Histone deacetylase inhibitors and compositions and methods of use thereof

Abstract

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

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, ##STR00210## wherein: R.sup.1 is —C(O)NH(OH) or —N(OH)C(O)R.sup.4; 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; X is absent, —O—, —NR.sup.6—, or —[C(R.sup.7R.sup.8)].sub.p—; R.sup.3 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, —CONR.sup.bR.sup.c, alkyl, alkyl substituted with —NR.sup.bR.sup.c, cycloalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkoxy substituted with —NR.sup.bR.sup.c, aryl, heteroaryl, and nitrile; R.sup.4 is hydrogen, lower alkyl or lower haloalkyl; for each occurrence, R.sup.5 is independently selected from halo, lower alkyl, lower haloalkyl, and hydroxyl; or R.sup.3 taken together with R.sub.5, and any intervening atoms, forms a 3- to 7-membered heterocycloalkyl or cycloalkyl ring; m and m′ are independently selected from 1, 2, and 3, provided that m+m′≦4; n is 0, 1, 2 or 3; p is 1 or 2; R.sup.6 is hydrogen, lower alkyl, cycloalkyl, or lower haloalkyl; and for each occurrence, R.sup.7 and R.sup.8 are each independently selected from hydrogen, halo, lower alkyl, and lower haloalkyl, R.sup.b is selected from H, C.sub.1-C.sub.6 alkyl, aryl, and heteroaryl; and R.sup.c is selected from hydrogen and C.sub.1-C.sub.4 alkyl; or R.sup.b and R.sup.c, and the nitrogen to which they are attached, form a heterocycloalkyl group; and where for R.sup.b and R.sup.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-O—C.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 compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula II: ##STR00211##

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 2.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 3.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein m′ is 1.

7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein m′ is 2.

8. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein m′ is 3.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is —C(O)NH(OH).

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is —N(OH)C(O)R.sup.4.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is hydrogen or lower alkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is lower alkyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 2.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 3.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, for each occurrence, R.sup.5 is independently selected from halo and lower alkyl.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, and haloalkyl.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is 3-fluoro-2-methylphenyl or 2-methylphenyl.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is heteroaryl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, and haloalkyl.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is pyridinyl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, and haloalkyl.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is 2-methylpyridin-3-yl.

24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1.

25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 2.

26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, for each occurrence, R.sup.7 and R.sup.8 are each independently selected from hydrogen, halo, and lower alkyl.

27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is absent.

28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is —O—.

29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is —NR.sup.6—.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein R.sup.6 is hydrogen, lower alkyl, or cycloalkyl.

31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently selected from halo, —CONR.sup.bR.sup.c, alkyl, alkyl substituted with —NR.sup.bR.sup.c, cycloalkyl, haloalkyl, hydroxyl, alkoxy, alkoxy substituted with —NR.sup.bR.sup.c, and nitrile.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is aryl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is phenyl, 2-methylphenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4,4-difluoro-1,2,3 ,4-tetrahydroquinolin-7-yl, or 4,4, 8-trifluoro-1,2,3 ,4-tetrahydroquinolin-6-yl.

34. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is heteroaryl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is 6-methylpyridin-3-yl, 5-fluoropyridin-3-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5-methylpyrimidin-2-yl, pyrimidin-2-yl, 2-(trifluoromethyl)pyrimidin-5-yl, 2-methylpyrimidin-5-yl, pyrimidin-5-yl, 2-(trifluoromethyl)pyrimidin-4-yl, 2-methylpyrimidin-4-yl, pyrimidin-4-yl, 6-(trifluoromethyl)pyridazin-4-yl, 6-methylpyridazin-4-yl, pyridazin-4-yl, 6-cyclopropylpyridazin-4-yl, pyrazin-2-yl, 5-(trifluoromethyl)pyrazin-2-yl, 5-methylpyrazin-2-yl, 3-cyclopropylpyrazin-2-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl, 2-cyclopropyloxazol-5-yl, 2-cyclopropylthiazol-5-yl, 2-methylbenzo[d]oxazol-5-yl, 1H-pyrrolo[2,3-b]pyridin-6-yl, imidazo[1,2-a]pyridin-7-yl, 1H-indazol-6-yl, or 2-oxo-1,2-dihydropyridin-3-yl.

36. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, aryl, heteroaryl, and nitrile.

37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is 1H-pyrrolo[3,4-c]pyridin-2(3H)-yl, 3,4-dihydroisoquinolin-2(1H)-yl, 4-cyclopropylpiperazin-1-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, or 1-cyclopropylpiperidin-4-yl.

38. A compound selected from: 1-(3 -fluoro-2-methylphenyl)-N-hydroxy-3 -(pyridin-3 -yl)cyclopentanecarboxamide; (±)-(1S*,3R*)-1-(3 -fluoro-2-methylphenyl)-N-hydroxy-3 -(pyrimidin-5-yl)cyclopentanecarboxamide; (±)-(1S*,3S*)-1-(3 -fluoro-2-methylphenyl)-N-hydroxy-3 -(pyrimidin-5-yl)cyclopentanecarboxamide; (1R*,3S*)-1-(3 -fluoro-2-methylphenyl)-N-hydroxy-3 -phenylcyclopentanecarboxamide; (1S*,3R*)-1-(3 -fluoro-2-methylphenyl)-N-hydroxy-3 -phenylcyclopentanecarboxamide; (1S*,3S*)-1-(3 -fluoro-2-methylphenyl)-N-hydroxy-3 -phenylcyclopentanecarboxamide; (1R*,3R*)-1-(3 -fluoro-2-methylphenyl)-N-hydroxy-3 -phenylcyclopentanecarboxamide; (±)-(1S*,3S*)-1-(3 -fluoro-2-methylphenyl)-N-hydroxy-3 -(o-tolyl)cyclopentanecarboxamide; (1S,3S*)-1-(3 -fluoro-2-methyl-phenyl)-3 -(5-fluoropyridin-3 -yl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-1-(3 -fluoro-2-methyl-phenyl)-3 -(5-fluoropyridin-3 -yl)-N-hydroxycyclopentanecarboxamide; (1S,3S*)-1-(3 -fluoro-2-methylphenyl)-3 -(5-fluoropyridin-2-yl)-N-hydroxycyclpentane carboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)-N-hydroxycyclopentane carboxamide; (1r,4r)-4-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclohexanecarboxamide; (1s,4s)-4-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclohexanecarboxamide; 1-(2,3-difluorophenyl)-N-hydroxycyclopentanecarboxamide; 1-(2,3-dihydrobenzofuran-7-yl)-N-hydroxycyclopentanecarboxamide; 1-(3-chloro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; 1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; N-hydroxy-1-phenylcyclopentanecarboxamide; 1-(2-chloro-6-fluorophenyl)-N-hydroxycyclopentanecarboxamide; N-hydroxy-1-(2-methoxyphenyl)cyclopentanecarboxamide; N-hydroxy-1-o-tolylcyclopentanecarboxamide; N-hydroxy-1-m-tolylcyclopentanecarboxamide; 1-(2-cyanophenyl)-N-hydroxycyclopentanecarboxamide; 1-(3-cyanophenyl)-N-hydroxycyclopentanecarboxamide; 1-(3,4-difluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; 1-(3,5-difluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; 1-(2-chloro-6-methylphenyl)-N-hydroxycyclopentanecarboxamide; 1-(2-ethylphenyl)-N-hydroxycyclopentanecarboxamide; N-hydroxy-1-(3-methoxy-2-(trifluoromethyl)phenyl)cyclopentanecarboxamide; N-hydroxy-1-(2-(trifluoromethyl)phenyl)cyclopentanecarboxamide; 1-(4-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; 1-(5-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; 1-(2-fluoro-6-methylphenyl)-N-hydroxycyclopentanecarboxamide; 1-(benzo[b]thiophen-7-yl)-N-hydroxycyclopentanecarboxamide; (1R, 3S*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopentanecarboxamide; (1R,3R*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopentanecarboxamide; (1S,3R)-3-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclopentanecarboxamide; (1S,3S)-3-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclopentanecarboxamide; (1S,3R)-3-(2-cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3S*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-3-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxy cyclopentane carboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopentanecarboxamide; (1S,3R*)-1-(3-Fluoro-2-methylphenyl)-3-(5-fluoro-6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)cyclopentane carboxamide; (1S,3S*)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)cyclopentanecarboxamide; (1S,3R*)-3-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; N-((R)-1-(dipropylamino)propan-2-yl)-4(1R*,3S)-3-(3-fluoro-2-methylphenyl)-3-(hydroxycarbamoyl)cyclopentyl)benzamide; N-((R)-1-(dipropylamino)propan-2-yl)-4S*,3S)-3-(3-fluoro-2-methylphenyl)-3-(hydroxycarbamoyl)cyclopentyl)benzamide; (1S,3R*)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3S*)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopentanecarboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(imidazo[1,2-a]pyridin-7-yl)cyclopentanecarboxamide; (1S,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(imidazo[1,2-a]pyridin-7-yl)cyclopentanecarboxamide; (1S,3R*)-3-(2-cyclopropyl-1-oxoisoindolin-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-7-yl)cyclopentanecarboxamide; (1S,3R*)-3-(7-fluoro-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S, 3R *)-3-(2-Cyclopropylbenzo[d]oxazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-5-yl) cyclopentanecarboxamide; (1S,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-5-yl) cyclopentanecarboxamide; (1S,3R*)-3-(2-(difluoromethyl)-2H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3S*)-3-(2-(difluoromethyl)-2H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-3-(3-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3S*)-3-(3-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-benzo[d]imidazol-5-yl )cyclopentanecarboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)cyclopentanecarboxamide; (1S,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)cyclopentanecarboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopentanecarboxamide; (1S,3S*)-3-(benzo[d]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-3 -(benzo [d]thiazol -2 -yl)- 1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3S*)-3-(2-cyclopropylbenzo[d]thiazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-3 - (2 -cyclopropylbenzo[d]thiazol -6 -yl)- 1 -(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3S*)-3-(2-cyclopropylbenzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-3 -(2-cyclopropylbenzo[d]thiazol-5-yl)- 1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3R)-3-(5-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3S*)-3-(7-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3R*)-3-(7-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide; (1S,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(quinolin-6-yl)cyclopentanecarboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(quinolin-6-yl)cyclopentanecarboxamide; (1S,3R*)-1-(3,4-difluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopentanecarboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrrolidin-1-yl)cyclopentanecarboxamide; (1S,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrrolidin-1-yl)cyclopentanecarboxamide; (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-morpholinocyclopentanecarboxamide; (1S,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-morpholinocyclopentanecarboxamide; (1S,3R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-((1-methyl-1H-indazol-6-yl)oxy)cyclopentanecarboxamide; (1S,3S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-((1-methyl-1H-indazol-6-yl)oxy)cyclopentanecarboxamide; (1S,3R)-1-(3-fluoro-2-methylphenyl)-3-((5-fluoropyridin-3-yl)oxy)-N-hydroxycyclopentanecarboxamide; (1S,3S)-1-(3-fluoro-2-methylphenyl)-3-((5-fluoropyridin-3-yl)oxy)-N-hydroxycyclopentanecarboxamide; (1S,3R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenoxycyclopentanecarboxamide; (1S,3S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenoxycyclopentanecarboxamide; (1S,3S)-1-(3-fluoro-2-methylphenyl)-3((4-fluorobenzyl)oxy)-N-hydroxycyclopentanecarboxamide; 1-phenyl-N-hydroxycyclohexylcarboxamide; (1r,4r)-1-(3-fluoro-2-methylphenyl)-4-(5-fluoropyridin-3-yl)-N-hydroxycyclohexanecarboxamide; (1s,4s)-1-(3-fluoro-2-methylphenyl)-4-(5-fluoropyridin-3-yl)-N-hydroxycyclohexanecarboxamide; (1r,4-1-(3-fluoro-2-methylphenyl)-N-hydroxy-4-phenoxycyclohexanecarboxamide; (1s,4s)-1-(3-fluoro-2-methylphenyl)-4((4-fluorobenzyl)oxy)-N-hydroxycyclohexanecarboxamide; (1s,4s)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxamide; (1r,4r)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxamide; (±)-2-(3-fluoro-2-methylphenyl)-N-hydroxy-8-oxaspiro[4.5]decane-2-carboxamide; N-hydroxy-l-phenylcycloheptanecarboxamide; and 1-(3-fluoro-2-methylphenyl)-N-hydroxycycloheptanecarboxamide, or a pharmaceutically acceptable salt thereof.

39. A pharmaceutically acceptable composition comprising a pharmaceutically acceptable carrier and at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition of claim 39, wherein the composition is formulated as a tablet, a capsule, a powder, a liquid, a suspension, a suppository, or an aerosol.

41. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula III: ##STR00212##

42. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula IV: ##STR00213##

43. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula V: ##STR00214##

Description

EXAMPLES

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

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

(3) Abbreviations

(4) aq: Aqueous DCM: Dichloromethane DCE: Dichloroethane DIPEA: Diisopropylethylamine DME: Dimethoxyethane DMF: Dimethylformamide DMSO: Dimethylsulfoxide d.r.: Diastereomeric ratio ee: Enantiomeric excess ES+: Electrospray Positive Ionisation ES−: Electrospray Negative Ionisation Et.sub.2O: Diethyl ether EtOAc: Ethyl acetate FA: Formic acid h: Hour HPLC: High Performance Liquid Chromatography i-hex: iso-Hexane IPA: iso-propanol LCMS: Liquid Chromatography Mass Spectrometry LiHMDS: Lithium bis(trimethylsilyl)amide M: Mass MeCN: Acetonitrile MeOH: Methanol N/A: Not available 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(0) Pd(dppf)Cl.sub.2: [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM Pd(PPh.sub.3).sub.4: Tetrakis(triphenylphosphine)palladium(0) RT: Retention time r.t.: Room temperature sat: Saturated SFC: Supercritical fluid chromatography TFFH: Tetramethylfluoroformamidinium hexafluorophosphate THF: Tetrahydrofuran Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
Analytical Conditions

(5) TABLE-US-00001 Analytical Condition Method Description 10 cm_ESI_ 1 Solvents: Acetonitrile (far UV grade) Formic_MeCN, with 0.1% (v/v) formic acid. Water (high 10 cm_ESCI_ purity via PureLab Option unit) with 0.1% Formic_MeCN formic acid Column: Phenomenex Luna 5 μm C18 (2), 100 × 4.6 mm (Plus guard cartridge) Flow Rate: 2 mL/min gradient: A: Water/formic acid B: MeCN/formic acid Time A % B % 0.00 95  5 3.50  5 95 5.50  5 95 5.60 95  5 6.50 95  5 Typical Injections 2-7 μL (concentration ~0.2-1.0 mg/mL) 15 cm_Formic_ 2 Solvents: Acetonitrile (Far UV grade) Ascentis_HPLC_ with 0.1% (V/V) formic acid Water (High MeCN purity via PureLab Ultra unit) with 0.1% formic acid Column: Supelco, Ascentis ® Express C18 or Hichrom Halo C18, 2.7 μm C18, 150 × 4.6 mm. Flow Rate: 1 mL/min gradient: A: Water/formic B: MeCN/formic Time A % B %  0.00 96  4  3.00 96  4  9.00  0 100 13.6  0 100 13.7 96  4 15 96  4 Typical Injections 2-7 μL (concentration ~0.2-1 mg/mL) 10 cm_Formic_ 3 Solvents: Acetonitrile (Far UV ACE-AR_HPLC_ grade) with 0.1% (V/V) formic acid Water CH3CN (High purity via PureLab Ultra unit) with 0.1% formic acid Column: Hichrom ACE 3 C18-AR mixed mode column 100 × 4.6 mm Flow Rate: 1 mL/min gradient: A: Water/formic B: MeCN/formic Time A % B %  0.00 98  2  3.00 98  2 12.00  0 100 15.4  0 100 15.5 98  2 17 98  2 Typical Injections 0.2-10 μL

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

(7) 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

(8) ##STR00005## ##STR00006##

Step 1: (S)-2-hydroxybutane-1,4-diyldimethanesulfonate

(9) (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 −1° 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 reaction contents 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 in vacuo 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 −2° 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 δ (ppm): (DMSO-d.sub.6): 5.33 (1 H, s), 4.35-4.23 (2 H, m), 4.19-3.99 (2 H, m), 3.89-3.81 (1 H, m), 3.19 (3 H, s), 3.18 (3 H, s), 1.94-1.84 (1 H, m), 1.77-1.66 (1 H, m).

Step 2: (S)-2-((tert-butyldiphenylsilyl)oxy)butane-1,4-diyldimethanesulfonate

(10) 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 (2×200 mL), and then sat. NaCl solution (250 mL). The combined organic layers were dried, filtered (phase separation cartridge) and concentrated in vacuo to give a yellow oil. Purification by flash silica column chromatography (gradient elution, 0-50% 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 δ (ppm)(DMSO-d.sub.6): 7.67-7.63 (4 H, m), 7.52-7.41 (6 H, m), 4.31-4.16 (2 H, m), 4.13-4.01 (3 H, m), 3.08 (3H, s), 3.02 (3 H, s), 1.92 (2 H, dd, J=12.2, 6.1 Hz), 1.02 (9 H, s).

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

(11) 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 (2×300 mL) and sat. NaCl solution (400 mL). The combined organic layers were dried, filtered (phase separation cartridge) and concentrated in vacuo to give a yellow oil. Purification by flash silica column chromatography (gradient elution, 0-10% EtOAc in iso-hexane) gave the title compound as a colorless oil which darkened 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 δ (ppm)(DMSO-d.sub.6): 7.69-7.63 (4 H, m), 7.52-7.41 (6 H, m), 4.07-3.99 (1 H, m), 3.53-3.40 (4 H, m), 2.10 (2 H, dd, J=13.0, 6.5 Hz), 1.04 (9 H, s).

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

(12) 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, 0.75 mmol). 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 (2×150 mL), sat. NaCl solution (200 mL), then dried, filtered (phase separation cartridge) and concentrated in vacuo to give a yellow oil. The resultant oil was dissolved in anhydrous THF (80 mL) and TBAF (1 M in THF, 30 mL, 0.03 mol) was added. Reaction mixture was then stirred at r.t. for 3 h. After this time the reaction mixture was concentrated in vacuo under reduced pressure and purified by flash silica column chromatography (gradient elution, 0-33% 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

(13) To a solution of (1S,3S)-methyl 1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (5:1 (1S,3S):(1R:3S) mixture of isomers, 2.10 g, 0.0086 mol) in anhydrous acetonitrile (100 mL) was added DBU (1.44 g, 1.42 mL, 0.0095 mol). The reaction mixture was stirred at 80° C. for 20 h. The reaction mixture was cooled to r.t. and partitioned between DCM (125 mL) and 1 M HCl (100 mL). The organic layer was extracted, washed with water (100 mL), then dried, filtered (phase separation cartridge) and concentrated in vacuo to give a yellow oil. The residue was purified by flash silica column chromatography (gradient elution, 0-40% 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 δ (ppm)(CDCl.sub.3): 7.18-7.10 (1 H, m), 7.09-6.98 (2 H, m), 5.00 (1 H, d, J=2.1 Hz), 2.81 (1 H, dd, J=10.4, 2.4 Hz), 2.39-2.32 (1 H, m), 2.32 (3 H, d, J=2.8 Hz), 2.3-2.21 (1 H, m), 2.15-2.07 (2 H, m), 1.93 (1 H, 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 δ (ppm)(CDCl.sub.3): 7.24 (1 H, d, J=8.03 Hz), 7.19-7.11 (1 H, m), 6.97-6.90 (1 H, m), 4.56-4.49 (1 H, m), 3.62 (3 H, s), 3.07 (1 H, dd, J=13.8, 6.6 Hz), 2.47-2.42 (2 H, m), 2.11 (3 H, d, J=2.8 Hz), 2.10-2.01 (1 H, m), 1.92 (1 H, ddd, J=13.9, 4.5, 1.1 Hz), 1.79-1.70 (1 H, m), 1.38 (1 H, d, J=4.2 Hz); .sup.19F NMR: −114.83.

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

(14) To a solution of (1S,3S)-methyl 1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (1.60 g, 6.5 mmol) in anhydrous DCM (100 mL) was added Dess-Martin Periodinane (3.32 g, 7.8 mmol). The reaction mixture was stirred at r.t. for 4 h. Reaction mixture was quenched with a mixture of 10% Na.sub.2S.sub.2O.sub.3 and sat. NaHCO.sub.3 solution (1:1, 100 mL) and then rapidly stirred for 30 min. Organic layers were extracted with further DCM (2×50 mL), then dried, filtered (phase separation cartridge) and concentrated in vacuo 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 (1.42 g, 84%). R.sub.f=0.25 (33% EtOAc/iso-hexane); .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.28-7.19 (1 H, m), 7.17-7.02 (2 H, m), 3.76 (3 H, s), 3.28 (1 H, d, J=17.9 Hz), 2.88-2.79 (1 H, m), 2.69-2.33 (4 H, m), 2.19 (3 H, 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

(15) ##STR00007##

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 (1 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 (2×100 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 in vacuo and the resulting oil purified by flash silica column chromatography (gradient elution 5% EtOAc in i-hex to 10% EtOAc in i-hex) to give the title compound as a colourless oil (1.5 g, 35%). .sup.1 H NMR δ (ppm)(CDCl.sub.3): 4.09-4.01 (1 H, m), 3.61-3.50 (3 H, m), 3.42 (1 H, dd, J=10.4, 6.7 Hz), 2.18 (1 H, dd, J=5.4, 0.8 Hz), 2.13-2.01 (2 H, 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, 0.16 mmol) 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 (30×25 mL). The filtrate was collected and washed with 1 M HCl (30 mL), sat. brine solution (30 mL) and the organics passed through a phase separator and concentrated in vacuo. Purification by flash silica chromatography (gradient elution i-hex to 20% EtOAc in i-hex) gave the title compound as a white crystalline solid (2.06 g, 96%). .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.15-7.07 (1 H, m), 7.02-6.93 (2 H, m), 5.20-5.12 (1 H, m), 3.70 (2 H, s), 3.58 (1 H, dd, J=11.1, 4.7 Hz), 3.45 (1 H, dd, J=11.1, 4.3 Hz), 3.34 (1 H, ddd, J=10.3, 6.6, 5.5 Hz), 3.25 (1 H, ddd, J=10.3, 8.4, 6.1 Hz), 2.35-2.26 (1 H, m), 2.24 (3 H, d, J=2.7 Hz), 2.26-2.12 (1 H, 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 (20 mL) and then extracted into EtOAc (3×50 mL). The combined organics were washed with water (50 mL) and sat. brine solution (50 mL), separated, dried (MgSO.sub.4), filtered and concentrated in vacuo. Purification by flash silica chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a white crystalline solid (890 mg, 75%). .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.17-7.08 (1 H, m), 7.07-6.97 (2 H, m), 5.00 (1 H, d, J=2.10 Hz), 2.81 (1 H, dd, J=10.4, 2.4 Hz), 2.40-2.18 (2 H, m), 2.30 (3 H, d, 2.3 Hz), 2.13-2.07 (2 H, m), 1.93 (1 H, 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 in vacuo. Purification by flash silica chromatography (gradient elution i-hex to 30% EtOAc in i-hex) gave the title compound as a white crystalline solid (766 mg, 75% [95% based on recovered starting material]). .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.18-7.06 (2 H, m), 6.98-6.89 (1 H, m), 4.42-4.37 (1 H, m), 3.66 (3 H, s), 2.74-2.69 (1 H, m), 2.66-2.58 (1 H, m), 2.55 (1 H, d, J=7.85 Hz), 2.29-2.13 (3 H, m), 2.13 (3 H, d, J=2.7 Hz), 1.83-1.72 (1 H, 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 DCM (20 mL) was added Dess-Martin Periodinane (1.55 g, 3.64 mmol). The reaction mixture was stirred at r.t. for 4 h. The reaction mixture was quenched with a mixture of 10% Na.sub.2S.sub.2O.sub.3 and sat. NaHCO.sub.3 solution (1:1, 50 mL) and then rapidly stirred for 30 min. Organic layers were extracted with further DCM (2×50 mL), then dried, filtered (phase separation cartridge) and concentrated in vacuo to give a pale yellow oil. The residue was purified by flash silica column chromatography (gradient elution i-hex to 20% EtOAc in i-hex) to give the title compound as a colorless solid (656 mg, 86%). .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.28-7.19 (1 H, m), 7.17-7.02 (2 H, m), 3.76 (3 H, s), 3.23 (1 H, d, J=17.9 Hz), 2.88-2.79 (1 H, m), 2.69-2.33 (4 H, m), 2.19 (3 H, 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) ##STR00008##

(23) 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 δ (ppm)(CDCl.sub.3): 7.28-7.19 (1 H, m), 7.17-7.02 (2 H, m), 3.76 (3 H, s), 3.28 (1 H, d, J=17.9 Hz), 2.88-2.79 (1 H, m), 2.69-2.33 (4 H, m), 2.19 (3 H, d, J=2.7 Hz).

Preparation of Intermediate 4: methyl 3-bromo-1-(3-fluoro-2-methylphenyl)cyclopentane carboxylate

(24) ##STR00009##

(25) Bromine (0.225 mL, 4.4 mmol) was added dropwise to a stirred suspension of triphenylphosphine (1.15 g, 4.4 mmol) in MeCN (6.2 mL) under nitrogen at 0° C. Subsequently, a solution of methyl 1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (made following the procedure for the formation of Intermediate 1, steps 1-4, 1.01 g, 4 mmol) in MeCN (2 mL) was added dropwise and the reaction mixture was left to warm up to r.t. and was stirred for 18 h. The excess MeCN was removed in vacuo to give a pale yellow oil. Trituration in ether gave an off-white solid which was filtered and washed with ether and i-hex. The filtrate was evaporated in vacuo to give a pale yellow oil. Purification by flash silica column chromatography (elution 3% EtOAc in i-hex, R.sub.f=0.25) gave the title compound as a colorless oil (0.08 g, 64%). MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR δ (ppm)(CDCl.sub.3) (1:8 mixture of diastereoisomers): 7.20-7.11 (1H, m), 7.04 (1H, d, J=7.6 Hz), 7.02-6.92 (1 H, m), 4.36-4.28 (1 H, m), 3.68 (3H, s), 3.01 (1 H, dd, J=14.4, 7.6 Hz), 2.80-2.70 (2 H, m), 2.45-2.32 (1 H, m), 2.29-2.15 (2 H, m), 2.10 (3 H, d, J=2.4 Hz).

Preparation of Intermediate 5: (±)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate

(26) ##STR00010##

(27) To a solution of Intermediate 3 (1.50 g, 6.00 mmol) in anhydrous THF (12 mL) was added drop-wise NaHMDS (1 M in THF, 6.00 mL, 6.00 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. After this time N-phenylbistriflimide (2.40 g, 6.48 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). The organic layer was separated, washed with brine (50 mL), then dried (MgSO.sub.4), filtered using a phase separation cartridge and concentrated in vacuo to give a yellow oil. The residue was purified by flash silica column chromatography (gradient elution i-hex to 30% EtOAc in i-hex) to give the title compound as a colorless oil (1.73 g, 75%). MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.14 (1 H, q, J=1.6 Hz), 6.97 (2 H, dd, J=1.6 Hz), 5.96 (1 H, s), 3.69 (3 H, s), 3.62-3.30 (1 H, m), 2.88-2.84 (1 H, m), 2.69-2.64 (1 H, m), 2.08 (3 H, d, J=2.4 Hz), 2.02-1.95 (1 H, m).

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

Preparation of Intermediate 6: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate

(29) ##STR00011##

(30) Prepared from Intermediate 1 following the procedure for the preparation of Intermediate 5. .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.14 (1 H, q, J=1.6 Hz), 6.97 (2 H, dd, J=1.6 Hz), 5.96 (1 H, s), 3.69 (3 H, s), 3.62-3.30 (1 H, m), 2.88-2.84 (1 H, m), 2.69-2.64 (1 H, m), 2.08 (3 H, d, J=2.4 Hz), 2.02-1.95 (1 H, m).

Preparation of Intermediate 7: (S)-Methyl 1-phenyl-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate

(31) ##STR00012##

Step 1: (R)-1,4-Dibromobutan-2-yl 2-phenyl acetate

(32) 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 (3×25 mL). The filtrate was collected and washed with 1 M HCl(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 (3.95 g, >99%).

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

(33) To a stirred solution of (R)-1,4-dibromobutan-2-yl 2-phenyl acetate (3.54 g, 1.1 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(aq) (20 mL) and then extracted into EtOAc (3×50 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%).

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

(34) 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%).

Step 4: (S)-Methyl 3-oxo-1-phenylcyclopentanecarboxylate

(35) 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 1% 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 (2×50 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%).

Step 5: (S)-Methyl 1-phenyl-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (Intermediate 7)

(36) (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 Intermediate 8: Methyl 1-(3-fluoro-2-methylphenyl)-4-oxocyclohexanecarboxylate

(37) ##STR00013##

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

(38) 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 (6% 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

(39) 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.+.

Preparation of Intermediate 9: (S)-4-methoxybenzyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate

(40) ##STR00014##

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

(41) To a solution of Intermediate 1 (4.00 g, 15.6 mmol) in methanol (60 mL) was added lithium hydroxide hydrate (0.36 g, 85.0 mmol) and the reaction mixture heated to 65° C. under N.sub.2 for 2 h. After this time the reaction mixture was cooled to r.t. and residual methanol was removed under reduced pressure. The aqueous layer was diluted with additional water (45 mL) and extracted with dichloromethane (3×20 mL). Combined organics were discarded and the aqueous layer acidified to pH 5 using 1 N HCl, then extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (65 mL), then dried, filtered (phase separation cartridge) and concentrated to give the crude carboxylic acid.

(42) To a solution of the crude acid (3.70 g, assumed quantitative yield, 15.6 mmol) in anhydrous acetonitrile (150 mL) was added cesium carbonate (9.76 g, 34.0 mmol), potassium iodide (0.40 g) and 4-methoxybenzychloride (3.20 g, 20.4 mmol) and the reaction mixture heated to 65° C. under N.sub.2 for 24 h. After this time the reaction mixture was cooled to r.t. and filtered through Celite, washing with EtOAc (3×50 mL). The filtrate was dried, filtered (phase separation cartridge) and concentrated. The crude reaction material was purified by silica chromatography (gradient elution, 0-33% EtOAc in iso-hexane) to give the title compound as a pale yellow oil (3.88 g, 64%).

(43) .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.23-7.15 (1 H, m), 7.14 (2 H, d, J=8.3 Hz), 7.09-6.94 (2 H, m), 6.83 (2 H, d, J=8.2 Hz), 5.07 (2 H, d, J=2.2 Hz), 3.80 (3 H, s), 3.20 (1 H, d, J=17.9 Hz), 2.76-2.66 (1 H, m), 2.59-2.50 (1 H, m), 2.47 (1 H, d, J=17.8 Hz), 2.41-2.25 (2 H, m), 1.97 (3 H, d, J=2.8 Hz).

Step 2: (S)-4-methoxybenzyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2 enecarboxylate (Intermediate 9)

(44) To a solution of (S)-4-methoxybenzyl 1-(3-fluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate (2.00 g, 5.61 mmol) in anhydrous THF (65 mL) was added drop-wise KHMDS (0.7 M in Toluene, 10 mL, 6.75 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h. After this time (N,N-bis(trifluoromethylsulfonyl)-5-chloro-2-pyridylamine) (3.80 g, 6.75 mmol) was added dropwise as solution in THF (10 mL) with 2 h additional stirring. The reaction mixture was quenched via addition of sat. aq. 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. The crude reaction material was purified by flash silica chromatography (gradient elution, 0-20% EtOAc in iso-hexane) to give the title compound as a pale yellow oil (3.80 g, 75%).

(45) .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.18-7.10 (3 H, m), 7.01-6.91 (2 H, m), 6.85-6.80 (2 H, m), 5.90 (1 H, t, J=1.9 Hz), 5.12-5.01 (2 H, m), 3.80 (3H, s), 3.29 (1 H, ddd, J=13.2, 9.3, 4.2 Hz), 2.90-2.80 (1 H, m), 2.64 (1 H, dddd, J=16.5, 9.7, 4.2, 1.9 Hz), 2.01-1.93 (1 H, m), 1.93 (3 H, d, J=2.5 Hz).

Preparation of Intermediate 10: (S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate

(46) ##STR00015##

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

(47) 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) 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

(48) 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

(49) 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 (2×200 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

(50) 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 (3×5 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

(51) 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 (2×50 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

(52) 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). 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

(53) To a solution of (1S,3S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (0.6 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 (2×50 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).

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

(54) Prepared following the method used in step 2 in the synthesis of Intermediate 9 using (S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate in place of (S)-4-methoxybenzyl 1-(3-fluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate.

Preparation of Examples

(55) General Synthetic Methods

(56) ##STR00016##
Method A (Suzuki-Miyaura Coupling) To Intermediate 4 (394 mg, 1.25 mmol) in a sealed tube under nitrogen was added bathophenanthroline (41.6 mg, 0.125 mmol), aryl trifluoroborate potassium salt (1.275 mmol), NiBr.sub.2.glyme (38.6 mg, 0.125 mmol) and s-BuOH (2.5 mL). To this was added LiHMDS (1 M in THF, 3.75 mL, 3.75 mmol). The reaction mixture was stirred at 60° C., under nitrogen, for 16 h. The mixture was diluted with EtOAc and passed through a short plug of silica, which was washed thoroughly with EtOAc. The filtrate was concentrated in vacuo.

(57) ##STR00017##
Method B (Suzuki Coupling)

(58) 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. at 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 (3×10 mL). Combined organics were extracted with water (15 mL) then brine (20 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated to give a brown residue.

(59) Method B (ii) (Suzuki Coupling)

(60) 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 (00.6 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(0) (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 r.t. and filtered through Celite, washing with EtOAc (3×10 mL). Combined organics were extracted with water (15 mL) then brine (20 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated.

(61) Method B (iii) (Suzuki Coupling)

(62) 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(), (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 (3×10 mL). Combined organics were extracted with water (15 mL) then brine (20 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated.

(63) Method B (iv) (Suzuki Coupling)

(64) To a solution of aryl halide (0.400 g, 1.58 mmol) in dioxane (7 mL) was added bis(neopentyl glycolato)diboron (0.356 g, 1.58 mmol), potassium acetate (0.281 g, 2.87 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.035 g, 0.04 mmol) and the reaction mixture heated to 100° C. under N.sub.2 for 1 h. After this time the reaction mixture was cooled to r.t. and a solution of (S)-4-methoxybenzyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2 enecarboxylate (0.70 g, 1.43 mmol) in anhydrous dioxane (1 mL) was added followed by a solution of cesium carbonate (0.70 g, 2.15 mmol) in water (1.2 mL). The reaction mixture was recapped and heated to 1° C. under N.sub.2 for a further 2 h. Reaction mixture water was decanted, and the dioxane layers were then concentrated under reduced pressure.

(65) Method C (Ester Hydrolysis)

(66) To a solution of the ester 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 1 M aqueous HCl (20 mL). Organic layers were extracted, washed with brine (40 mL), dried, filtered (phase separation cartridge) and concentrated to give a colorless residue.

(67) Method C (ii) (Ester Hydrolysis)

(68) To a solution of the ester (0.0393 mmol) in MeOH (2 mL) was added 2 M KOH (0.075 mL, 1.5 mmol). The reaction mixture was heated at 120° C. for 2 h under microwave irradiation. The mixture was chilled (ice bath), neutralized to pH˜7 with 2 M HCl (0.75 mL) and diluted with H.sub.2O (5 mL). The mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were dried (MgSO.sub.4), filtered and concentrated in vacuo.

(69) Method C (iii) (Ester Hydrolysis)

(70) 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.

(71) Method D (Hydroxamic Acid Formation)

(72) To a solution of carboxylic acid (0.08 g, 0.27 mmol) and triethylamine (0.08 g, 115 μL, 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.

(73) Method D (ii) (Hydroxamic Acid Formation)

(74) To a solution of the cyclopentanecarboxylic acid (0.284 mmol) in anhydrous DCM (4.2 mL) was added oxalyl chloride (0.106 mL, 1.25 mmol). The reaction was stirred at r.t. under nitrogen for 16 h. The excess reagent and DCM were removed under reduced pressure and the solid obtained was resuspended in anhydrous DCM (3 mL). To this was added 50% aqueous NH.sub.2OH (0.5 mL) and the reaction mixture was stirred at r.t. for 4 h. The mixture was chilled (ice bath), neutralized to pH˜7 with 2 M HCl (0.8 mL) and diluted with H.sub.2O (2 mL). The mixture was extracted with EtOAc (3 mL) and the organic layer was dried (MgSO.sub.4), filtered and concentrated in vacuo. Purification by preparative HPLC.

(75) ##STR00018##
Method E (Cyclopentane Formation) Substituted benzene acetic acid methyl ester (5.38 mmol), DMF (20 mL), 1,4-diiodobutane (0.71 mL, 5.38 mmol) and NaH (60% in oil, 440 mg, 11 mmol), were combined at r.t. under a nitrogen atmosphere and stirred for 22 h. Reaction mixture was then diluted with EtOAc (50 mL) and washed with water (4×20 mL) and brine (20 mL). The organic layer was dried (MgSO.sub.4) and concentrated in vacuo.
Method F (Alkene Hydrogenation)

(76) Alkene (0.74 mmol), 20% w/w Pd/C (60 mg) and ammonium formate (7.4 mmol) were suspended in MeOH (40 mL) or EtOH (40 mL) and stirred at reflux for 2 h. After cooling to r.t. the solids were removed by filtration through Celite, washing with EtOAc (3×20 mL). The filtrate was concentrated and the residue partitioned between water (40 mL) and DCM (20 mL). The organic layer was extracted with DCM (3×20 mL) and the combined organic extracts were dried (phase separation cartridge) and concentrated.

EXAMPLES

(77) Where the absolute configuration of a single isomer is not known the configuration has been putatively assigned and is shown with an asterisk. For example (1S,3R*)-1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopentanecarboxamide is a single isomer for which the configuration at C1 is known absolutely but the configuration at C3 has been putatively assigned. Similarly, (1R*,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopentanecarboxamide is a single isomer for which the configuration at both C1 and C3 has been putatively assigned.

(78) Compounds are referred to as Diastereomer 1 (D1), Diastereomer 2 (D2) etc. where single isomers have been separated and tested but the absolute configuration of each isomer has not been determined.

(79) Compounds are referred to as Diastereomer 1 racemic (D1, rac), Diastereomer 2 racemic (D2, rac) where diastereomers have been separated and tested as racemic mixtures and the relative configuration of each diastereomer has not been determined.

Example 1

1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyridin-3-yl)cyclopentanecarboxamide

(80) ##STR00019##

Step 1: methyl 1-(3-fluoro-2-methylphenyl)-3-(pyridin-3-yl)cyclopentanecarboxylate

(81) Following Method A, from Intermediate 4 (394 mg, 1.25 mmol), bathophenanthroline (41.6 mg, 0.125 mmol), potassium pyridine-3-trifluoroborate (236 mg, 1.275 mmol), NiBr.sub.2.glyme (38.6 mg, 0.125 mmol) and s-BuOH (2.5 mL) were combined. To this was added LiHMDS (1 M in THF, 3.75 mL, 3.75 mmol). The brown product was purified by flash silica column chromatography (elution 50% EtOAc in i-hex, R.sub.f=0.47) to give the title compound as a pale yellow oil (123 mg, 31%). MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR δ (ppm)(CDCl.sub.3) (1:1 mixture of diastereoisomers): 8.55-8.49 (1 H, m), 8.48-8.40 (1 H, m), 7.78-7.72 (0.5 H, m), 7.55-7.48 (0.5 H, m), 7.30-7.12 (3 H, m), 7.05-6.95 (1 H, m), 3.68 (1.5 H, s), 3.67 (1.5 H, s), 3.42-3.30 (0.5 H, m), 3.25-3.13 (0.5 H, m), 3.08 (0.5 H, dd, J=14.4, 7.6 Hz), 2.80-2.65 (2 H, m), 2.55-2.45 (0.5 H, m), 2.42-2.29 (2 H, m), 2.28-2.19 (0.5H, m), 2.18-2.05 (0.5H, m), 2.15 (1.5H, d, J=2.4 Hz), 2.10 (1.5H, d, J=2.4 Hz).

Step 2: 1-(3-fluoro-2-methylphenyl)-3-(pyridin-3-yl)cyclopentanecarboxylic acid

(82) Following Method C (ii) from methyl 1-(3-fluoro-2-methylphenyl)-3-(3-pyridyl)cyclopentanecarboxylate (123 mg, 0.393 mmol) to give the title compound as an off-white solid (85 mg, 72%). MS (ES+) consistent with target (M+H).sup.+.

Step 3: 1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyridin-3-yl)cyclopentanecarboxamide

(83) Following Method D (ii) from 1-(3-fluoro-2-methylphenyl)-3-(3-pyridyl)cyclopentanecarboxylic acid (85 mg, 0.284 mmol). Purification by preparative HPLC gave the title compound as a racemic 2:1 mixture of diastereoisomers (6.8 mg, 8%). LCMS (ES+) 315 (M+H).sup.+, RT 2.22 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.01 (0.33 H, s), 9.92 (0.67H, s), 8.69 (0.33 H, s), 8.67 (0.67 H, s), 8.57-8.39 (2 H, m), 7.85-7.65 (1 H, m), 7.39-6.95 (4 H, m), 3.20-3.05 (1 H, m), 2.80-2.56 (2 H, m), 2.41-2.32 (1 H, m), 2.25-1.95 (5 H, m), 1.80-1.65 (1 H, m).

Example 2

(±)-(1S*,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrimidin-5-yl)cyclopentanecarboxamide (D1, rac)

Example 3

(±)-(1S*,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrimidin-5-yl)cyclopentanecarboxamide (D2, rac)

(84) ##STR00020##

Relative Stereochemistry Putatively Assigned

(85) Prepared following Method A, C (ii) and D (ii) from Intermediate 4 and potassium pyrimidine-5-trifluoroborate, analogous to the example described above.

(86) Example 2 (Diastereomer 1 (D1, rac)): LCMS (ES+) 316 (M+H).sup.+, RT 2.82 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.02 (1 H, s), 9.03 (1 H, s), 8.72 (2 H, s), 8.69 (1 H, d, J=1.8 Hz), 7.31 (1 H, d, J=8.0 Hz), 7.25-7.16 (1 H, m), 7.06 (1 H, t, J=8.9 Hz), 3.30-3.18 (1 H, m), 2.99 (1 H, dd, J=12.5, 6.8 Hz), 2.80-2.70 (1 H, m), 2.30-2.20 (2 H, m), 2.14 (3 H, d, J=2.8 Hz), 2.12-2.07 (1 H, m), 1.80-1.72 (1 H, m).

(87) Example 3 (Diastereomer 2 (D2, rac)): LCMS (ES+) 316 (M+H).sup.', RT 2.94 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.95 (1 H, s), 9.05 (1 H, s), 8.82 (2 H, s), 8.69 (1 H, d, J=1.7 Hz), 7.32-7.19 (2 H, m), 7.08 (1 H, t, J=8.9 Hz), 3.19-3.08 (1 H, m), 2.68 (1 H, dd, J=13.2, 10.1 Hz), 2.63-2.55 (1 H, m), 2.42-2.32 (1 H, m), 2.28-2.11 (2 H, m), 2.09 (3 H, d, J=2.7 Hz), 1.83-1.71 (1 H, m).

Example 4

(1R*,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopentanecarboxamide (D1)

Example 5

(1S*,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopentanecarboxamide (D2)

Example 6

(1S*,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopentanecarboxamide (D3)

Example 7

(1R*,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopentanecarboxamide (D4)

(88) ##STR00021##

Relative and Absolute Stereochemistry Putatively Assigned

Step 1: methyl 1-(3-fluoro-2-methylphenyl)-3-phenylcyclopentanecarboxylate

(89) Following Method A from Intermediate 4 (0.63 g, 2.00 mmol) and phenyl trifluoroborate potassium salt. The residue was purified by flash silica column chromatography (gradient elution iso-hexane to 50% EtOAc in i-hex) to give the title compound as a colorless oil (0.4 g, 64%). .sup.1H NMR δ (ppm)(CDCl.sub.3) (1:1 mixture of diastereoisomers): 7.33-7.07 (6 H, m), 6.95-6.91 (2 H, m), 3.68 (1.5 H, s), 3.67 (1.5 H, s), 3.42-3.28 (1 H, m), 3.22-3.13 (1H, m), 3.08 (0.5H, dd, J=14.4, 7.6 Hz), 2.8-2.65 (1 H, m), 2.55-2.45 (0.5 H, m), 2.32-2.18 (2 H, m), 2.15 (1.5 H, d, J=2.4 Hz), 2.10 (1.5 H, d, J=2.4 Hz), 1.91-1.80 (1H, m).

Step 2: 1-(3-fluoro-2-methylphenyl)-3-phenylcyclopentanecarboxylic acid

(90) Following Method C (ii) from methyl 1-(3-fluoro-2-methylphenyl)-3-phenylcyclopentanecarboxylate (0.4 g, 0.52 mmol) without further purification gave the title compound as a pale yellow solid (0.3 g, 79%). MS (ES−) consistent with target (M−H).sup.−; .sup.1H NMR δ (ppm)(CDCl.sub.3) (1:1 mixture of diastereoisomers): 11.38 (1 H, br s), 7.30-7.10 (6 H, m), 6.95-6.88 (2 H, m), 3.38-3.31 (1 H, m), 3.20-3.05 (1.5 H, m), 2.80-2.65 (1.0 H, m), 2.62-2.55 (1.0 H, m), 2.50-2.41 (0.5 H, m), 2.39-2.21 (1 H, m), 2.15 (1.5 H, d, J=2.4 Hz), 2.10 (1.5 H, d, J=2.4 Hz), 1.92-1.81 (1H, m).

Step 3: 1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenylcyclopentanecarboxamide

(91) Following Method D (ii) from 1-(3-fluoro-2-methylphenyl)-3-phenylcyclopentanecarboxylic acid (0.3 g, 0.1 mmol). Purification by preparative HPLC gave the title compound as a mixture of diastereoisomers (239 mg, 76%). LCMS (ES+) 314 (M+H).sup.+, Chiral preparative HPLC gave the 4 diastereomers.

(92) Example 4 (Diastereomer 1 (D1)): LCMS (ES+) 331 (M+H).sup.+, RT 3.92 min (Analytical method 1); RT 6.97 min (Chiralpak IA 30/70 IPA/MeOH/FA (30/70/0.1%)/heptane, 1.0 mL/min); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.02 (1H, s), 8.74 (1H, s), 7.35-7.20 (7 H, m), 7.06 (1 H, t, J=8.4 Hz), 3.06-3.04 (1 H, m), 2.63-2.54 (2 H, m), 2.39-2.34 (1 H, m), 2.16-2.15 (2 H, m), 2.09 (3 H, s), 1.75-1.69 (1.0 H, m).

(93) Example 5 (Diastereomer 2 (D2)): LCMS (ES+) 331 (M+H).sup.+; HPLC RT 11.04 min (Analytical method 3); RT 9.5 min (Chiralpak IA 20/80 IPA/MeOH/FA (20/80/0.1%)/heptane, 5.0 mL/min); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.02 (1H, s), 8.74 (1H, s), 7.35-7.20 (7 H, m), 7.06 (1 H, t, J=8.4 Hz), 3.06-3.04 (1 H, m), 2.63-2.54 (2 H, m), 2.39-2.34 (1 H, m), 2.16-2.15 (2 H, m), 2.09 (3 H, s), 1.75-1.69 (1.0 H, m).

(94) Example 6 (Diastereomer 3 (D3)): LCMS (ES+) 331 (M+H).sup.+; HPLC RT 11.01 (Analytical method 3); RT 12.7 min (Chiralpak IA 20/80 IPA/MeOH/FA (20/80/0.1%)/heptane, 5.0 mL/min); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.02 (1 H, s), 8.74 (1 H, s), 7.35-7.18 (7 H, m), 7.05 (1 H, t, J=8.4 Hz), 3.22-3.14 (1 H, m), 2.99-294 (1 H, m), 2.75-268 (1 H, m), 2.23-2.06 (2 H, m), 2.15 (3 H, s), 2.01-1.92 (1.0 H, m), 1.75-1.65 (1.0 H, m).

(95) Example 7 (Diastereomer 4 (D4)): LCMS (ES+) 331 (M+H).sup.+, RT 3.90 (Analytical method 1); RT 13.3 min (Chiralpak IA 30/70 IPA/MeOH/FA (30/70/0.1%)/heptane, 1.0 mL/min); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.02 (1 H, s), 8.74 (1 H, s), 7.35-7.18 (7 H, m), 7.05 (1 H, t, J=8.4 Hz), 3.22-3.14 (1 H, m), 2.99-294 (1 H, m), 2.75-268 (1 H, m), 2.23-2.06 (2 H, m), 2.15 (3 H, s), 2.01-1.92 (1.0 H, m), 1.75-1.65 (1.0 H, m).

Example 8

(±)-(1S*,3S*)1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(o-tolyl)cyclopentane carboxamide

(96) ##STR00022##

Relative Stereochemistry Putatively Assigned

Step 1: methyl 1-(3-fluoro-2-methylphenyl)-3-(o-tolyl)cyclopent-2-enecarboxylate

(97) Intermediate 5 (1 g, 2.62 mmol), o-tolylboronic acid (356 mg, 2.62 mmol), CsF (400 mg), DME (15 mL), MeOH (3 mL) and palladium tetrakis(triphenylphosphine) (20 mg) were combined in a sealed tube and heated with microwave irradiation to 120° C. for 1 h. The reaction mixture was then evaporated onto silica and purified by flash chromatography to give the title compound as a clear oil (922 mg).

Step 2: methyl 1-(3-fluoro-2-methylphenyl)-3-(o-tolyl)cyclopentanecarboxylate

(98) Methyl 1-(3-fluoro-2-methylphenyl)-3-(o-tolyl)cyclopent-2-enecarboxylate (300 mg, 0.93 mmol), EtOAc (30 mL) and 10% Pd/C were combined and shaken under a hydrogen atmosphere at 15 psi for 6 h. Catalyst was filtered off and solvents removed by evaporation to give the title compound as a clear gum (263 mg).

Step 3: 1-(3-fluoro-2-methylphenyl)-3-(o-tolyl)cyclopentanecarboxylic acid

(99) Methyl 1-(3-fluoro-2-methylphenyl)-3-(o-tolyl)cyclopentanecarboxylate (26 mg, 0.8 mmol), THF (3 mL), MeOH (3 mL) and 15% Aq. NaOH (1 mL) were combined in a sealed tube and heated with microwave irradiation to 120° C. for 1 h. Reaction mixture was then partitioned between EtOAc and 1 N HCl. The organic layer was dried (MgSO.sub.4) and solvents removed by evaporation to give a clear gum (238 mg).

Step 4: 1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(o-tolyl)cyclopentanecarboxamide

(100) 1-(3-Fluoro-2-methylphenyl)-3-(o-tolyl)cyclopentanecarboxylic acid (238 mg, 0.76 mmol), DCM (20 mL) and oxalyl chloride (0.17 mL, 2 mmol) were combined and stirred at r.t. under a nitrogen atmosphere for 3 days. Reaction mixture was evaporated to dryness. To the residue was added DCM (1 mL) and 50% Aq hydroxylamine (1 mL) and the reaction stirred for 10 min at r.t. Reaction mixture was evaporated to dryness and purified by preparative HPLC to give the title compound as an off-white solid (99 mg). LCMS (ES+) 328 (M+H).sup.+; RT 4.16 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.88 (1 H, s), 8.65 (1 H, s), 7.46 (1 H, d, J=8.0 Hz), 7.28-7.06 (6 H, m), 3.30-3.20 (1 H, m), 2.52-2.51 (1 H, m), 2.51-2.50 (1 H, m), 2.40-2.30 (1 H, m), 2.24 (3 H, s), 2.20-1.95 (2 H, m), 2.08 (3H, d, J=2.8 Hz), 1.52-1.51 (1H, m).

Example 9

(1S,3S*)-1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopentanecarboxamide (D1)

Example 10

(1S,3R*)-1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopentanecarboxamide (D2)

(101) ##STR00023##

C3 Stereochemistry Putatively Assigned

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

(102) Following Method B from Intermediate 6 (500 mg, 1.3 mmol) and 3-fluoropyridine-5-boronic acid utilizing CsCO.sub.3, dioxane, water, palladium tetrakis(triphenylphosphine) at 100° C. The crude product was purified by flash column chromatography to give the title compound as a clear gum (350 mg, 81%). LCMS (ES+) consistent with target (M+H).sup.+, .sup.1H NMR δ (ppm)(CDCl.sub.3): 8.60 (1 H, d, J=2.7 Hz), 8.41 (1 H, d, J=2.7 Hz), 7.53-7.48 (1 H, m), 7.17-7.08 (1 H, m), 7.04 (1 H, d, J=7.08 Hz), 6.96 (1H, t, J=7.8 Hz), 6.46 (1 H, s), 3.70 (3 H, s), 3.38 (1 H, ddd, J=13.2, 8.9, 4.5 Hz), 3.07-2.98 (1H, m), 2.83 (1H, dddd, J=16.1, 9.3, 4.5, 1.9 Hz), 2.14 (3H, d, J=2.6 Hz), 2.06 (1 H, ddd, J=13.2, 9.3, 6.0 Hz).

Step 2: (1S,3S*) and (1S,3R*)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-cyclopentanecarboxylate

(103) To a solution of (S)-methyl-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)cyclopent-2-enecarboxylate (0.125 g, 0.38 mmol) in methanol (20 mL) was added ammonium formate (0.125 g, 2.0 mmol), and palladium on charcoal (10%, 0.01 g). The reaction mixture was heated to 65° C. for 2 h. Reaction mixture was cooled to r.t. and filtered through Celite, washing with MeOH (3×10 mL). The solvent was removed in vacuo and the resulting solid was partitioned between water and DCM (3×20 mL). The combined organics were dried (MgSO.sub.4), filtered (phase separation cartridge) and the solvent removed to yield the title compound as a pale yellow oil (0.12 g, 95%). LCMS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR δ (ppm)(CDCl.sub.3): 8.43-8.19 (2 H, m), 7.53-7.48 (1 H, m), 7.25-7.12 (2 H, m), 7.03-6.94 (1 H, m), 3.70 (3 H, s), 3.30-3.05 (1 H, m), 2.76 (1 H, dd, J=13.5, 10.3 Hz), 2.66 (1 H, ddd, J=13.2, 7.8, 3.4 Hz), 2.55-2.32 (2 H, m), 2.29-2.18 (1 H, m), 2.14 (3 H, d, J=2.6 Hz), 1.96-1.81 (1 H, m).

Step 3: (1S,3S*) and (1S,3R*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)cyclopentane carboxylic acid

(104) Following Method C from (S)methyl-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)cyclopentane carboxylate (120 mg, 0.36 mmol) and purified by preparative HPLC to give the title compound as a white solid (85 mg, 74%). LCMS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR δ (ppm)(CDCl.sub.3): 11.0 (1 H, brs), 8.55 (1 H, s), 8.32 (1 H, s), 7.51 (1 H, t, J=9.7 Hz), 7.25-7.21 (2 H, m), 7.03-6.94 (1 H, m), 3.31-3.14 (1 H, m), 2.93-2.78 (1 H, m), 2.77-2.66 (1 H, m), 2.54-2.38 (2 H, m), 2.24-2.16 (1 H, m), 2.14 (3 H, d, J=2.6 Hz), 2.02-1.86 (1 H, m).

Step 4: (1S,3S*) 1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopentanecarboxamide and (1S,3R*) 1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopentanecarboxamide

(105) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)cyclopentanecarboxylic acid (170 mg, 0.54 mmol) and purified by preparative HPLC to give the racemic product as a cream solid (0.064 g, 35%). Preparative chiral purification provided the two diastereomers.

(106) Example 9 (Diastereoisomer 1 (D1)): LCMS (ES+) 333 (M+H).sup.+; HPLC RT 9.49 min (Analytical method 3); RT 21.5 min (Chiralpak IC 10/90 IPA/MeOH (50/50/0.1% formic acid)/heptane, 5.0 mL/min, RT); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.02 (1 H, s), 8.73 (1 H, s), 8.52 (2 H, m), 7.86 (1 H, d, J=12.2 Hz), 7.35-7.26 (2 H, m), 7.12 (1 H, t, J=8.4 Hz), 3.28-3.04 (1 H, m), 2.75-2.54 (2 H, m), 2.41-2.32 (1 H, m), 2.31-2.15 (2 H, m), 2.12 (3 H, d, J=2.4 Hz), 1.83-1.79 (1.0 H, m). Example 10 (Diastereoisomer 2 (D2)): LCMS (ES+) 333 (M+H).sup.+; RT 3.22 min (Analytical method 1); RT 23.5 min (Chiralpak IC 10/90 IPA/MeOH (50/50/0.1% formic acid)/heptane, 5.0 mL/min, RT); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.06 (1 H, s), 8.75 (1 H, s), 8.45 (1 H, d, J=2.8 Hz), 8.42 (1 H, s), 7.70 (1 H, d, J=12.2 Hz), 7.34 (1 H, d, J=8.4 Hz), 7.28 (1 H, q, J=8.4 Hz), 7.13 (1 H, t, J=8.4 Hz), 3.34-3.28 (1 H, m), 3.04-2.99 (1 H, m), 2.83-2.72 (1 H, m), 2.31-2.23 (1H, m), 2.19-2.07 (5 H, m), 1.83-1.73 (1.0 H, m).

Example 11

(1S,3S*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)-N-hydroxycyclopentane carboxamide (D1)

Example 12

(1S,3R*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)-N-hydroxycyclopentane carboxamide (D2)

(107) ##STR00024##

C3 Stereochemistry Putatively Assigned

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

(108) Following Method B(iii) from Intermediate 6 (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, (0.215 g, 0.24 mmol) and S-Phos (0.038 g, 0.094 mmol) The reaction mixture was heated at 80° C. under N.sub.2 for 2 h. After this time the reaction mixture was cooled to r.t. and 2-bromo-5-fluoropyridine (0.152 g, 0.86 mmol), cesium carbonate (0.51 g, 1.57 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.045 g, 0.039 mmol) were added and the reaction mixture heated at 110° C. under N.sub.2 for 1 h. Reaction mixture was cooled to r.t. and filtered through Celite, washing with EtOAc (3×10 mL). Combined organics were extracted with water (15 mL) then brine (20 mL). EtOAc layers were then dried (MgSO.sub.4), filtered (phase separation cartridge) and concentrated. The crude product was purified by flash column chromatography to give the title compound as a pale yellow gum (217 mg, 84%). LCMS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR δ (ppm)(CHCl.sub.3-d): 8.48 (1 H, d, J=2.8 Hz), 7.49-7.33 (2 H, m), 7.16-7.06 (2 H, m), 7.00-6.92 (1 H, m), 6.67 (1 H, s), 3.76-3.62 (3 H, m), 3.37 (1 H, ddd, J=13.0, 8.9, 4.5 Hz), 3.12-3.01 (1 H, m), 2.89 (1 H, dddd, J=16.0, 9.3, 4.5, 2.5 Hz), 2.13 (3 H, dd, J=8.9, 2.5 Hz), 2.11-1.99 (1 H, m).

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

(109) 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. The title compound was obtained as a pale yellow solid (187 mg, 72%). LCMS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 12.71 (1 H, s), 8.56 (1 H, d, J=2.9 Hz), 7.85 (1 H, dd, J=8.8, 4.5 Hz), 7.74 (1 H, td, J=8.8, 2.9 Hz), 7.21-7.13 (1 H, m), 7.13-7.01 (2 H, m), 6.77 (1 H, s), 3.15 (1 H, ddd, J=13.0, 8.9, 4.6 Hz), 2.99-2.89 (1 H, m), 2.85-2.75 (1 H, m), 2.52 (1 H, under solvent peak), 2.13 (3 H, d, J=2.4 Hz).

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

(110) 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.+. .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.16 (1 H, s), 8.73 (1 H, s), 8.57 (1 H, d, J=2.88 Hz), 7.77-7.64 (2 H, m), 7.22-7.00 (3 H, m), 6.79 (1 H, s), 3.29-3.22 (1 H, m), 2.93-2.82 (1 H, m), 2.80-2.70 (1 H, m), 2.12 (3 H, d, J=2.4 Hz), 1.90-1.79 (1 H, m).

Step 4: (1S,3S*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)-N-hydroxycyclopentane carboxamide and (1S,3R*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)-N-hydroxy cyclopentanecarboxamide

(111) (S)-1-(3-Fluoro-2-methylphenyl)-3-(5-fluoropyridin-2-yl)-N-hydroxycyclopent-2-enecarboxamide (50 mg, 0.15 mmol) in ethanol (5 mL) was treated with ammonium formate (95 mg, 1.5 mmol) and 10% Pd/C (5 mg, 10% wt) and heated at 70° C. under N.sub.2 for 1 h. The crude products were filtered and evaporated to yield a colorless gum (45 mg) which was purified by chiral preparative HPLC to give the title compounds as pale orange solids, Diastereomer 1 (6.3 mg) and Diastereomer 2 (10.4 mg).

(112) Example 11 (Diastereomer 1 (D1)): LCMS (ES+) 333 (M+H).sup.+; RT 9.82 min (Analytical method 3); RT 5.71 min (Chiralpak IC 20/80 IPA/MeOH (50/50/0.1% formic acid)/heptane, 5.0 mL/min, RT); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.04 (1 H, s), 8.71 (1 H, s), 8.51 (1 H, d, J=3.0 Hz), 7.66 (1 H, td, J=8.7, 3.0 Hz), 7.42 (1 H, dd, J=8.8, 4.5 Hz), 7.28-7.21 (2 H, m), 7.09 (1H, t, J=8.8 Hz), 3.44 (1 H, t, J=8.8 Hz), 3.01 (1 H, dd, J=12.5, 7.0 Hz), 2.75-2.69 (2 H, m), 2.21-2.13 (5 H, m), 1.91-1.84 (1 H, m).

(113) Example 12 (Diastereomer 2 (D2)): LCMS (ES+) 333 (M+H).sup.+; RT 9.79 min (Analytical method 3); RT 7.07 min (Chiralpak IC 2/8 IPA/MeOH (50/50/0.1% formic acid)/heptane, 5.0 mL/min, RT); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.04 (1 H, s), 8.69 (1 H, s), 8.54 (1 H, d, J=3.0 Hz), 7.70 (1 H, td, J=8.8, 3.0 Hz), 7.5 (1 H, dd, J=8.8, 4.5 Hz), 7.34-7.25 (2 H, m), 7.12 (1 H, t, J=8.8 Hz), 3.32 (1 H, d, J=11.1 Hz), 2.74-2.62 (2 H, m), 2.45 (1 H, dd, J=13.4, 7.7 Hz), 2.22-2.08 (5 H, m), 1.95-1.87 (1 H, m).

Example 13

(1 r,4r)-4-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclohexanecarboxamide (D1)

Example 14

(1s,4s)-4-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclohexanecarboxamide (D2)

(114) ##STR00025##

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

(115) Methyl 4-oxo-1-phenylcyclohexanecarboxylate (993 mg, 4.28 mmol), and THF (30 mL) were combined under nitrogen at r.t. 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 min N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (1.68 g, 4.28 mmol) was added and the reaction mixture allowed to warm to r.t. with stirring over 4 h. Reaction mixture was diluted with CH.sub.2Cl.sub.2, washed with water and the organics evaporated to dryness on to 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

(116) 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. The reaction mixture was allowed to cool to r.t., evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a white solid (216 mg, 57%). LCMS (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

(117) 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 h. 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%). LCMS (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

(118) 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 r.t. 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 remaining concentrated solution was purified by preparative HPLC to give the title compound as a white solid (136 mg, 76%). LCMS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 1.46 (1H, s), 8.69 (1H, s), 8.52 (1H, m), 8.42 (1H, d, J=2.4 Hz), 7.73 (1H, dt, J=10.8 Hz, J=2 Hz), 7.46-7.22 (5H, m), 6.53 (1H, s), 2.99 (1H, m), 2.66 (1H, m), 2.48 (2H, m), 2.26-2.19 (2H, m).

Step 5: 4-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclohexanecarboxamide

(119) 4-(5-Fluoropyridin-3-yl)-N-hydroxy-1,2,3,6-tetrahydro-[1,1′-biphenyl]-1-carboxamide (80 mg, 0.26 mmol), ethanol (20 mL), ammonium formate (100 mg) and Pd/C (10% Pd content, 5 mg) were combined in a round bottomed flask and heated at 65° C. for 1 h. Reaction mixture was then diluted with EtOAc, washed with water, dried (MgSO.sub.4) and solvents removed in vacuo to give crude product which was purified by preparative HPLC to give the title compounds, Diastereomer 1 as a white solid (15 mg, 19%) where the aryl groups are syn relative to each other and Diastereomer 2 as a white solid (26 mg, 31%) where the aryl groups are anti relative to each other, as determined by nOe NMR experiments.

(120) Example 13 (Diastereomer 1 (D1): LCMS (ES+) 315 (M+H).sup.+; RT 8.98 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.03 (1 H, s), 8.80 (1 H, s), 8.34 (1 H, d, J=2.8 Hz), 8.22 (1 H, m), 7.45 (2 H, m), 7.39 (3 H, m), 7.22 (1 H, m), 2.86-2.75 (3 H, m), 1.98-1.70 (4 H, m), 1.50-1.35 (2 H, m).

(121) Example 14 (Diastereomer 2 (D2): LCMS (ES+) 315 (M+H).sup.+; RT 3.28 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.63 (1 H, s), 8.73 (1 H, s), 8.46 (1 H, d, J=2.8 Hz), 8.40 (1 H, m), 7.55 (1 H, m), 7.45 (2 H, m), 7.38 (2 H, m), 7.28 (1 H, m), 2.82-2.70 (3 H, m), 1.98-1.90 (2 H, m), 1.73-1.63 (4 H, m).

Example 15

1-(2,3-difluorophenyl)-N-hydroxycyclopentanecarboxamide

(122) ##STR00026##

Step 1: methyl 1-(2,3-difluorophenyl)cyclopentanecarboxylate

(123) Following Method E from methyl 2-(2,3-difluorophenyl)acetate (1 g, 5.38 mmol), DMF (20 mL), 1,4-diiodobutane (0.71 mL, 5.38 mmol) and NaH (60% in oil, 440 mg, 11 mmol) gave the title compound as a pale yellow oil (1.41 g). MS (ES+) consistent with (M+H).sup.+.

Step 2: 1-(2,3-difluorophenyl)cyclopentanecarboxylic acid

(124) Following Method C(ii) from methyl 1-(2,3-difluorophenyl)cyclopentanecarboxylate (1.41 g), MeOH (1 mL) and 15% aq. NaOH (3 mL) gave the title compound as a brown oil (1.2 g).

Step 3: 1-(2,3-difluorophenyl)-N-hydroxycyclopentanecarboxamide

(125) Following Method D(ii) from 1-(2,3-difluorophenyl)cyclopentanecarboxylic acid (345 mg, 1.53 mmol), DCM (2 mL) and oxalyl chloride (0.25 mL, 3 mmol). Reaction mixture was evaporated to dryness and purified by preparative HPLC to give the title compound as a white solid (135 mg). LCMS (ES+) 242 (M+H).sup.+; RT 3.23 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.21 (1 H, s), 8.67 (1 H, s), 7.32-7.29 (1 H, m), 7.20-7.15 (2 H, m), 2.52-2.45 (2 H, m), 1.88-1.83 (2 H, m), 1.66-1.61 (4 H, m).

Example 16

1-(2,3-dihydrobenzofuran-7-yl)-N-hydroxycyclopentanecarboxamide

(126) ##STR00027##

Step 1: 1-(2,3-dihydrobenzofuran-7-yl)cyclopentanecarbonitrile

(127) 2-(2,3-Dihydrobenzofuran-7-yl)acetonitrile (750 mg, 4.71 mmol), DMF (15 mL), 1,4-diiodobutane (0.62 mL, 4.71 mmol) and NaH (60% in oil, 400 mg, 10 mmol), were combined at r.t. under a nitrogen atmosphere and stirred for 18 h. Reaction mixture was then diluted with EtOAc, washed with water (3×), brine (1×), dried (MgSO.sub.4) and solvents removed by evaporation to give the title compound as a yellow oil (1.16 g).

Step 2: 1-(2,3-dihydrobenzofuran-7-yl)cyclopentanecarboxylic acid

(128) 1-(2,3-Dihydrobenzofuran-7-yl)cyclopentanecarbonitrile (1.16 g), ethylene glycol (6 mL) and 15% aq. KOH solution (1 mL) were combined in a sealed tube and heated with microwave irradiation to 170° C. for 5 h. The reaction mixture was then partitioned between EtOAc and 1 N HCl. The organic layer was dried (MgSO.sub.4) and solvents removed by evaporation to give a tan solid (226 mg). MS (ES−) consistent with target (M−H).sup.−.

Step 3: 1-(2,3-dihydrobenzofuran-7-yl)-N-hydroxycyclopentanecarboxamide

(129) Following Method D(ii) from 1-(2,3-dihydrobenzofuran-7-yl)cyclopentanecarboxylic acid to give the title compound as a cream solid (134 mg). LCMS (ES+) 248 (M+H).sup.+; RT 3.24 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.91 (1 H, s), 8.54 (1 H, s), 7.10 (1 H, d, J=7.2 Hz), 7.08 (1H, d, J=7.2 Hz), 6.76 (1 H, t, J=7.2 Hz), 4.47 (2 H, t, J=8.8 Hz), 3.13 (2 H, t, J=8.8 Hz), 2.45-2.35 (2 H, m), 1.91-1.88 (2 H, m), 1.60-1.56 (4 H, m).

Example 17

1-(3-chloro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(130) ##STR00028##

Step 1: 2-(3-chloro-2-methylphenyl)acetonitrile

(131) 2-Methyl-3-chlorobenzyl chloride (880 mg, 5 mmol), NaCN (294 mg, 6 mmol) and DMSO (20 mL) were combined and stirred at r.t. for 23 h. Reaction mixture was then diluted with EtOAc, washed with water (3×), dried (MgSO.sub.4) and solvents removed by evaporation in vacuo to give an off-white solid (745 mg).

Step 2: 2-(3-chloro-2-methylphenyl)acetic acid

(132) 2-(3-Chloro-2-methylphenyl)acetonitrile (740 mg, 4.47 mmol), MeOH (10 mL) and 15% aq. KOH solution (2 mL) were combined in a sealed tube and heated with microwave irradiation to 120° C. for 12 h. Reaction mixture was then partitioned between EtOAc and 1 N HCl. Organic layer was dried (MgSO.sub.4) and solvent removed by evaporation to give an off-white solid (995 mg).

Step 3: methyl 2-(3-chloro-2-methylphenyl)acetate

(133) 2-(3-Chloro-2-methylphenyl)acetic acid (995 mg), MeOH (10 mL) and 2 N HCl in diethyl ether (6 mL) were combined and stirred at r.t. for 17 h. The reaction mixture was then evaporated onto silica and purified by flash chromatography to give a clear oil (635 mg). MS (ES+) consistent with target (M+H).sup.+.

1-(3-Chloro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(134) Methyl 2-(3-chloro-2-methylphenyl)acetate was converted using Methods E, C(ii) and D(ii) analogous to the examples described above, to give the title compound as an off-white solid (50 mg). LCMS (ES+) 254/256 (M+H).sup.+, RT 10.03 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.85 (1 H, s), 8.59 (1 H, s), 7.33-7.30 (2 H, m), 7.20-7.16 (1 H, m), 2.43-2.36 (2 H, m), 2.23 (3 H, s), 1.92-1.86 (2 H, m), 1.71-1.56 (4 H, m).

Example 18

1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(135) ##STR00029##

Step 1: methyl 2-(3-fluoro-2-methylphenyl)acetate

(136) 2-(3-Fluoro-2-methylphenyl)acetic acid (1 g, 5.95 mmol), MeOH (10 mL) and 2 N HCl in diethyl ether (6 mL) were combined and stirred at r.t. for 17 h. The reaction mixture was then evaporated to dryness to give a clear oil (1.07 g). 1-(3-Fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(137) Methyl 2-(3-fluoro-2-methylphenyl)acetate was converted using Methods E, C(ii) and D(ii) analogous to the examples described above, to give the title compound as an off white solid (4 mg). LCMS (ES+) 238 (M+H).sup.+, RT 9.56 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.89 (1 H, s), 8.61 (1 H, s), 7.21-7.15 (2 H, m), 7.05-7.00 (1 H, m), 2.44-2.39 (2 H, m), 2.10 (3 H, d, J=2.8 Hz), 1.90-1.84 (2 H, m), 1.67-1.54 (4 H, m).

Example 19

1-(2-fluorophenyl)-N-hydroxycyclopentanecarboxamide

(138) ##STR00030##

(139) Methyl 2-(2-fluorophenyl)acetate was converted using Methods E, C(ii) and D(ii) analogous to the examples described above, to give the title compound as a white solid (147 mg). LCMS (ES+) 224 (M+H).sup.', RT 3.05 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.11 (1 H, s), 8.60 (1 H, s), 7.45-7.05 (4 H, m), 2.50-2.40 (2 H, m), 1.90-1.80 (2 H, m), 1.70-1.50 (4 H, m).

Example 20

1-(4-chlorophenyl)-N-hydroxycyclopentanecarboxamide

(140) ##STR00031##

Step 1: tert-butyl 1-(4-chlorophenyl)cyclopentanecarboxylate

(141) Following Method E from tert-Butyl 2-(4-chlorophenyl)acetate (1 g, 4.41 mmol) gave the title compound as a white solid (1.14 g).

Step 2: 1-(4-chlorophenyl)cyclopentanecarboxylic acid

(142) tert-Butyl 1-(4-chlorophenyl)cyclopentanecarboxylate (545 mg, 1.94 mmol) was combined with DCM (4 mL) and TFA (2 mL) and stirred at r.t. for 20 h. The reaction mixture was then evaporated onto silica and purified by flash chromatography to give the title compound as a white solid (153 mg).

Step 3: 1-(4-chlorophenyl)-N-hydroxycyclopentanecarboxamide

(143) Following Method D(ii) from 1-(4-chlorophenyl)cyclopentanecarboxylic acid (150 mg) gave the title compound as an off-white solid (111 mg). LCMS (ES+) 240/242 (M+H).sup.+, RT 8.70 min (Analytical method 2); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.45 (1 H, s), 8.65 (1 H, s), 7.36 (4 H, s), 2.55-2.45 (2 H, m), 1.85-1.70 (2 H, m), 1.65-1.55 (4 H, m).

Examples 21-37

(144) The compounds in the Table below were prepared from commercially available starting materials using procedures analogous to those described above.

(145) TABLE-US-00002 Example ES # Structure Name (M + H)+ 21 N-Hydroxy-1- phenylcyclopentanecarboxamide 206 22 1-(2-Chloro-6-fluorophenyl)-N- hydroxycyclopentanecarboxamide 258/260 23 N-Hydroxy-1-(2- methoxyphenyl) cyclopentanecarboxamide 236 24 N-Hydroxy-1-o- tolylcyclopentanecarboxamide 220 25 N-Hydroxy-1-m- tolylcyclopentanecarboxamide 220 26 1-(2-Chlorophenyl)-N- hydroxycyclopentanecarboxamide 240/242 27 1-(2-Cyanophenyl)-N- hydroxycyclopentanecarboxamide 231 28 1-(3-Cyanophenyl)-N- hydroxycyclopentanecarboxamide 231 29 0 1-(3,4-Difluoro-2-methylphenyl)-N- hydroxycyclopentanecarboxamide 256 30 1-(3,5-Difluoro-2-methylphenyl)-N- hydroxycyclopentanecarboxamide 256 31 1-(2-Chloro-6-methylphenyl)-N- hydroxycyclopentanecarboxamide 254/256 32 1-(2-Ethylphenyl)-N- hydroxycyclopentanecarboxamide 234 33 N-Hydroxy-1-(3-methoxy-2- (trifluoromethyl)phenyl) cyclopentanecarboxamide 304 34 N-Hydroxy-1-(2- (trifluoromethyl)phenyl) cyclopentanecarboxamide 274 35 1-(4-Fluoro-2-methylphenyl)-N- hydroxycyclopentanecarboxamide 238 36 1-(5-Fluoro-2-methylphenyl)-N- hydroxycyclopentanecarboxamide 238 37 1-(2-Fluoro-6-methylphenyl)-N- hydroxycyclopentanecarboxamide 238 38 1-(Benzo[b]thiophen-7-yl)-N- hydroxycyclopentanecarboxamide 262

Example 39

(1R,3S*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopentanecarboxamide (D1)

Example 40

(1R,3R*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopentanecarboxamide (D2)

(146) ##STR00050##

C3 Stereochemistry Putatively Assigned

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

(147) Following Method B from Intermediate 6 (500 mg, 1.3 mmol) and 3-fluoropyridine-5-boronic 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 (350 mg, 81%). LCMS (ES+) consistent with target (M+H).sup.+, .sup.1H NMR δ (ppm)(CDCl.sub.3): 8.60 (1 H, d, J=2.7 Hz), 8.41 (1 H, d, J=2.7 Hz), 7.53-7.48 (1 H, m), 7.17-7.08 (1 H, m), 7.04 (1 H, d, J=7.8 Hz), 6.96 (1H, t, J=7.8 Hz), 6.46 (1 H, s), 3.70 (3 H, s), 3.38 (1 H, ddd, J=13.2, 8.9, 4.5 Hz), 3.07-2.98 (1 H, m), 2.83 (1 H, dddd, J=16.1, 9.3, 4.5, 1.9 Hz), 2.14 (3 H, d, J=2.6 Hz), 2.06 (1 H, ddd, J=13.2, 9.3, 6.0 Hz).

Step 2: (1R,3S*) and (1R,3R*)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)-cyclopentanecarboxylate

(148) To a solution of (R)-methyl-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)cyclopent-2-enecarboxylate (0.32 g, 0.98 mmol) in ethanol (20 mL) was added ammonium formate (0.125 g, 2.0 mmol), and palladium on charcoal (10 wt % Pd, 0.01 g). The reaction mixture was heated to 65° C. for 2 h. Reaction mixture was cooled to r.t. and filtered through Celite, washing with EtOH (3×10 mL). The solvent was removed in vacuo and the resulting solid was suspended in water (20 mL) and extracted with DCM (3×20 mL). The combined organics were dried (MgSO.sub.4), filtered (phase separation cartridge) and the solvent removed to yield the title compound as a pale yellow oil (0.302 g, 96%). LCMS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR δ (ppm)(CDCl.sub.3): 8.43-8.19 (2 H, m), 7.53-7.48 (1 H, m), 7.25-7.12 (2 H, m), 7.03-6.94 (1 H, m), 3.70 (3 H, s), 3.30-3.05 (1 H, m), 2.76 (1 H, dd, J=13.5, 10.3 Hz), 2.66 (1 H, ddd, J=13.2, 7.8, 3.4 Hz), 2.55-2.32 (2 H, m), 2.29-2.18 (1 H, m), 2.14 (3 H, d, J=2.6 Hz), 1.96-1.81 (1 H, m).

Step 3: (1R,3S*) and (1R,3R*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoropyridin-3-yl)cyclopentane carboxylic acid

(149) Following Method C from the mixture of isomers obtained in the previous step (302 mg, 0.36 mmol) to give the title compound as a white solid (255 mg, 88%). LCMS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR δ (ppm)(CDCl.sub.3): 11.0 (1 H, brs), 8.55 (1 H, s), 8.32 (1 H, s), 7.51 (1 H, t, J=9.7 Hz), 7.25-7.21 (2 H, m), 7.03-6.94 (1 H, m), 3.31-3.14 (1 H, m), 2.93-2.78 (1 H, m), 2.77-2.66 (1 H, m), 2.54-2.38 (2 H, m), 2.24-2.16 (1 H, m), 2.14 (3 H, d, J=2.6 Hz), 2.02-1.86 (1 H, m).

Step 4: (1R,3S*) 1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopentanecarboxamide (D1) and (1R,3R*) 1-(3-fluoro-2-methyl-phenyl)-3-(5-fluoropyridin-3-yl)-N-hydroxycyclopentanecarboxamide (D2)

(150) Following Method D from the mixture of isomers obtained in the previous step (255 mg, 0.80 mmol) and purified by preparative HPLC to give a mixture of diastereomers as a cream solid (0.085 g, 31%). Purification by preparative chiral HPLC provided diastereomer 1 (D1) as a beige solid (6.87 mg, 3%) and diastereomer 2 (D2) as a beige solid (17.7 mg, 7%).

(151) Example 39 (Diastereomer 1 (D1)): LCMS (ES+) 333 (M+H).sup.+, RT 9.48 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.04 (1H, s), 8.72 (1H, s), 8.43 (1H, d, J=2.6 Hz), 8.39 (1H, s), 7.69 (1H, dt, J=10.4, 2.2 Hz), 7.34 (1H, d, J=7.7 Hz), 7.28-7.21 (1H, m), 7.09 (1H, t, J=8.8 Hz), 3.33-3.29 (1H, m), 2.99 (1H, dd, J=12.8, 6.5 Hz), 2.82-2.74 (1H, m), 2.29-2.21 (1H, m), 2.17 (3H, d, J=2.6 Hz), 2.15-2.05 (2H, m), 1.81-1.71 (1H, m).

(152) Example 40 (Diastereomer 2 (D2)): LCMS (ES+) 333 (M+H).sup.+, RT 9.49 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.99 (1H, s), 8.72 (1H, s), 8.47-8.44 (2H, m), 7.85 (1H, dt, J=10.3, 2.3 Hz), 7.34-7.26 (2H, m), 7.10 (1H, t, J=8.8 Hz), 3.27-3.17 (1H, m), 2.71 (1H, dd, J=13.0, 10.1 Hz), 2.41-2.34 (1H, m), 2.31-2.15 (2H, m), 2.12 (3H, d, J=2.8 Hz), 1.82-1.71 (1H, m). 1H obscured by DMSO peak.

Example 41

(1S,3R)-3-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclopentanecarboxamide

Example 42

(1S,3S)-3-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclopentanecarboxamide

(153) ##STR00051##

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

(154) Following Method B from Intermediate 7 (4 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

(155) 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

(156) 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%).

Step 4: (1S,3R)-3-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclopentanecarboxamide (Example 41) and (1S,3S)-3-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclopentanecarboxamide (Example 42)

(157) A solution of (S)-3-(5-fluoropyridin-3-yl)-N-hydroxy-1-phenylcyclopent-2-enecarboxamide (70 mg, 0.23 mmol) in MeOH (6 mL) was passed through a H-cube apparatus (ThalesNano) in full H.sub.2 mode equipped with a 10% Pd/C catalyst cartridge at r.t. Purification by preparative HPLC gave example 41 as a white solid (6.15 mg) and example 42 as a white solid (1.6 mg). The relative stereochemistry of example 41 was assigned by nOe NMR experiments.

(158) Example 41: LCMS (ES+) 31 (M+H).sup.+, RT 3.07 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.49 (1H, s), 8.75 (1H, s), 8.45-8.38 (2H, m), 7.79-7.69 (1H, m), 7.45 (2H, d, J=7.1 Hz), 7.42-7.25 (3H, m), 3.29-3.21 (1H, m), 2.69-2.59 (3H, m), 2.27-2.12 (2H, m), 1.69-1.59 (1H, m).

(159) Example 42: LCMS (ES+) 31 (M+H).sup.+, RT 9.18 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 8.44-8.40 (2H, m), 7.76-7.69 (1H, m), 7.44-7.39 (2H, m), 7.37-7.21 (3H, m), 2.97-2.86 (1H, m), 2.74-2.64 (1H, m), 2.32-2.19 (1H, m), 2.16-1.88 (2H, m), 1.82-1.73 (1H, m). NH and OH not observed. 1H obscured by water peak.

Example 43

(1S,3R)-3-(2-cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(160) ##STR00052##

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

(161) 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

(162) 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

(163) 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 (25 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

(164) 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%).

Step 5: (1S,3R)-3-(2-cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(165) (S)-3-(2-Cyclopropyl-5-fluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopent-2-enecarboxamide (40 mg, 0.11 mmol) was dissolved in MeOH (11 mL) and passed through a H-cube apparatus (ThalesNano) in full H.sub.2 mode equipped with a 1% Pd/C catalyst cartridge at r.t. Purification by preparative HPLC gave the title compound as a white solid (24.7 mg, 61%). The stereochemical configuration was assigned by nOe NMR experiments. LCMS (ES+) 373 (M+H).sup.+; .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.20 (1 H, s), 8.72 (1 H, br s), 8.38 (1 H, d, J=1.5 Hz), 7.35-7.27 (3 H, m), 7.13-7.09 (1 H, m), 3.85 (1 H, m), 2.73-2.67 (2 H, m), 2.15 (3 H, s) 2.13-1.96 (4 H, m), 0.98-0.96 (2 H, m), 0.76-0.73 (2 H, m). (1H obscured by DMSO peak).

Example 44

(1S,3S*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)-N-hydroxycyclopentanecarboxamide (D1)

Example 45

(1S,3R*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)-N-hydroxycyclopentanecarboxamide (D2)

(166) ##STR00053##

C3 Stereochemistry Putatively Assigned

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

(167) 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)cyclopentanecarboxylic acid

(168) (S)-Methyl-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)cyclopent-2-enecarboxylate (165 mg, 0.46 mmol), MeOH (20 mL), ammonium formate (200 mg) and 10% palladium on carbon (20 mg) were combined and heated to 65° C. for 16 h. 15% aq. NaOH solution (3 mL) was then added and heating continued for 19 days. Reaction mixture was partitioned between EtOAc and acetic acid/water. The organic layer was dried (MgSO.sub.4) and evaporated in vacuo to give the title compound as a tan solid (526 mg). LCMS (ES+) 348 (M+H).sup.+.

Step 3: (1S,3S*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)-N-hydroxycyclopentanecarboxamide (Example 45, D1) and (1S,3R*)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)-N-hydroxycyclopentanecarboxamide (Example 46, D2)

(169) (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-methoxypyridin-3-yl)cyclopentanecarboxylic acid (70 mg, 0.2 mmol), TFFH (75 mg, 0.28 mmol), DMF (2 mL) and Et.sub.3N (0.14 mL, 1 mmol) were combined and stirred at room temperature under a nitrogen atmosphere. After 2 hours O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (80 mg, 0.68 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 crude product was purified by preparative HPLC to give diastereomer 1 (D1) as a white solid (9.8 mg) and diastereomer 2 (D2) as a colorless glass (27.8 mg).

(170) Example 44 (Diastereomer 1 (D1)): LCMS (ES+) 363 (M+H).sup.+; .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.91 (1 H, s), 8.67 (1 H, br s), 7.61 (1 H, dd, J=11.2, 2.0 Hz), 7.44 (1 H, s), 7.30-7.15 (2 H, m), 7.10-7.00 (1 H, m), 3.46 (3 H, s), 2.90-2.80 (1 H, m), 2.65-2.50 (2 H, m), 2.25-2.10 (2 H, m), 2.07 (3 H, d, J=2.8 Hz), 2.05-1.95 (1 H, m), 1.70-1.55 (1 H, m).

(171) Example 45 (Diastereomer 2 (D2)): LCMS (ES+) 363 (M+H).sup.+; .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.93 (1 H, s), 8.67 (1 H, br s), 7.89 (1 H, d, J=1.6 Hz), 7.80 (1 H, dd, J=12.0, 1.6 Hz), 7.30-7.20 (2 H, m), 7.10-7.00 (1 H, m), 3.92 (3 H, s), 3.15-3.05 (1 H, m), 2.65-2.50 (2 H, m), 2.35-2.05 (3 H, m), 2.08 (3H, d, J=2.8 Hz), 1.75-1.60 (1 H, m).

Example 46

(1S,3R*)-3-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxy cyclopentane carboxamide

(172) ##STR00054##

C3 Stereochemistry Putatively Assigned

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

(173) 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 (3×20 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, 0-33% 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

(174) 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, 0-33% 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)-methyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopentane carboxylate

(175) To a stirred solution of (S)-methyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (0.28 g, 0.80 mmol) in CH.sub.3OH (20 mL) was added ammonium formate (0.2 g, 3.2 mmol), 20% w/w Pd/C (0.07 g, catalytic) and the mixture was stirred at reflux for 1 h. The black suspension was filtered through Celite and washed with EtOAc (3×10 mL). The filtrate was collected and washed with water (20 mL), brine (20 mL) and the organics passed through a phase separator and concentrated. This gave the title compound as a white solid (0.27 g, 97%, 8:1 mixture of diasteromers). The mixture of isomers was purified by SFC to give the major isomer as a colorless oil (0.16 g, d.r.>50:1). .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.70 (1 H, s), 7.60(1 H, s), 7.22-7.12 (3 H, m), 7.02-6.92 (1 H, m), 3.65 (3 H, s), 3.19-3.06 (1 H, m), 2.70-2.56 (2 H, m), 2.48 (1 H, dd, J=13.38, 8.04 Hz), 2.34-2.15 (2 H, m), 2.10 (3 H, d, J=2.80 Hz), 1.89-1.75 (1 H, m).

Step 4: (1S,3R*)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(176) To a stirred solution of (S)-methyl 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopentane carboxylate (0.9 g, 0.23 mmol) in methanol (4 mL), THF (4 mL) and water (0.4 mL) at r.t., was added LiOH.H.sub.2O (0.20 g, 4.68 mmol) and the mixture was stirred at 65° C. for 72 h. The colourless suspension was concentrated under reduced pressure and partitioned between CH.sub.2Cl.sub.2 (15 mL) and sat. NaHCO.sub.3 solution (15 mL). The aqueous layers were acidified to pH=3 and extracted with EtOAc (3×15 mL). Combined organic layers were washed with sat. NaCl solution (20 mL), and the organics passed through a phase separator and concentrated. This gave the title compound as a white solid (0.08 g, 88%). .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.68 (1 H, s), 7.60 (1 H, s), 7.23-7.12 (3 H, m), 7.03-6.95 (1 H, m), 3.18-3.09 (1 H, m), 2.74-2.66 (1 H, m), 2.64 (1 H, dd, J=13.43, 10.16 Hz), 2.52 (1 H, dd, J=13.43, 8.15 Hz), 2.35 (1 H, ddd, J=13.20, 9.51, 7.16 Hz), 2.28-2.20 (1 H, m), 2.18 (3 H, d, J=2.76 Hz), 1.90-1.80 (1 H, m).

Step 5: (1S,3R*)-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxy cyclopentane carboxamide

(177) (1S,3R)-3-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid (0.9 g, 0.25 mmol), TFFH (0.8 mg, 0.30 mmol), DMF (3 mL) and Et.sub.3N (0.11 mL, 0.75 mmol) were combined and stirred at room temperature under a nitrogen atmosphere. After 1 h O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.06 g, 0.50 mmol) was added and the mixture stirred for 24 h. The yellow solution was taken up in EtOAc (10 mL), washed with water (2×10 mL) and brine (10 mL). The organic layer was passed through a phase separator and concentrated. To the crude residue was added MeOH (2 mL) and 4 M HCl in dioxane (0.5 mL) and the mixture stirred for 2 h. Volatile solvents were removed under reduced pressure and the remaining crude product was purified by preparative HLPC to give the title compound as a white solid. LCMS (ES+) 354 (M+H).sup.+; RT 3.54 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.85 (1 H, s), 8.62 (1 H, s), 8.05 (1 H, s), 7.72 (1 H, s), 7.71 (1 H, t, J=59.6 Hz), 7.25-7.16 (2 H, m), 7.07-7.01 (1 H, m), 3.02-2.94 (1 H, m), 2.42 (1 H, dd, J=13.1, 10.0 Hz), 2.37-2.28 (1 H, m), 2.12-2.05 (2 H, m), 2.06 (4 H, d, J=2.9 Hz), 1.66-1.59 (1 H, m).

Example 47

(1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopentanecarboxamide

(178) ##STR00055## ##STR00056##

C3 Stereochemistry Putatively Assigned

Step 1: (S)-tert-butyl 4-(3-(3-fluoro-2-methylphenyl)-3-(methoxycarbonyl)cyclopent-1-en-1-yl)-1H-pyrazole-1-carboxylate

(179) To a solution of methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (1.0 g, 2.61 mmol) in 1,2 dimethoxyethane (15 mL) was added 1-Boc-pyrazole-4-boronic acid pinacol ester (0.77 g, 2.65 mmol), cesium carbonate (2.55 g, 7.83 mmol) and water (4 mL). The reaction mixture was rapidly stirred under N.sub.2 for until a colorless solution formed. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.9 g, 0.10 mmol) was added and the reaction mixture was heated to 85° 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 (3×10 mL). Combined organics were extracted with water (30 mL) then brine (30 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated to give a brown residue. The crude reaction material was purified by flash silica chromatography (gradient elution i-hex to 33% EtOAc in i-hex) to give the title compound as a colourless solid (0.73 g, 70%).

(180) NMR: .sup.1H NMR δ (ppm)(CDCl.sub.3): 8.00 (1 H, s), 7.85 (1 H, s), 7.22 (1 H, s), 7.11-7.03 (1 H, m), 7.01 (1 H, d, J=7.70 Hz), 6.94-6.86 (1 H, m), 6.9-6.7 (1 H, m), 3.64 (3 H, s), 3.27 (1 H, ddd, J=13.29, 8.79, 4.31 Hz), 2.90-2.79 (1 H, m), 2.70-2.61 (1 H, m), 2.08 (3 H, d, J=2.51 Hz), 1.93 (1 H, ddd, J=13.11, 9.35, 6.06 Hz), 1.62 (9 H, s).

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

(181) To a solution of (S)-tert-butyl 4-(3-(3-fluoro-2-methylphenyl)-3-(methoxycarbonyl)cyclopent-1-en-1-yl)-1H-pyrazole-1-carboxylate (0.73 g, 1.82 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (1.5 mL). The reaction mixture was stirred at r.t. for 16 h. After this time the reaction mixture was extracted (3×10 mL CH.sub.2Cl.sub.2) with sat. NaHCO.sub.3 (15 mL). Dichloromethane layers were then dried, filtered (phase separation cartridge) and concentrated to give a colourless solid which was used without further purification (0.54 g, 98%).

(182) NMR: .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.67 (2 H, s), 7.22 (1 H, s), 7.10-7.03 (2 H, m), 6.93-6.86 (1 H, m), 6.14 (1 H, br s), 6.00-5.98 (1 H, m), 3.64 (3 H, s), 3.27 (1 H, ddd, J=13.25, 8.78, 4.29 Hz), 2.92-2.81 (1 H, m), 2.71-2.62 (1 H, m), 2.09 (3 H, d, J=2.52 Hz), 1.91 (1 H, ddd, J=13.06, 9.34, 6.09 Hz).

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

(183) To a solution of ((S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1H-pyrazol-4-yl)cyclopent-2-enecarboxylate (0.58 g, 1.93 mmol) in methanol (20 mL) was added ammonium formate (1.24 g, 19.3 mmol) and 20% palladium on carbon (0.15 g). The reaction mixture was refluxed for 1 h. After this time the reaction mixture was cooled to r.t. and filtered through Celite, washing with EtOAc (3×15 mL). Combined organics were extracted with water (30 mL) then brine (30 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated to give the title compound as a colorless oil (0.57 g, 98%, 6:1 mixture of isomers).

(184) NMR (Major Isomer): .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.53 (1 H, s), 7.23-7.14 (2 H, m), 7.04-6.94 (1 H, m), 6.73 (1 H, s), 3.68 (3 H, s), 3.23-3.10 (1 H, m), 2.78-2.50 (3 H, m), 2.32-2.18 (2 H, m), 2.13 (3 H, d, J=2.74 Hz), 1.91-1.75 (1 H, m).

Step 4: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopentanecarboxylate

(185) To a solution of (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1H-pyrazol-4-yl)cyclopentanecarboxylate (0.27 g, 0.89 mmol) in acetonitrile (15 mL) was added cesium carbonate (0.87 g, 2.68 mmol) and potassium iodide (0.02 g). 4-(2-Chloroethyl) morpholine hydrochloride (0.22 g, 1.07 mmol) was added and the reaction mixture was heated to 65° C. under N.sub.2 for 18 h. After this time the reaction mixture was cooled to r.t. and filtered through Celite, washing with acetonitrile (3×15 mL) and the combined organics concentrated under reduced pressure. The crude residue was partitioned between EtOAc (30 mL) and water (30 mL). The organic layers were extracted washed with brine (30 mL), then dried, filtered (phase separation cartridge) and concentrated. The crude reaction material was purified by flash silica chromatography (gradient elution, 0-4% CH.sub.3OH in CH.sub.2Cl.sub.2) to give the title compound as a colorless oil (0.36 g, 96%).

Step 5: (1S,3R)-1-(3-fluoro-2-methylphenyl)-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopentanecarboxylic acid

(186) Following Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopentanecarboxylate (300 mg, 0.72 mmol). Purification by preparative HPLC gave the title compound as a colorless oil (21 mg). NMR (Major Isomer): .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 12.50 (1H, br s), 7.65 (1 H, s), 7.37 (1 H, s), 7.32-7.26 (2 H, m), 7.14-7.08 (1 H, m), 4.20 (2 H, t, J=6.79 Hz), 3.60 (4 H, t, J=4.49 Hz), 3.04 (1 H, s), 2.72 (2 H, t, J=6.71 Hz), 2.60 (2 H, d, J=10.78 Hz), 2.49-2.38 (5 H, m), 2.21-2.16 (1 H, m), 2.15 (3 H, d, J=2.77 Hz), 1.80-1.61 (1 H, m).

Step 6: (1S,3R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopentanecarboxamide

(187) Following Method D from (1S,3R)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)cyclopentanecarboxylate (160 mg, 0.40 mmol) and purified by preparative HPLC to give the title compound as a colorless solid (54.2 mg, 33%). LCMS (ES+) 417 (M+H).sup.+. .sup.1H NMR δ (ppm)(CD.sub.3OD): 7.70 (1 H, s), 7.57 (1 H, s), 7.39-7.26 (2 H, m), 7.08 (1 H, t, J=8.8 Hz), 4.49 (2 H, t, J=6.2 Hz), 3.89 (4 H, t, J=4.6 Hz), 3.34 (2 H, t, J=6.2 Hz), 3.24-3.13 (1 H, m), 3.05 (4 H, br s), 2.79-2.69 (1 H, m), 2.63 (1H, dd, J=13.2, 10.3 Hz), 2.52 (1 H, dd, J=13.2, 7.6 Hz), 2.34-2.23 (2 H, m), 2.24 (3 H, d, J=2.9 Hz), 1.96-1.83 (1 H, m). Two exchangeable protons not observed.

Example 48

(1 S,3R*)-1-(3-Fluoro-2-methylphenyl)-3-(5-fluoro-6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-N-hydroxycyclopentanecarboxamide

(188) ##STR00057## ##STR00058##

C3 Stereochemistry Putatively Assigned

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

(189) Following Method B (ii) from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (0.36 g, 1.0 mmol) and 5-bromo-2,3-difluoropyridine (0.19 g, 0.1 mmol). The crude product was purified by flash silica column chromatography (gradient elution, 0-25% EtOAc in iso-hexane) to give the title compound as a pale yellow oil (0.23 g, 66%). MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR δ (ppm)(CDCl.sub.3): 8.09 (1H, d, J=1.1 Hz), 7.73-7.68 (1 H, m), 7.14-7.10 (1 H, m), 7.03-6.95 (2 H, m), 6.36 (1 H, t, J=1.8 Hz), 3.74 (3 H, s), 3.40 (1 H, ddd, J=13.2, 8.7, 4.3 Hz), 3.15-3.04 (1 H, m), 2.83-2.81 (1 H, m), 2.14 (3 H, d, J=2.5 Hz), 2.10-2.00 (1 H, m).

Step 2: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)cyclo pent-2-enecarboxylate

(190) To a solution of 2-hydroxyethylpyrrolidine (0.08 g 0.7 mmol) in DMF (10.0 mL) was added NaH (0.03 g, 0.75 mmol) and the reaction mixture stirred at r.t. for 20 min. (S)-Methyl 3-(5,6-difluoropyridin-3-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (0.23 g, 0.67 mmol) was added and stirring continued for 16 h. The reaction was quenched with water, extracted with ethyl acetate (3×30 mL), concentrated onto silica and purified by silica column chromatography (gradient elution, 0-100% EtOAc in iso-hexane) to yield the title compound as a yellow oil (0.160 g, 55%). LCMS (ES+) consistent with target (M+H).sup.+, .sup.1H NMR δ (ppm)(CDCl.sub.3): 8.09 (1 H, s) 7.53 (1 H, d, J=12.8 Hz), 7.14-7.10 (1 H, m), 7.04 (1 H, d, J=6.8 Hz), 6.96 (1 H, t, J=6.8 Hz), 6.21 (1 H, t, J=1.8 Hz), 4.56 (2 H, t, J=6.0 Hz), 3.69 (3 H, s), 3.40-3.32 (1 H, m), 3.08-2.96 (3 H, m), 2.83-2.81 (1 H, m), 2.66-2.61 (4 H, m), 2.14 (3 H, d, J=2.5 Hz), 2.10-2.00 (1 H, m), 1.84-1.78 (4 H, m).

Step 3: (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)cyclo pentanecarboxylate

(191) To a solution of (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)cyclopent-2-enecarboxylate (0.16 g, 0.36 mmol) in ethanol (20 mL) was added ammonium formate (0.125 g, 2.0 mmol), and palladium on charcoal (10% w/w, 0.01 g). The reaction mixture was heated to 65° C. for 2 h. Reaction mixture was cooled to r.t. and filtered through Celite, washing with EtOH (3×10 mL). The solvent was removed in vacuo and the resulting solid was partitioned between water and DCM (3×20 mL). The combined organics were dried (MgSO.sub.4), filtered (phase separation cartridge) and the solvent removed to yield the title compound as a pale yellow oil (0.155 g, 95.5%) which was used in the next step without further purification. LCMS (ES+) consistent with target (M+H).sup.+.

Step 4: (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)cyclopentane carboxylic acid

(192) Following Method C from (S)-methyl-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)cyclopentanecarboxylate (0.155 mg, 0.35 mmol) to give the title compound as a cream solid (100 mg, 66%), which was used in the next step without further purification. LCMS (ES+) consistent with target (M+H).sup.+.

Step 5: (1S,3R)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)-N-hydroxy cyclopentanecarboxamide

(193) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(5-fluoro-6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)cyclopentanecarboxylic acid (100 mg, 0.23 mmol) and purified by preparative HPLC to give the title compound as a white solid (24 mg, 23%). LCMS (ES+) 446 (M+H).sup.+, RT 8.75 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.93 (1 H, s), 8.68 (1 H, s), 7.90 (1 H, s), 7.71 (1 H, d, J=12.8 Hz), 7.28-7.02 (3 H, m), 4.46 (2 H, t, J=6.0 Hz), 3.12-3.08 (1 H, m), 2.92-2.86 (3 H, m), 2.75-2.65 (1 H, m), 2.64-2.51 (5 H, m), 2.39-2.29 (1 H, m), 2.28-2.15 (1 H, m) 2.14 (3 H, d, J=2.5 Hz), 2.10-2.00 (1 H, m), 1.78-1.70 (4 H, m).

Example 49

(1S,3R*)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)cyclopentane carboxamide (D1)

Example 50

(1S,3S*)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)cyclopentanecarboxamide (D2)

(194) ##STR00059##

C3 Stereochemistry Putatively Assigned

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

(195) 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)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-5-yl)cyclopentanecarboxylate

(196) A solution of (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-5-yl)cyclopent-2-enecarboxylate (326 mg, 1.04 mmol) in EtOH (10 mL) in a pressure tube was purged with nitrogen and treated with 20% w/w Pd/C (163 mg, 0.31 mmol) and ammonium formate (653 mg, 10.4 mmol). The tube was sealed and heated to 80° C. for 1.5 h. The solids were removed by filtration through Celite and the filtrate concentrated. The residue was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried (phase separation cartridge) and concentrated to give a mixture of isomers of the title compound as a colorless gum (283 mg).

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

(197) 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 4: (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)cyclopentane carboxamide (Example 49, D1) and (1S,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)cyclopentane carboxamide (Example 50, D2)

(198) Following Method D using the diastereomeric mixture of (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-pyrazol-5-yl)cyclopentanecarboxylate from the previous step (0.205 g, 0.68 mmol). Purification by preparative HPLC gave Example 49 (D1) as a white solid (22 mg) and Example 50 (D2) as a white solid (5.5 mg).

(199) Example 49 (diastereomer 1 (D1)): LCMS (ES+) 318 (M+H).sup.+, RT 8.92 min (Analytical method 3); .sup.1H NMR δ (ppm) (400 MHz, CDCl.sub.3); 7.76 (2H, s), 7.39 (1H, d, J=1.9 Hz), 7.26-7.19 (2H, m), 7.09-7.03 (1H, m), 6.23 (1H, d, J=1.6 Hz), 3.78 (3H, s), 3.19-3.09 (1H, m), 2.77-2.66 (2H, m), 2.49 (1H, dd, J=13.4, 7.6 Hz), 2.33-2.20 (2H, m), 2.14 (3H, d, J=2.9 Hz), 2.05-1.88 (1H, m).

(200) Example 50 (diastereomer 2 (D2)): LCMS (ES+) 318 (M+H).sup.+, RT 9.09 min (Analytical method 3); .sup.1H NMR δ (ppm) (400 MHz, CDCl.sub.3); 7.72 (1H, s), 7.34 (1H, d, J=1.6 Hz), 7.24-7.21 (2H, m), 7.8-7.2 (2H, m), 5.91 (1H, d, J=1.5 Hz), 3.84 (3H, s), 3.58-3.49 (1H, m), 3.00 (1H, dd, J=12.9, 7.3 Hz), 2.73-2.66 (1H, m), 2.39-2.27 (2H, m), 2.14 (3H, d, J=2.4 Hz), 1.83-1.74 (1H, m). OH not observed.

Example 51

(1S,3R*)-3-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(201) ##STR00060##

C3 Stereochemistry Putatively Assigned

Step 1: N,N-diethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine

(202) To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 5.15 mmol) in acetonitrile (15 mL) was added cesium carbonate (6.00 g, 15.5 mmol), potassium iodide (0.30 g) and 2-chloro-N,N-diethylethanamine hydrochloride (1.30 g, 7.73 mmol) and the reaction mixture heated to 50° C. under N.sub.2 for 1.5 h. After this time the reaction mixture was cooled to r.t. and filtered through Celite, washing with EtOAc (3×20 mL). Combined organics were concentrated under reduced pressure to give the title compound as a pale yellow oil which was used without further purification (1.32 g, 87%).

(203) .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.77 (1 H, s), 7.72 (1 H, s), 4.18 (2 H, t, J=7.05 Hz), 2.86 (2 H, t, J=7.05 Hz), 2.53 (4 H, q, J=7.06 Hz), 1.32-1.30 (12 H, m), 1.00 (6 H, t, J=3.71 Hz). Contaminated with ˜20% 2-chloro-N,N-diethylethanamine.

Step 2: (S)-4-methoxybenzyl 3-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(204) To a solution of (S)-4-methoxybenzyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (0.488 g, 1.0 mmol) in 1,2 dimethoxyethane (6 mL) was added N,N-diethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine (0.293 g, 1.00 mmol), cesium carbonate (0.8 g, 2.0 mmol) and water (2 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 (0.4 g, 0.4 mmol) was added and the reaction mixture was heated to 85° C. under N.sub.2 for 1 h. After this time the reaction mixture was cooled to r.t. and filtered through Celite, washing with EtOAc (3×10 mL). Combined organics were extracted with water (15 mL) then brine (20 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated to give a brown residue. The crude reaction material was purified by SCX cartridge (gradient elution CH.sub.2Cl.sub.2 to CH.sub.3OH to 1.5N NH.sub.3 in CH.sub.3OH) to give the title compound as a pale yellow oil (0.26 g, 78%).

(205) .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.63 (1 H, s), 7.50 (1 H, s), 7.18-7.11 (2 H, m), 7.12-7.06 (2 H, m), 6.97-6.89 (1 H, m), 6.84-6.79 (2 H, m), 5.96 (1 H, t, J=1.79 Hz), 5.07 (2 H, s), 4.39-4.31 (2 H, m), 3.79 (3 H, s), 3.26 (1 H, ddd, J=13.28, 8.82, 4.34 Hz), 3.26-3.11 (2 H, m), 2.91-2.79 (6 H, m), 2.70-2.61 (1 H, m), 1.98 (3 H, d, J=2.53 Hz), 1.97-1.88 (1 H, m), 1.11 (6 H, t, J=7.18 Hz).

Step 3: (1S,3R*)-3-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(206) To a solution of (S)-4-methoxybenzyl 3-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (0.25 g, 0.51 mmol) in methanol (15 mL) was added ammonium formate (0.33 g, 5.20 mmol) and 2% palladium on carbon (0.06 g). The reaction mixture was refluxed for 2 h. After this time the reaction mixture was cooled to r.t. and filtered through Celite, washing with CH.sub.3OH (3×15 mL). Combined organics were concentrated under reduced pressure and the residue resuspended in EtOAc (30 mL). The organic layer was extracted with water (25 mL) then brine (20 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated. The crude reaction material was purified by SCX cartridge (gradient elution CH.sub.2Cl.sub.2 to CH.sub.3OH to 1.5 M NH.sub.3 in CH.sub.3OH) to give a 3:1 diastereomeric mixture of the title compound as a pale yellow oil (0.08 g, 65%). Purification by preparative chiral HPLC gave a single diastereomer, putatively assigned (3R) stereochemistry.

Step 4: (1S,3R*)-3-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(207) Following Method D from (1S,3R*)-3-(1-(2-(diethylamino)ethyl)-1H-pyrazol-4-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid (47 mg, 0.12 mmol) and purified by preparative HPLC to give the title compound as a colorless solid (18.0 mg, 18%). LCMS (ES+) 403 (M+H).sup.+, RT 8.30 min (Analytical method 3); .sup.1H NMR δ (ppm)(400 MHz, CD.sub.3OD): 7.62 (1H, s), 7.48 (1H, s), 7.33-7.23 (2H, m), 7.03 (1H, t, J=8.7 Hz), 4.30-4.25 (2H, m), 3.18-3.03 (3H, m), 2.75-2.67 (6H, m), 2.57-2.49 (2H, m), 2.27-2.15 (3H, m), 2.18 (3H, d, J=3.3 Hz), 1.90-1.78 (1H, m), 1.14-1.07 (6H, m).

Example 52

N—((R)-1-(dipropylamino)propan-2-yl)-4-((1R*,3S)-3-(3-fluoro-2-methylphenyl)-3-(hydroxycarbamoyl)cyclopentyl)benzamide (D1)

Example 53

N—((R)-1-(dipropylamino)propan-2-yl)-4-((1S*,3S)-3-(3-fluoro-2-methylphenyl)-3-(hydroxycarbamoyl)cyclopentyl)benzamide (D2)

(208) ##STR00061## ##STR00062##

Step 1: (R)-tert-butyl(1-hydroxypropan-2-yl)carbamate

(209) To a solution of D-alaninol (5.0 g, 66.58 mmol) in anhydrous THF (50 mL) at 0° C. was added dropwise Boc.sub.2O (15.26 g, 70.0 mmol) as a solution in anhydrous THF (20 mL) over 30 minutes. The reaction mixture was stirred at 0° C. for a further 1 h and then warmed to r.t. over a further 16 h. After this time the organics were concentrated under reduced pressure and the residue triturated with iso-hexane to give a solid which was filtered and air dried to give the title compound as a colorless solid (10.4 g, 89%).

(210) .sup.1H NMR δ (ppm)(CDCl.sub.3): 4.64 (1 H, s), 3.77 (1 H, s), 3.64 (1 H, d, J=11.0 Hz), 3.51 (1 H, t, J=7.8 Hz), 2.62 (1 H, br s), 1.70 (2 H, s), 1.45 (9 H, s), 1.15 (3 H, d, J=6.8 Hz).

Step 2: (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate

(211) To a solution of (R)-tert-butyl(1-hydroxypropan-2-yl)carbamate (3.0 g, 17.2 mmol) in anhydrous dichloromethane (65 mL) at 0° C. was added triethylamine (2.59 g, 25.68 mmol), followed by mesyl chloride (2.16 g, 18.92 mmol) as a solution in anhydrous dichloromethane (30 mL), added dropwise over 1 h. The reaction mixture was stirred at 0° C. for a further 1 h and then warmed to r.t. for a further 2 h. After this time the organics layers were washed with water (65 mL), sat. aq. NaHCO.sub.3 solution (60 mL) and brine (6 mL). Dichloromethane layers were then dried, filtered (phase separation cartridge) and concentrated. The residue was triturated with iso-hexane to give a solid which was filtered and air dried to give the title compound as a colorless solid (4.10 g, 94%).

(212) .sup.1H NMR δ (ppm)(CDCl.sub.3): 4.55 (1 H, s), 4.15 (1 H, s), 4.08 (1 H, ddd, J=10.0, 4.3, 1.6 Hz), 3.90 (1 H, s), 2.96 (3 H, d, J=1.3 Hz), 1.66-1.47 (1 H, m), 1.38 (9 H, s), 1.17 (3 H, dd, J=6.9, 1.7 Hz).

Step 3: (R)-tert-butyl(1-(dipropylamino)propan-2-yl)carbamate

(213) To a solution of (R)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (3.2 g, 12.6 mmol) in anhydrous DMF (30 mL) was added cesium carbonate (12.4 g, 37.9 mmol) and dipropylamine (2.60 g, 25.27 mmol) and the reaction mixture was heated at 65° C. for 18 h. After this time the reaction mixture was cooled to r.t. and filtered through Celite, washing with CH.sub.3OH (3×30 mL). The combined organic layers were then dried, filtered (phase separation cartridge) and concentrated to minimum volume. The crude reaction material was purified by SCX cartridge (gradient elution CH.sub.2Cl.sub.2 to CH.sub.3OH to 1.5 M NH.sub.3 in CH.sub.3OH) to give the title compound as a colorless solid after drying under high vacuum (1.80 g, 55%).

(214) .sup.1H NMR δ (ppm)(CDCl.sub.3): 4.81 (1 H, s), 3.62-3.52 (1 H, m), 2.46-2.24 (7H, m), 1.48-1.37 (13 H, m), 1.14 (3 H, d, J=6.4 Hz), 0.91-0.83 (6 H, m).

Step 4: (R)—N1,N1-dipropylpropane-1,2-diamine

(215) To a solution of (R)-tert-butyl(1-(dipropylamino)propan-2-yl)carbamate (1.8 g, 6.97 mmol) in anhydrous dichloromethane (15 mL) at 0° C. was added trifluoroacetic acid (3 mL) and the reaction mixture was stirred at 0° C. for 1 h and then at r.t. for a further 1 h. After this time the reaction mixture was concentrated to minimum volume. The crude reaction material was purified by SCX cartridge (gradient elution CH.sub.2Cl.sub.2 to CH.sub.3OH to 1.5N NH.sub.3 in CH.sub.3OH) to give the title compound as a pale brown oil (0.61 g, 55%).

(216) .sup.1H NMR δ (ppm)(CHCl.sub.3-d): 3.00-2.89 (1 H, m), 2.47-2.20 (6 H, m), 2.18-2.05 (1 H, m), 0.99 (3 H, d, J=6.32 Hz), 0.87 (6 H, t, J=7.34 Hz).

Step 5: (R)-4-bromo-N-(1-(dipropylamino)propan-2-yl)benzamide

(217) To a solution of (R)—N.sup.1,N.sup.1-dipropylpropane-1,2-diamine (0.25 g, 1.58 mmol) in anhydrous DMF (5 mL) was added 4-bromobenzoic acid (0.32 g, 1.58 mmol), HATU (0.90 g, 2.37 mmol) and DIPEA (0.62 g, 4.74 mmol). The reaction mixture was then stirred at r.t. under N.sub.2 for 4 h. After this time the reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL), sat. aq. NaHCO.sub.3 (2×15 mL) and brine (20 mL). The organic layer was dried, filtered and concentrated under reduced pressure to give an orange residue. The crude reaction material was purified by flash silica chromatography (gradient elution, 0-100% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.28 g, 52%), which was used without further purification.

Step 6: (S)-4-methoxybenzyl 3-(4-(((R)-1-(dipropylamino)propan-2-yl)carbamoyl)phenyl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(218) To a solution of (R)-4-bromo-N-(1-(dipropylamino)propan-2-yl)benzamide (0.28 g, 0.82 mmol) in anhydrous dioxane (5 mL) was added bis(neopentyl glycolato)diboron (0.20g, 0.90 mmol), potassium acetate (0.16 g, 1.64 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.04 g, 0.04 mmol) were added and the reaction mixture heated to 85° C. under N.sub.2 for 16 h. After this time the reaction mixture was cooled to r.t. and a solution of (S)-4-methoxybenzyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2 enecarboxylate (0.4 g, 0.82 mmol) in anhydrous dioxane (1 mL) was added followed by a solution of cesium carbonate (0.40 g, 1.25 mmol) in water (1 mL). The reaction mixture was recapped and heated to 85° C. under N.sub.2 for a further 24 h. Reaction mixture water was decanted, and the dioxane layers were then concentrated under reduced pressure. The crude reaction material was purified by flash silica chromatography (KP-NH cartridge, gradient elution, 0-25% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.30 g, 60%).

(219) .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.77 (2 H, d, J=8.18 Hz), 7.54 (2 H, d, J=8.19 Hz), 7.17-7.11 (2 H, m), 7.11-7.03 (2 H, m), 6.96-6.90 (1 H, m), 6.84-6.77 (2 H, m), 6.37 (1 H, s), 5.07 (2 H, s), 4.04-3.95 (1 H, m), 3.78 (3 H, s), 3.32 (1 H, ddd, J=13.22, 8.77, 4.35 Hz), 3.5-2.95 (1 H, m), 2.87-2.78 (1 H, m), 2.52-2.32 (6 H, m), 2.06-1.97 (4 H, m), 1.53-1.38 (4 H, m), 1.32 (3 H, d, J=6.27 Hz), 0.86 (6 H, t, J=7.34 Hz).

Step 7: (S)-3-(4-(((R)-1-(dipropylamino)propan-2-yl)carbamoyl)phenyl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(220) To a solution of (S)-4-methoxybenzyl 3-(4-(((R)-1-(dipropylamino)propan-2-yl)carbamoyl)phenyl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (0.30 g, 0.50 mmol) in methanol (15 mL) was added ammonium formate (0.47 g, 4.70 mmol) and 20% palladium on carbon (0.06 g). The reaction mixture was refluxed for 2 h. After this time the reaction mixture was cooled to r.t. and filtered through Celite, washing with CH.sub.3OH (3×15 mL). Combined organics were concentrated under reduced pressure and the residue resuspended in EtOAc (30 mL). The organic layer was extracted with water (25 mL) then brine (20 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated. The crude reaction material was purified by SCX cartridge (gradient elution CH.sub.2Cl.sub.2 to CH.sub.3OH to 1.5 M NH.sub.3 in CH.sub.3OH) to give the title compound as a colorless semi-solid (0.15 g, 70%, d.r.=1:1).

Step 8: N—((R)-1-(dipropylamino)propan-2-yl)-4-((1R*,3S)-3-(3-fluoro-2-methylphenyl)-3-(hydroxycarbamoyl)cyclopentyl)benzamide (Example 52, diastereomer 1 (D1)) and N—((R)-1-(dipropylamino)propan-2-yl)-4-((1S*,3S)-3-(3-fluoro-2-methylphenyl)-3-(hydroxycarbamoyl)cyclopentyl)benzamide (Example 53, diastereomer 2 (D2))

(221) Following Method D from (S)-3-(4-(((R)-1-(dipropylamino)propan-2-yl)carbamoyl)phenyl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid (150 mg, 0.31 mmol) and purified by preparative HPLC to give example 52 (D1) as a colorless solid (21.0 mg, 21%) and example 53 (D2) as a colorless solid.

(222) Example 52 (D1): LCMS (ES+) 498 (M+H).sup.+, RT 2.69 (Analytical method 1); .sup.1H NMR δ (ppm)(CD.sub.3OD): 7.81 (2 H, d, J=8.1 Hz), 7.50 (2H, d, J=8.3 Hz), 7.38 (1H, d, J=7.7 Hz), 7.31-7.25 (1H, m), 7.6 (1H, t, J=8.9 Hz), 3.51 (1H, dd, J=1.7, 3.2 Hz), 3.29-3.16 (2H, m), 2.77-2.68 (6H, m), 2.51 (1H, dd, J=13.6, 7.3 Hz), 2.37-2.29 (1H, m), 2.27-2.21 (1H, m), 2.19 (3H, d, J=2.9 Hz), 2.03-1.94 (1H, m), 1.62 (6H, br s), 1.32 (3H, d, J=6.5 Hz), 0.97 (6H, t, J=7.2 Hz). Two exchangeable protons not observed.

(223) Example 53 (D2): LCMS (ES+) 498 (M+H).sup.+, RT 2.63 min (Analytical method 1); .sup.1H NMR δ (ppm)(CD.sub.3OD): 7.78 (2H, d, J=8.3 Hz), 7.37-7.33 (3H, m), 7.28-7.21 (1H, m), 7.03 (1H, t, J=8.9 Hz), 3.52-3.42 (2H, m), 3.12-3.06 (1H, m), 2.77-2.68 (4H, m), 2.39-2.29 (2H, m), 2.20 (3H, d, J=2.6 Hz), 2.12-2.04 (1H, m), 1.96-1.84 (1H, m), 1.63-1.62 (4H, m), 1.32 (3H, d, J=6.7 Hz), 0.97 (6H, t, J=7.3 Hz). Two exchangeable protons not observed. Four protons obscured by methanol peak.

Example 54

(1S,3R*)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

Example 55

(1S,3S*)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(224) ##STR00063## ##STR00064##

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

(225) Following Method B from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-enecarboxylate (0.3 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

(226) 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 (0.2 g, 0.9 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 (3×20 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)-methyl 3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylate

(227) A suspension of (S)-methyl 3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (210 mg, 0.52 mmol), ammonium formate (340 mg, 5.20 mmol) and 20% w/w Pd/C (65 mg) in MeOH (10 mL) was stirred at reflux for 10 h. After cooling to r.t. the mixture was filtered through Celite, washing with MeOH (3×15 mL). The filtrate was concentrated and the residue partitioned between water (40 mL) and DCM (20 mL). The organic layer was extracted with DCM (3×20 mL) and the combined organic extracts were dried (phase separation cartridge) and concentrated to give a colorless oil. Purification by preparative SFC isolated the two diastereomers of the title compound as colorless oils (48 mg and 128 mg), which were reacted separately in the following step.

Step 4: (S)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(228) Following Method C(iii) from each diastereomer of (S)-methyl 3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylate isolated in the previous step (48 mg and 128 mg), using 25 equivalents of LiOH and heating for 72 h. The title compounds were obtained as colorless solids (28 mg and 48 mg respectively) which were reacted separately in the following step.

Step 5: (1S,3R*)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1) and (1S,3S*)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2)

(229) Following Method D from each diastereomer of (S)-3-(1-(difluoromethyl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid isolated in the previous step (28 mg and 48 mg). Example 54 (D1, 14.7 mg) and example 55 (D2, 1.4 mg) were obtained as colorless solids.

(230) Example 54 (diastereomer 1 (D1)): LCMS (ES+) 44 (M+H).sup.+, RT 3.75 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.95 (1H, s), 8.83 (1H, s), 8.70 (1H, s), 8.14 (1H, t, J=59.2 Hz), 7.78 (1H, d, J=8.8 Hz), 7.59 (1H, s), 7.37-7.26 (3H, m), 7.11 (1H, t, J=8.6 Hz), 3.28-3.17 (1H, m), 2.75-2.62 (2H, m), 2.43 (1H, dd, J=12.8, 8.1 Hz), 2.28-2.15 (2H, m), 2.13 (3H, d, J=2.8 Hz), 1.89-1.78 (1H, m).

(231) Example 55 (diastereomer 2 (D2)): LCMS (ES+) 3.65 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 1.5 (1H, s), 8.82 (1H, s), 8.72 (1H, br s), 8.13 (1H, t, J=58.7 Hz), 7.74 (1H, d, J=9.1 Hz), 7.52 (1H, s), 7.35 (1H, d, J=7.6 Hz), 7.29-7.21 (1H, m), 7.12-7.06 (2H, m), 3.06 (1H, dd, J=12.4, 7.1 Hz), 2.82-2.70 (1H, m), 2.29-2.03 (3H, m), 2.18 (3H, d, J=2.5 Hz), 1.87-1.76 (1H, m). 1H obscured by water peak.

Example 56

(1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopentanecarboxamide

(232) ##STR00065##

C3 Stereochemistry Putatively Assigned

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

(233) Following Method B from (1-methyl-1H-indazol-6-yl)boronic acid (152 mg, 0.86 mmol) and Intermediate 9 (350 mg, 0.72 mmol). Purification by flash chromatography (gradient elution, 0-50% EtOAc in iso-hexane) gave the title compound as a pale yellow foam (338 mg, 96%).

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

(234) Following Method F from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxylate (338 mg). Purification by silica column chromatography (gradient elution, 0-100% EtOAc in DCM) gave the title compound as a colorless solid (180 mg) in a 4:1 d.r. The diastereomers were separated by chiral preparative HPLC and the major diastereomer used in the following step.

Step 3: (1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopentanecarboxamide

(235) Following Method D from (S)-1-(3-fluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopentanecarboxylic acid. The title compound was obtained as a colorless solid. LCMS (ES+) 368 (M+H).sup.+, RT 3.63 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.94 (1H, s), 8.70 (1H, s), 7.99 (1H, s), 7.71 (1H, d, J=8.4 Hz), 7.55 (1H, s), 7.37-7.26 (2H, m), 7.20 (1H, d, J=8.4 Hz), 7.11 (1H, t, J=8.8 Hz), 4.05 (3H, s), 3.29-3.20 (1H, m), 2.73-2.63 (2H, m), 2.47 (1H, dd, J=12.9, 7.6 Hz), 2.25-2.16 (2H, m), 2.14 (3H, d, J=2.5 Hz), 1.93-1.82 (1H, m).

Example 57

(1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(imidazo[1,2-a]pyridin-7-yl)cyclopentanecarboxamide (D1)

Example 58

(1S,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(imidazo[1,2-a]pyridin-7-yl)cyclopentanecarboxamide (D2)

(236) ##STR00066##

C3 Stereochemistry Putatively Assigned

(237) Following Methods B, F, C and D from Intermediate 6 and imidazo[1,2-a]pyridin-7-ylboronic acid. The title compounds were obtained as white solids.

(238) Example 57 (diastereomer 1 (D1)): LCMS (ES+) 354 (M+H).sup.+, RT 7.16 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.96 (1H, s), 8.71 (1H, s), 8.53 (1H, d, J=7.0 Hz), 7.91 (1H, s), 7.56 (1H, s), 7.47 (1H, s), 7.36-7.25 (2H, m), 7.11 (1H, t, J=8.8 Hz), 7.03 (1H, d, J=7.2 Hz), 3.24-3.14 (1H, m), 2.76-2.60 (2H, m), 2.42-2.34 (1H, m), 2.29-2.14 (2H, m), 2.13 (3H, d, J=2.6 Hz), 1.85-1.74 (1H, m).

(239) Example 58 (diastereomer 2 (D2)): LCMS (ES+) 354 (M+H).sup.+, RT 8.05 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.05 (1H, s), 8.71 (1H, s), 8.49 (1H, d, J=7.0 Hz), 7.90 (1H, s), 7.55 (1H, s), 7.39 (1H, s), 7.35 (1H, d, J=7.8 Hz), 7.28-7.21 (1H, m), 7.09 (1H, t, J=8.8 Hz), 6.84 (1H, dd, J=7.0, 1.6 Hz), 3.04 (1H, dd, J=6.9, 12.3 Hz), 2.80-2.70 (1H, m), 2.17 (3H, d, J=2.6 Hz), 2.28-2.02 (3H, m), 1.83-1.73 (1H, m). 1 proton obscured by water peak.

Example 59

(1S,3R*)-3-(2-cyclopropyl-1-oxoisoindolin-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(240) ##STR00067##

C3 Stereochemistry Putatively Assigned

Step 1: 4-bromo-N-cyclopropyl-2-(hydroxymethyl)benzamide

(241) A solution of cyclopropylamine (0.98 mL, d=0.824, 14.1 mmol) in dry CH.sub.2Cl.sub.2 (35 mL) was treated with AlMe.sub.3 (2 M in hexanes, 7.0 mL, 14 mmol) and the mixture stirred for 15 min. 5-Bromoisobenzofuran-1(3H)-one (2.00 g, 9.39 mmol) was added in two portions 60 s apart and the reaction mixture was then stirred at 40° C. for 16 h. After cooling to rt, the reaction vessel was placed in a cold water bath and 1 M HCl (100 mL) was added cautiously. The resulting slurry was extracted with CH.sub.2Cl.sub.2 (4×75 mL), dried (Na.sub.2SO.sub.4) and concentrated to yield the title compound as a white powder.

Step 2: 5-bromo-2-cyclopropylisoindolin-1-one

(242) A stirred solution of 4-bromo-N-cyclopropyl-2-(hydroxymethyl)benzamide (925 mg, 3.42 mmol) in N,N′-dimethylimidazol-2-one (11 mL) held at 0° C. under N.sub.2 was treated with i-PrMgCl (2 M in THF, 3.8 mL, 7.6 mmol) over 60 s. The reaction was stirred at r.t. for 30 min before cooling to 0° C. and being treated with bis(dimethylamino)phosphoryl chloride (0.64 mL, d=1.18, 4.43 mmol) over 60 s. The reaction was allowed to warm to r.t. over 1 h and stirred for a further 63 h before being quenched at 0° C. with 3 M HCl (10 mL). The mixture was extracted with EtOAc (3×50 mL) and the combined organics were washed with water (2×20 mL), dried (Na.sub.2SO.sub.4) and concentrated. Purification by flash silica chromatography (gradient elution, 0-100% EtOAc in iso-hexane) gave the title compound as a white powder (269 mg, 33% over two steps).

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

(243) A suspension of Intermediate 6 (386 mg, 1.01 mmol), bis(pinacolato)diboron (281 mg, 1.11 mmol), PdCl.sub.2(dppf) (38.0 mg, 0.05 mmol) and KOAc (112 mg, 1.14 mmol) in DME (8 mL) was purged with N.sub.2 and stirred at 75° C. for 2 h. After cooling to rt, Pd(PPh.sub.3).sub.4 (46 mg, 0.04 mmol), Cs.sub.2CO.sub.3 (389 mg, 1.19 mmol) and a solution of 5-bromo-2-cyclopropylisoindolin-1-one (269 mg, 1.07 mmol) in 2:1 DME:MeOH (3 mL) were added. The mixture was purged again with N.sub.2 and stirred at 110° C. for 30 min. After cooling to r.t., the reaction was partitioned between water (20 mL) and EtOAc (40 mL) and the organics were washed with water (2×20 mL), brine (20 mL), dried (Na.sub.2SO.sub.4) and concentrated. Purification by flash silica chromatography (gradient elution, 0-100% EtOAc in iso-hexane) gave the title compound as an orange liquid (293 mg, 72%).

Step 4: (S)-methyl 3-(2-cyclopropyl-1-oxoisoindolin-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylate

(244) A suspension of (S)-methyl 3-(2-cyclopropyl-1-oxoisoindolin-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (293 mg, 0.72 mmol), ammonium formate (432 mg, 6.85 mmol) and 10% Pd/C (30 mg) in EtOH (10 mL) was stirred at reflux under N.sub.2 for 1.5 h. Solids were removed by filtration through Celite, washing with MeOH (5×5 mL). The filtrate was concentrated, then partitioned between water (20 mL) and CH.sub.2Cl.sub.2 (20 mL). The organic layer was concentrated to yield a 3:1 mixture of diastereomers of the title compound as a colorless liquid (261 mg, 89%).

Step 5: (S)-3-(2-cyclopropyl-1-oxoisoindolin-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(245) (S)-Methyl 3-(2-cyclopropyl-1-oxoisoindolin-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylate (3:1 diastereomeric mixture, 261 mg, 0.64 mmol) and KOH (14.6 M in H.sub.2O, 0.5 mL, 7.32 mmol) in MeOH (2 mL) were stirred at 75° C. in a sealed tube for 19 h. The mixture was partitioned between water (20 mL) and CH.sub.2Cl.sub.2 (20 mL); the aqueous layer was acidified to pH 1 using 3 M HCl and extracted with CH.sub.2Cl.sub.2 (2×20 mL) and EtOAc (2×20 mL), dried (phase separator) and concentrated to yield a 3:1 diastereomeric mixture of the title compound as a white foam (108 mg, 43%).

Step 6: (1S,3R*)-3-(2-cyclopropyl-1-oxoisoindolin-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(246) A stirred solution of (S)-3-(2-cyclopropyl-1-oxoisoindolin-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid (3:1 mixture of diastereomers, 108 mg, 0.27 mmol) in dry DMF (1 mL) at 0° C. under N.sub.2 was treated with Et.sub.3N (0.11 mL, 0.79 mmol) and TFFH (93 mg, 0.35 mmol). After stirring at r.t. for 40 min, the mixture was cooled to 0° C. and O-THP hydroxylamine (60.2 mg, 0.51 mmol) was added. The mixture was then stirred at r.t. for 17 h before cautious addition of HCl (4 M in dioxane, 1 mL, 4 mmol) and MeOH (2 mL). After a further 3 h at r.t. the mixture was concentrated. Purification by preparative HPLC yielded the title compound (1.4 mg, 1%) as a white solid. LCMS (ES+) 49 (M+H).sup.+; .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.91 (1H, s), 8.67 (1H, s), 7.57 (1H, d, J=8.0 Hz), 7.53 (1H, s), 7.45 (1H, d, J=8.0 Hz), 7.37-7.22 (2H, m), 7.07 (1H, t, J=8.6 Hz), 4.37 (2H, s), 3.20-3.16 (1H, m), 2.95-2.89 (1H, m), 2.67-2.60 (2H, m), 2.43-2.34 (1H, m), 2.23-2.8 (2H, m), 2.9 (3H, d, J=1.6 Hz), 1.84-1.73 (1H, m), 0.87-0.73 (4H, m).

Example 60

(1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-7-yl)cyclopentanecarboxamide

(247) ##STR00068##

C3 Stereochemistry Putatively Assigned

(248) Following Methods B, F, C and D from Intermediate 6 and (1-methyl-1H-indazol-7-yl)boronic acid. The title compound was the major diastereomer obtained. LCMS (ES+) 367 (M+H).sup.+, RT 10.22 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.96 (1 H, s), 8.69 (1 H, d, J=1.6 Hz), 7.98 (1 H, d, J=0.3 Hz), 7.64-7.53 (2 H, m), 7.35 (1 H, d, J=7.9 Hz), 7.32-7.22 (1 H, m), 7.18-7.03 (2 H, m), 4.09 (3 H, s), 3.96-3.84 (1 H, m), 2.87 (1 H, dd, J=13.1, 10.0 Hz), 2.65-2.54 (1 H, m), 2.43-2.25 (2 H, m), 2.24-2.13 (1 H, m), 2.11 (3 H, d, J=2.7 Hz), 1.90-1.77 (1 H, m).

Example 61

(1S,3R*)-3-(7-fluoro-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(249) ##STR00069##

C3 Stereochemistry Putatively Assigned

Step 1: 6-bromo-7-fluoro-1H-indazole

(250) 4-Bromo-2,3 difluorobenzaldehyde (1.0 g, 4.52 mmol), potassium carbonate (0.75 g, 5.50 mmol), methoxyamine HCl (0.42 g, 5.0 mmol) and 1,2 dimethoxyethane (12 mL) were charged to an oven-dried 25 mL screw capped tube. The reaction mixture was then heated at 40° C. for 3 h—TLC shows complete consumption of the aldehyde. After this time the suspension was cooled to r.t. and filtered through a pad of Celite washing with EtOAc (3×5 mL). Combined organic layers were concentrated to ˜5 mL volume to give the crude methoxyamine intermediate. This material was transferred to a new screw capped vial and diluted with 1,2 dimethoxyethane (10 mL), hydrazine monohydrate (3 mL) was then added and the reaction mixture was heated to 90° C. overnight. After this time the reaction mixture was cooled to r.t. and the solvent volume was removed to ˜5 mL volume, water (20 mL) was added and the solid residues filtered and air dried to yield the title compound as a colorless solid (0.79 g, 81%). .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 13.82 (1 H, s), 8.22 (1 H, s), 7.58 (1 H, d, J=8.55 Hz), 7.31 (1 H, dd, J=8.55, 5.67 Hz).

Steps 2-3: (1S,3R*)-methyl 3-(7-fluoro-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylate

(251) Following Methods B(iii) and F from Intermediate 6 (0.7 g, 1.83 mmol) and 6-bromo-7-fluoro-1H-indazole (0.395 g, 1.84 mmol). Purification by preparative HPLC yielded one diastereomer in sufficient purity for further reaction, putatively assigned (1S,3R) stereochemistry. .sup.1H NMR δ (ppm)(CDCl.sub.3): 10.08 (1 H, s), 8.08 (1 H, d, J=3.57 Hz), 7.56-7.51 (1 H, m), 7.33 (2 H, dd, J=8.49, 5.91 Hz), 7.28-7.20 (2 H, m), 7.04-6.98 (1 H, m), 3.71 (3 H, s), 2.80-2.73 (2 H, m), 2.58 (1 H, dd, J=13.47, 8.10 Hz), 2.40 (1 H, ddd, J=13.10, 9.55, 7.06 Hz), 2.29-2.19 (1 H, m), 2.13 (3 H, d, J=2.79 Hz), 2.09-1.98 (1 H, m).

Step 4: (1S,3R*)-3-(7-fluoro-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(252) Following Method C from (1S,3R*)-methyl 3-(7-fluoro-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylate (120 mg, 0.32 mmol). The title compound was obtained as a colorless solid (100 mg, 92%).

Step 5: (1S,3R*)-3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(253) To a solution of (1S,3R*)-3-(7-fluoro-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid (80.0 mg, 0.22 mmol) in dichloromethane (1 mL) was added dihydropyran (50.0 mg, 0.60 mmol) and pTSA.H.sub.2O (10 mg). The reaction mixture was stirred at r.t. for 16 h. After this time the crude reaction mixture was washed with sat. aq. NaHCO.sub.3 solution (1 mL) and the organic layers were dried, filtered (phase separation cartridge) and concentrated. The crude reaction material was used without further purification.

Step 6: (1S,3R*)-3-(7-fluoro-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentane carboxamide

(254) Following Method D from (1S,3R*)-3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid (60 mg, 0.14 mmol) and purified by preparative HPLC to give the title compound as a colorless solid (11.2 mg, 14%). LCMS (ES+) 372 (M+H).sup.+, 9.79 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 13.47 (1 H, s), 9.93 (1 H, s), 8.68 (1 H, s), 8.11 (1 H, s), 7.56 (1 H, d, J=8.4 Hz), 7.33-7.24 (3 H, m), 7.09 (1 H, s), 3.50-3.43 (1 H, m), 2.70-2.65 (2 H, m), 2.42-2.34 (1 H, m), 2.25-2.18 (1 H, m), 2.15-2.11 (1 H, m), 2.09 (3 H, d, J=2.8 Hz), 1.86-1.80 (1 H, m).

Example 62

(1S,3R*)-3-(2-cyclopropylbenzo[d]oxazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(255) ##STR00070##

C3 Stereochemistry Putatively Assigned

(256) Following Methods B(iii), F and D from Intermediate 9 and 5-bromo-2-cyclopropyl-1,3-benzoxazole. The title compound was obtained as an off-white solid. LCMS (ES+) 395 (M+H).sup.+, RT 10.93 (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.93 (1H, d, J=1.8 Hz), 8.69 (1H, d, J=1.8 Hz), 7.61 (1H, d, J=1.3 Hz), 7.55 (1H, d, J=8.3 Hz), 7.35-7.24 (3H, m), 7.13-7.7 (1H, m), 3.26-3.16 (1H, m), 2.72-2.63 (2H, m), 2.45-2.36 (1H, m), 2.33-2.14 (3H, m), 2.12 (3H, d, J=2.9 Hz), 1.83-1.72 (1H, m), 1.24-1.13 (4H, m).

Example 63

(1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-5-yl)cyclopentanecarboxamide (D1)

Example 64

(1S,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-5-yl)cyclopentanecarboxamide (D2)

(257) ##STR00071##

C3 Stereochemistry Putatively Assigned

(258) Following Methods B, F, C and D from Intermediate 6 (0.28 g, 0.72 mmol) and (1-methyl-1H-indazol-5-yl)boronic acid (0.15 g, 0.80 mmol). The 3:1 diastereomeric mixture resulting from step 3 was separated by preparative HPLC.

(259) Example 63 (diastereomer 1 (D1)) was obtained as a colorless solid (24.2 mg). LCMS (ES+) 368 (M+H).sup.+, RT 10.3 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.91 (1 H, d, J=1.8 Hz), 8.67 (1 H, d, J=1.7 Hz), 7.97 (1 H, d, J=0.9 Hz), 7.66 (1 H, s), 7.59 (1 H, d, J=8.7 Hz), 7.45 (1 H, dd, J=8.7, 1.6 Hz), 7.33 (1 H, d, J=7.9 Hz), 7.31-7.23 (1 H, m), 7.09 (1 H, t, J=8.9 Hz), 4.04 (3 H, s), 3.20 (1 H, t, J=9.1 Hz), 2.72-2.60 (2 H, m), 2.43 (1 H, dd, J=13.3, 7.8 Hz), 2.23-2.12 (2 H, m), 2.11 (3 H, d, J=2.8 Hz), 1.83-1.74 (1 H, m).

(260) Example 64 (diastereomer 2 (D2)) was obtained as a colorless solid (11.2 mg). LCMS (ES+) 368 (M+H).sup.+, RT 10.1 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.03 (1 H, s), 8.70 (1 H, s), 7.95 (1 H, s), 7.60-7.54 (2 H, m), 7.35-7.25 (3 H, m), 7.23 (1 H, d, J=8.1 Hz), 7.07 (1 H, t, J=8.9 Hz), 4.03 (3 H, s), 3.13-2.92 (1 H, m), 2.78-2.74 (1 H, m), 2.27-2.16 (2 H, m), 2.16 (3 H, d, J=2.7 Hz), 2.04 (1 H, t, J=12.0 Hz), 1.89-1.61 (1 H, m).

Example 65

(1S,3R*)-3-(2-(difluoromethyl)-2H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1)

Example 66

(1S,3S*)-3-(2-(difluoromethyl)-2H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2)

(261) ##STR00072##

C3 Stereochemistry Putatively Assigned

Step 1: 6-bromo-2-(difluoromethyl)-2H-indazole

(262) A suspension of NaH (6 wt % in oil, 320 mg, 8.16 mmol) in dry DMF (20 mL) under N.sub.2 was treated with a solution of 6-bromo-1H-indazole (1.32 g, 6.80 mmol) in dry DMF (4 mL), added dropwise over 5 min. The mixture was stirred for 30 min before chlorodifluoromethane was bubbled through the solution for 5 min. The mixture was then heated at 80 ° C. in a sealed tube for 16 h. After cooling to r.t. the mixture was diluted with EtOAc (60 mL) and washed with sat. aq. NH.sub.4Cl (50 mL), water (50 mL) and brine (50 mL), dried (phase separation cartridge) and concentrated. The residue was purified by silica column chromatography (gradient elution, 0-15% EtOAc in iso-hexane) to give the title compound as an orange solid (554 mg, 33%).

Steps 2-4: (1S,3R*)-3-(2-(difluoromethyl)-2H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1) and (1S,3S*)-3-(2-(difluoromethyl)-2H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2)

(263) Following Methods B(iii), F and D from Intermediate 9 (391 mg) and 6-bromo-2-(difluoromethyl)-2H-indazole (197 mg). The 1:1 diastereomeric mixture resulting from step 3 was separated by preparative HPLC.

(264) Example 65 (diastereomer 1 (D1)) was obtained as a colorless solid (53 mg). LCMS (ES+) 404 (M+H).sup.+, RT 3.84 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.06 (1 H, s), 8.72 (1 H, s), 8.36 (1 H, s), 8.19 (1 H, t, J=58.2 Hz), 7.82 (1 H, d, J=8.3 Hz), 7.72 (1 H, s), 7.34 (1 H, d, J=7.9 Hz), 7.29-7.20 (2 H, m), 7.09 (1 H, t, J=8.9 Hz), 3.42-3.35 (1 H, m), 3.06 (1 H, dd, J=12.4, 6.7 Hz), 2.81-2.74 (1 H, m), 2.31-2.23 (1 H, m), 2.21-2.13 (4 H, m), 2.13-2.04 (1 H, m), 1.87-1.79 (1 H, m).

(265) Example 66 (diastereomer 2 (D2)) was obtained as a colorless solid (19 mg). LCMS (ES+) 404 (M+H).sup.+, RT 3.89 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.79 (1 H, s), 8.56 (1 H, s), 8.23 (1 H, s), 8.05 (1 H, t, J=58.3 Hz), 7.71 (1 H, d, J=8.4 Hz), 7.65 (1 H, s), 7.29 (1 H, d, J=8.4 Hz), 7.20 (1 H, d, J=7.9 Hz), 7.18-7.10 (1 H, m), 6.96 (1 H, t, J=8.9 Hz), 3.14 (1 H, t, J=9.4 Hz), 2.33 (1 H, dd, J=13.5, 7.7 Hz), 2.13-2.02 (2 H, m), 1.98 (3 H, d, J=2.7 Hz), 1.70 (1 H, t, J=9.4 Hz).

Example 67

(1S,3R*)-3-(3-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1)

Example 68

(1S,3S*)-3-(3-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2)

(266) ##STR00073##

C3 Stereochemistry Putatively Assigned

Step 1: 6-bromo-3-fluoro-1H-indazole

(267) To a solution of 6-bromo-1H-indazole (2.19 g, 10.7 mmol) in acetonitrile (30 mL) was added Selectfluor® (7.50 g, 21.4 mmol) and acetic acid (1.5 mL) and the reaction mixture heated to 95° 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 CH.sub.2Cl.sub.2 (3×40 mL). Combined organics were concentrated under reduced pressure and the residue resuspended in CH.sub.2Cl.sub.2 (1 mL). The organic layer was extracted with water (2×75 mL) then brine (50 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated. 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 solid (0.42 g, 18%).

(268) .sup.1H NMR δ (ppm)(CDCl.sub.3): 9.36 (1 H, s), 7.92 (1 H, s), 7.61-7.57 (1 H, m), 7.36 (1 H, dd, J=8.96, 2.37 Hz).

Step 2: 6-bromo-3-fluoro-1-methyl-1H-indazole

(269) To a solution of 6-bromo-3-fluoro-1H-indazole (0.30 g, 1.40 mmol) in acetonitrile (10 mL) was added cesium carbonate (0.91 g, 2.80 mmol) and iodomethane (0.24 g, 1.70 mmol, 110 μL) and the reaction mixture heated to 65° C. under N.sub.2 for 2.5 h. After this time the reaction mixture was cooled to r.t. and filtered through Celite, washing with EtOAc (3×20 mL). Combined organics were concentrated under reduced pressure. The crude reaction material was purified by flash silica chromatography (gradient elution, 0-20% EtOAc in iso-hexane) to give the title compound as colorless needles (0.12 g, 38%).

(270) .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.62-7.54 (2 H, m), 7.32-7.29 (1 H, m), 3.96 (3 H, d, J=1.11 Hz).

Steps 3-5: (1S,3R*)-3-(3-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1) and (1S,3S*)-3-(3-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2)

(271) Following Methods B(iii), F and D from Intermediate 9 (244 mg, 0.50 mmol) and 6-bromo-3-fluoro-1-methyl-1H-indazole (115 mg, 0.50 mmol). Example 67 (D1) was obtained as a colorless solid. LCMS (ES+) 386 (M+H).sup.+, RT 11.0 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.96 (1H, s), 8.71 (1H, s), 7.66 (1H, d, J=8.5 Hz), 7.56 (1H, s), 7.36-7.26 (3H, m), 7.11 (1H, t, J=8.9 Hz), 3.92 (3H, d, J=1.1 Hz), 3.27-3.22 (1H, m), 2.72-2.64 (2H, m), 2.45 (1H, dd, J=13.2, 7.7 Hz), 2.27-2.15 (2H, m), 2.13 (3H, d, J=2.6 Hz), 1.92-1.81 (1H, m).

(272) Example 68 (D2) was obtained as a colorless solid. LCMS (ES+) 386 (M+H).sup.+, RT 10.9 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.09 (1 H, s), 8.79 (1 H, s), 7.66-7.60 (1 H, m), 7.54 (1 H, s), 7.38 (1 H, d, J=7.99 Hz), 7.33-7.22 (1 H, m), 7.15-7.06 (2H, m), 3.93 (3 H, d, J=1.06 Hz), 3.4 (1 H, dd, J=12.47, 6.69 Hz), 2.87-2.76 (1 H, m), 2.34-2.21 (2 H, m), 2.20 (3 H, d, J=2.74 Hz), 2.19-2.09 (2 H, m), 1.88-1.79 (1 H, m).

Example 69

(1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-benzo[d]imidazol-5-yl)cyclopentanecarboxamide

(273) ##STR00074##

C3 Stereochemistry Putatively Assigned

(274) Following Methods B, F and D from (1-methyl-1H-benzo[d]imidazol-5-yl)boronic acid and Intermediate 9. The title compound was the major diasteromer formed and was obtained as a white solid. LCMS (ES+) 368 (M+H).sup.+, RT 8.49 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.94 (1H, s), 8.69 (1H, s), 8.64 (1H, s), 7.71 (1H, s), 7.66 (1H, d, J=8.4 Hz), 7.44 (1H, d, J=8.4 Hz), 7.35 (1H, d, J=7.4 Hz), 7.32-7.25 (1H, m), 7.11 (1H, t, J=8.9 Hz), 3.94 (3H, s), 3.30-3.25 (1H, m), 2.74-2.65 (2H, m), 2.48-2.36 (1H, m), 2.26-2.15 (2H, m), 2.14-2.11 (3H, m), 1.85-1.76 (1H, m).

Example 70

(1S,3R*)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)cyclopentanecarboxamide (D1)

Example 71

(1S,3S*)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)cyclopentanecarboxamide (D2)

(275) ##STR00075##

C3 Stereochemistry Putatively Assigned

(276) Following Methods B, F and D from Intermediate 9 (0.57 g, 1.2 mmol) and (1-methyl-1H-benzo[d]imidazol-6-yl)boronic acid (227 mg, 1.3 mmol). The diastereomers were separated after the final synthetic step.

(277) Example 70 (D1) was obtained as an off-white solid (8.6 mg). LCMS (ES+) 368 (M+H).sup.+, RT 8.42 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.73 (1H, s), 8.49 (1H, s), 7.94 (1H, s), 7.40 (1H, d, J=8.3 Hz), 7.32 (1H, s), 7.16-7.03 (3H, m), 6.94-6.88 (1H, m), 3.66 (3H, s), 3.09-3.01 (1H, m), 2.99-2.49 (1H, m), 2.28 (1H, dd, J=13.4, 7.6 Hz), 2.2-1.95 (2H, m), 1.95-1.91 (4H, m), 1.70-1.61 (1H, m).

(278) Example 71 (D2) was obtained as an off-white solid (8.7 mg). LCMS (ES+) 368 (M+H).sup.+, RT 2.40 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.06 (1H, s), 8.75 (1H, s), 8.14 (1H, s), 7.58 (1H, d, J=8.3 Hz), 7.46 (1H, s), 7.37 (1H, d, J=7.8 Hz), 7.31-7.23 (1H, m), 7.13 (2H, dd, J=8.5, 1.6 Hz), 3.85 (3H, s), 3.22 (1H, s), 3.04 (1H, dd, J=12.3, 6.7 Hz), 2.87-2.78 (1H, m), 2.31-2.22 (1H, m), 2.20 (3H, d, J=2.5 Hz), 2.17-2.12 (2H, m), 1.90-1.79 (1H, m).

Example 72

(1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)cyclopentanecarboxamide (D1)

Example 73

(1S,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)cyclopentanecarboxamide (D2)

(279) ##STR00076##

C3 Stereochemistry Putatively Assigned

Step 1: (S)-4-methoxybenzyl 3-(2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(280) Following Method B(iii) from Intermediate 9 (0.50 g, 1.0 mmol) and 6-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.36 mg, 1.5 mmol). Purification by flash silica chromatography (gradient elution, 0-40% EtOAc in iso-hexane) gave the title compound as a yellow oil (0.37 g, 74%). LCMS (ES+) consistent with target (M+H).sup.+.

Step 2: (1 S)-3-(2,2-Dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(281) A solution of (S)-4-Methoxybenzyl 3-(2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (0.37 g, 0.74 mmol) in methanol (20 mL) was passed through the H-cube (20% Pd(OH).sub.2/C cartridge at 50° C. and 60 bar pressure) on a continuous flow for 2 h. After removing the solvent the title compound was obtained as a yellow oil (0.4 g, 100%). LCMS (ES+) consistent with target (M+H).sup.+.

Step 3: Following Method D from (1S)-3-(2,2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid (99 mg, 0.26 mmol) and purified by preparative HPLC

(282) Example 72 (D1) was obtained as a white solid (5.3 mg). LCMS (ES+) 399 (M+H).sup.+, RT 10.8 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.99 (1H, s), 8.69 (1H, s), 7.31-7.22 (2H, m), 7.07 (1H, t, J=9.0 Hz), 6.52 (1H, d, J=8.1 Hz), 6.46 (1H, d, J=2.0 Hz), 6.35 (1H, dd, J=1.9, 8.2 Hz), 5.75 (1H, s), 2.97 (2H, s), 2.36 (2H, dd, J=1.6, 3.7 Hz), 2.15 (3H, d, J=2.8 Hz), 2.13-2.05 (3H, m), 1.87 (1H, t, J=11.7 Hz), 1.70-1.63 (1H, m), 1.24 (6H, s).

(283) Example 73 (D2) was obtained as a white solid (29.6 mg). LCMS (ES+) 399 (M+H).sup.+, RT 3.92 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.86 (1H, s), 7.29-7.24 (2H, m), 7.11-7.05 (H, m), 6.58-6.56 (1H, m), 6.54 (1H, s), 6.46 (1H, dd, J=8.1, 2.0 Hz), 2.99 (2H, s), 2.93-2.84 (1H, m), 2.68-2.61 (1H, m), 2.50-2.32 (3H, m), 2.10 (3H, d, J=2.8 Hz), 2.09-1.99 (2H, m), 1.73-1.63 (1H, m), 1.25 (6H, s). One exchangeable proton not observed.

Example 74

(1S,3R*)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopentanecarboxamide

(284) ##STR00077##

Step 1: (S)-4-Methoxybenzyl 1-(3-fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopent-2-enecarboxylate

(285) Following Method B (iii) from (S)-4-methoxybenzyl 1-(3-fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopent-2-enecarboxylate (600 mg, 1.23 mmol) and 6-bromo-2-(trifluoromethyl)-1H-benzo[d]imidazole (489 mg, 1.84 mmol). Purification by flash column chromatography (gradient elution i-hex to EtOAc) gave the title compound as an orange oil (230 mg, 36%).

Step 2: (1 S)-1-(3-Fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopentanecarboxylic acid

(286) Prepared in a similar manner to Example 73 from (S)-4-methoxybenzyl 1-(3-fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopent-2-enecarboxylate (230 mg, 0.44 mmol). The title compound was isolated as a colorless oil (198 mg, 85%).

Step 3: (1 S,3R*)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopentanecarboxamide

(287) Following Method D from (1S)-1-(3-fluoro-2-methylphenyl)-3-(2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopentanecarboxylic acid (198 mg, 0.44 mmol). Purification by preparative HPLC gave the title compound as a white solid (71 mg). LCMS (ES+) 422 (M+H).sup.+, RT 3.64 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 13.86-13.84 (1H, m), 9.95 (1H, d, J=1.3 Hz), 8.72 (1H, s), 7.79-7.77 (1H, m), 7.64-7.60 (1H, m), 7.52-7.23 (3H, m), 7.15-7.09 (1H, m), 3.35-3.20 (2H, m), 2.73-2.68 (3H, m), 2.30-2.11 (4H, m), 1.87-1.78 (1H, m).

Example 75

(1S,3S*)-3-(Benzo[d]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1)

Example 76

(1S,3R*)-3-(Benzo[d]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2)

(288) ##STR00078##

C3 Stereochemistry Putatively Assigned

Step 1: (S)-Methyl 3-(4-bromobenzo[d]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(289) Following Method B (ii) from Intermediate 6 (0.50 g, 1.31 mmol) and 5-bromo-2-chlorobenzo[d]thiazole (0.32 g, 1.31 mmol). Purification by flash silica chromatography (gradient elution i-hex to 50% EtOAc in i-hex) gave the title compound as a pale yellow gum (0.45 g, 74%).

Step 2: (S)-Methyl 3-(benzo[d]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylate

(290) To a solution of (S)-methyl 3-(4-bromobenzo[d]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (0.43 g, 0.096 mmol) in ethanol (20 mL) was added 20% Pd/C (43 mg) and the mixture was treated with hydrogen at atmospheric pressure for 2 h. The reaction was filtered to remove the Pd/C and evaporated in vacuo to yield title compound as a pale yellow gum (0.36 g, 3:2 mixture of diastereoisomers).

Step 3: (S)-3-(Benzo[d]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(291) Following Method C from (S)-methyl 3-(benzo[c]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylate (361 mg, 0.096 mmol) gave the title compound as a pale yellow gum (330 mg, 90% over 2 steps).

Step 4: (1S,3S*)-3-(Benzo[d]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide and (1S,3S*)-3-(benzo[d]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(292) Following Method D from (S)-3-(benzo[d]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid (170 mg, 0.43 mmol). Purification by preparative HPLC gave the title compounds as off white solids. LCMS (ES+) consistent with target (M+H).sup.+. The enantiomers were separated by Chiralpak IA 30/70 EtOH (0.1% FA)/heptane, 1.0 ml/min, r.t. (1S,3S*)-3-(Benzo[d]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1) (15 mg). LCMS (ES+) 371 (M+H).sup.', RT 3.86 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.08 (1 H, s), 8.73 (1 H, s), 8.04 (1 H, d, J=7.9 Hz), 7.92 (1 H, d, J=8.1 Hz), 7.50-7.45 (1 H, m), 7.42-7.37 (1 H, m), 7.28 (1 H, d, J=7.9 Hz), 7.25-7.17 (1 H, m), 7.06 (1 H, t, J=8.9 Hz), 3.76 (1 H, t, J=8.9 Hz), 3.22 (1 H, dd, J=12.7, 7.6 Hz), 2.72-2.61 (1 H, m), 2.37-2.14 (6 H, m), 2.11-2.1 (1 H, m). (1S,3R*)-3-(benzo[d]thiazol-2-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2) (15 mg). LCMS (ES+) 371 (M+H).sup.+, RT 3.84 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.98 (1 H, s), 8.70 (1 H, s), 8.09-8.05 (1 H, m), 7.95 (1 H, d, J=8.1 Hz), 7.52-7.47 (1 H, m), 7.41 (1 H, td, J=7.6, 1.2 Hz), 7.32-7.22 (2 H, m), 7.10 (1 H, t, J=8.7 Hz), 3.64 (1 H, t, J=8.7 Hz), 2.88 (1 H, dd, J=13.3, 10.0 Hz), 2.63-2.56 (1 H, m), 2.34-2.18 (3 H, m), 2.13 (3 H, dd, J=13.3, 2.8 Hz), 2.08-1.97 (1 H, m).

Example 77

(1 S,3S*)-3-(2-cyclopropylbenzo[d]thiazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1)

Example 78

(1 S,3R*)-3-(2-cyclopropylbenzo[d]thiazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2)

(293) ##STR00079## ##STR00080##

C3 Stereochemistry Putatively Assigned

Step 1: 6-bromo-2-cyclopropylbenzo[d]thiazole

(294) To a solution of 6-bromo-2-chlorobenzo[d]thiazole (0.50 g, 2.02 mmol) and Pd(PPh.sub.3).sub.4 (70 mg, 0.06 mmol) in THF (5 mL) was added dropwise cyclopropyl zinc bromide (0.5 M in THF, 4.0 mL, 2.02 mmol), over 15 min. The reaction mixture heated to 60° C. under N2 for 18 h. The reaction mixture was cooled to 0° C. and quenched with saturated sodium hydrogen carbonate solution (10 mL). The corresponding solution was partitioned with ethyl acetate (50 mL), washed with saturated sodium hydrogen carbonate solution (30 mL), dried over MgSO4 and concentrated to give an orange solid. The crude reaction material was purified by flash silica chromatography (gradient elution i-hex to 50% EtOAc in i-hex) to give the title compound as a pale orange solid (0.40 g, 78%). LCMS (ES+) consistent with target (M+H).sup.+. .sup.1H NMR δ (ppm)(CHCl.sub.3-d): 7.92 (1 H, dd, J=5.48, 1.97 Hz), 7.76-7.67 (1 H, m), 7.54-7.43 (1 H, m), 2.41-2.33 (1 H, m), 1.29-1.18 (4 H, m).

Step 2: (S)-4-Methoxybenzyl 3-(2-cyclopropylbenzo[d]thiazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(295) Following Method B (iv) from 6-bromo-2-cyclopropylbenzo[d]thiazole (0.2590 g, 1.0 mmol) and Intermediate 9 (0.50 g, 1.02 mmol). Purification by flash silica chromatography (gradient elution i-hex to 40% EtOAc in i-hex) gave the title compound as a pale yellow oil (0.303 g, 59%).

Step 4: (S)-3-(2-Cyclopropylbenzo[d]thiazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(296) Following Method F from (S)-4-methoxybenzyl 3-(2-cyclopropylbenzo[d]thiazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (303 mg, 0.59 mmol) gave the title compound as a pale yellow gum (171 mg, 73%).

Step 5: (1S,3S*)-3-(2-Cyclopropylbenzo[d]thiazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide and (1S,3R*)-3-(2-cyclopropylbenzo[c]thiazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(297) Following Method D from (S)-3-(2-cyclopropylbenzo[d]thiazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid (170 mg, 0.43 mmol) and purified by preparative HPLC to give the title compounds as white solids. LCMS (ES+) consistent with target (M+H).sup.+. (1S,3S*)-3-(2-Cyclopropylbenzo[d]thiazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1) (6 mg). LCMS (ES+) 411 (M+H).sup.+, RT 4.07 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.99 (1 H, s), 8.67 (1 H, s), 7.86 (1 H, d, J=1.7 Hz), 7.71 (1 H, d, J=8.3 Hz), 7.28 (2 H, dd, J=7.8, 1.7 Hz), 7.23-7.15 (1 H, m), 7.03 (1 H, t, J=8.9 Hz), 3.02-2.91 (1 H, m), 2.75-2.67 (1 H, m), 2.23-2.05 (5 H, m), 2.00 (2 H, t, J=12.0 Hz), 1.72 (1 H, t, J=9.9 Hz), 1.21-1.14 (2 H, m), 1.09-1.04 (2 H, m), 1 H obscured by water. (1S,3R*)-3-(2-Cyclopropylbenzo[d]thiazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2) (18 mg). LCMS (ES+) 411 (M+H).sup.+, RT 4.12 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.91 (1 H, s), 8.67 (1 H, s), 7.95 (1 H, d, J=1.7 Hz), 7.77 (1 H, d, J=8.4 Hz), 7.45 (1 H, dd, J=8.45, 1.7 Hz), 7.33-7.21 (2 H, m), 7.07 (1 H, t, J=8.4 Hz), 3.23-3.14 (1 H, m), 2.63 (2 H, m), 2.45-2.35 (2 H, m), 2.22-2.07 (5 H, m), 1.83-1.73 (1 H, m), 1.25-1.17 (2 H, m), 1.14-1.08 (2 H, m).

Example 79

(1S,3S*)-3-(2-Cyclopropylbenzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1)

Example 80

(1 S,3R*)-3-(2-Cyclopropylbenzo[c]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2)

(298) ##STR00081## ##STR00082##

C3 Stereochemistry Putatively Assigned

Step 1: 5-Bromo-2-cyclopropylbenzo[d]thiazole

(299) To a solution of 5-bromo-2-chlorobenzo[d]thiazole (0.50 g, 2.02 mmol) and Pd(PPh.sub.3).sub.4 (70 mg, 0.06 mmol) in THF (5 mL) was added dropwise cyclopropyl zinc bromide (0.5 M in THF, 4.0 mL, 2.02 mmol), over 15 min. The reaction mixture heated to 60° C. under N.sub.2 for 18 h. The reaction mixture was cooled to 0° C. and quenched with saturated sodium hydrogen carbonate solution (10 mL). The corresponding solution was partitioned with ethyl acetate (50 mL), washed with saturated sodium hydrogen carbonate solution (30 mL), dried over MgSO.sub.4 and concentrated to give an orange solid. The crude reaction material was purified by flash silica chromatography (gradient elution i-hex to 50% EtOAc in i-hex) to give the title compound as a pale yellow solid (0.45 g, 88%). LCMS (ES+) consistent with target (M+H).sup.+.

Step 2: (S)-4-Methoxybenzyl 3-(2-cyclopropylbenzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(300) Following Method B (iv) from 5-bromo-2-cyclopropylbenzo[d]thiazole (0.400 g, 1.58 mmol) and Intermediate 9 (0.70 g, 1.43 mmol). Purification by flash silica chromatography (gradient elution i-hex to 40% EtOAc in i-hex) gave the title compound as a pale yellow oil (0.49 g, 66%).

Step 3: (S)-3-(2-Cyclopropylbenzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(301) Following Method F from (S)-4-methoxybenzyl 3-(2-cyclopropylbenzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (490 mg, 0.95 mmol) gave the title compound as a pale yellow gum (340 mg, 90%).

Step 4: (1S,3S*)-3-(2-Cyclopropylbenzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1) and (1 S,3R*)-3-(2-cyclopropylbenzo[c]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2)

(302) Following Method D from (S)-3-(2-cyclopropylbenzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid (340 mg, 0.86 mmol) and purified by preparative HPLC to give the title compounds as off white solids. LCMS (ES+) consistent with target (M+H).sup.+. (1S,3S*)-3-(2-cyclopropylbenzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1) (44 mg). LCMS (ES+) 411 (M+H).sup.+, RT 4.12 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.01 (1 H, s), 8.69 (1 H, s), 7.88 (1 H, d, J=8.2 Hz), 7.68 (1 H, d, J=1.6 Hz), 7.34-7.15 (3 H, m), 7.05 (1 H, t, J=8.9 Hz), 3.30-3.24 (1 H, m), 3.03 (1 H, dd, J=12.5, 6.8 Hz), 2.77-2.64 (1 H, m), 2.50-2.43 (1 H, m), 2.27-2.07 (5 H, m), 2.08-1.95 (1 H, m), 1.83-1.69 (1 H, m), 1.25-1.07 (4 H, m). (1S,3R*)-3-(2-cyclopropylbenzo[d]thiazol-5-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2) (84 mg). LCMS (ES+) 411 (M+H).sup.+, RT 4.10 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.93 (1 H, s), 8.67 (1 H, s), 7.90 (1 H, d, J=8.2 Hz), 7.84 (1 H, d, J=1.6 Hz), 7.37 (1 H, dd, J=8.2, 1.7 Hz), 7.34-7.20 (2 H, m), 7.07 (1 H, t, J=8.8 Hz), 3.27-3.14 (1 H, m), 2.69-2.61 (2 H, m), 2.50-2.35 (2 H, m), 2.24-2.07 (5 H, m), 1.83-1.72 (1 H, m), 1.25-1.09 (4 H, m).

Example 81

(1S,3R)-3-(5-Fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(303) ##STR00083##

C3 Stereochemistry Putatively Assigned

Step 1: 6-Bromo-5-fluoro-1-methyl-1H-indazole

(304) A stirred solution of 6-bromo-5-fluoro-1H-indazole (1.00 g, 4.65 mmol) in dry MeCN (10 mL) was treated at r.t. with Cs.sub.2CO.sub.3 (3.06 g, 9.39 mmol) and MeI (0.35 mL, 5.62 mmol). The reaction was heated to 70° C. for 3 h. After cooling to r.t., the mixture was filtered, washing with EtOAc (50 mL), and concentrated. Purification by silica column chromatography gave the title compound (562 mg, 2.45 mmol, 53%) as a cream powder.

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

(305) Following Method B(ii) using 6-bromo-5-fluoro-1-methyl-1H-indazole (304 mg, 1.33 mmol), bis(neopentylglycolato)diboron (403 mg, 1.78 mmol) and Intermediate 6 (452 mg, 1.18 mmol). Purification by silica column chromatography gave the title compound (410 mg, 1.07 mmol, 81%) as a colorless oil.

Step 3: Methyl 3-(5-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylate

(306) Following Method F from (S)-methyl 3-(5-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (410 mg, 1.07 mmol). The mixture was filtered and concentrated to yield a diastereomeric mixture of the title compound (417 mg) as a white powder which was used without further purification.

Step 4: 3-(5-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(307) Following Method C(ii) from methyl 3-(5-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylate (412 mg). The title compound was obtained as a diastereomeric mixture (305 mg, 0.82 mmol, 77% over two steps) as a white powder.

Step 5: (1S,3R)-3-(5-Fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(308) Following Method D(ii) from the diastereomeric mixture of 3-(5-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentane carboxylic acid (221 mg, 0.60 mmol). Purification by preparative HPLC gave the title compound (149 mg, 0.39 mmol, 65%) as a white solid. LCMS (ES+) 386 (M+H).sup.+, RT 3.79 min. (Analytical method 1); .sup.1H NMR δ (ppm)(4 MHz, DMSO-d.sub.6): 9.91 (1H, s), 8.67 (1H, s), 7.97 (1H, s), 7.70 (1H, d, J=6 Hz), 7.49 (1H, d, J=10.8 Hz), 7.30-7.26 (2H, m), 7.08 (1H, app t, J=8 Hz), 4.06 (3H, s), 3.35-3.30 (1H, m), 2.72-2.65 (1H, m), 2.57-2.50 (2H, m), 2.19-2.15 (2H, m), 2.11 (3H, d, J=2.8 Hz), 1.95-1.84 (1H, m).

Example 82

(1S,3S*)-3-(7-Fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D1)

Example 83

(1S,3R*)-3-(7-Fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (D2)

(309) ##STR00084##

C3 Stereochemistry Putatively Assigned

Step 1: 6-Bromo-7-fluoro-1H-indazole

(310) 4-Bromo-2,3-difluorobenzaldehyde (1.0 g, 4.52 mmol), methoxyamine hydrochloride (418 mg, 5.00 mmol) and potassium carbonate (749 mg, 5.50 mmol) in DME (12 mL) were stirred at 4° C. for 3.5 h. The resulting suspension was cooled to r.t. and filtered through a celite pad, washing with EtOAc (3×1 mL). The combined organics were concentrated to ˜5 mL and to this was added hydrazine monohydrate (3 mL). The reaction mixture was stirred at 9° C. overnight. The mixture was cooled to r.t. and poured onto H.sub.2O (2 mL). The solvents were partially removed under reduced pressure and the resulting solid was filtered, washed with H.sub.2O (2×10 mL) and i-hex (3×15 mL) and dried to constant weight to give the title compound as a colorless solid (791 mg, 81%).

Step 2: 6-Bromo-7-fluoro-1-methyl-1H-indazole

(311) To a stirred solution of 6-bromo-7-fluoro-1H-indazole (1.00 g, 4.65 mmol) and potassium carbonate (1.28 g, 9.30 mmol) in MeCN (10 mL) was added iodomethane (434 μl, 6.98 mmol). The reaction mixture was heated to 60° C. for 2.5 h, then allowed to cool to r.t. and filtered through celite, washing with EtOAc (3×20 mL). The combined organics were combined and concentrated. Purification by flash column chromatography (gradient elution i-hex to 33% EtOAc in i-hex) gave the title compound as a colorless solid (610 mg, 57%).

Step 3: (S)-4-Methoxybenzyl 3-(7-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate

(312) Following Method B (iv) from 6-bromo-7-fluoro-1-methyl-1H-indazole (188 mg, 0.82 mmol) and Intermediate 9 (400 mg, 0.82 mmol). Purification by flash column chromatography gave the title compound as a colorless oil (280 mg, 70%).

Step 4: (S)-3-(7-Fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid

(313) Following Method F from (S)-4-methoxybenzyl 3-(7-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopent-2-enecarboxylate (150 mg, 0.25 mmol). The crude product was purified by SCX cartridge to give the title compound as a colorless semi-solid (150 mg, 98%, 1:1 mixture of diastereoisomers).

Step 5: (1S,3S*)-3-(7-Fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide and (1S,3R*)-3-(7-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide

(314) Following Method D from (S)-3-(7-fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)cyclopentanecarboxylic acid (150 mg, 0.31 mmol). Purification by preparative HPLC gave the title compounds as colorless solids. LCMS (ES+) consistent with target (M+H).sup.+. (1S,3S*)-3-(7-Fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (60 mg). LCMS (ES+) 386 (M+H).sup.+, RT 3.82 min (Analytical method 1); .sup.1H NMR δ (ppm)(400 MHz, MeOD): Hydroxamic acid protons not observed, 7.94 (1H, d, J=2.4 Hz), 7.44 (1H, d, J=8.4 Hz), 7.36 (1H, d, J=7.8 Hz), 7.31-7.22 (1H, m), 7.06-6.95 (2H, m), 4.21 (3H, s), 3.94-3.81 (1H, m), 3.15-3.04 (1H, m), 2.79-2.71 (1H, m), 2.42-2.27 (3H, m), 2.20 (3H, d, J=2.8 Hz), 2.04-1.93 (1H, m); (1S,3R*)-3-(7-Fluoro-1-methyl-1H-indazol-6-yl)-1-(3-fluoro-2-methylphenyl)-N-hydroxycyclopentanecarboxamide (22 mg). LCMS (ES+) 386 (M+H).sup.+, RT 3.84 min (Analytical method 1); .sup.1H NMR δ (ppm)(4 MHz, MeOD): Hydroxamic acid protons not observed, 7.96 (1H, d, J=2.3 Hz), 7.52 (1H, d, J=8.3 Hz), 7.38 (1H, d, J=7.8 Hz), 7.35-7.26 (2H, m), 7.05 (1H, dd, J=8.8, 8.8 Hz), 4.22 (3H, s), 3.70-3.58 (1H, m), 2.84-2.69 (2H, m), 2.52 (1H, dd, J=7.3, 13.1 Hz), 2.37-2.28 (1H, m), 2.19 (4H, d, J=2.5 Hz), 2.11-2.01 (1H, m).

Example 84

(1S,3S*)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(quinolin-6-yl)cyclopentanecarboxamide (D1)

Example 85

(1 S,3R*)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(quinolin-6-yl)cyclopentanecarboxamide (D2)

(315) ##STR00085##

C3 Stereochemistry Putatively Assigned

Step 1: (S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-(quinolin-6-yl)cyclopent-2-enecarboxylate

(316) Intermediate 6 (550 mg, 1.44 mmol), quinolin-6-ylboronic acid (260 mg, 1.5 mmol), CsF (200 mg), DME (15 ml), MeOH (3 ml) and palladiumtetrakistriphenylphosphine (2 mg) were combined in a sealed tube and heated in a 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 (459 mg). LCMS (ES+) consistent with target (M+H).sup.+.

Step 2: (1S)-1-(3-Fluoro-2-methylphenyl)-3-(quinolin-6-yl)cyclopentanecarboxylic acid

(317) Following Method F and Method C from (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-(quinolin-6-yl)cyclopent-2-enecarboxylate (450 mg, 1.24 mmol). Purification by preparative HPLC gave the title compound as a tan foam (191 mg, 44%). LCMS (ES+) consistent with target (M+H).sup.+.

Step 3: (1S,3S)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(quinolin-6-yl)cyclopentanecarboxamide and (1S,3R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(quinolin-6-yl)cyclopentanecarboxamide

(318) Following Method D from (1 S)-1-(3-fluoro-2-methylphenyl)-3-(quinolin-6-yl)cyclopentanecarboxylic acid (191 mg, 0.547 mmol). Purification by preparative HPLC gave the title compounds. (1S,3S)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(quinolin-6-yl)cyclopentanecarboxamide as a white solid (D1) (4 mg). LCMS (ES+) 365 (M+H).sup.+, RT 2.56 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.05 (1 H, s), 8.90-8.80 (1 H, m), 8.72 (1 H, s), 8.35-8.20 (1 H, m), 8.00-7.85 (1 H, m), 7.82 (1 H, s), 7.70-7.60 (1 H, m), 7.50-7.40 (1 H, m), 7.35-6.95 (3 H, m), 3.10-3.00 (1 H, m), 3.00-2.80 (1 H, m), 2.80-2.70 (1 H, m), 2.40-2.00 (6 H, m), 1.90-1.70 (1 H, m). (1S,3R)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(quinolin-6-yl)cyclopentanecarboxamide (D2) as a clear glass (16 mg). LCMS (ES+) 365 (M+H).sup.+, RT 2.62 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.93 (1 H, br s), 8.84 (1H, dd, J=4 Hz and 1.6 Hz), 8.71 (1H, br s), 8.30 (1H, dd, J=8.8 Hz and 1.2 Hz), 7.98 (1 H, d, J=8.4 Hz), 7.90-7.75 (2 H, m), 7.51 (1 H, dd, J=8.4 Hz and 4.4 Hz), 7.40-7.20 (2 H, m), 7.15-7.5 (1 H, m), 3.4-3.25 (1 H, m), 2.80-2.60 (2 H, m), 2.60-2.40 (1 H, m), 2.30-2.10 (2 H, m), 2.13 (3 H, d, J=2.8 Hz), 1.95-1.75 (1 H, m).

Example 86

(1S,3R*)-1-(3,4-difluoro-2-methylphenyl)-N-hydroxy-3-(1-methyl-1H-indazol-6-yl)cyclopentanecarboxamide

(319) ##STR00086## ##STR00087##

C3 Stereochemistry Putatively Assigned

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

(320) Following Method B (ii) from Intermediate 10 (0.62 g, 1.55 mmol) and (1-methyl-1H-indazol-6-yl) boronic acid (0.34 g, 1.90 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 35% EtOAc in i-hex) gave the title compound as a colorless oil (0.58 g, 97%). .sup.1H NMR δ (ppm)(CHCl.sub.3-d): 7.96 (1 H, d, J=0.95 Hz), 7.70 (1 H, dd, J=8.45, 0.80 Hz), 7.47-7.39 (2 H, m), 7.06 (1 H, ddd, J=8.79, 4.98, 1.76 Hz), 7.01-6.89 (1 H, m), 6.36 (1 H, t, J=1.80 Hz), 4.10 (3 H, s), 3.71 (3 H, s), 3.37 (1 H, ddd, J=13.01, 8.92, 4.62 Hz), 3.16-3.07 (1 H, m), 2.92 (1 H, dddd, J=15.91, 9.24, 4.61, 1.88 Hz), 2.23-2.16 (3 H, m), 2.06-1.97 (1 H, m).

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

(321) Following Method C (iii) from (S)-methyl 1-(3,4-difluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxylate (0.57 g, 1.55 mmol). Crude reaction material was azeotroped from CHCl.sub.3 to give the title compound as a colorless foam (0.55 g, 95%). .sup.1H NMR δ (ppm)(CHCl.sub.3-d): 7.97 (1 H, d, J=0.92 Hz), 7.75-7.66 (1 H, m), 7.46-7.39 (2 H, m), 7.08 (1 H, ddd, J=8.81, 4.89, 1.65 Hz), 6.95 (1 H, q, J=8.71 Hz), 6.42 (1 H, s), 4.09 (2 H, s), 3.33 (1 H, ddd, J=13.16, 8.72, 4.35 Hz), 3.17-3.6 (1 H, m), 2.98-2.89 (1 H, m), 2.28 (3 H, d, J=2.72 Hz), 2.09-1.99 (1 H, m).

Step 3: (S)-1-(3,4-difluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopentanecarboxylic acid

(322) Following Method F from (S)-1-(3,4-difluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopent-2-enecarboxylic acid (430 mg, 1.22 mmol). Azeotroping from CHCl.sub.3 gave the title compound as a colorless foam as a 2:1 mixture of diastereoisomers (360 mg, 83%).

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

(323) Following Method D from (S)-1-(3,4-difluoro-2-methylphenyl)-3-(1-methyl-1H-indazol-6-yl)cyclopentanecarboxylic acid (300 mg, 0.81 mmol). Purification by preparative HPLC gave the title compound as a colorless solid (65 mg, 64%). LCMS (ES+) 386 (M+H).sup.+, RT 3.76 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.93 (1H, s), 8.69 (1H, s), 7.96 (1H, s), 7.68 (1H, d, J=8.4 Hz), 7.52 (1H, s), 7.33-7.23 (2H, m), 7.17 (1H, d, J=8.5 Hz), 4.02 (3H, s), 3.26-3.15 (1H, m), 2.68-2.59 (2H, m), 2.45-2.33 (1H, m), 2.18-2.13 (5H, m), 1.92-1.80 (1H, m).

Example 87

(1 S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrrolidin-1-yl)cyclopentanecarboxamide (D1)

Example 88

(1 S,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrrolidin-1-yl)cyclopentanecarboxamide (D2)

(324) ##STR00088##

C3 Stereochemistry Putatively Assigned

Step 1: (1S)-1-(3-fluoro-2-methylphenyl)-3-oxocyclopentanecarboxylic acid

(325) To a solution of Intermediate 1 (0.5 g, 2 mmol) in methanol (10 mL) was added 15% NaOH solution (5.3 mL) were combined in a sealed tube and heated to 70° C. for 24 h. The reaction mixture was then in vacuo partitioned between EtOAc and H.sub.2O/adjusted to pH 7 with 1M HCl. Organic layer was dried (MgSO.sub.4) and evaporated in vacuo to give the title compound as a pale orange gum (501 mg). This was used crude in the next step.

Step 2: (1S)-1-(3-Fluoro-2-methylphenyl)-3-(pyrrolidin-1-yl)cyclopentanecarboxylic acid

(326) To a solution of (1S)-1-(3-fluoro-2-methylphenyl)-3-oxocyclopentanecarboxylic acid (25 mg, 1.6 mmol) in DCM (5 mL) and acetic acid (0.125 mL) was added pyrrolidine (0.266 mL, 3.18 mmol) and stirred for 45 min. PS-Me.sub.3N(CNBH.sub.3) (4 mg, 1.6 mmol) was added and stirred slowly for 17 h. The resin was filtered off and the filtrate evaporated in vacuo. The crude product was applied to an SCX (5 g) cartridge and eluted with ˜1.5 m NH.sub.3 in MeOH. The filtrate was evaporated in vacuo to give a brown gum (0.34 g). Used in the next step without further purification.

Step 3: (1S,3R)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(pyrrolidin-1-yl)cyclopentanecarboxamide and (1S,3S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-(pyrrolidin-1-yl)cyclopentanecarboxamide

(327) Following Method D from (1S)-1-(3-fluoro-2-methylphenyl)-3-(pyrrolidin-1-yl)cyclopentanecarboxylic acid (0.34 g, 1.16 mmol). Purification by preparative HPLC gave the title compounds as pale orange solids (58 mg 17% and 68 mg, 20%). LCMS (ES+) consistent with target (M+H).sup.+. (1S,3R)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(pyrrolidin-1-yl)cyclopentanecarboxamide (D1). LCMS (ES+) 37 (M+H).sup.+, RT 1.96 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.94 (1 H, s), 8.22 (1 H, s), 7.27-7.09 (2 H, m), 7.08-6.98 (1 H, m), 2.96-2.76 (3 H, m), 2.68 (2 H, s), 2.49-2.37 (2 H, m), 2.17 (3 H, dd, J=5.3, 2.6 Hz), 2.12-2.04 (1 H, m), 2.01-1.87 (1 H, m), 1.82-1.61 (6 H, m). (1S,3S)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-(pyrrolidin-1-yl)cyclopentanecarboxamide (D2). LCMS (ES+) 307 (M+H).sup.+, RT 2.13 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 8.25 (1 H, s), 7.26-6.98 (3 H, m), 2.84 (2 H, s), 2.67 (2 H, s), 2.55-2.43 (1 H, m), 2.42-2.26 (1 H, m), 2.28-2.17 (1 H, m), 2.14-1.95 (4 H, m), 1.93-1.82 (1 H, m), 1.94-1.48 (6H, m).

Example 89

(1S,3R*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-morpholinocyclopentanecarboxamide (D1)

Example 9

(1S,3S*)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-morpholinocyclopentanecarboxamide (D2)

(328) ##STR00089##

C3 Stereochemistry Putatively Assigned

(329) Prepared in a similar manner to Examples 87 and 88 from morpholine. Purification by preparative HPLC gave the title compounds. LCMS (ES +) consistent with target (M+H).sup.+. (1S,3R)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-morpholinocyclopentanecarboxamide (D1). LCMS (ES+) 323 (M+H).sup.+, RT 1.95 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.93-9.89 (1H, m), 8.28 (1H, s), 7.24-7.15 (2H, m), 7.3 (1H, t, J=8.8 Hz), 3.58-3.48 (4H, m), 2.84 (1H, dd, J=7.0, 12.4 Hz), 2.47-2.34 (4H, m), 2.17 (1H, dd, J=2.6, 13.9 Hz), 2.09 (3H, d, J=2.6 Hz), 2.04-1.85 (3H, m), 1.64 (1H, dd, J=9.6, 12.4 Hz), 1.49 (1H, ddd, J=8.5, 12.2, 17.0 Hz); (1S,3S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-morpholinocyclopentanecarboxamide (D2). LCMS (ES+) 323 (M+H).sup.+, RT 2.04 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.94-9.94 (1H, m), 8.71 (1H, s), 7.22-7.14 (3H, m), 7.04 (2H, dd, J=8.9, 8.9 Hz), 3.57 (4H, dd, J=4.5, 4.5 Hz), 2.46-2.04 (8H, m), 2.04-1.94 (2H, m), 1.85-1.75 (2H, m), 1.55 (2H, ddd, J=8.4, 12.3, 16.8 Hz).

Example 91

(1S,3R)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-((1-methyl-1H-indazol-6-yl)oxy)cyclopentanecarboxamide

Example 92

(1S,3S)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-((1-methyl-1H-indazol-6-yl)oxy)cyclopentanecarboxamide

(330) ##STR00090##

Step 1: (1S,3S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-((5-fluoropyridin-3-yl)oxy)cyclopentanecarboxylate and (1S,3R)-methyl 1-(3-fluoro-2-methylphenyl)-3-((5-fluoropyridin-3-yl)oxy)cyclopentanecarboxylate

(331) Sodium borohydride (0.38 g, 1.25 mmol) was added portionwise over 15 min to a solution of Intermediate 1 (2.0 g, 1.0 mmol) in methanol at 0° C. The reaction was stirred for 1 h at 0° C. before quenching with brine (10 mL). The reaction was poured into water (120 mL) and extracted with EtOAc. Combined organics were washed with brine, dried (MgSO.sub.4) and evaporated in vacuo to yield a colorless oil (2.06 g). Purification by flash silica chromatography (gradient elution i-hex to 55% EtOAc in i-hex) to yield partial separation of the two isomers of the title compounds as colorless gums. (1S,3S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-((5-fluoropyridin-3-yl)oxy)cyclopentanecarboxylate (18 mg, 9%), .sup.1H NMR δ (ppm)(CHCl.sub.3-d): 7.19-7.10 (1 H, m), 6.95 (1 H, t, J=8.8 Hz), 4.54 (1 H, t, J=5.3 Hz), 3.62 (2 H, s), 3.08 (1 H, dd, J=13.8, 6.5 Hz), 2.49-2.40 (2 H, m), 2.13-2.08 (3 H, m), 1.91 (1 H, ddd, J=13.8, 4.5, 1.1 Hz), 1.80-1.70 (1 H, m), 1.38 (1 H, dd, J=14.9, 4.0 Hz), (OH not seen) and (1S,3R)-methyl 1-(3-fluoro-2-methylphenyl)-3-((5-fluoropyridin-3-yl)oxy)cyclopentanecarboxylate (670 mg, 33%), .sup.1H NMR δ (ppm)(CHCl.sub.3-d): 7.19-7.05 (2 H, m), 7.00-6.90 (1 H, m), 4.45-4.36 (1 H, m), 3.67 (2 H, s), 2.75-2.70 (1 H, m), 2.65-2.56 (2 H, m), 2.27-2.09 (6 H, m), 1.84-1.71 (1 H, m), (OH not seen).

Step 2: (1S,3R)Methyl 1-(3-fluoro-2-methylphenyl)-3-((1-methyl-1H-indazol-6-yl)oxy)cyclopentanecarboxylate

(332) Di-isopropylazodicarboxylate (0.12 mL, 0.59 mmol) was added dropwise over 15 min at 0° C. to a solution of (1S,3S)-methyl 1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (100 mg, 0.39 mmol), 6-hydroxy-1-methyl-1H-indazole (88.1 mg, 0.59 mmol) and triphenylphosphine (156 mg, 0.59 mmol) in THF (2 mL). The reaction was warmed to r.t. and stirred for 2 h. The solution was poured into EtOAc (35 mL), washed with 1 N NaOH, dried (MgSO.sub.4) and evaporated in vacuo to yield a bright yellow gum (450 mg). Purification by flash silica chromatography (gradient elution i-hex to 60% EtOAc in i-hex) gave the title compound as a pale yellow gum (296 mg).

Step 3: (1S,3S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-((1-methyl-1H-indazol-6-yl)oxy)cyclopentanecarboxylate

(333) Procedure as for Step 2 gave the title compound as a pale yellow gum (640 mg).

Step 4: (1S,3R)-1-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-((1-methyl-1H-indazol-6-yl)oxy)cyclopentanecarboxamide

(334) Following Method C and D from (1S,3R)-methyl 1-(3-fluoro-2-methylphenyl)-3-phenoxycyclopentanecarboxylate (295 mg, 0.39 mmol) Preparative HPLC gave the title compound as a white solid (34 mg). LCMS (ES+) 384 (M+H).sup.+, RT 3.48 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.88 (1 H, s), 8.59 (1 H, s), 7.81 (1 H, d, J=0.8 Hz), 7.52 (1 H, d, J=8.8 Hz), 7.22-7.12 (2 H, m), 7.08-6.94 (2 H, m), 6.67 (1 H, dd, J=8.8, 2.0 Hz), 4.97-4.84 (1 H, m), 3.96-3.82 (3 H, m), 2.66-2.45 (3 H, m), 2.08-1.93 (5 H, m), 1.83-1.73 (1 H, m).

Step 5: (1S,3S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-((1-methyl-1H-indazol-6-yl)oxy)cyclopentanecarboxamide

(335) Following Method C and D from (1S,3R)-methyl 1-(3-fluoro-2-methylphenyl)-3-((5-fluoropyridin-3-yl)oxy). Purification by preparative HPLC gave the title compound as a white solid (138 mg, 76%). LCMS (ES+) 384 (M+H).sup.+, RT 3.52 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.92 (1 H, s), 8.63 (1 H, s), 7.80 (1 H, d, J=0.8 Hz), 7.48 (1 H, d, J=8.8 Hz), 7.25-7.08 (2 H, m), 7.04-6.90 (2 H, m), 6.55 (1 H, dd, J=8.8, 2.0 Hz), 5.00-4.95 (1 H, m), 3.91 (3 H, s), 3.34-3.25 (1 H, m), 2.36-2.26 (2 H, m), 2.11-1.98 (4 H, m), 1.81-1.72 (2 H, m).

Example 93

(1S,3R)-1-(3-fluoro-2-methylphenyl)-3-((5-fluoropyridin-3-yl)oxy)-N-hydroxycyclopentanecarboxamide

Example 94

(1S,3S)-1-(3-fluoro-2-methylphenyl)-3-((5-fluoropyridin-3-yl)oxy)-N-hydroxycyclopentanecarboxamide

(336) ##STR00091##

(337) Prepared in a similar manner to Examples 91 and 92 from 3-fluoro-5-hydroxy pyridine (188 mg, 1.67 mmol). Purification by preparative HPLC gave the title compounds. LCMS (ES+) 349 (M+H).sup.+, RT 3.29 min (Analytical method 1); (1S,3R)-1-(3-fluoro-2-methylphenyl)-3-((5-fluoropyridin-3-yl)oxy)-N-hydroxycyclopentanecarboxamide as a white solid (36 mg). .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.97 (1 H, s), 8.67 (1 H, s), 8.18-8.13 (2 H, m), 7.42 (1 H, dt, J=11.2, 2.4 Hz), 7.28-7.13 (2 H, m), 7.13-7.03 (1 H, m), 4.98 (1 H, t, J=5.1 Hz), 2.74-2.66 (1 H, m), 2.60-2.51 (2 H, m), 2.20-2.00 (5 H, m), 1.88-1.79 (1 H, m) and (1S,3S)-1-(3-fluoro-2-methylphenyl)-3-((5-fluoropyridin-3-yl)oxy)-N-hydroxycyclopentanecarboxamide as a white solid (52 mg). LCMS (ES+) 349 (M+H).sup.+, RT 3.38 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.97 (1H, s), 8.67 (1H, s), 8.17 (2H, d, J=2.3 Hz), 7.45-7.40 (1H, m), 7.25-7.19 (2H, m), 7.11-7.04 (1H, m), 4.99-4.96 (1H, m), 2.75-2.67 (1H, m), 2.6-2.52 (1H, m, obscured by DMSO), 2.12-2.08 (6H, m), 1.89-1.80 (1H, m).

Example 95

(1S,3R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenoxycyclopentanecarboxamide

Example 96

(1S,3S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenoxycyclopentanecarboxamide

(338) ##STR00092##

(339) Prepared in a similar manner to Example 91 and 92 from phenol (136 mg, 1.45 mmol). Purification by preparative HPLC gave the title compounds. LCMS (ES+) consistent with target (M+H).sup.+. (1S,3R)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenoxycyclopentanecarboxamide as a white solid (99 mg). LCMS (ES+) 33 (M+H).sup.+, RT 3.82 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.94 (1 H, s), 8.66 (1 H, s), 7.31-7.17 (4 H, m), 7.10-7.02 (1 H, m), 6.91 (3 H, t, J=7.8 Hz), 4.84 (1 H, s), 2.69-2.61 (1 H, m), 2.58-2.51 (2 H, m), 2.15-1.93 (5 H, m), 1.84-1.75 (1 H, m). (1S,3S)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenoxycyclopentanecarboxamide as a pale yellow glass (170 mg). LCMS (ES+) 330 (M+H).sup.+, RT 3.93 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.98 (1 H, s), 8.68 (1 H, s), 7.30-7.15 (4 H, m), 7.5 (1 H, t, J=8.9 Hz), 6.93-6.80 (3 H, m), 4.91 (1 H, tt, J=6.6, 3.4 Hz), 3.28 (1 H, dd, J=14.0, 6.8 Hz), 2.43-2.26 (2 H, m), 2.12-1.99 (4 H, m), 1.85-1.75 (2 H, m).

Example 97

(1S,3S)-1-(3-fluoro-2-methylphenyl)-3-((4-fluorobenzyl)oxy)-N-hydroxycyclopentanecarboxamide

(340) ##STR00093##

Step 1: (1S,3S)-methyl 1-(3-fluoro-2-methylphenyl)-3-((4-fluorobenzyl)oxy)cyclopentanecarboxylate

(341) Sodium hydride (9.5 mg, 0.24.mmol) was added portionwise over 2 min to a solution of (1S,3S)-methyl 1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (50 mg, 0.20 mmol) in DMF (1 mL) at 0° C. The reaction was stirred for 20 min at 0° C. then 4-fluorobenzyl bromide (27 μL, 0.22 mmol) was added and warmed to r.t. for 1 h. The reaction was poured into water (10 mL) and extracted with diethyl ether. Combined organics were washed with brine, dried (MgSO.sub.4) and evaporated in vacuo to yield a colorless oil (89 mg). This purified by flash silica chromatography (gradient elution i-hex to 60% EtOAc in i-hex) to yield the title compound as a colorless gum (46 mg, 64%).

Step 2: (1S,3S)-1-(3-fluoro-2-methylphenyl)-3-((4-fluorobenzyl)oxy)cyclopentanecarboxylic acid

(342) Following Method C from (1S,3S)-methyl 1-(3-fluoro-2-methylphenyl)-3-((4-fluorobenzyl)oxy)cyclopentanecarboxylate (46 mg, 0.13 mmol) gave the title compound as a white foam (43.1 mg, 97%).

Step 3: (1S,3S)-1-(3-fluoro-2-methylphenyl)-3-((4-fluorobenzyl)oxy)-N-hydroxycyclopentanecarboxamide

(343) Following Method D from (1S,3S)-1-(3-fluoro-2-methylphenyl)-3-((4-fluorobenzyl)oxy)cyclopentanecarboxylic acid (43 mg, 0.12 mmol). Purification by preparative HPLC to give the title compound as a white solid (25 mg, 55%). LCMS (ES+) 362 (M+H).sup.+, RT 3.81 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.91 (1 H, s), 8.63 (1 H, s), 7.32-7.24 (3 H, m), 7.22-7.08 (3 H, m), 7.04 (1 H, t, J=8.9 Hz), 4.44-4.33 (2 H, m), 4.10 (1 H, p, J=5.3 Hz), 3.04 (1 H, dd, J=13.6, 6.8 Hz), 2.33 (1 H, dt, J=12.5, 6.0 Hz), 2.26-2.08 (4 H, m), 1.92-1.79 (1 H, m), 1.78-1.69 (2 H, m).

Example 98

1-phenyl-N-hydroxycyclohexylcarboxamide

(344) ##STR00094##

(345) Following Method D(ii) from 1-phenyl-1-cyclohexylcarboxylic acid (0.204 g, 0.1 mmol). Purification by recrystallization from EtOAc gave the title compound as a white solid (180 mg, 82%). LCMS (ES+) 22 (M+H).sup.+, RT 9.47 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.4 (1 H, s), 8.62 (1 H, s), 7.38-7.29 (4 H, m), 7.20 (1 H, t, J=7.2 Hz), 2.36 (2 H, d, J=13.4 Hz), 1.67-1.42 (7 H, m), 1.28-1.23 (1 H, m).

Example 99

(1r,4r)-1-(3-fluoro-2-methylphenyl)-4-(5-fluoropyridin-3-yl)-N-hydroxycyclohexanecarboxamide (D1)

Example 1

(1s,4s)-1-(3-fluoro-2-methylphenyl)-4-(5-fluoropyridin-3-yl)-N-hydroxycyclohexanecarboxamide (D2)

(346) ##STR00095## ##STR00096##

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

(347) Intermediate 8 (79 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 DCM, 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 2: methyl 3′-fluoro-4-(5-fluoropyridin-3-yl)-2′-methyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-1-carboxylate

(348) 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 (12 mg), DME (12 mL), MeOH (2 mL) and palladium tetrakis(triphenylphosphine) (1 mg) were combined in a sealed tube and heated by microwave to 12° 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 3: 3′-fluoro-4-(5-fluoropyridin-3-yl)-2′-methyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-1-carboxylic acid

(349) Following Method C from methyl 3′-fluoro-4-(5-fluoropyridin-3-yl)-2′-methyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-1-carboxylate (23 mg, 0.67 mmol). 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 4: 3′-fluoro-4-(5-fluoropyridin-3-yl)-N-hydroxy-2′-methyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-1-carboxamide

(350) 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+) consistent with target (M+H).sup.+

Step 5: (1r,4r)-1-(3-fluoro-2-methylphenyl)-4-(5-fluoropyridin-3-yl)-N-hydroxycyclohexanecarboxamide and (1s,4s)-1-(3-fluoro-2-methylphenyl)-4-(5-fluoropyridin-3-yl)-N-hydroxycyclohexanecarboxamide

(351) 3-Fluoro-4-(5-fluoropyridin-3-yl)-N-hydroxy-2′-methyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-1-carboxamide (50 mg, 0.145 mmol), EtOH (10 mL) and Pd/C (10% Pd content) (5 mg) were combined and stirred under a hydrogen atmosphere for 21 h. The catalyst was filtered off and solvents removed in vacuo. Purification by preparative HPLC gave (1r,4r)-1-(3-fluoro-2-methylphenyl)-4-(5-fluoropyridin-3-yl)-N-hydroxycyclohexanecarboxamide (D1) as a white solid (12 mg). LCMS (ES+) 347 (M+H).sup.+, RT 3.47 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.88 (1 H, s), 8.63 (1 H, s), 8.38 (1 H, d, J=2.8 Hz), 8.29 (1 H, t, J=1.6 Hz), 7.46 (1 H, dt, J=2 Hz and 10 Hz), 7.34 (1 H, d, J=8 Hz), 7.26 (1 H, dd, J=8 Hz and 14.4 Hz), 7.08 (1 H, t, J=8.8 Hz), 2.82-2.72 (1 H, m), 2.65-2.50 (1 H, m), 2.45-2.35 (2 H, m), 2.12 (3 H, d, J=3.2 Hz), 2.15-2.05 (1 H, m), 1.85-1.75 (2 H, m), 1.55-1.40 (2 H, m); and (1s,4s)-1-(3-fluoro-2-methylphenyl)-4-(5-fluoropyridin-3-yl)-N-hydroxycyclohexanecarboxamide (D2) as a white solid (28 mg). LCMS (ES+) 347 (M+H).sup.+, RT 3.22 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.15 (1 H, s), 8.65 (1 H, s), 8.42 (1 H, d, J=2.8 Hz), 8.36 (1 H, t, J=2 Hz), 7.49 (1 H, dt, J=2.4 Hz and 10.4 Hz), 7.30-7.20 (2 H, m), 7.10-7.00 (1 H, m), 2.80-2.70 (1 h, m), 2.60-2.50 (2 H, m), 2.25 (3 H, d, J=3.2 Hz), 2.10-1.90 (2 H, m), 1.85-1.75 (2 H, m), 1.75-1.65 (2 H, m).

Example 101

(1r,4r)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-4-phenoxycyclohexanecarboxamide

(352) ##STR00097##

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

(353) Intermediate 8 (8 mg, 3.3 mmol) and MeOH (100 ml) were combined. NaBH.sub.4 (152 mg, 4 mmol) was added portionwise—care effervescence. Reaction mixture was stirred for 18 hours. Reaction mixture was evaporated to dryness and partitioned between EtOAc and 1N HCl. Organic layer was dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a clear gum (795 mg, 99%). LCMS (ES+) consistent with target (M-OH).sup.+.

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

(354) Methyl 1-(3-fluoro-2-methylphenyl)-4-hydroxycyclohexanecarboxylate (490 mg, 1.8 mmol), phenol (346 mg, 3.68 mmol), triphenyl phosphine (725 mg, 2.76 mmol) and THF (10 ml) were combined under a nitrogen atmosphere. Reaction mixture was ice bath cooled and DEAD (0.43 ml, 2.76 mmol) was added dropwise. Reaction mixture was stirred for 17 hours as it warmed to room temperature. Reaction mixture was diluted with EtOAc, washed with 10% NaOH soln. (2×), water (1×), dried (MgSO.sub.4), evaporated onto silica and purified by flash chromatography to give the title compound as a clear gum (244 mg). Used crude in next step.

Step 3: 1-(3-fluoro-2-methylphenyl)-4-phenoxycyclohexanecarboxylic acid

(355) Methyl 1-(3-fluoro-2-methylphenyl)-4-phenoxycyclohexanecarboxylate (240 mg), MeOH (10 ml) and 15% aq. NaOH soln. (2 ml) were combined in a sealed tube and hot block heated to 65° C. for 9 days. Reaction was cooled and evaporated to dryness. Residue was partitioned between 1N HCl and EtOAc. Organics were dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a clear gum (212 mg). LCMS (ES−) consistent with target (M−H).sup.−.

Step 4: (1r,4r)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-4-phenoxycyclohexanecarboxamide

(356) 1-(3-Fluoro-2-methylphenyl)-4-phenoxycyclohexanecarboxylic acid (212 mg, 0.65 mmol), TFFH (211 mg, 0.8 mmol), DMF (2 ml) and triethylamine (0.42 ml) were combined and stirred for 3 hours. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was then added and stirring continued for 4 days. Volatile solvents were removed in vacuo. MeOH (3 ml) and 2N HCl in diethyl ether (2 ml) were added and reaction mixture was stirred for 4 hours. Volatile solvents were removed in vacuo and remaining crude material was purified by Prep HPLC to give the title compound as a white solid (59 mg). LCMS (ES+) 344 (M+H).sup.+, RT 3.98 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.02 (1 H, s), 8.64 (1 H, s), 7.30-7.20 (4 H, m), 7.12-7.02 (1 H, m), 6.95-6.85 (3 H, m), 4.60-4.50 (1 H, m), 2.20 (3 H, d, J=2.4 Hz), 2.20-1.95 (6 H, m), 1.70-1.60 (2 H, m).

Example 102

(1s,4s)-1-(3-fluoro-2-methylphenyl)-4-((4-fluorobenzyl)oxy)-N-hydroxycyclohexanecarboxamide

(357) ##STR00098##

Step 1: (1 s,4s)-methyl 1-(3-fluoro-2-methylphenyl)-4-((4-fluorobenzyl)oxy)cyclohexanecarboxylate

(358) (1 s,4s)-Methyl 1-(3-fluoro-2-methylphenyl)-4-hydroxycyclohexanecarboxylate (793 mg, 2.98 mmol), DMF (15 ml) and 4-fluorobenzyl bromide (0.37 ml, 2.98 mmol) were combined under nitrogen at room temperature. NaH (60% disperse in oil) (120 mg, 3 mmol) was added and the reaction mixture was stirred for 19 hours. Reaction mixture was then diluted with EtOAc, washed with water (4×), dried (MgSO4), evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a white solid (149 mg).

Step 2: (1s,4s)-1-(3-fluoro-2-methylphenyl)-4-((4-fluorobenzyl)oxy)cyclohexanecarboxylic acid

(359) (1 s,4s)-Methyl 1-(3-fluoro-2-methylphenyl)-4-((4-fluorobenzyl)oxy)cyclohexanecarboxylate (149 mg, 0.4 mmol), MeOH (15 ml) and 15% Aq. NaOH soln. (2 ml) were combined in a sealed tube and hot block heated to 70° C. for 10 days. Reaction mixture was evaporated to dryness, diluted with EtOAc, washed with 1N HCl and evaporated to dryness once more to give a clear glass (133 mg) which was purified by prep HPLC to give the title compound as a white solid (53 mg). LCMS (ES−) consistent with target (M−H).sup.−.

Step 3: (1s,4s)-1-(3-fluoro-2-methylphenyl)-4-((4-fluorobenzyl)oxy)-N-hydroxycyclohexanecarboxamide

(360) (1s,4s)-1-(3-fluoro-2-methylphenyl)-4-((4-fluorobenzyl)oxy)cyclohexanecarboxylic acid (53 mg, 0.147 mmol), TFFH (53 mg, 0.2 mmol), DMF (1 ml) and Et.sub.3N (0.2 ml) were combined and stirred at room temperature for 1 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was then added and stirring continued for 1 day. Volatile solvents were removed in vacuo. MeOH (5 ml) and 2N HCl in diethyl ether (2 ml) were added and reaction mixture was stirred for 2 hours. Volatile solvents were removed in vacuo and remaining crude material was purified by Prep HPLC to give the title compound as an off white solid (18 mg, 33%). LCMS (ES+) 376 (M+H).sup.+, RT 3.97 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.08 (1 H, s), 8.62 (1 H, s), 7.40-7.35 (2 H, m), 7.25-7.10 (4 H, m), 7.10-7.00 (1 H, m), 4.48 (2 H, s), 2.45-2.35 (3 H, m), 2.20 (3 H, d, J=2.4 Hz), 1.9-1.55 (6 H, m).

Example 103

(1s,4s)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxamide

Example 104

(1r,4r)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxamide

(361) ##STR00099##

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

(362) To a solution of methyl 3′-fluoro-2′-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,6-tetrahydro-[1,1′-biphenyl]-1-carboxylate (6 mg, 1.51 mmol) in dry DME (8 mL) in a reaction tube was added 1-methyl-1H-indazol-6-yl boronic acid (27 mg, 1.51 mmol) and Cs.sub.2CO.sub.3 (1.48 g, 4.55 mmol). The resulting mixture was degassed with nitrogen bubbling for 5 min. Pd(dppf)Cl.sub.2.CHCl.sub.3 (49 mg, 0.61 mmol) was added, the tube sealed and the reaction heated at 85° C. for 24 h. The reaction was evaporated to dryness and partitioned between water (25 mL) and EtOAc (2×25 mL). The organic layers were combined and condensed. The crude product was purified using a Biotage 25 g SNAP column eluting with 0-20% EtOAc in hexane to give the title compound as a colourless oil (500 mg, 88%).

Step 2: (1 s,4s)-methyl 1-(3-fluoro-2-methylphenyl)-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxylate and (1 r,4r)-methyl 1-(3-fluoro-2-methylphenyl)-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxylate

(363) To ammonium formate (8 mg, 13.3 mmol) in a round bottom flask was added methyl 3′-fluoro-2′-methyl-4-(1-methyl-1H-indazol-6-yl)-1,2,3,6-tetrahydro-[1,1′-biphenyl]-1-carboxylate (5 mg, 1.33 mmol) as a solution in MeOH (20 mL). 20% Pd/C (˜100 mg) was added under a funnel of nitrogen. The reaction was refluxed overnight. The reaction was cooled, filtered through celite and condensed (420 mg, 84%). LCMS indicated a mixture of 2 diastereomers in an approximately 1:1 ratio. The material was used without further purification.

Step 3: (1r,4r)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxamide

(364) Following Method C (iii) from (1s,4s)-methyl 1-(3-fluoro-2-methylphenyl)-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxylate and (1 r,4r)-methyl 1-(3-fluoro-2-methylphenyl)-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxylate (420 mg, 1.1 mmol). After 3 d LCMS indicated that one diastereomer had hydrolysed and one remained unchanged. Additional LiOH.H.sub.2O (230 mg, 5.5 mmol) and solvents were added (2 mL THF, 2 mL MeOH, 2 mL water) and heating continued at 80° C. for 2 d. No further reaction was observed by LCMS. The reaction was cooled, condensed and the residue partitioned between water (30 mL) and ether (50 mL) and the water extracted again with EtOAc (50 mL). The combined organic layers were condensed to give unreacted (1 s,4s)-methyl 1-(3-fluoro-2-methylphenyl)-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxylate (220 mg). The aqueous layer was acidified to pH4 by dropwise addition of c.HCl, causing a white precipitate to form. The suspension was extracted with EtOAc (3×5 mL). The combined organic layers were filtered through a phase separation cartridge and condensed to give (1r,4r)-1-(3-fluoro-2-methylphenyl)-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxylic acid (200 mg). This was subjected to Method D and subsequent purification by preparative HPLC gave the title compound as an off white solid (61 mg). LCMS (ES+) 382 (M+H).sup.+, RT 3.55 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.89 (1H, s), 8.63 (1H, d, J=1.5 Hz), 7.93 (1H, s), 7.61 (1H, d, J=8.4 Hz), 7.38 (1H, d, J=7.9 Hz), 7.33-7.27 (2H, m), 7.09 (1H, dd, J=8.9, 8.9 Hz), 6.91 (1H, dd, J=1.1, 8.4 Hz), 3.98 (3H, s), 2.82-2.74 (1H, m), 2.44 (2H, d, J=13.7 Hz), 2.17 (1H, d, J=4.1 Hz), 2.16-2.08 (4H, m), 1.84 (2H, d, J=10.9 Hz), 1.57-1.52 (2H, m).

Step 4: (1s,4s)-1-(3-fluoro-2-methylphenyl)-N-hydroxy-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxamide

(365) Trimethylaluminium (2 M in heptanes, 1.80 mL, 3.6 mmol) was added cautiously to a stirred suspension of hydroxylamine hydrochloride (0.27 g, 3.95 mmol) in DCM (8 mL) at r.t. under nitrogen. After 1 h a solution of (1 s,4s)-methyl 1-(3-fluoro-2-methylphenyl)-4-(1-methyl-1H-indazol-6-yl)cyclohexanecarboxylate (220 mg, 0.58 mmol) in DCM (4 mL) was added dropwise. The reaction was stirred at r.t. for 30 min after which time LCMS indicated complete conversion to product. The reaction was quenched by the dropwise addition of saturated ammonium chloride solution (1 mL) and water (2.5 mL) and stirred for 30 min. The DCM was removed in vacuo and the resulting slurry diluted with MeOH. The solid was removed by filtration and rinsed with MeOH. The filtrate was concentrated and partitioned between H.sub.2O and EtOAc. The aqueous portion was washed with EtOAc (2×20 mL), and the combined organics dried (MgSO.sub.4), filtered and concentrated. Purification by preparative HPLC gave the title compound as a white solid (5 mg). LCMS (ES+) 382 (M+H).sup.+, RT 3.87 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.15 (1H, s), 8.67 (1H, s), 7.96 (1H, s), 7.68 (1H, d, J=8.4 Hz), 7.38 (1H, s), 7.33-7.24 (2H, m), 7.06 (2H, dd, J=8.8, 17.9 Hz), 4.02 (3H, s), 2.78-2.67 (1H, m), 2.60-2.50 (1H, m, obscured by DMSO), 2.34-2.29 (1H, m), 2.27 (3H, d, J=2.8 Hz), 2.13-2.06 (2H, m), 1.85-1.72 (4H, m).

Example 105

(±)-2-(3-fluoro-2-methylphenyl)-N-hydroxy-8-oxaspiro[4.5]decane-2-carboxamide

(366) ##STR00100##

Step 1: methyl 4-allyltetrahydro-2H-pyran-4-carboxylate

(367) A solution of LiHMDS (1 M in hexane, 25 mL, 25 mmol) in dry THF (25 mL) was cooled to −78° C. under N.sub.2. A solution of methyl tetrahydro-2H-pyran-4-carboxylate (3.0 g, 20.8 mmol) in dry THF (10 mL) was added dropwise, maintaining the temperature below −7° C. The mixture was stirred at −78° C. for 1 h then a solution of allyl bromide (2.0 mL, 22.9 mmol) in dry THF (2 mL) was added over 15 min. The reaction mixture was stirred at −78° C. for 1.5 h then allowed to warm to r.t. over 16 h. The mixture was then cooled to −78° C. and quenched by the addition of sat. aq. NH.sub.4Cl. After warming to r.t. the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1 M HCl, sat. aq. NaHCO.sub.3 and brine, dried (phase separation cartridge) and concentrated to give the title compound as a pale yellow oil (3.66 g).

Step 2: 2-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)ethanol

(368) A solution of methyl 4-allyltetrahydro-2H-pyran-4-carboxylate (4.0 g, 21.7 mmol) in methanol (1 mL) at −78° C. was sparged with ozone for approximately 3 min whereupon the reaction mixture turned blue. The mixture was purged with oxygen and nitrogen gases before warming to 0° C. and treating with NaBH.sub.4 (1.64 g, 43.4 mmol). Once gas evolution ceased the reaction was allowed to warm to r.t. and diluted with water. The mixture was extracted with DCM (3×); the combined extracts were dried (phase separation cartridge) and concentrated to yield a white solid, identified as 2,8-dioxaspiro[4.5]decan-1-one.

(369) This white solid (0.5 g, 3.2 mmol) was dissolved in MeOH (10 mL) and treated with NaBH.sub.4 (0.24 g). The reaction was heated to 40° C. for 2 h. TLC analysis indicated incomplete reaction, so further NaBH.sub.4 (0.24 g) was added and heating at 04° C. continued for a further 1 h. After cooling to r.t. the reaction was acidified to pH 2 with 1 M HCl and extracted with DCM (3×). The combined extracts were dried (phase separation cartridge) and concentrated to give the title compound (274 mg, 53%).

Step 3: (4-(2-((methylsulfonyl)oxy)ethyl)tetrahydro-2H-pyran-4-yl)methyl methanesulfonate

(370) A solution of 2-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)ethanol (274 mg, 1.71 mmol) and Et.sub.3N (0.525 mL, 3.76 mmol) in DCM (10 mL) at 0° C. was treated with methanesulfonyl chloride (0.291 mL, 3.76 mmol), added dropwise. The reaction was stirred at r.t. for 1 h. The mixture was washed with 1 M HCl, dried (phase separation cartridge) and concentrated. The residue was purified by silica column chromatography (gradient elution, 0-100% EtOAc in iso-hexane) to give the title compound as a colorless gum (150 mg).

Step 4: 4-(2-bromoethyl)-4-(bromomethyl)tetrahydro-2H-pyran

(371) A suspension of (4-(2-((methylsulfonyl)oxy)ethyl)tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (484 mg, 1.53 mmol) and LiBr (797 mg, 9.18 mmol) in dry DMF (2 mL) was heated to 105° C. for 1 h. Further LiBr (797 mg) was added and heating resumed for 1.5 h. After cooling to r.t. the mixture was diluted with water and extracted with Et.sub.2O (4×). The combined extracts were washed with brine, dried (phase separation cartridge) and concentrated. The residue was purified by silica column chromatography (gradient elution, 0-50% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.229 g).

Step 5: methyl 2-(3-fluoro-2-methylphenyl)-8-oxaspiro[4.5]decane-2-carboxylate

(372) A solution of 4-(2-bromoethyl)-4-(bromomethyl)tetrahydro-2H-pyran (303 mg, 1.06 mmol), methyl 2-(3-fluoro-2-methylphenyl)acetate (193 mg, 1.06 mmol) and NaH (60 wt % in oil, 106 mg, 2.65 mmol) in dry DMF (5 mL) was stirred at r.t. for 2 days. The reaction was quenched with water and extracted with EtOAc (3×). The combined extracts were dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by silica column chromatography (gradient elution, 0-50% EtOAc in iso-hexane) to give the title compound as a colorless oil (0.147 mg).

Steps 6-7: 2-(3-Fluoro-2-methylphenyl)-N-hydroxy-8-oxaspiro[4.5]decane-2-carboxamide

(373) Following Methods C and D from methyl 2-(3-fluoro-2-methylphenyl)-8-oxaspiro[4.5]decane-2-carboxylate (139 mg, 0.48 mmol). The title compound was obtained as a white solid (67 mg). LCMS (ES+) 38 (M+H).sup.+, RT 9.33 min (Analytical method 3); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 9.90 (1H, s), 8.63 (1H, s), 7.27-7.20 (2H, m), 7.09-7.02 (1H, m), 3.59 (2H, t, J=5.4 Hz), 3.50 (2H, tt, J=17.1, 5.7 Hz), 2.88 (1H, d, J=13.4 Hz), 2.42-2.35 (1H, m), 2.3-2.23 (1H, m), 2.15 (3H, d, J=2.8 Hz), 1.68-1.5 (5H, m), 1.32 (2H, t, J=5.1 Hz).

Example 106

N-hydroxy-1-phenylcycloheptanecarboxamide

(374) ##STR00101##

Step 1: methyl 1-phenylcycloheptanecarboxylate

(375) n-BuLi (1.6 M in hexane, 2.5 mL, 4.03 mmol) was added to a solution of dicyclohexyl amine (0.73 g, 0.80 mL, 4.03 mmol) in toluene (4 mL) under nitrogen at r.t. and the solution was stirred for 10 min. To this solution at r.t. was added a solution of methyl cycloheptanecarboxylate (0.60 g, 3.85 mmol) in toluene (2 mL) and the combined solution was stirred at r.t. for 5 min. In a second reaction flask Pd(OAc).sub.2 (11 mg, 0.048 mmol), P(tBu)3.HBF4 (28 mg, 0.096 mmol), bromobenzene (0.30 g, 0.20 mL, 1.92 mmol) and toluene (4 mL) were combined and brought rapidly to 100° C. The first reaction solution was added to the catalyst mixture via syringe. The cloudy brown reaction was stirred at 95° C. for 1 h and then allowed to stir at r.t. overnight. The reaction was partitioned between water and DCM (2×). The organic layers were combined, dried over MgSO.sub.4 and condensed to give an oil which was purified by gradient column chromatography, eluting with 2-10% EtOAc in i-hex, to give the title compound as a colourless oil (0.60 g) which contained approximately 40 mol % ester starting material.

Step 2: 1-phenylcycloheptanecarboxylic acid

(376) To a solution of methyl 1-phenylcycloheptanecarboxylate (contains some methyl cycloheptanecarboxylate, 0.59 g, 2.54 mmol) in EtOH (4 mL) was added a solution of KOH (1.1 g) in water (1.1 mL) and the resulting mixture refluxed for 3 h. The reaction was cooled, condensed, diluted with water and extracted with ether. The organic layer was dried over MgSO.sub.4 and condensed to give the title compound as a colourless gum (0.42 g) containing approximately 40 mol % cycloheptane carboxylic acid; .sup.1H NMR δ (ppm)(CDCl.sub.3) 10.50 (1 H, br s), 7.39-7.27 (3 H, m), 7.26-7.16 (2 H, m), 2.49-2.35 (2 H, m), 2.12-2.02 (2 H, m), 1.80-1.45 (8H, m).

Step 3: N-hydroxy-1-phenylcycloheptanecarboxamide

(377) Following Method D(ii) from 1-phenylcycloheptanecarboxylic acid (0.42 g, 1.93 mmol) followed by gradient column chromatography, eluting with 0-100% EtOAc in iso-hexane, gave the title compound as a white solid (0.23 g, 53%). LCMS (ES+) 234 (M+H).sup.+; RT 3.49 min (Analytical method 1); .sup.1H NMR δ (ppm)(CDCl.sub.3) 7.61 (1 H, s), 7.40-7.31 (4 H, m), 7.30-7.26 (2 H, m), 2.41-2.34 (2 H, m), 2.25-2.13 (2 H, m), 1.83-1.75 (2 H, m), 1.67-1.33 (6 H, m).

Example 107

1-(3-Fluoro-2-methylphenyl)-N-hydroxycycloheptanecarboxamide

(378) ##STR00102##

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

(379) To a solution of methyl 1-(3-fluoro-2-methylphenyl)-4-oxocyclohexanecarboxylate (500 mg, 1.9 mmol) in DCM (20 mL) at 0° C. was added boron trifluoride diethyletherate (330 mg, 2.3 mmol) followed by drop wise addition of ethyldiazoacetate (260 mg, 2.3 mmol). The reaction mixture was stirred at 0° C. for 3 h. Reaction mixture quenched with saturated NaHCO.sub.3 solution layers separated organics collected solvent removed. The crude product was purified by flash column chromatography to give the title compound as a clear oil (350 mg, 54%). .sup.1H NMR δ (ppm)(CDCl3): 12.75 (1 H, s), 7.22-7.09 (2 H, m), 6.96 (1H, t, J=7.8 Hz), 4.26-4.10 (2 H, m), 3.69 (3 H, s), 2.77-2.68 (1 H, m), 2.65-2.55 (2 H, m), 2.54-2.40 (1 H, m), 2.35-2.23 (2 H, m), 2.22-2.18 (2 H, m), 2.14 (3 H, d, J=2.6 Hz), 1.35 (3 H, t, J=12.6 Hz).

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

(380) To a solution of 4-ethyl-1-methyl 1-(3-fluoro-2-methylphenyl)-5-oxocycloheptane-1,4-dicarboxylate (345 mg, 0.98 mmol) in methanol (10 mL) was added 15% aq. NaOH solution (3 mL). The reaction mixture was heated to 80° C. for 24 h. Reaction mixture was cooled to r.t. acidified with HCl (5 M sol) and extracted with DCM (3×40 mL). The solvent was removed in vacuo. The crude product was purified by flash column chromatography to give the title compound as a clear oil (250 mg, 94%).

Step 3: Methyl 4-(((1,1-difluoroethyl)sulfonyl)oxy)-1-(3-fluoro-2-methylphenyl)cyclohept-4-enecarboxylate

(381) Methyl 1-(3-fluoro-2-methylphenyl)-4-oxocycloheptanecarboxylate (250 mg, 0.95 mmol) and THF (30 mL) were combined under a nitrogen atmosphere and cooled with an ice bath. NaHMDS (1 M in THF) (1.2 mL, 1.2 mmol) was added dropwise followed after 20 min by N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (500 mg, 1.27 mmol). Reaction mixture was allowed to warm to room temperature and stirred for 3 h, then diluted with DCM, washed with water, evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a clear oil (280 mg, 69%). .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.17-7.12 (1 H, m), 7.02-6.90 (2 H, m), 5.92 (1H, d, J=6.4 Hz), 3.69 (3 H, s), 2.49-2.15 (12 H, m).

Step 4: Methyl-1-(3-fluoro-2-methylphenyl)cycloheptanecarboxylic acid

(382) To a solution of methyl 4-(((1,1-difluoroethyl)sulfonyl)oxy)-1-(3-fluoro-2-methylphenyl)cyclohept-4-enecarboxylate (280 mg, 0.66 mmol) in ethanol (2 mL) was added ammonium formate (125 mg, 2.0 mmol), and palladium on charcoal (10%, 10 mg). The reaction mixture was heated to 65° C. for 2 h. Reaction mixture was cooled to r.t. and filtered through celite, washing with EtOH (3×10 mL). The solvent was removed in vacuo and the resulting solid was partitioned between water and DCM (3×20 mL). The combined organics were dried (MgSO.sub.4), filtered (phase separation cartridge) and the solvent removed to yield the title compound as a pale yellow oil (0.150 g, 86.2%). .sup.1H NMR δ (ppm)(CDCl.sub.3): 7.12-7.02 (1 H, m), 7.00-6.99 (1 H, m), 6.90-6.81 (1 H, m), 3.69 (3 H, s), 2.47-2.35 (1 H, m), 2.34 (3 H, d, J=2.6 Hz), 2.28-2.20 (1 H, m), 2.12-1.90 (6 H, m), 1.84-1.67 (4 H, m).

Step 5: 1-(3-Fluoro-2-methylphenyl)cycloheptanecarboxylic acid

(383) Following Method C from methyl-1-(3-fluoro-2-methylphenyl)cycloheptanecarboxylic acid (150 mg, 0.56 mmol) to give the title compound as a white solid (115 mg, 81%) used crude in next step. LCMS (ES+) consistent with target (M+H).sup.+.

Step 5: 1-(3-Fluoro-2-methylphenyl)-N-hydroxycycloheptanecarboxamide

(384) To a solution of 1-(3-fluoro-2-methylphenyl)cycloheptanecarboxylic acid (115 mg, 0.46 mmol) in DCM (20 mL) was added oxalyl chloride (0.127 g, 1.0 mmol), and DMF (1 drop). Reaction mixture was stirred for 1 h solvent was removed in vacuo and the resulting solid was dissolved in THF (5 mL) and added drop wise to a vigorously stirred solution of hydroxylamine (50% in water). Stirred for 1 h partitioned between water and DCM (3×20 mL). The combined organics were dried (MgSO.sub.4), filtered (phase separation cartridge) and concentrated. Purification by preparative HPLC gave the title compound as a yellow oil (8 mg, 66%). LCMS (ES+) 266 (M+H).sup.+, RT 3.73 min (Analytical method 1); .sup.1H NMR δ (ppm)(DMSO-d.sub.6): 10.21 (1H, s), 8.56 (1H, s), 7.18-7.11 (1H, m), 7.4-6.97 (2H, m), 2.29 (3H, d, J=3.0 Hz), 2.06-2.02 (2H, m), 1.89-1.80 (4H, m), 1.70-1.51 (6H, m).

Example 108

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

(385) 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.

(386) Serially dilute HDAC inhibitor compounds. 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 6 μl aliquots of the 10 mM compound in DMSO are prepared and stored at −2° 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 μl 16-channel Matrix multi-channel pipette (Matrix Technologies Ltd).

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

(388) 2 μl (200×) of each diluted solution and each control (full activity: 100% DMSO alone or full inhibition 1 mM) is stamped into V-bottomed polypropylene 384-well compound plates using either the Bravo (384-well head from Agilent) or 12.5 μl 16-channel Matrix multi-channel pipette (Matrix Technologies Ltd). Each well with the 200× compound solution is diluted 1:20 by the addition of 38 μl assay buffer+DMSO (10.5% DMSO, 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl, and 0.9 mM MgCl.sub.2 at pH 8.0 and equilibrated to r.t.).

(389) Prepare HDAC4 catalytic domain enzyme (0.2 μg/mL). 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 μg/mL stock aliquot of HDAC4 catalytic domain (thawed on ice) diluted to 0.2 μg/mL with assay buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl, and 1 mM MgCl.sub.2 at pH 8 and equilibrated to r.t.) just prior to the addition of the enzyme to the assay.

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

(391) Prepare 3× (30 μM) Developer/Stop Solution. 3× (30 μM) Developer/Stop Solution is prepared just prior to addition to the plate by diluting a stock solution of 1 mM reference compound 1:333 in 25 mg/mL trypsin (PAA Laboratories Ltd.) equilibrated to r.t.

(392) Assay. 5 μl of each solution of 1:20 diluted compound from above is transferred to a clear bottomed, black, 384-well assay plate using the Bravo or the Janus (384-well MDT head from Perkin Elmer). Using a 16-channel Matrix multi-channel pipette, 35 μl of the working solution of HDAC4 catalytic domain enzyme (0.2 μg/mL in assay buffer) is transferred to the assay plate. The assay is then started by adding 10 μl of 5× (50 μM) substrate to the assay plates using either the Bravo, Janus or 16-channel Matrix multi-channel pipette. The assay plate is then shaken for two minutes on an orbital shaker at 900 rpm (rotations per minute). Next the plate is incubated for 15 minutes at 37° C. The reaction is stopped by adding 25 μl of 3× (3 μM) developer/stop solution to the assay plates using either the Bravo, Janus or a 16-channel Matrix multi-channel pipette. Assay plates are then shaken for 5 minutes on an orbital shaker at 1200 rpm. Next, the assay plates are incubated at 37° C. for 1 hour in a tissue culture incubator. Finally, the fluorescence is measured (Excitation: 355 nm, Emission: 460 nm) using PerkinElmer EnVision in top read mode.

Example 109

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

(393) 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.

(394) Serially dilute HDAC inhibitor compounds. 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 6 μl aliquots of the 10 mM compound in DMSO are prepared and stored at −2° 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 μl 16-channel Matrix multi-channel pipette.

(395) 2 μl (200×) of each diluted solution and each control (full activity: 100% DMSO alone or full inhibition 1 mM) is stamped into V-bottom polypropylene 384-well compound plates using either Bravo, Janus, or a 12.5 μl 16-channel Matrix multi-channel pipette. Each well with the 2 μl of the 200×stamped compound solution is diluted 1:2 by the addition of 38 μl assay buffer+DMSO (10.5% DMSO, 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl, and 0.9 mM MgCl.sub.2 at pH 8.0 and equilibrated to 37° C.).

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

(397) Prepare 5× (40 μM) Boc-Lys(Tfa)-AMC Substrate. 5× (4 μM) substrate is prepared just prior to the addition to the assay. The 5× substrate is prepared by diluting the 100 mM Boc-Lys(Tfa)-AMC in DMSO solution 1:2500 by adding it drop-wise to assay buffer (equilibrated to 37° C.) while vortexing at slow speed to prevent precipitation.

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

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

Example 110

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

(400) 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.

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

(402) 2 μl (200×) of each diluted solution and each control (full activity: 100% DMSO alone or full inhibition 1 mM) is stamped into V-bottom polypropylene 384-well compound plates using either the Bravo, Janus, or a 12.5 μl 16-channel Matrix multi-channel pipette. Each well with the 2× compound solution is diluted 1:20 by the addition of 38 μl assay buffer+DMSO (10.5% DMSO, 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl, and 0.9 mM MgCl.sub.2 at pH 8.0 and equilibrated to 37° C.).

(403) Prepare HDAC7 enzyme (71 ng/mL). 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.

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

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

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

Example 111

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

(407) 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.

(408) Serially dilute HDAC inhibitor compounds. 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 1% DMSO. Stocks of 60 μl aliquots of the 10 mM compound in DMSO are prepared and stored at −20° C. From one stock aliquot of each compound to be tested and the reference compound, a 16-point serial dilution is prepared according to Table 1 using a 125 μl 16-channel Matrix multi-channel pipette.

(409) 2 μl (200×) of each diluted solution and each control (full activity: 100% DMSO alone or full inhibition 1 mM) is stamped into V-bottom polypropylene 384-well compound plates using either the Bravo, Janus, or 12.5 μl 16-channel Matrix multi-channel pipette. Each well with the stamped 200×compound solution is diluted 1:20 by the addition of 38 μl assay buffer+DMSO (10.5% DMSO, 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl, and 0.9 mM MgCl.sub.2 at pH 8.0 and equilibrated to 37° C.).

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

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

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

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

Example 112

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

(414) 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.

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

(416) Serially dilute HDAC inhibitor compounds. 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 1% DMSO. Stocks of 70 μl aliquots of the 10 mM compound in DMSO are prepared and stored at −20° C. From one stock aliquot of each compound to be tested and the reference compound, a 16-point serial dilution is prepared according to Table 1 using a 125 μl 16-channel Matrix multi-channel pipette.

(417) 2 μl (200×) of each diluted solution and each control (full activity: 100% DMSO alone or full inhibition 1 mM) is stamped into V-bottom polypropylene 384-well compound plates using either the Bravo, Janus, or 12.5 μl 16-channel Matrix multi-channel pipette. Each well with the 200× compound solution is diluted 1:20 by the addition of 38 μl Jurkat assay buffer+DMSO (9.5% DMSO, RPMI without phenol red, 0.09% FBS, 9 mM Hepes, and 0.9 mM Sodium Pyruvate equilibrated to r.t.)

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

(419) Prepare 3× Lysis Buffer. 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 r.t.) and 1.2 mL of 3 mg/mL Trypsin equilibrated to r.t.

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

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

(422) TABLE-US-00004 Biochemical Example HDAC4 Cell # Structure Name IC.sub.50 μM IC.sub.50 μM 1 03 1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(pyridin-3- yl)cyclopentanecarboxamide 0.19 1.23 2 04   D1, rac (±)-(1S*,3R*)-1-(3-Fluoro- 2-methylphenyl)-N- hydroxy-3-(pyrimidin-5- yl)cyclopentanecarboxamide 0.29 1.91 3 05   D2, rac (±)-(1S*,3S*)-1-(3-Fluoro- 2-methylphenyl)-N- hydroxy-3-(pyrimidin-5- yl)cyclopentanecarboxamide 0.39 1.60 4 06   D1 (1R*,3S*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3- phenylcyclopentanecarboxamide 0.04 0.44 5 07   D2 (1S*,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3- phenylcyclopentanecarboxamide 1.1 7.85 6 08   D3 (1S*,3S*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3- phenylcyclopentanecarboxamide 0.10 0.61 7 09   D4 (1R*,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3- phenylcyclopentanecarboxamide 0.05 1.12 8 0 (±)-(1S*,3S*)-1-(3-Fluoro- 2-methylphenyl)-N- hydroxy-3-(o- tolyl)cyclopentanecarboxamide 0.17 0.48 9   D1 (1S,3S*)-1-(3-Fluoro-2- methyl-phenyl)-3-(5- fluoropyridin-3-yl)-N- hydroxycyclopentanecarboxamide 0.15 1.28 10   D2 (1S,3R*)-1-(3-Fluoro-2- methyl-phenyl)-3-(5- fluoropyridin-3-yl)-N- hydroxycyclopentanecarboxamide 0.14 1.39 11   D1 (1S,3S*)-1-(3-Fluoro-2- methylphenyl)-3-(5- fluoropyridin-2-yl)-N- hydroxycyclopentanecarboxamide 0.20 1.83 12   D2 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-3-(5- fluoropyridin-2-yl)-N- hydroxycyclopentanecarboxamide 0.24 2.37 13   D1 (1r,4r)-4-(5-Fluoropyridin- 3-yl)-N-hydroxy-1- phenylcyclohexanecarboxamide 6.4 48.8 14   D2 (1s,4s)-4-(5- Fluoropyridin-3-yl)-N- hydroxy-1- phenylcyclohexanecarboxamide >50 >50 15 1-(2,3-Difluorophenyl)-N- hydroxycyclopentanecarboxamide 2.5 18.5 16 1-(2,3- Dihydrobenzofuran-7-yl)- N- hydroxycyclopentanecarboxamide >50 >50 17 1-(3-Chloro-2- methylphenyl)-N- hydroxycyclopentanecarboxamide 0.28 2.53 18 0 1-(3-Fluoro-2- methylphenyl)-N- hydroxycyclopentanecarboxamide 0.27 1.70 19 1-(2-Fluorophenyl)-N- hydroxycyclopentanecarboxamide 4.6 44.7 20 1-(4-Chlorophenyl)-N- hydroxycyclopentanecarboxamide 24.0 >50 21 N-Hydroxy-1- phenylcyclopentanecarboxamide 11.4 >50 22 1-(2-Chloro-6- fluorophenyl)-N- hydroxycyclopentanecarboxamide 2.5 15.6 23 N-Hydroxy-1-(2- methoxyphenyl) cyclopentanecarboxamide >50 >50 24 N-Hydroxy-1-o- tolylcyclopentanecarboxamide 0.73 8.12 25 N-Hydroxy-1-m- tolylcyclopentanecarboxamide 8.2 43.7 26 1-(2-Chlorophenyl)-N- hydroxycyclopentanecarboxamide 1.90 15.1 27 1-(2-Cyanophenyl)-N- hydroxycyclopentanecarboxamide >50 >50 28 0 1-(3-Cyanophenyl)-N- hydroxycyclopentanecarboxamide >50 >50 29 1-(3,4-Difluoro-2- methylphenyl)-N- hydroxycyclopentanecarboxamide 0.15 1.41 30 1-(3,5-Difluoro-2- methylphenyl)-N- hydroxycyclopentanecarboxamide 0.33 2.63 31 1-(2-Chloro-6- methylphenyl)-N- hydroxycyclopentanecarboxamide 0.91 8.1 32 1-(2-Ethylphenyl)-N- hydroxycyclopentanecarboxamide 1.1 6.5 33 N-Hydroxy-1-(3-methoxy- 2- (trifluoromethyl)phenyl) cyclopentanecarboxamide >50 >50 34 N-Hydroxy-1-(2- (trifluoromethyl)phenyl) cyclopentanecarboxamide 11 46 35 1-(4-Fluoro-2- methylphenyl)-N- hydroxycyclopentanecarboxamide 0.57 5.6 36 1-(5-Fluoro-2- methylphenyl)-N- hydroxycyclopentanecarboxamide 0.83 7.5 37 1-(2-Fluoro-6- methylphenyl)-N- hydroxycyclopentanecarboxamide 1.5 12 38 0 1-(Benzo[b]thiophen-7- yl)-N- hydroxycyclopentanecarboxamide 0.61 4.6 39   D1 (1R,3S*)-1-(3-Fluoro-2- methylphenyl)-3-(5- fluoropyridin-3-yl)-N- hydroxycyclopentanecarboxamide 0.72 8.4 40   D2 (1R,3R*)-1-(3-Fluoro-2- methylphenyl)-3-(5- fluoropyridin-3-yl)-N- hydroxycyclopentanecarboxamide 3.6 8.4 41   D1 (1S,3R)-3-(5- Fluoropyridin-3-yl)-N- hydroxy-1- phenylcyclopentanecarboxamide 1.9 13 42   D2 (1S,3S)-3-(5- Fluoropyridin-3-yl)-N- hydroxy-1- phenylcyclopentanecarboxamide 1.4 7.2 43 (1S,3R)-3-(2-Cyclopropyl- 5-fluoropyridin-3-yl)-1-(3- fluoro-2-methylphenyl)-N- hydroxycyclopentanecarboxamide 0.24 0.61 44   D1 (1S,3S*)-1-(3-Fluoro-2- methylphenyl)-3-(5-fluoro- 6-methoxypyridin-3-yl)-N- hydroxycyclopentanecarboxamide 0.33 1.7 45 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-3-(5-fluoro- 6-methoxypyridin-3-yl)-N- hydroxycyclopentanecarboxamide 0.19 0.42 46 (1S,3R*)-3-(1- (Difluoromethyl)-1H- pyrazol-4-yl)-1-(3-fluoro- 2-methylphenyl)-N- hydroxycyclopentanecarboxamide 0.095 0.54 47 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(1-(2-morpholinoethyl)- 1H-pyrazol-4- yl)cyclopentanecarboxamide 0.14 0.83 48 0 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-3-(5-fluoro- 6-(2-(pyrrolidin-1- yl)ethoxy)pyridin-3-yl)-N- hydroxycyclopentanecarboxamide 0.32 0.75 49   D1 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(1-methyl-1H-pyrazol-5- yl)cyclopentanecarboxamide 0.17 0.40 50   D2 (1S,3S*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(1-methyl-1H-pyrazol-5- yl)cyclopentanecarboxamide 0.25 1.8 51 (1S,3R*)-3-(1-(2- (Diethylamino)ethyl)-1H- pyrazol-4-yl)-1-(3-fluoro- 2-methylphenyl)-N- hydroxycyclopentanecarboxamide 0.082 0.29 52   D1 N-((R)-1- (Dipropylamino)propan-2- yl)-4-((1R*,3S)-3-(3- fluoro-2-methylphenyl)-3- (hydroxycarbamoyl) cyclopentyl)benzamide 0.20 0.18 53   D2 N-((R)-1- (Dipropylamino)propan-2- yl)-4-((1S*,3S)-3-(3- fluoro-2-methylphenyl)-3- (hydroxycarbamoyl) cyclopentyl)benzamide 0.16 0.15 54   D1 (1S,3R*)-3-(1- (Difluoromethyl)-1H- indazol-6-yl)-1-(3-fluoro- 2-methylphenyl)-N- hydroxycyclopentanecarboxamide 0.072 0.11 55   D2 (1S,3S*)-3-(1- (Difluoromethyl)-1H- indazol-6-yl)-1-(3-fluoro- 2-methylphenyl)-N- hydroxycyclopentanecarboxamide 0.046 0.16 56 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(1-methyl-1H-indazol-6- yl)cyclopentanecarboxamide 0.14 0.23 57   D1 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(imidazo[1,2-a]pyridin- 7- yl)cyclopentanecarboxamide 0.098 0.18 58 0   D2 (1S,3S*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(imidazo[1,2-a]pyridin- 7- yl)cyclopentanecarboxamide 0.082 0.30 59 (1S,3R*)-3-(2- Cyclopropyl-1- oxoisoindolin-5-yl)-1-(3- fluoro-2-methylphenyl)-N- hydroxycyclopentanecarboxamide 0.14 0.19 60 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(1-methyl-1H-indazol-7- yl)cyclopentanecarboxamide 0.36 0.81 61 (1S,3R*)-3-(7-Fluoro-1H- indazol-6-yl)-1-(3-fluoro- 2-methylphenyl)-N- hydroxycyclopentanecarboxamide 0.073 0.081 62 (1S,3R*)-3-(2- Cyclopropylbenzo[d]oxazol- 5-yl)-1-(3-fluoro-2- methylphenyl)-N- hydroxycyclopentanecarboxamide 0.28 0.41 63   D1 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(1-methyl-1H-indazol-5- yl)cyclopentanecarboxamide 0.11 0.14 64   D2 (1S,3S*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(1-methyl-1H-indazol-5- yl)cyclopentanecarboxamide 0.10 0.22 65   D1 (1S,3R*)-3-(2- (Difluoromethyl)-2H- indazol-6-yl)-1-(3-fluoro- 2-methylphenyl)-N- hydroxycyclopentanecarboxamide 0.11 0.099 66   D2 (1S,3S*)-3-(2- (Difluoromethyl)-2H- indazol-6-yl)-1-(3-fluoro- 2-methylphenyl)-N- hydroxycyclopentanecarboxamide 0.22 0.19 67   D1 (1S,3R*)-3-(3-Fluoro-1- methyl-1H-indazol-6-yl)-1- (3-fluoro-2-methylphenyl)- N- hydroxycyclopentanecarboxamide 0.40 0.36 68 0   D2 (1S,3S*)-3-(3-Fluoro-1- methyl-1H-indazol-6-yl)-1- (3-fluoro-2-methylphenyl)- N- hydroxycyclopentanecarboxamide 0.32 0.21 69 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(1-methyl-1H- benzo[d]imidazol-5- yl)cyclopentanecarboxamide 0.090 0.20 70   D1 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(1-methyl-1H- benzo[d]imidazol-6- yl)cyclopentanecarboxamide 0.11 0.13 71   D2 (1S,3S*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(1-methyl-1H- benzo[d]imidazol-6- yl)cyclopentanecarboxamide 0.059 0.11 72   D1 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(1-methyl-1H- benzo[d]imidazol-6- yl)cyclopentanecarboxamide 0.30 0.47 73   D2 (1S,3S*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(1-methyl-1H- benzo[d]imidazol-6- yl)cyclopentanecarboxamide 0.27 0.41 74 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(2-(trifluoromethyl)-1H- benzo[d]imidazol-6- yl)cyclopentanecarboxamide 0.074 0.11 75   D1 (1S,3S*)-3- (Benzo[d]thiazol-2-yl)-1- (3-fluoro-2-methylphenyl)- N- hydroxycyclopentanecarboxamide 0.080 0.16 76   D2 (1S,3R*)-3- (Benzo-[d]thiazol-2-yl)-1- (3-fluoro-2-methylphenyl)- N- hydroxycyclopentanecarboxamide 0.16 0.24 77   D1 (1S,3S*)-3-(2- Cyclopropylbenzo[d]thiazol- 6-yl)-1-(3-fluoro-2- methylphenyl)-N- hydroxycyclopentanecarboxamide 0.31 0.42 78 0   D2 (1S,3R*)-3-(2- Cyclopropylbenzo[d]thiazol- 6-yl)-1-(3-fluoro-2- methylphenyl)-N- hydroxycyclopentanecarboxamide 0.34 0.42 79   D1 (1S,3S*)-3-(2- Cyclopropylbenzo[d]thiazol- 5-yl)-1-(3-fluoro-2- methylphenyl)-N- hydroxycyclopentanecarboxamide 0.29 0.38 80   D2 (1S,3R*)-3-(2- Cyclopropylbenzo[d]thiazol- 5-yl)-1-(3-fluoro-2- methylphenyl)-N- hydroxycyclopentanecarboxamide 0.33 0.38 81 (1S,3R)-3-(5-Fluoro-1- methyl-1H-indazol-6-yl)-1- (3-fluoro-2-methylphenyl)- N- hydroxycyclopentanecarboxamide 0.15 0.58 82   D1 (1S,3S*)-3-(7-Fluoro-1- methyl-1H-indazol-6-yl)-1- (3-fluoro-2-methylphenyl)- N- hydroxycyclopentanecarboxamide 0.11 0.25 83   D2 (1S,3R*)-3-(7-Fluoro-1- methyl-1H-indazol-6-yl)-1- (3-fluoro-2-methylphenyl)- N- hydroxycyclopentanecarboxamide 0.055 0.059 84   D1 (1S,3S*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(quinolin-6- yl)cyclopentanecarboxamide 0.048 0.18 85   D2 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(quinolin-6- yl)cyclopentanecarboxamide 0.062 0.12 86 (1S,3R*)-1-(3,4-Difluoro- 2-methylphenyl)-N- hydroxy-3-(1-methyl-1H- indazol-6- yl)cyclopentanecarboxamide 0.090 0.16 87   D1 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(pyrrolidin-1- yl)cyclopentanecarboxamide 20 >50 88 0   D2 (1S,3S*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-(pyrrolidin-1- yl)cyclopentanecarboxamide >50 >50 89   D1 (1S,3R*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3- morpholinocyclopentanecarboxamide 1.1 7.3 90   D2 (1S,3S*)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3- morpholinocyclopentanecarboxamide 2.5 24 91 (1S,3R)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-((1-methyl-1H-indazol- 6- yl)oxy)cyclopentanecarboxamide 0.29 1.6 92 (1S,3S)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3-((1-methyl-1H-indazol- 6- yl)oxy)cyclopentanecarboxamide 0.14 0.47 93 (1S,3R)-1-(3-Fluoro-2- methylphenyl)-3-((5- fluoropyridin-3-yl)oxy)-N- hydroxycyclopentanecarboxamide 0.2 1.9 94 (1S,3S)-1-(3-Fluoro-2- methylphenyl)-3-((5- fluoropyridin-3-yl)oxy)-N- hydroxycyclopentanecarboxamide 0.16 0.83 95 (1S,3R)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3- phenoxycyclopentanecarboxamide 0.16 1.5 96 (1S,3S)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 3- phenoxycyclopentanecarboxamide 0.13 0.26 97 (1S,3S)-1-(3-Fluoro-2- methylphenyl)-3-((4- fluorobenzyl)oxy)-N- hydroxycyclopentanecarboxamide 0.24 0.66 98 00 1-Phenyl-N- hydroxycyclohexylcarboxamide >50 >50 99 01   D1 (1r,4r)-1-(3-Fluoro-2- methylphenyl)-4-(5- fluoropyridin-3-yl)-N- hydroxycyclohexanecarboxamide 4.1 38 100 02   D2 (1s,4s)-1-(3-Fluoro-2- methylphenyl)-4-(5- fluoropyridin-3-yl)-N- hydroxycyclohexanecarboxamide 0.66 0.37 101 03 (1r,4r)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 4- phenoxycyclohexanecarboxamide 0.68 0.54 102 04 (1s,4s)-1-(3-Fluoro-2- methylphenyl)-4-((4- fluorobenzyl)oxy)-N- hydroxycyclohexanecarboxamide 14 49 103 05 (1s,4s)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 4-(1-methyl-1H-indazol-6- yl)cyclohexanecarboxamide 4.2 26 104 06 (1r,4r)-1-(3-Fluoro-2- methylphenyl)-N-hydroxy- 4-(1-methyl-1H-indazol-6- yl)cyclohexanecarboxamide 0.95 0.65 105 07 (±)-2-(3-Fluoro-2- methylphenyl)-N-hydroxy- 8-oxaspiro[4.5]decane-2- carboxamide 1.4 12 106 08 N-Hydroxy-1- phenylcycloheptanecarboxamide 6.9 41.1 107 09 1-(3-Fluoro-2- methylphenyl)-N- hydroxycycloheptanecarboxamide >50 >50

(423) 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.