) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (300 mg, 0.79 mmol) and 2-methyl-3-chloropyridine-5-boronic acid utilizing CsF, DME, MeOH and palladium tetrakis(triphenylphosphine) at 120 C. The crude material was purified by flash column chromatography to give the title compounds as clear oils (24 mg and 180 mg). MS (ES+) consistent with targets (M+H).sup.+.

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(6-methylpyridin-3-yl)cyclopent-2-enecarboxylic Acid

(146) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(6-methylpyridin-3-yl)cyclopent-2-enecarboxylate (170 mg) and used without further purification (172 mg). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(6-methylpyridin-3-yl)cyclopent-2-enecarboxamide

(147) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(6-methylpyridin-3-yl)cyclopent-2-enecarboxylic acid (172 mg, 0.46 mmol) and purified by preparative HPLC to give the title compound as a white solid (72 mg, 48%). LCMS (ES+) 327 (M+H).sup.+; RT 2.53 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.14 (1H, s), 8.75 (1H, s), 8.57 (1H, s), 8.35 (1H, s), 8.14 (1H, s), 7.25-7.05 (3H, m), 6.61 (1H, s), 3.30-3.20 (1H, m), 2.95-2.85 (1H, m), 2.75-2.65 (1H, m), 2.31 (3H, s), 2.16 (3H, d, J=2.8 Hz), 1.95-1.80 (1H, m).

Step 4: (S)-3-(5-chloro-6-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic Acid

(148) Following Method C from (S)-methyl 3-(5-chloro-6-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (350 mg) and used without further purification (199 mg). MS (ES+) consistent with target (M+H).sup.+.

Step 5: (S)-3-(5-chloro-6-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(149) Following Method D from (S)-3-(5-chloro-6-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic acid (199 mg, 0.58 mmol) and purified by preparative HPLC to give the title compound as a white solid (137 mg, 66%). LCMS (ES+) 361/363 (M+H).sup.+, RT 10.6 min (Analytical method 3); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.16 (1H, s), 8.76 (1H, s), 8.41 (1H, s), 8.03 (1H, s), 7.25-7.05 (3H, m), 6.65 (1H, s), 3.30-3.20 (1H, m), 2.95-2.85 (1H, m), 2.75-2.65 (1H, m), 2.38 (3H, s), 2.16 (3H, d, J=2.8 Hz), 1.95-1.80 (1H, m).

Example 27: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-enecarboxamide

(150) ##STR00034##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-enecarboxylate

(151) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (300 mg, 0.79 mmol) and (1-methyl-1H-pyrazol-5-yl)boronic acid utilizing CsF, DME, MeOH and palladium tetrakis(triphenylphosphine) at 120 C. The crude product was purified by flash column chromatography to give the title compound as a clear oil (221 mg). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-enecarboxylic Acid

(152) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-enecarboxylate (220 mg) and the impure crude material used without further purification (313 mg). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-enecarboxamide

(153) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-enecarboxylic acid (200 mg, 0.66 mmol) and purified by preparative HPLC to give the title compound as a white solid (16 mg, 8%). LCMS (ES+) 316 (M+H).sup.+, RT 3.15 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.13 (1H, s), 8.76 (1H, s), 7.40 (1H, s), 7.25-7.05 (3H, m), 6.34 (1H, s), 4.00 (3H, s), 3.30-3.20 (1H, m), 2.95-2.85 (1H, m), 2.75-2.65 (1H, m), 2.18 (3H, d, J=2.8 Hz), 1.85-1.75 (1H, m). 1H obscured by DMSO.

Example 28: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)cyclopent-2-enecarboxamide

(154) ##STR00035##

Step 1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole

(155) A 25 mL teflon cap tube was charged with 4-pyrazoleboronic acid pinacol ester (0.94 g, 4.87 mmol), cesium carbonate (2.58 g, 7.31 mmol), 2,2,2 trifluoroethyl methanesulfonate (1.30 g, 0.86 mL, 7.31 mmol) and anhydrous DMF (8 mL). The reagents were capped under N.sub.2 and heated at 100 C. under microwave irradiation for 1 h. After this time the reaction mixture was cooled to rt and partitioned with EtOAc (60 mL) and water (100 mL). Organic layers were extracted, washed with brine (265 mL), then dried and filtered (phase separator) to give a pale yellow oil. The crude product was purified by flash silica column chromatography (gradient elution iso-hexane to 33% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.37 g, 35%mixture of target material and 2,2,2 trifluoroethyl methanesulfonate 1:2). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)cyclopent-2-enecarboxylate

(156) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.15 g, 0.40 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (0.33 g, 1.2 mmol, 30% purity). The crude product was purified by flash silica column chromatography (gradient elution iso-hexane to 33% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.32 g, 77%, 1:1 mixture of TM and 2,2,2 trifluoroethyl methanesulfonate). MS (ES+) consistent with target (M+H).sup.+.

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)cyclopent-2-enecarboxylic Acid

(157) Following Method C (ii) from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)cyclopent-2-enecarboxylate (0.32 g, 0.84 mmol, 50% purity) as far as removal of methanol under reduced pressure. Aqueous residues were then partitioned between CH.sub.2Cl.sub.2 (15 mL) and water (15 mL). Organic layers were discarded and basic aqueous layers acidified to pH=3 (1 M HCl). Acidic aqueous layers were then partitioned with EtOAc (20 mL). Organic layers were extracted, washed with brine (20 mL), dried, filtered (phase separation cartridge) and concentrated to give a colorless oil (0.13 g, 82%). MS (ES+) consistent with target (M+H).sup.+.

Step 4: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)cyclopent-2-enecarboxamide

(158) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)cyclopent-2-enecarboxylic acid (0.12 g, 0.33 mmol) and purified by preparative HPLC (70 mg, 52%). LCMS (ES+) 384 (M+H).sup.+; RT 10.0 min (Analytical method 3); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.06 (1H, s), 8.69 (1H, s), 7.97 (1H, s), 7.84 (1H, s), 7.21-7.09 (2H, m), 7.04 (1H, t, J=8.9 Hz), 6.16 (1H, s), 5.13 (2H, q, J=9.1 Hz), 3.20 (1H, ddd, J=13.2, 8.7, 4.4 Hz), 2.76-2.65 (1H, m), 2.62-2.53 (1H, m), 2.12 (3H, d, J=2.5 Hz), 1.83-1.75 (1H, m).

Example 29: (S)-3-(benzo[d]isothiazol-7-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(159) ##STR00036##

Step 1: 3-bromo-2-(tert-butylthio)benzaldehyde

(160) A 25 mL screw cap tube was charged with 3-bromo-2-fluorobenzaldehyde (4.0 g, 19.7 mmol), potassium carbonate (5.44 g, 39.4 mmol), 2-methyl-2-propanethiol (2.13 g, 2.70 mL, 23.6 mmol) and anhydrous DMF (15 mL). The tube was capped and the reaction mixture heated at 80 C. for 18 h. After this time only 50% of starting material was consumed, so the reaction was heated at 110 C. for a further 24 h. Once completed, the reaction mixture was cooled to r.t. and solids were dissolved in water (15 mL). Solution was then partitioned between Et.sub.2O (75 mL) and further water (125 mL). Combined organics were washed with brine (120 mL), then dried and filtered (phase separator) to give a yellow oil. The crude product was purified by flash silica column chromatography (gradient elution iso-hexane to 20% EtOAc in iso-hexane) to give the title compound as a pale yellow semi-solid (4.70 g, 88%). MS (ES+) consistent with target (M+H).sup.+.

Step 2: (E)-3-bromo-2-(tert-butylthio)benzaldehyde Oxime

(161) A 250 mL round-bottom flask was charged with 3-bromo-2-(tert-butylthio)benzaldehyde (4.75 g, 18.2 mmol). To this was added a pre-mixed solution of hydroxylamine hydrochloride (5.70 g, 82.0 mmol) in iso-propanol/water (130 mL/25 mL). The reaction was then heated at 70 C. for 6 h. After this time mixture was cooled to r.t. and volatiles removed under reduced pressure. To the resulting residue was added water (50 mL) followed by sat. aq. NaHCO.sub.3 solution (40 mL)the pH became 8.5. Aqueous layers were then extracted with EtOAc (2100 mL). Combined organics were washed with water (100 mL) then brine (150 mL), then dried, filtered and concentrated under reduced pressure to give a yellow oil. Trituration from iso-hexane/Et.sub.2O gave a colorless solid which was filtered and air dried to give the title compound (3.70 g, 71%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: 7-bromobenzo[d]isothiazole

(162) A 100 mL round-bottom flask was charged with (E)-3-bromo-2-(tert-butylthio)benzaldehyde oxime (3.50 g, 12.1 mmol), pTSA.H.sub.2O (0.46 g, 2.42 mmol) and anhydrous 1-butanol (40 mL). Reaction mixture was then refluxed for 36 h. After this time volatiles were removed under reduced pressure and the resulting residue partitioned between EtOAc (120 mL) and sat. aq. NaHCO.sub.3 solution (50 mL). Organic layers were extracted, washed with brine (50 mL) then dried, filtered and concentrated under reduced pressure to give a pale brown residue. The crude product was purified by flash silica column chromatography (gradient elution iso-hexane to 20% EtOAc in iso-hexane) to give the title compound as a colorless solid (2.41 g, 93%). MS (ES+) consistent with target (M+H).sup.+.

Step 4: (S)-methyl 3-(benzo[d]isothiazol-7-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(163) Following Method B (iii) from methyl-1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.2 g, 0.52 mmol) and 7-bromobenzo[d]isothiazole (0.1 g, 0.52 mmol). Reaction mixture was cooled to r.t. and filtered through silica, washing with CH.sub.2Cl.sub.2 (310 mL). Combined organics were then concentrated to give an orange residue. The crude product was purified by flash silica column chromatography (gradient elution iso-hexane to 20% EtOAc in iso-hexane) to give the title compound as a pale yellow oil (0.15 g, 79%). MS (ES+) consistent with target (M+H).sup.+.

Step 5: (S)-3-(benzo[d]isothiazol-7-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic Acid

(164) Following Method C (ii) from (S)-methyl 3-(benzo[d]isothiazol-7-yl)-1-(3-fluoro-2-methylphenyl) cyclopent-2-enecarboxylate (0.15 g, 0.4 mmol) as far as removal of methanol under reduced pressure. Aqueous residues were partitioned between CH.sub.2Cl.sub.2 (15 mL) and water (15 mL). Organic layers were discarded and basic aqueous layers acidified to pH 3 using 1 M HCl. Acidic aqueous layers were then partitioned with EtOAc (20 mL). Organic layers were extracted, washed with brine (20 mL), dried by filtering through a hydrophobic frit and concentrated to give a colorless oil (0.12 g, 89%). MS (ES+) consistent with target (M+H).sup.+.

Step 6: (S)-3-(benzo[d]isothiazol-7-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(165) Following Method D from (S)-3-(benzo[d]isothiazol-7-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic acid (0.12 g, 0.34 mmol) and purified by preparative HPLC (40 mg, 47%). LCMS (ES+) 369 (M+H).sup.+; RT 10.8 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.30 (1H, s), 9.27 (1H, s), 8.79 (1H, d, J=1.5 Hz), 8.25 (1H, d, J=7.9 Hz), 7.70 (1H, d, J=7.2 Hz), 7.62 (1H, t, J=7.6 Hz), 7.26-7.22 (1H, m), 7.12-7.05 (1H, m), 6.58 (1H, s), 3.43-3.33 (1H, m), 3.19-3.08 (1H, m), 2.94-2.83 (1H, m), 2.68 (1H, d, J=4.4 Hz), 2.17 (3H, d, J=2.5 Hz), 1.92-1.84 (1H, m).

Example 30: N-hydroxy-1-phenyl-cyclopent-3-enecarboxamide

(166) ##STR00037##

Step 1: methyl 2-allyl-2-phenylpent-4-enoate

(167) Methyl phenyl acetate (2 mL, 13.9 mmol), allyl bromide (2.42 mL, 28 mmol), DMF (20 mL) and NaH (60% dispersion in oil, 1.12 g, 28 mmol) were combined under nitrogen at room temperature and stirred for 18 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with water (320 mL) and evaporated to dryness onto silica. Purification by flash chromatography gave a clear oil (2.92 g).

Step 2: methyl 1-phenylcyclopent-3-enecarboxylate

(168) The clear oil from step 1 (1.49 g, 6.48 mmol), dichloromethane (300 mL) and Grubbs 2.sup.nd generation catalyst (50 mg) were combined and stirred for 12 days. The reaction mixture was then evaporated to dryness onto silica and purified by flash chromatography to give a clear oil (1.34 g).

Step 3: 1-phenylcyclopent-3-enecarboxylic Acid

(169) The clear oil from step 2 (425 mg, 2.1 mmol), MeOH (5 mL) and 15% aq. NaOH (1 mL) were combined in a sealed tube and heated to 120 C. for 36 h. Reaction mixture was then partitioned between EtOAc (20 mL) and 1 N aq. HCl (20 mL). Organic layer was dried (MgSO.sub.4) and evaporated to dryness onto silica. Purification by flash chromatography gave an off-white solid (235 mg).

Step 4: N-hydroxy-1-phenyl-cyclopent-3-enecarboxamide

(170) The off-white solid from step 3 (235 mg, 1.25 mmol), dichloromethane (10 mL) and oxalyl chloride (0.21 mL, 2.5 mmol) were combined and stirred at room temperature under nitrogen for 18 h. Reaction mixture was evaporated to dryness. Dichloromethane (10 mL) and 50% aq. hydroxylamine (1.5 mL) were added and the mixture stirred at room temperature for 2 h. Reaction mixture was then evaporated to dryness and purified by preparative HPLC to give the title compound as a white solid (160 mg); LCMS (ES+) 204 (M+H).sup.+, RT 2.97 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.49 (1H, s), 8.68 (1H, s), 7.31-7.20 (5H, m), 5.74 (2H, s), 3.26-3.22 (2H, m), 2.61-2.57 (2H, m).

Example 31: 1-(2-fluorophenyl)-N-hydroxy-cyclopent-3-enecarboxamide

(171) ##STR00038##

Step 1: 1-(2-fluorophenyl)cyclopent-3-enecarbonitrile

(172) 1-(2-Fluorophenyl)acetonitrile (803 mg, 5.95 mmol), cis-1,4-dichloro-2-butene (0.63 mL, 5.95 mmol), DMF (20 mL) and NaH (60% dispersion in oil, 595 mg, 14.87 mmol) were combined under nitrogen at room temperature and stirred for 3 days. The reaction mixture was then diluted with EtOAc (50 mL), washed with water (425 mL) and evaporated to dryness onto silica. Purification by flash chromatography gave a colorless solid (746 mg).

Step 2: 1-(2-fluorophenyl)cyclopent-3-enecarboxylic Acid

(173) The colorless solid from step 1 (706 mg) was combined with KOH (500 mg), water (2 mL) and MeOH (10 mL). Reaction mixture was heated to 90 C. for 10 days then partitioned between 1 N aq. HCl (20 mL) and EtOAc (50 mL). Organic layer was evaporated to dryness onto silica and purified by flash chromatography to give a white solid (313 mg).

Step 3: 1-(2-fluorophenyl)-N-hydroxy-cyclopent-3-enecarboxamide

(174) The white solid from step 2 (204 mg), DCM (10 mL) and oxalyl chloride (0.17 mL, 2 mmol) were combined and stirred at room temperature under nitrogen for 18 h. Reaction mixture was evaporated to dryness. DCM (20 mL) and 50% aq. hydroxylamine (2 mL) were added and the mixture stirred at room temperature for 2 h. The reaction mixture was then evaporated to dryness and purified by preparative HPLC to give the title compound as an off white solid (38 mg). LCMS (ES+) 222 (M+H).sup.+, RT 7.94 min (Analytical method 2); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.20 (1H, s), 8.65 (1H, s), 7.33-7.27 (2H, m), 7.16-7.10 (2H, m), 5.69 (2H, s), 3.21-3.17 (2H, m), 2.65-2.61 (2H, m).

Example 32: (S)-3-cyclopropyl-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(175) ##STR00039##

Step 1: (S)-methyl-3-cyclopropyl-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(176) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (100 mg, 0.26 mmol) and cyclopropylboronic acid utilizing Cs.sub.2CO.sub.3, dioxane, water and palladium tetrakis(triphenylphosphine) at 100 C. The crude product was purified by flash column chromatography to give the title compound as a clear gum (65 mg).

Step 2: (S)-3-cyclopropyl-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic Acid

(177) Following Method C from (S)-methyl-3-cyclopropyl-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (65 mg, 0.24 mmol) to give the title compound as a cream solid (50 mg).

Step 3: (S)-3-cyclopropyl-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(178) Following Method D from (S)-3-cyclopropyl-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic acid (50 mg, 0.19 mmol) and purified by preparative HPLC to give the title compound as a white solid (10 mg, 20%). LCMS (ES+) 276 (M+H).sup.+, RT 3.64 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 9.91 (1H, s), 8.62 (1H, s), 7.18-7.12 (1H, m), 7.08-6.96 (2H, m), 5.65 (1H, s), 3.15-3.08 (1H, m), 2.51-2.43 (1H, m), 2.18-2.11 (1H, m), 2.17 (3H, d, J=2.4 Hz), 1.78-1.61 (2H, m), 0.77-0.70 (2H, m), 0.61-0.54 (2H, m).

Example 33: (S)-N-hydroxy-1,3-diphenylcyclopent-2-enecarboxamide

(179) ##STR00040##

Step 1: (S)-methyl 1,3-diphenylcyclopent-2-enecarboxylate

(180) Following Method B from Intermediate 4 (190 mg, 0.54 mmol) and phenylboronic acid (65 mg) utilizing Cs.sub.2CO.sub.3 (352 mg) in place of K.sub.2CO.sub.3. The crude product was purified by flash column chromatography (gradient elution, 0-5% EtOAc in iso-hexane) to give the title compound as a crystalline solid (115 mg).

Step 2: (S)-1,3-diphenylcyclopent-2-enecarboxylic Acid

(181) Following Method C from (S)-methyl 1,3-diphenylcyclopent-2-enecarboxylate (115 mg, 0.41 mmol), utilizing KOH in place of NaOH and heating for 2 h to give the title compound as a white solid (100 mg).

Step 3: (S)-N-hydroxy-1,3-diphenylcyclopent-2-enecarboxamide

(182) Following Method D from (S)-1,3-diphenylcyclopent-2-enecarboxylic acid (100 mg, 0.38 mmol), running the reaction at r.t. Purification by silica column chromatography (gradient elution, 0-50% EtOAc in iso-hexane) gave the title compound as a white solid (20 mg, 49%). LCMS (ES+) 280 (M+H).sup.+, RT 3.66 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.35 (1H, d, J=1.7 Hz), 8.71 (1H, d, J=1.6 Hz), 7.49-7.44 (2H, m), 7.34-7.19 (7H, m), 7.17-7.12 (1H, m), 6.67 (1H, s), 2.92 (1H, dt, J=13.0, 6.4 Hz), 2.66-2.60 (2H, m), 2.03 (1H, dt, J=13.0, 7.5 Hz).

Example 34: (R)-N-hydroxy-1,3-diphenylcyclopent-2-enecarboxamide

(183) ##STR00041##

Step 1: (R)-methyl 1,3-diphenylcyclopent-2-enecarboxylate

(184) Following Method B from Intermediate 4 (110 mg, 0.31 mmol) and phenylboronic acid (42 mg) utilizing Cs.sub.2CO.sub.3 (195 mg) in place of K.sub.2CO.sub.3. The crude product was purified by flash column chromatography (gradient elution, 0-50% EtOAc in iso-hexane) to give the title compound as a crystalline solid (50 mg).

Step 2: (R)-1,3-diphenylcyclopent-2-enecarboxylic Acid

(185) Following Method C (ii) from (R)-methyl 1,3-diphenylcyclopent-2-enecarboxylate (50 mg, 0.18 mmol), running the reaction at r.t. for 16 h. The title compound was obtained as a white solid (48 mg).

Step 3: (R)-N-hydroxy-1,3-diphenylcyclopent-2-enecarboxamide

(186) Following Method D from (R)-1,3-diphenylcyclopent-2-enecarboxylic acid (45 mg, 0.17 mmol). The title compound was obtained as a white solid (37 mg, 78%). LCMS (ES+) 280 (M+H).sup.+, RT 3.67 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.35 (1H, d, J=1.7 Hz), 8.71 (1H, d, J=1.6 Hz), 7.49-7.44 (2H, m), 7.34-7.19 (7H, m), 7.17-7.12 (1H, m), 6.67 (1H, s), 2.92 (1H, dt, J=13.0, 6.4 Hz), 2.66-2.60 (2H, m), 2.03 (1H, dt, J=13.0, 7.5 Hz).

Example 35: (S)-3-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclopent-2-enecarboxamide

(187) ##STR00042##

Step 1: (S)-methyl 3-(5-fluoropyridin-3-yl)-1-phenylcyclopent-2-enecarboxylate

(188) Following Method B from Intermediate 4 (400 mg, 1.14 mmol) and (5-fluoropyridin-3-yl)boronic acid (160 mg) utilizing Cs.sub.2CO.sub.3 (743 mg) in place of K.sub.2CO.sub.3. The crude product was purified by flash column chromatography (gradient elution, 0-50% EtOAc in iso-hexane) to give the title compound as a crystalline solid (300 mg).

Step 2: (S)-3-(5-fluoropyridin-3-yl)-1-phenylcyclopent-2-enecarboxylic Acid

(189) Following Method C from (S)-methyl 3-(5-fluoropyridin-3-yl)-1-phenylcyclopent-2-enecarboxylate (300 mg, 1.01 mmol), utilizing KOH in place of NaOH and heating for 2 h to give the title compound as a white solid (276 mg).

Step 3: (S)-3-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclopent-2-enecarboxamide

(190) Following Method D from (S)-3-(5-fluoropyridin-3-yl)-1-phenylcyclopent-2-enecarboxylic acid (276 mg, 0.98 mmol). The title compound was obtained as a white solid (52 mg, 18%). LCMS (ES+) 299 (M+H).sup.+, RT 3.20 min(Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.47 (1H, s), 8.87 (1H, s), 8.69 (1H, t, J=1.6 Hz), 8.54 (1H, d, J=2.8 Hz), 7.93-7.88 (1H, m), 7.43-7.34 (4H, m), 7.30-7.24 (1H, m), 7.00 (1H, s), 3.05-2.97 (1H, m), 2.82-2.76 (2H, m), 2.24-2.16 (1H, m).

Example 36: (S)-3-(5-chloro-2-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

Example 37: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyridin-3-yl)cyclopent-2-enecarboxamide

(191) ##STR00043##

Step 1: (S)-methyl 3-(5-chloro-2-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate and (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(2-methylpyridin-3-yl)cyclopent-2-enecarboxylate

(192) (S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (400 mg, 1.05 mmol), 5-chloro-2-methylpyridine-3-boronic acid (179 mg, 1.05 mmol), CsF (200 mg), DME (15 mL), MeOH (2 mL) and palladium tetrakis(triphenylphosphine) (10 mg) were combined in a sealed tube and heated by microwave to 120 C. for 2 h. The reaction mixture was then evaporated to dryness onto silica and purified by flash chromatography to give: (S)-Methyl 3-(5-chloro-2-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (266 mg) as a clear gum.

(193) (S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-(2-methylpyridin-3-yl)cyclopent-2-enecarboxylate (75 mg) as a clear gum.

Step 2: (S)-3-(5-chloro-2-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic Acid

(194) (S)-Methyl 3-(5-chloro-2-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (265 mg, 0.737 mmol), MeOH (10 mL) and 15% aq. NaOH solution (2 mL) were combined in a sealed tube and heated to 65 C. for 2 days. The reaction mixture was evaporated in vacuo then partitioned between EtOAc and H.sub.2O/AcOH. The organic layer was dried (MgSO.sub.4) and evaporated in vacuo to give the title compound as an off white solid (200 mg, 79%).

Step 3: (S)-3-(5-chloro-2-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(195) (S)-3-(5-chloro-2-methylpyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic acid (200 mg, 0.58 mmol), TFFH (214 mg, 0.81 mmol), DMF (2 mL) and Et.sub.3N (0.28 mL, 2 mmol) were combined and stirred at room temperature under a nitrogen atmosphere. After 18 hours O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was added and the mixture stirred for 3 days. MeOH (2 mL) and 2 N HCl in diethyl ether (2 mL) were added and the mixture stirred for 5 hours. Volatile solvents were removed in vacuo and the crude material was purified by preparative HPLC to give the title compound as a tan solid (139 mg). LCMS (ES+) 361/363 (M+H).sup.+, RT 3.71 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.16 (1H, s), 8.76 (1H, br s), 8.19 (1H, dd, J=2.4, 0.8 Hz), 7.74 (1H, d, J=1.6 Hz), 7.25-7.15 (2H, m), 7.10-7.05 (1H, m), 6.53 (1H, s), 3.40-3.25 (1H, m), 3.05-2.95 (1H, m), 2.75-2.65 (1H, m), 2.33 (3H, s), 2.14 (3H, d, J=2.4 Hz), 1.85-1.75 (1H, m).

Step 4: (S)-1-(3-fluoro-2-methylphenyl)-3-(2-methylpyridin-3-yl)cyclopent-2-enecarboxylic Acid

(196) (S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-(2-methylpyridin-3-yl)cyclopent-2-enecarboxylate (75 mg), MeOH (10 mL) and 15% aq. NaOH solution (2 mL) were combined in a sealed tube and heated to 65 C. for 1 day. The reaction mixture was evaporated in vacuo then partitioned between EtOAc and H.sub.2O/AcOH. Organic layer was dried (MgSO.sub.4) and evaporated in vacuo to give the title compound as an off white solid (70 mg).

Step 5: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-methylpyridin-3-yl)cyclopent-2-enecarboxamide

(197) (S)-1-(3-fluoro-2-methylphenyl)-3-(2-methylpyridin-3-yl)cyclopent-2-enecarboxylic acid (70 mg, 0.23 mmol), TFFH (130 mg, 0.5 mmol), DMF (1 mL) and Et.sub.3N (0.21 mL, 1.5 mmol) were combined and stirred at room temperature under a nitrogen atmosphere. After 30 minutes O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (100 mg, 0.85 mmol) was added and the mixture stirred for 1 day. MeOH (2 mL) and 2 N HCl in diethyl ether (2 mL) were added and the mixture stirred for 1 h. Volatile solvents were removed in vacuo and the crude material was purified by preparative HPLC to give the title compound as a pale yellow solid (37 mg). LCMS (ES+) 327 (M+H).sup.+, RT 2.47 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.14 (1H, s), 8.77 (1H, br s), 8.57 (1H, d, J=1.6 Hz), 8.35 (1H, d, J=1.2 Hz), 7.79 (1H, s), 7.25-7.00 (3H, m), 6.61 (1H, s), 3.40-3.25 (1H, m), 2.95-2.85 (1H, m), 2.80-2.65 (1H, m), 2.34 (3H, s), 2.14 (3H, d, J=2.4 Hz), 1.95-1.85 (1H, m).

Example 38: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxamide

(198) ##STR00044##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxylate

(199) (S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (300 mg, 0.79 mmol), (1-methyl-1H-indazol-6-yl)boronic acid (139 mg, 0.79 mmol), CsF (200 mg), DME (15 mL), MeOH (3 mL) and palladium tetrakis(triphenylphosphine) (20 mg) were combined in a sealed tube and heated by microwave to 120 C. for 2 h. The reaction mixture was then evaporated to dryness onto silica and purified by flash chromatography (gradient elution, 0-100% EtOAc in iso-hexane) to give the title compound as a colorless gum (176 mg).

Step 2: (S)-1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxylic Acid

(200) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxylate (170 mg). The title compound was obtained as a tan solid (150 mg).

Step 3: (S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxamide

(201) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxylic acid (150 mg). The title compound was obtained as a colorless solid (59 mg, 38%). LCMS (ES+) 366 (M+H).sup.+, RT 10.2 min (Analytical method 3); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.17 (1H, s), 8.78 (1H, d, J=1.1 Hz), 8.06 (1H, d, J=0.8 Hz), 7.78 (1H, dd, J=8.6, 0.5 Hz), 7.72 (1H, s), 7.48 (1H, dd, J=8.5, 1.1 Hz), 7.24-7.20 (2H, m), 7.13-7.07 (1H, m), 6.64 (1H, s), 4.11 (3H, s), 3.34-3.30 (1H, m), 3.06-2.97 (1H, m), 2.90-2.82 (1H, m), 2.19 (3H, d, J=2.4 Hz), 1.96-1.88 (1H, m).

Example 39: (S)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(202) ##STR00045##

Step 1: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)cyclopent-2-enecarboxylate

(203) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl) oxy)cyclopent-2-enecarboxylate (0.30 g, 0.79 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.26 g, 0.16 mmol). The crude product was purified by silica column chromatography (gradient elution, 0-25% EtOAc in iso-hexane) to give the title compound as a colorless solid (0.15 g, 56%).

Step 2: (S)-methyl 3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(204) A 25 mL round bottom flask was charged with (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)cyclopent-2-enecarboxylate (0.14 g, 0.48 mmol), 18-crown-6 (0.02 g, 0.09 mmol) and anhydrous acetonitrile (10 mL). The reagents were stirred until a colorless solution formed then sodium chlorodifluoroacetate (0.08 g, 0.48 mmol) was added and the reaction mixture refluxed for 18 h. After this time a further portion of 18-crown-6 (0.02 g, 0.09 mmol) and sodium chlorodifluoroacetate (0.08 g, 0.48 mmol) were added and the reaction mixture was refluxed for a further 20 h. After this time the reaction was cooled to r.t. and precipitated solid filtered through Celite, washing with EtOAc (320 mL). The combined organics were then dried and filtered (phase separator) to give a yellow residue. The crude product was purified by silica column chromatography (gradient elution, 0-20% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.07 g, 28%).

Step 3: (S)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic Acid

(205) Following Method C (ii) from (S)-methyl 3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (0.06 g, 0.16 mmol). After removing methanol, the aqueous residues were partitioned between CH.sub.2Cl.sub.2 (15 mL) and water (15 mL). Organic layers were discarded and basic aqueous layers acidified to pH 3 using 1 M HCl. Acidic aqueous layers were then partitioned with EtOAc (20 mL); the organic layers were extracted, washed with brine (20 mL), dried, filtered (phase separation cartridge) and concentrated to give the title compound as a colorless solid (0.04 g, 70%).

Step 4: (S)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(206) Following Method D from (S)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic acid (0.04 g, 0.26 mmol) and purified by preparative HPLC (0.007 g, 18%). LCMS (ES+) 402 (M+H).sup.+; RT 10.5 min (Analytical method 3); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.19 (1H, s), 8.88 (1H, d, J=0.9 Hz), 8.80 (1H, s), 8.17 (1H, t, J=59.1 Hz), 7.83 (1H, dd, J=9.0, 0.6 Hz), 7.68 (1H, s), 7.59 (1H, dd, J=9.0, 1.2 Hz), 7.24-7.18 (2H, m), 7.13-7.06 (1H, m), 6.68 (1H, s), 3.34-3.29 (1H, m), 3.03-2.95 (1H, m), 2.88-2.81 (1H, m), 2.19 (3H, d, J=2.4 Hz), 1.96-1.88 (1H, m).

Example 40: (S)-3-(benzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(207) ##STR00046##

Step 1: (S)-methyl 3-(benzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(208) (S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (250 mg, 0.65 mmol), benzthiazole-5-boronic acid (170 mg, 0.65 mmol), CsF (200 mg), DME (15 mL), MeOH (2 mL) and palladium tetrakis(triphenylphosphine) (10 mg) were combined in a sealed tube and heated by microwave to 120 C. for 2 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 (204 mg, 86%). LCMS (ES+) 368 (M+H).sup.+.

Step 2: (S)-3-(benzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic Acid

(209) (S)-Methyl 3-(benzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (200 mg), MeOH (10 mL) and 15% aq. NaOH solution (2 mL) were combined in a sealed tube and heated to 65 C. for 4 days. The reaction mixture was evaporated in vacuo then partitioned between EtOAc and H.sub.2O/AcOH. Organic layer was dried (MgSO.sub.4) and evaporated in vacuo to give the crude title compound as a brown solid (239 mg). LCMS (ES+) 354 (M+H).sup.+.

Step 3: (S)-3-(benzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(210) (S)-3-(Benzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic acid (239 mg), TFFH (201 mg, 0.76 mmol), DMF (3 mL) and Et.sub.3N (0.42 mL, 3 mmol) were combined and stirred at room temperature under a nitrogen atmosphere. After 16 hours O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was added and the mixture stirred for 3 days. MeOH (2 mL) and 2 N HCl in diethyl ether (2 mL) were both added and the mixture stirred for 4 h. Volatile solvents were removed in vacuo and the remaining crude product was purified by preparative HPLC to give the title compound as a brown solid (16 mg). LCMS (ES+) 369 (M+H).sup.+, RT 3.67 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.15 (1H, s), 9.42 (1H, s), 8.75 (1H, br s), 8.25-8.15 (2H, m), 7.80-7.70 (1H, m), 7.25-7.15 (2H, m), 7.15-7.00 (1H, m), 6.50 (1H, s), 3.40-3.35 (1H, m), 3.05-2.95 (1H, m), 2.85-2.75 (1H, m), 2.16 (3H, d, J=2.4 Hz), 1.95-1.85 (1H, m).

Example 41: (S)-3-(benzo[b]thiophen-2-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(211) ##STR00047##

Step 1: (S)-methyl 3-(benzo[b]thiophen-2-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(212) (S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (550 mg, 1.44 mmol), benzothiophene-2-boronic acid (256 mg, 1.44 mmol), CsF (300 mg), DME (15 mL), MeOH (2 mL) and palladium tetrakis(triphenylphosphine) (10 mg) were combined in a sealed tube and heated by microwave to 120 C. for 2 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 (392 mg, 74%).

Step 2: (S)-3-(benzo[b]thiophen-2-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic Acid

(213) (S)-Methyl 3-(benzo[b]thiophen-2-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (390 mg, 1.06 mmol), MeOH (15 mL) and 15% aq. NaOH solution (3 mL) were combined in a sealed tube and heated to 65 C. for 3 days. The reaction mixture was evaporated in vacuo then partitioned between EtOAc and H.sub.2O/AcOH. Organic layer was dried (MgSO.sub.4) and evaporated in vacuo to give the title compound as an off white solid (351 mg, 94%). MS (ES) consistent with target (MCO.sub.2H).sup.

Step 3: (S)-3-(benzo[b]thiophen-2-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide

(214) (S)-3-(Benzo[b]thiophen-2-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylic acid (350 mg, 0.99 mmol), TFFH (370 mg, 1.4 mmol), DMF (2 mL) and Et.sub.3N (0.42 mL, 3 mmol) were combined and stirred at room temperature under a nitrogen atmosphere. After 16 hours O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was added and the mixture stirred for 3 days. MeOH (2 mL) and 2 N HCl in diethyl ether (2 mL) were both added and the mixture stirred for 5 h. Volatile solvents were removed in vacuo and the remaining crude product was purified by preparative HPLC to give the title compound as a tan solid (113 mg). LCMS (ES+) 368 (M+H).sup.+, RT 4.30 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.18 (1H, s), 8.80 (1H, s), 8.00-7.90 (1H, m), 7.85-7.78 (1H, m), 7.44 (1H, s), 7.40-7.30 (2H, m), 7.25-7.15 (1H, m), 7.15-7.00 (2H, m), 6.39 (1H, s), 3.45-3.30 (1H, m), 3.00-2.85 (1H, m), 2.85-2.75 (1H, m), 2.14 (3H, d, J=2.4 Hz), 1.95-1.80 (1H, m).

Example 42: (S)-1-(3,4-difluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxamide

(215) ##STR00048##

Step 1: (3,4-difluoro-2-methylphenyl)methanol

(216) To a solution of 3,4-difluoro-2-methylbenzoic acid (9.50 g, 55.2 mmol) in anhydrous dichloromethane (200 mL) was added oxalyl chloride (8.57 g, 67.5 mmol, 6 mL) and DMF (0.1 mL, cat.) and the reaction mixture stirred at r.t. for 1 h and then refluxed for a further 1.5 h. After this time the reaction mixture was cooled to r.t. and concentrated under reduced pressure to give the crude acid chloride as a yellow oil. The crude mixture was dissolved in anhydrous THF (150 mL) and sodium borohydride (6.26 g, 166 mmol) added portion-wise at 0 C. The pale yellow suspension was stirred at 0 C. for 1 h then at r.t. for a further 20 h. After this time the reaction was carefully quenched with ice-water (25 mL), and volatile solvents removed under reduced pressure. The residue was partitioned between EtOAc (200 mL) and water (150 mL). The organic layers were extracted, washed with brine (150 mL) then dried, filtered (phase separation cartridge) and concentrated to give a colorless oil. The oil was triturated from iso-hexane/diethyl ether to give the title compound as a colorless solid (7.2 g, 82%).

Step 2: 1-(bromomethyl)-3,4-difluoro-2-methylbenzene

(217) To a 4 C. solution of (3,4-difluoro-2-methylphenyl)methanol (7.0 g, 44.2 mmol) and carbon tetrabromide (17.6 g, 53.2 mmol) in anhydrous dichloromethane (100 mL) was added a dropwise solution of triphenylphosphine (14.0 g, 53.2 mmol) in DCM (25 mL). The reaction mixture was warmed to r.t. and stirred for 20 h. After this time the reaction mixture was concentrated under reduced pressure and the crude residue passed through a pad of silica gel (elution: iso-hexane/diethyl ether). Fractions containing the desired product were concentrated under reduced pressure to give a pale yellow oil. The crude reaction material was purified by flash silica chromatography (gradient elution iso-hexane to 20% EtOAc in iso-hexane) to give the title compound as a pale yellow oil (11.8 g) in an approximately 5:1 ratio with bromoform.

Step 3: 2-(3,4-difluoro-2-methylphenyl)acetonitrile

(218) To a 4 C. solution of 1-(bromomethyl)-3,4-difluoro-2-methylbenzene (10.0 g, 45.2 mmol) and sodium cyanide (3.32 g, 67.8 mmol) in DMF (65 mL) was added water (8 mL). The reaction mixture was stirred at 4 C. for 3 hours. After this time the reaction mixture was partitioned between sat. aq. NaHCO.sub.3/water (1:1, 300 mL) and diethyl ether (200 mL). The aqueous layer was extracted with diethyl ether (2200 mL); the combined organics were washed with brine (150 mL) then dried, filtered (phase separation cartridge) and concentrated to give a brown oil. The crude reaction material was purified by flash silica chromatography (gradient elution, 0-33% EtOAc in iso-hexane) to give the title compound as a yellow oil (6.2 g, 83%).

Step 4: 2-(3,4-difluoro-2-methylphenyl)acetic Acid

(219) To a solution of 2-(3,4-difluoro-2-methylphenyl)acetonitrile (6.20 g, 37.1 mmol) in acetic acid (30 mL) was added c.H.sub.2SO.sub.4/water (1:1, 25 mL) and the reaction mixture was refluxed for 24 h. After this time the reaction mixture was cooled to r.t. and adjusted to pH 3 using solid Na.sub.2CO.sub.3. The aqueous reaction mixture was then extracted with dichloromethane (350 mL). The combined organics were washed with water (65 mL) and brine (65 mL), then dried, filtered (phase separation cartridge) and concentrated to give a pale yellow solid. The solid was triturated from iso-hexane/diethyl ether to give the title compound as a colorless solid (6.5 g, 94%).

Step 5: methyl 2-(3,4-difluoro-2-methylphenyl)acetate

(220) To a solution of 2-(3,4-difluoro-2-methylphenyl)acetic acid (6.52 g, 35.0 mmol) in methanol (100 mL) was added c.H.sub.2SO.sub.4 (0.1 mL, cat.) and the reaction mixture was refluxed for 20 h. After this time the reaction mixture was cooled to r.t. and concentrated under reduced pressure. The crude residue was partitioned between EtOAc (75 mL) and sat. aq. NaHCO.sub.3/water (1:1, 50 mL). The aqueous layer was extracted with EtOAc (250 mL); the combined organics washed with brine (50 mL), dried, filtered (phase separation cartridge) and concentrated to give a pale yellow oil. The crude reaction material was purified by flash silica chromatography (gradient elution, 0-15% EtOAc in iso-hexane) to give the title compound as a colorless oil (7.12 g, 95%).

Step 6: (1S,3S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate

(221) To a solution of (S)-tert-butyl((1,4-dibromobutan-2-yl)oxy)diphenylsilane (4.70 g, 0.010 mol) and methyl 2-(3,4-difluoro-2-methylphenyl)acetate (2.0 g, 0.010 mol) in anhydrous DMF (90 mL) was added 18-crown-6 (0.1 g, catalytic). The reaction mixture was stirred at r.t. for 10 min then sodium hydride (60% dispersion in mineral oil 0.96 g, 0.025 mol) was added portion-wise over 1.5 h. Reaction mixture was stirred at r.t. for a further 1.5 h. The reaction mixture was cooled to 4 C. and quenched by drop-wise addition of sat. aq. NH.sub.4Cl solution (10 mL) and residual DMF removed under reduced pressure. The residue was then partitioned between Et.sub.2O (240 mL) and water (100 mL). The organic layer was washed with further water (150 mL) and brine (200 mL), then dried, filtered (phase separation cartridge) and concentrated to give a yellow oil. This oil was dissolved in anhydrous THF (75 mL) and TBAF (1 M in THF, 0.02 mol, 20 mL) was added. Reaction mixture was then stirred at r.t. for 2 h. After this time the reaction mixture was concentrated under reduced pressure and purified by silica column chromatography (gradient elution, 0-40% EtOAc in iso-hexane) to give the title compound as a colorless oil (2.30 g, 83%, 8:1 mixture with (1R,3S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate). 625 mg of the title compound was separated from the mixture of isomers. R.sub.f=0.1 (20% EtOAc/iso-hexane); MS (ES+) consistent with target (M+H).sup.+.

Step 7: (S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate

(222) To a solution of (1S,3S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (0.60 g, 2.2 mmol) in anhydrous dichloromethane (30 mL) was added Dess-Martin Periodinane (1.20 g, 2.76 mmol). The reaction mixture was stirred at r.t. for 20 h. Reaction mixture was quenched with a mixture of 10% Na.sub.2S.sub.2O.sub.3 and sat. aq. NaHCO.sub.3 solution (1:1, 100 mL) and then rapidly stirred for 30 min. Organic layers were extracted with further CH.sub.2Cl.sub.2 (250 mL), then dried, filtered (phase separation cartridge) and concentrated to give a pale yellow oil. The residue was purified by silica column chromatography (gradient elution, 0-20% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.58 g, 92%, >99.5% ee).

(223) ##STR00049##

Step 8: (S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate

(224) Following Method A using (S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate (0.62 g, 2.32 mmol). The residue was purified by silica column chromatography (gradient elution, 0-25% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.64 g, 81%).

Step 9: (S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxylate

(225) Following Method B (ii) using (S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (0.62 g, 1.55 mmol) and (1-methyl-1H-indazol-6-yl) boronic acid (0.34 g, 1.90 mmol). The residue was purified by silica column chromatography (gradient elution, 0-35% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.58 g, 97%).

Step 10: (S)-1-(3,4-difluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxylic Acid

(226) Following Method C (ii) using (S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxylate (0.57 g, 1.55 mmol). The crude reaction material was azeotroped with CHCl.sub.3 to give the title compound as a colorless foam (0.55 g, 95%).

Step 11: (S)-1-(3,4-difluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxamide

(227) Following Method D using (S)-1-(3,4-difluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxylic acid (0.10 g, 0.27 mmol). The crude residue was purified by preparative HPLC to give the title compound as a colorless solid (65 mg, 64%). LCMS (ES+) 384 (M+H).sup.+, RT 3.73 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.13 (1H, s), 8.74 (1H, s), 8.00 (1H, d, J=0.9 Hz), 7.72 (1H, d, J=8.47 Hz), 7.68 (1H, s), 7.43 (1H, dd, J=8.5, 1.4 Hz), 7.20-7.10 (2H, m), 6.54 (1H, s), 4.05 (3H, s), 3.28-3.21 (1H, m), 3.02-2.91 (1H, m), 2.84-2.75 (1H, m), 2.17 (3H, d, J=2.7 Hz), 1.89-1.81 (1H, m).

Example 43: 4-(5-fluoropyridin-3-yl)-N-hydroxy-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxamide

(228) ##STR00050##

Step 1: methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylate

(229) Methyl 4-oxo-1-phenylcyclohexanecarboxylate (993 mg, 4.28 mmol), and THF (30 mL) were combined under nitrogen at room temperature. Reaction mixture was cooled with an ice bath and NaHMDS (1 M in THF, 5.64 mL, 5.64 mmol) was added dropwise. After 30 mins N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (1.68 g, 4.28 mmol) was added and the reaction mixture allowed to warm to room temperature with stirring over 4 h. Reaction mixture was diluted with CH.sub.2Cl.sub.2, washed with water and the organics evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a clear oil (445 mg, 29%).

Step 2: methyl 4-(5-fluoropyridin-3-yl)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylate

(230) Methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylate (445 mg, 1.22 mmol), 3-fluoropyridine-5-boronic acid (171 mg, 1.22 mmol), CsF (200 mg), DME (12 mL), MeOH (3 mL) and palladium tetrakis(triphenylphosphine) (20 mg) were combined in a sealed tube and microwave heated to 120 C. for 4 h. Reaction mixture was allowed to cool to room temperature, evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a white solid (216 mg, 57%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: 4-(5-fluoropyridin-3-yl)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylic Acid

(231) Methyl 4-(5-fluoropyridin-3-yl)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylate (215 mg, 0.69 mmol), MeOH (20 mL), 15% aq. NaOH soln. (2 mL) were combined in a sealed tube and heated to 65 C. for 24 hours. Reaction mixture was evaporated to dryness then partitioned between EtOAc and H.sub.2O/AcOH. Organic layer was dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a white solid (176 mg, 86%). MS (ES+) consistent with target (M+H).sup.+.

Step 4: 4-(5-fluoropyridin-3-yl)-N-hydroxy-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxamide

(232) 4-(5-Fluoropyridin-3-yl)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylic acid (176 mg, 0.57 mmol), DMF (3 mL), Et.sub.3N (0.24 mL, 1.7 mmol) and TFFH (225 mg, 0.855 mmol) were combined and stirred at room temperature under a nitrogen atmosphere. After 30 min H.sub.2NOTHP (94 mg, 0.8 mmol) was added and the reaction stirred for 18 h. MeOH (3 mL) and 2 N HCl in diethyl ether (2 mL) were then added and reaction stirred for 2 h. Volatile solvents were removed in vacuo and the residue purified by preparative HPLC to give the title compound as a white solid (136 mg, 76%). LCMS (ES+) 313 (M+H).sup.+, RT 3.20 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.49 (1H, s), 8.73 (1H, s), 8.56 (1H, t, J=2.0 Hz), 8.46 (1H, d, J=2.6 Hz), 7.79-7.74 (1H, m), 7.43 (2H, d, J=7.4 Hz), 7.37 (2H, t, J=7.7 Hz), 7.27 (1H, t, J=7.2 Hz), 6.56 (1H, t, J=4.0 Hz), 3.06-2.97 (1H, m), 2.70-2.62 (1H, m), 2.52-2.46 (2H, m), 2.31-2.22 (2H, m).

Example 44: 3-fluoro-4-(5-fluoropyridin-3-yl)-N-hydroxy-2-methyl-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxamide

(233) ##STR00051##

Step 1: 3-tert-butyl 1-methyl 3-fluoro-4-hydroxy-2-methyl-1,2,5,6-tetrahydro-[1,1-biphenyl]-1,3-dicarboxylate

(234) Methyl 2-(3-fluoro-2-methylphenyl)acetate (3.13 g, 17.2 mmol), DMF (30 mL) and tert-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, then washed with water and brine and evaporated to dryness onto silica before purification by flash chromatography. The title compound was obtained as a white solid (2.14 g, 34%).

Step 2: methyl 1-(3-fluoro-2-methylphenyl)-4-oxocyclohexanecarboxylate

(235) 3-tert-Butyl 1-methyl 3-fluoro-4-hydroxy-2-methyl-1,2,5,6-tetrahydro-[1,1-biphenyl]-1,3-dicarboxylate (2.14 g, 5.88 mmol) and TFA (10 mL) were combined and stirred at room temperature for 20 h. The TFA was 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%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: methyl 3-fluoro-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylate

(236) Methyl 1-(3-fluoro-2-methylphenyl)-4-oxocyclohexanecarboxylate (790 mg, 2.99 mmol) and THF (20 mL) were combined under a nitrogen atmosphere and cooled with an ice bath. NaHMDS (1 M in THF, 4.5 mL, 4.5 mmol) was added dropwise followed after 20 minutes by N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.38 g, 3.5 mmol). Reaction mixture was allowed to warm to room temperature and stirred for 3 h. Reaction mixture was then diluted with CH.sub.2Cl.sub.2, washed with water, evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a colorless oil (730 mg, 62%).

Step 4: methyl 3-fluoro-4-(5-fluoropyridin-3-yl)-2-methyl-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylate

(237) Methyl 3-fluoro-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylate (326 mg, 0.82 mmol), 5-fluoropyridine-3-boronic acid (116 mg, 0.82 mmol), CsF (120 mg), DME (12 mL), MeOH (2 mL) and palladium tetrakis(triphenylphosphine) (10 mg) were combined in a sealed tube and heated by microwave to 120 C. for 2 h. The reaction mixture was then evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a crystalline solid (234 mg, 83%). MS (ES+) consistent with target (M+H).sup.+.

Step 5: 3-fluoro-4-(5-fluoropyridin-3-yl)-2-methyl-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylic Acid

(238) Methyl 3-fluoro-4-(5-fluoropyridin-3-yl)-2-methyl-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylate (230 mg, 0.67 mmol), MeOH (15 mL) and 15% aq. NaOH solution (2 mL) were combined in a sealed tube and heated to 65 C. for 13 days. The reaction mixture was then evaporated in vacuo then partitioned between EtOAc and H.sub.2O/AcOH. Organic layer was dried (MgSO.sub.4) and evaporated in vacuo to give the title compound as a cream solid (181 mg, 82%). MS (ES+) consistent with target (M+H).sup.+.

Step 6: 3-fluoro-4-(5-fluoropyridin-3-yl)-N-hydroxy-2-methyl-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxamide

(239) 3-Fluoro-4-(5-fluoropyridin-3-yl)-2-methyl-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylic acid (180 mg, 0.547 mmol), TFFH (188 mg, 0.71 mmol), DMF (3 mL) and Et.sub.3N (0.35 mL, 2.5 mmol) were combined and stirred at room temperature under a nitrogen atmosphere. After 1 h O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was added and the mixture stirred for 4 days. MeOH (2 mL) and 2 N HCl in diethyl ether (2 mL) were both added and the mixture stirred for 17 h. Volatile solvents were removed in vacuo and the crude material was purified by preparative HPLC to give the title compound as a white solid (92 mg, 49%). LCMS (ES+) 345 (M+H).sup.+, RT 3.27 min (Analytical method 1); .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.15 (1H, s), 8.71 (1H, br s), 8.51 (1H, t, J=1.6 Hz), 8.42 (1H, d, J=2.8 Hz), 7.71 (1H, dt, J=10.8, 2.4 Hz), 7.20-7.00 (3H, m), 6.54 (1H, s), 2.80-2.20 (5H, m), 2.17 (3H, d, J=2.8 Hz), 1.88-1.75 (1H, m).

Example 45: 3-fluoro-N-hydroxy-2-methyl-4-(quinoxalin-6-yl)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxamide

(240) ##STR00052##

Step 1: methyl 3-fluoro-2-methyl-4-(quinoxalin-6-yl)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylate

(241) Methyl 3-fluoro-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylate (399 mg, 1 mmol), quinoxaline-6-boronic acid.HCl (211 mg, 1 mmol), CsF (200 mg), DME (15 ml), MeOH (2 ml) and palladium tetrakis triphenylphosphine (10 mg) were combined in a sealed tube and heated by microwave to 120 C. for 2 h. The reaction mixture was then evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a tan gum (213 mg, 57%). LCMS (ES+) 377 (M+H).sup.+.

Step 2: 3-fluoro-2-methyl-4-(quinoxalin-6-yl)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylic Acid

(242) Methyl 3-fluoro-2-methyl-4-(quinoxalin-6-yl)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylate (210 mg, 0.56 mmol), MeOH (15 ml) and 15% aq. NaOH solution (2 ml) were combined in a sealed tube and heated to 65 C. for 20 days. The reaction mixture was then evaporated in vacuo then partitioned between EtOAc and H.sub.2O/AcOH. Organic layer was dried (MgSO.sub.4) and evaporated in vacuo to give the title compound as a brown solid (140 mg, 69%). LCMS (ES+) 363 (M+H).sup.+.

Step 3: 3-fluoro-N-hydroxy-2-methyl-4-(quinoxalin-6-yl)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxamide

(243) 3-Fluoro-2-methyl-4-(quinoxalin-6-yl)-1,2,3,6-tetrahydro-[1,1-biphenyl]-1-carboxylic acid (140 mg, 0.39 mmol), TFFH (143 mg, 0.54 mmol), DMF (2 mL) and Et.sub.3N (0.17 mL, 1.2 mmol) were combined and stirred at room temperature under a nitrogen atmosphere. After 40 minutes O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was added and the mixture stirred for 4 days. MeOH (2 mL) and 2 N HCl in diethyl ether (2 mL) were added and the mixture stirred for 4 h. Volatile solvents were removed in vacuo and the remaining material was purified by preparative HPLC to give the title compound as a pale yellow solid (64 mg, 44%). LCMS (ES+) 378 (M+H).sup.+; .sup.1H NMR (ppm) (DMSO-d.sub.6): 10.18 (1H, s), 8.91 (1H, d, J=1.6 Hz), 8.87 (1H, d, J=1.6 Hz), 8.72 (1H, s), 8.08-8.00 92H, m), 7.89 (1H, s), 7.20-7.00 (3H, m), 6.68 (1H, s), 2.85-2.25 (5H, m), 2.20 (3H, d, J=2.8 Hz), 2.05-1.90 (1H, m).

Example 46: Analysis of Inhibition of HDAC4 with Class IIa Histone Deacetylase (HDAC) Inhibitors

(244) The potency of Class IIa Histone Deacetylase (HDAC) inhibitors 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.

(245) Serially Dilute HDAC Inhibitor Compounds.

(246) Serial dilutions of the HDAC inhibitors and control reference compound (1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone) are made by first resuspending the lyophilized compound to a final concentration of 10 mM in 100% dimethyl sulfoxide (DMSO). Stocks of 60 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 7 using a 125 l 16-channel Matrix multi-channel pipette (Matrix Technologies Ltd).

(247) TABLE-US-00002 TABLE 1 Serial Dilution of Compounds Concen- Diluted tration Dilution Solutions Well (M) ratio Volumes Concen- A 10000 60 l 10 mM Test compound/ tration 1 reference control Concen- B 5000 1:2 30 l A + 30 l DMSO tration 2 Concen- C 2500 1:2 30 l B + 30 l DMSO tration 3 Concen- D 1000 .sup.1:2.5 30 l C + 45 l DMSO tration 4 Concen- E 500 1:2 30 l D + 30 l DMSO tration 5 Concen- F 250 1:2 .sup.30 l E + 30 l DMSO tration 6 Concen- G 125 1:2 .sup.30 l F + 30 l DMSO tration 7 Concen- H 62.5 1:2 30 l G + 30 l DMSO tration 8 Concen- I 31.25 1:2 30 l H + 30 l DMSO tration 9 Concen- J 15.63 1:2 .sup.30 l I + 30 l DMSO tration 10 Concen- K 7.81 1:2 30 l J + 30 l DMSO tration 11 Concen- L 3.91 1:2 30 l K + 30 l DMSO tration 12 Concen- M 1.95 1:2 .sup.30 l L + 30 l DMSO tration 13 Concen- N 0.98 1:2 30 l M + 30 l DMSO.sup. tration 14 Concen- O 0.49 1:2 30 l N + 30 l DMSO tration 15 Concen- P 0.24 1:2 30 l O + 30 l DMSO tration 16

(248) 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).

(249) Prepare HDAC4 Catalytic Domain Enzyme (0.2 g/ml).

(250) 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.

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

(252) 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.

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

(254) 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.

(255) Assay.

(256) 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 47: Analysis of Inhibition of HDAC5 with Class IIa Histone Deacetylase (HDAC) Inhibitors

(257) The potency of Class IIa Histone Deacetylase (HDAC) inhibitors 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.

(258) Serially Dilute HDAC Inhibitor Compounds.

(259) Serial dilutions of the HDAC inhibitors and control reference compound (1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone) are made by first resuspending the lyophilized compound to a final concentration of 10 mM in 100% DMSO. Stocks of 60 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 7 using a 125 l 16-channel Matrix multi-channel pipette.

(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-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.).

(261) Prepare HDAC5 Catalytic Domain Enzyme (0.57 g/ml).

(262) 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.

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

(264) 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.

(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 equilibrated to 37 C.

(267) Assay.

(268) 5 l of each solution of the 1:20 diluted inhibitor compounds and controls from above is transferred to a clear bottomed, black, 384-well assay plate using the Bravo or Janus. Using a 16-channel Matrix multi-channel pipette, 35 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 48: Analysis of Inhibition of HDAC7 with Class IIa Histone Deacetylase (HDAC) Inhibitors

(269) The potency of Class IIa Histone Deacetylase (HDAC) inhibitors 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.

(270) Serially Dilute HDAC Inhibitor Compounds.

(271) Serial dilutions of the HDAC inhibitors and control reference compound (1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone) are made by first resuspending the lyophilized compound to a final concentration of 10 mM in 100% DMSO. Stocks of 60 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 7 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 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.).

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

(274) 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.

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

(276) 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.

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

(281) The potency of Class IIa Histone Deacetylase (HDAC) inhibitors 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.

(282) Serially Dilute HDAC Inhibitor Compounds.

(283) Serial dilutions of the HDAC inhibitors and control reference compound (1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone) are made by first resuspending the lyophilized compound to a final concentration of 10 mM in 100% DMSO. Stocks of 60 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 7 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 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.).

(285) Prepare HDAC9 Enzyme (0.57 g/ml).

(286) 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.

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

(288) 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.

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

(293) The potency of Class IIa Histone Deacetylase (HDAC) inhibitors 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.

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

(295) 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.

(296) Serially Dilute HDAC Inhibitor Compounds.

(297) Serial dilutions of the HDAC inhibitors and control reference compound (1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone) are made by first resuspending the lyophilized compound to a final concentration of 10 mM in 100% DMSO. Stocks of 70 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.

(298) 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)

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

(300) 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.

(301) Prepare 3 Lysis Buffer.

(302) 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.

(303) Assay.

(304) 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 51

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

(306) TABLE-US-00003 Biochemical Cell Example HDAC-4 IC.sub.50 # Chemical Name Structure IC.sub.50 (M) (M) 1 (R)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3- phenylcyclopent-2- enecarboxamide 7.6 >50 2 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3- phenylcyclopent-2- enecarboxamide 0.02 0.17 3 (R)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(o- tolyl)cyclopent-2- enecarboxamide 0.23 4.6 4 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(o- tolyl)cyclopent-2- enecarboxamide 0.02 0.36 5 (R)-1-(3-Fluoro-2- methylphenyl)-3-(5- fluoropyridin-3-yl)-N- hydroxycyclopent-2- enecarboxamide 0.67 6.8 6 (S)-1-(3-Fluoro-2- methylphenyl)-3-(5- fluoropyridin-3-yl)-N- hydroxycyclopent-2- enecarboxamide 0.01 0.16 7 (R)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(pyrazin-2- yl)cyclopent-2- enecarboxamide >50 >50 8 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(pyrazin-2- yl)cyclopent-2- enecarboxamide 0 2.4 15.7 9 (R)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(2- methylpyrimidin-5- yl)cyclopent-2- enecarboxamide 26.8 >50 10 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(2- methylpyrimidin-5- yl)cyclopent-2- enecarboxamide 0.04 0.38 11 (S)-3-(5-Chloropyridin-3- yl)-1-(3-fluoro-2- methylphenyl)-N- hydroxycyclopent-2- enecarboxamide 0.02 0.12 12 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(quinoxalin-6- yl)cyclopent-2- enecarboxamide 0.01 0.02 13 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(2- (trifluoromethyl)pyridin- 4-yl)cyclopent-2- enecarboxamide 0.04 0.27 14 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(pyrimidin-5- yl)cyclopent-2- enecarboxamide 0.03 0.36 15 (S)-1-(3-Fluoro-2- methylphenyl)-3-(5- fluoropyridin-2-yl)-N- hydroxycyclopent-2- enecarboxamide 0.04 0.31 16 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(6- (trifluoromethyl)pyridin- 3-yl)cyclopent-2- enecarboxamide 0.02 0.10 17 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(5- (trifluoromethyl)pyridin- 3-yl)cyclopent-2- enecarboxamide 0.03 0.20 18 (S)-3-(1-(Difluoromethyl)- 1H-pyrazol-4-yl)-1-(3- fluoro-2-methylphenyl)- N-hydroxycyclopent-2- enecarboxamide 0 0.02 0.16 19 (S)-3-(2-Cyclopropyl-5- fluoropyridin-3-yl)-1-(3- fluoro-2-methylphenyl)- N-hydroxycyclopent-2- enecarboxamide 0.04 0.50 20 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(2- (trifluoromethyl)quinoxalin- 6-yl)cyclopent-2- enecarboxamide 0.07 0.14 21 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(imidazo[1,2- a]pyridin-7-yl)cyclopent- 2-enecarboxamide 0.01 0.06 22 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(3- methylbenzo[d]isoxazol- 5-yl)cyclopent-2- enecarboxamide 0.03 0.06 23 (S)-1-(3-Fluoro-2- methylphenyl)-3-(5- fluoro-6-methoxypyridin- 3-yl)-N- hydroxycyclopent-2- enecarboxamide 0.04 0.22 24 (S)-3-(2- Cyclopropylpyrimidin-5- yl)-1-(3-fluoro-2- methylphenyl)-N- hydroxycyclopent-2- enecarboxamide 0.02 0.08 25 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(6- methylpyridin-3- yl)cyclopent-2- enecarboxamide 0.01 0.12 26 (S)-3-(5-Chloro-6- methylpyridin-3-yl)-1-(3- fluoro-2-methylphenyl)- N-hydroxycyclopent-2- enecarboxamide 0.01 0.08 27 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(1-methyl-1H- pyrazol-5-yl)cyclopent-2- enecarboxamide 0.02 0.33 28 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(1-(2,2,2- trifluoroethyl)-1H- pyrazol-4-yl)cyclopent-2- enecarboxamide 0 0.02 0.16 29 (S)-3-(Benzo[d]isothiazol- 7-yl)-1-(3-fluoro-2- methylphenyl)-N- hydroxycyclopent-2- enecarboxamide 0.03 0.20 30 N-Hydroxy-1- phenylcyclopent-3- enecarboxamide 12.3 >50 31 1-(2-Fluorophenyl)-N- hydroxycyclopent-3- enecarboxamide 8.3 44.5 32 (S)-3-Cyclopropyl-1-(3- fluoro-2-methylphenyl)- N-hydroxycyclopent-2- enecarboxamide 0.04 0.73 33 (S)-N-Hydroxy-1,3- diphenylcyclopent-2- enecarboxamide 0.19 2.5 34 (R)-N-Hydroxy-1,3- diphenylcyclopent-2- enecarboxamide 31 >50 35 (S)-3-(5-Fluoropyridin-3- yl)-N-hydroxy-1- phenylcyclopent-2- enecarboxamide 0.34 3.1 36 (S)-3-(5-Chloro-2- methylpyridin-3-yl)-1-(3- fluoro-2-methylphenyl)- N-hydroxycyclopent-2- enecarboxamide 0.02 0.12 37 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(2- methylpyridin-3- yl)cyclopent-2- enecarboxamide 0.01 0.09 38 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(1-methyl-1H- indazol-6-yl)cyclopent-2- enecarboxamide 0 0.01 0.01 39 (S)-3-(1-(Difluoromethyl)- 1H-indazol-6-yl)-1-(3- fluoro-2-methylphenyl)- N-hydroxycyclopent-2- enecarboxamide 0.03 0.03 40 (S)-3-(Benzo[d]thiazol-5- yl)-1-(3-fluoro-2- methylphenyl)-N- hydroxycyclopent-2- enecarboxamide 0.01 0.05 41 (S)-3-(Benzo[b]thiophen- 2-yl)-1-(3-fluoro-2- methylphenyl)-N- hydroxycyclopent-2- enecarboxamide 0.02 0.04 42 (S)-1-(3,4-Difluoro-2- methylphenyl)-N- hydroxy-3-(1-methyl-1H- indazol-6-yl)cyclopent-2- enecarboxamide 0.01 0.02 43 4-(5-Fluoropyridin-3-yl)- N-hydroxy-1,2,3,6- tetrahydro-[1,1-biphenyl]- 1-carboxamide 3.6 39 44 3-Fluoro-4-(5- fluoropyridin-3-yl)-N- hydroxy-2-methyl- 1,2,3,6-tetrahydro-[1,1- biphenyl]-1-carboxamide 0.49 0.67 45 (S)-1-(3-Fluoro-2- methylphenyl)-N- hydroxy-3-(quinoxalin-6- yl)cyclopent-2- enecarboxamide 0.55 0.52

(307) 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.