Antibacterial agents

Abstract

Antibacterial compounds of formula (I) are provided: ##STR00001##
as well as stereoisomers and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of such compounds.

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula I: ##STR00306## or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of: (a) substituted C.sub.1-C.sub.6 alkyl, wherein at least one substituent is hydroxy; and (b) substituted C.sub.3-C.sub.6 cycloalkyl, wherein at least one substituent is selected from hydroxy and hydroxyalkyl; G is selected from the group consisting of: ##STR00307## and (g) phenyl; and D is selected from the group consisting of: ##STR00308## wherein R.sup.1 and R.sup.2 are each independently selected from hydrogen and methyl; and E is C(CH.sub.3).sub.2SCH.sub.3, C(CH.sub.3).sub.2S(O)CH.sub.3, C(CH.sub.3).sub.2S(O).sub.2CH.sub.3, or C(O)NHCH.sub.3.

2. The pharmaceutical composition according to claim 1, wherein A is substituted C.sub.1-C.sub.6 alkyl, wherein at least one substituent is hydroxy.

3. The pharmaceutical composition according to claim 2, wherein A is substituted C.sub.1-C.sub.6 alkyl, wherein at least two substituents are hydroxy.

4. The pharmaceutical composition according to claim 2, wherein A is hydroxymethyl, hydroxyethyl, hydroxypropyl or dihydroxpropyl.

5. The pharmaceutical composition according to claim 1, wherein A is substituted C.sub.3-C.sub.6 cycloalkyl, wherein at least one substituent is selected from hydroxy and hydroxyalkyl.

6. The pharmaceutical composition according to claim 5, wherein A is substituted C.sub.3-C.sub.6 cycloalkyl, wherein at least one substituent is hydroxymethyl.

7. The pharmaceutical composition according to claim 6, wherein A is hydroxymethylcyclopropyl.

8. The pharmaceutical composition according to claim 5, wherein A is substituted C.sub.3-C.sub.6 cycloalkyl, wherein at least one substituent is hydroxy.

9. The pharmaceutical composition according to claim 1, wherein G is CCCC.

10. The pharmaceutical composition according to claim 1, wherein D is ##STR00309##

11. The pharmaceutical composition according to claim 1, wherein D is ##STR00310##

12. The pharmaceutical composition according to claim 1, wherein D is ##STR00311##

13. The pharmaceutical composition according to claim 12, wherein R.sup.1 is hydrogen.

14. The pharmaceutical composition according to claim 13, wherein R.sup.2 is hydrogen.

15. The pharmaceutical composition according to claim 14, wherein E is C(CH.sub.3).sub.2SCH.sub.3.

16. The pharmaceutical composition according to claim 14, wherein E is C(CH.sub.3).sub.2S(O).sub.2CH.sub.3.

17. The pharmaceutical composition according to claim 14, wherein E is C(CH.sub.3).sub.2S(O)CH.sub.3.

18. The pharmaceutical composition according to claim 14, wherein E is C(O)NHCH.sub.3.

19. The pharmaceutical composition of claim 1 comprising a compound selected from the group consisting of: N-hydroxy-4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)picolinamide (Compound 2); N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide (Compound 3); N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide (Compound 4); N((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide (Compound 5); N((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamide (Compound 6); N((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamide (Compound 7); N1-hydroxy-2-(4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamido)-N3-methylmalonamide (Compound 8); N-hydroxy-4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 9); N-hydroxy-4-(4-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 35); N-hydroxy-4-(4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 36); N-hydroxy-4-(4-(((1R,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 37); N-hydroxy-4-(4-(((1S,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 38); N-hydroxy-4-(4-(5-hydroxypenta-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 39); N-hydroxy-4-(4-(6-hydroxyhexa-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 40); N-hydroxy-4-(4-(5-hydroxyhexa-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 41); N-hydroxy-4-(4-(6-hydroxy-5-methylhexa-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 42); 4-(4-(5,6-dihydroxyhexa-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 43); 4-(4-(6,7-dihydroxyhepta-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 44); N-hydroxy-4-(4-((3-hydroxycyclobutyl)buta-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 45); N-hydroxy-4-(4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 46); N-hydroxy-4-(4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 47); N-hydroxy-4-(4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 48); N-hydroxy-4-(4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 49); N-hydroxy-4-(4-(6-hydroxyhexa-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 50); N-hydroxy-4-(4-(4-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 51); N-hydroxy-4-(4-(4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 52); N-hydroxy-4-(4-(4-(((1R,2S)-2-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 53); N-hydroxy-4-(4-(4-(((1S,2R)-2-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 54); N-hydroxy-4-(4-(4-(3-hydroxyprop-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 55); N-hydroxy-4-(4-(4-(4-hydroxybut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 56); N-hydroxy-4-(4-(4-(3-hydroxybut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 57); N-hydroxy-4-(4-(4-(4-hydroxy-3-methylbut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 58); 4-(4-(4-(3,4-dihydroxybut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 59); 4-(4-(4-(4,5-dihydroxypent-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 60); N-hydroxy-4-(4-(4-((3-hydroxycyclobutyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 61); N-hydroxy-4-(4-(4-((3-(hydroxymethyl)cyclobutyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 62); N-hydroxy-4-(4-(4-((3-(hydroxymethyl)cyclopentyl)ethynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 63); N-hydroxy-4-(4-(4-(4-hydroxy-3-methoxybut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 64); N-hydroxy-4-(4-(4-(5-hydroxy-4-methoxypent-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 65); N-hydroxy-4-(4-(6-hydroxyhexa-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 66); N-hydroxy-4-(4-(4-((2S)-2-(hydroxymethyl)cyclopropyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 67); N-hydroxy-4-(4-(4-((2R)-2-(hydroxymethyl)cyclopropyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 68); N-hydroxy-4-(4-(4-((2S)-2-(hydroxymethyl)cyclopropyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 69); N-hydroxy-4-(4-(4-((2R)-2-(hydroxymethyl)cyclopropyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 70); N-hydroxy-4-(4-(4-(hydroxymethyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 71); N-hydroxy-4-(4-(4-(2-hydroxyethyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 72); N-hydroxy-4-(4-(4-(1-hydroxyethyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 73); N-hydroxy-4-(4-(4-(1-hydroxypropan-2-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 74); 4-(4-(4-(1,2-dihydroxyethyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 75); 4-(4-(4-(2,3-dihydroxypropyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 76); N-hydroxy-4-(4-(4-(3-hydroxycyclobutyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 77); N-hydroxy-4-(4-(4-(3-(hydroxymethyl)cyclobutyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 78); N-hydroxy-4-(4-(4-(3-(hydroxymethyl)cyclopentyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 79); N-hydroxy-4-(4-(4-(2-hydroxy-1-methoxyethyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 80); N-hydroxy-4-(4-(4-(3-hydroxy-2-methoxypropyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 81); N-hydroxy-4-(4-(6-hydroxyhexa-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 82); N-hydroxy-4-(4-(4-((E)-2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 83); N-hydroxy-4-(4-(4-((E)-2-((1S,2R)-2-(hydroxymethyl)cyclopropyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 84); N-hydroxy-4-(4-(4-((E)-2-((1S,2S)-2-(hydroxymethyl)cyclopropyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 85); N-hydroxy-4-(4-(4-((E)-2-((1R,2R)-2-(hydroxymethyl)cyclopropyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 86); (E)-N-hydroxy-4-(4-(4-(3-hydroxyprop-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 87); (E)-N-hydroxy-4-(4-(4-(4-hydroxybut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 88); (E)-N-hydroxy-4-(4-(4-(3-hydroxybut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 89); (E)-N-hydroxy-4-(4-(4-(4-hydroxy-3-methylbut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 90); (E)-4-(4-(4-(3,4-dihydroxybut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 91); (E)-4-(4-(4-(4, 5-dihydroxypent-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 92); (E)-N-hydroxy-4-(4-(4-(2-(3-hydroxycyclobutyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 93); (E)-N-hydroxy-4-(4-(4-(2-(3-(hydroxymethyl)cyclobutyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 94); (E)-N-hydroxy-4-(4-(4-(2-(3-(hydroxymethyl)cyclopentyl)vinyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 95); (E)-N-hydroxy-4-(4-(4-(4-hydroxy-3-methoxybut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 96); (E)-N-hydroxy-4-(4-(4-(5-hydroxy-4-methoxypent-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 97); N-hydroxy-4-(4-(6-hydroxyhexa-1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 98); N-hydroxy-4-(4-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 99); N-hydroxy-4-(4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 100); N-hydroxy-4-(4-(((1R,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 101); N-hydroxy-4-(4-(((1S,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 102); N-hydroxy-4-(4-(5-hydroxypenta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 103); N-hydroxy-4-(4-(6-hydroxyhexa-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 104); N-hydroxy-4-(4-(5-hydroxyhexa-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 105); N-hydroxy-4-(4-(6-hydroxy-5-methylhexa-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 106); 4-(4-(5,6-dihydroxyhexa-1,3-diynyl)phenyl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 107); 4-(4-(6,7-dihydroxyhepta-1,3-diynyl)phenyl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 108); N-hydroxy-4-(4-((3-hydroxycyclobutyl)buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 109); N-hydroxy-4-(4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 110); N-hydroxy-4-(4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 111); N-hydroxy-4-(4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 112); N-hydroxy-4-(4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 113); N-hydroxy-4-(4-(6-hydroxyhexa-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 114); N-hydroxy-4-(4-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)ethynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 115); N-hydroxy-4-(4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)ethynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 116); N-hydroxy-4-(4-(((1R,2S)-2-(hydroxymethyl)cyclopropyl)ethynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 117); N-hydroxy-4-(4-(((1S,2R)-2-(hydroxymethyl)cyclopropyl)ethynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 118); N-hydroxy-4-(4-(3-hydroxyprop-1-ynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 119); N-hydroxy-4-(4-(4-hydroxybut-1-ynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 120); N-hydroxy-4-(4-(3-hydroxybut-1-ynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 121); N-hydroxy-4-(4-(4-hydroxy-3-methylbut-1-ynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 122); 4-(4-(3,4-dihydroxybut-1-ynyl)biphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 123); 4-(4-(4, 5-dihydroxypent-1-ynyl)biphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 124); N-hydroxy-4-(4-((3-hydroxycyclobutyl)ethynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 125); N-hydroxy-4-(4-((3-(hydroxymethyl)cyclobutyl)ethynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 126); N-hydroxy-4-(4-((3-(hydroxymethyl)cyclopentyl)ethynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 127); N-hydroxy-4-(4-(4-hydroxy-3-methoxybut-1-ynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 128); N-hydroxy-4-(4-(5-hydroxy-4-methoxypent-1-ynyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 129); N-hydroxy-4-(4-(6-hydroxyhexa-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 130); N-hydroxy-4-(4-((2S)-2-(hydroxymethyl)cyclopropyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 131); N-hydroxy-4-(4-((2R)-2-(hydroxymethyl)cyclopropyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 132); N-hydroxy-4-(4-((2S)-2-(hydroxymethyl)cyclopropyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 133); N-hydroxy-4-(4-((2R)-2-(hydroxymethyl)cyclopropyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 134); N-hydroxy-4-(4-(hydroxymethyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 135); N-hydroxy-4-(4-(2-hydroxyethyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 136); N-hydroxy-4-(4-(1-hydroxyethyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 137); N-hydroxy-4-(4-(1-hydroxypropan-2-yl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 138); 4-(4-(1,2-dihydroxyethyl)biphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 139); 4-(4-(2,3-dihydroxypropyl)biphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 140); N-hydroxy-4-(4-(3-hydroxycyclobutyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 141); N-hydroxy-4-(4-(3-(hydroxymethyl)cyclobutyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 142); N-hydroxy-4-(4-(3-(hydroxymethyl)cyclopentyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 143); N-hydroxy-4-(4-(2-hydroxy-1-methoxyethyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 144); N-hydroxy-4-(4-(3-hydroxy-2-methoxypropyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 145); N-hydroxy-4-(4-((E)-2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)vinyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 146); N-hydroxy-4-(4-((E)-2-((1S,2R)-2-(hydroxymethyl)cyclopropyl)vinyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 147); N-hydroxy-4-(4-((E)-2-((1S,2S)-2-(hydroxymethyl)cyclopropyl)vinyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 148); N-hydroxy-4-(4-((E)-2-((1R,2R)-2-(hydroxymethyl)cyclopropyl)vinyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 149); (E)-N-hydroxy-4-(4-(3-hydroxyprop-1-enyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 150); (E)-N-hydroxy-4-(4-(4-hydroxybut-1-enyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 151); (E)-N-hydroxy-4-(4-(3-hydroxybut-1-enyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 152); (E)-N-hydroxy-4-(4-(4-hydroxy-3-methylbut-1-enyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 153); (E)-4-(4-(3,4-dihydroxybut-1-enyl)biphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 154); (E)-4-(4-(4,5-dihydroxypent-1-enyl)biphenyl-4-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 155); (E)-N-hydroxy-4-(4-(2-(3-hydroxycyclobutyl)vinyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 156); (E)-N-hydroxy-4-(4-(2-(3-(hydroxymethyl)cyclobutyl)vinyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 157); (E)-N-hydroxy-4-(4-(2-(3-(hydroxymethyl)cyclopentyl)vinyl)biphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 158); (E)-N-hydroxy-4-(4-(4-(4-hydroxy-3-methoxybut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 159); (R)N-(1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)-4-(5-hydroxypenta-1,3-diynyl)benzamide (Compound 160); (R)N-(1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)-4-(6-hydroxyhexa-1,3-diynyl)benzamide (Compound 161); 4-(5,6-dihydroxyhexa-1,3-diynyl)-N((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)benzamide (Compound 162); 4-(6,7-dihydroxyhepta-1,3-diynyl)-N((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)benzamide (Compound 163); 4-(6-hydroxy-5-methylhexa-1,3-diynyl)-N((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)benzamide (Compound 164); (R)N-(1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)-4-((3-hydroxycyclobutyl)buta-1,3-diynyl)benzamide (Compound 165); (R)N-(1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)-4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)benzamide (Compound 166); N((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)-4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)benzamide (Compound 167); N((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)-4-(5-hydroxyhexa-1,3-diynyl)benzamide (Compound 168); 4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)-N((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)benzamide (Compound 169); 4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)-N((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)benzamide (Compound 170); N((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)-4-((2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide (Compound 171); N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-(5-hydroxypenta-1,3-diynyl)benzamide (Compound 172); N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-(6-hydroxyhexa-1,3-diynyl)benzamide (Compound 173); 4-(5,6-dihydroxyhexa-1,3-diynyl)-N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)benzamide (Compound 174); 4-(6, 7-dihydroxyhepta-1,3-diynyl)-N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)benzamide (Compound 175); 4-(6-hydroxy-5-methylhexa-1,3-diynyl)-N((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)benzamide (Compound 176); N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-((3-hydroxycyclobutyl)buta-1,3-diynyl)benzamide (Compound 177); N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)benzamide (Compound 178); N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)benzamide (Compound 179); N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-(5-hydroxyhexa-1,3-diynyl)benzamide (Compound 180); 4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)-N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)benzamide (Compound 181); 4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)-N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)benzamide (Compound 182); N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-((2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide (Compound 183); N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-((2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide (Compound 184); (R)N-(1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(5-hydroxypenta-1,3-diynyl)benzamide (Compound 185); (R)N-(1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(6-hydroxyhexa-1,3-diynyl)benzamide (Compound 186); 4-(5,6-dihydroxyhexa-1,3-diynyl)-N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)benzamide (Compound 187); 4-(6,7-dihydroxyhepta-1,3-diynyl)-N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)benzamide (Compound 188); 4-(6-hydroxy-5-methylhexa-1,3-diynyl)-N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)benzamide (Compound 189); (R)N-(1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-((3-hydroxycyclobutyl)buta-1,3-diynyl)benzamide (Compound 190); (R)N-(1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)benzamide (Compound 191); N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)benzamide (Compound 192); N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(5-hydroxyhexa-1,3-diynyl)benzamide (Compound 193); 4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)-N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)benzamide (Compound 194); 4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)-N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)benzamide (Compound 195); N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-((2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide (Compound 196); N1-hydroxy-2-(4-((2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamido)-N3-methylmalonamide (Compound 197); N1-hydroxy-2-(4-(5-hydroxypenta-1,3-diynyl)benzamido)-N3-methylmalonamide (Compound 198); N1-hydroxy-2-(4-(6-hydroxyhexa-1,3-diynyl)benzamido)-N3-methylmalonamide (Compound 199); N1-hydroxy-2-(4-(5-hydroxyhexa-1,3-diynyl)benzamido)-N3-methylmalonamide (Compound 200); 2-(4-(5,6-dihydroxyhexa-1,3-diynyl)benzamido)-N1-hydroxy-N3-methylmalonamide (Compound 201); 2-(4-(6,7-dihydroxyhepta-1,3-diynyl)benzamido)-N1-hydroxy-N3-methylmalonamide (Compound 202); N1-hydroxy-2-(4-(6-hydroxy-5-methylhexa-1,3-diynyl)benzamido)-N3-methylmalonamide (Compound 203); N1-hydroxy-2-(4-((3-hydroxycyclobutyl)buta-1,3-diynyl)benzamido)-N3-methylmalonamide (Compound 204); N1-hydroxy-2-(4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)benzamido)-N3-methylmalonamide (Compound 205); N1-hydroxy-2-(4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)benzamido)-N3-methylmalonamide (Compound 206); N1-hydroxy-2-(4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)benzamido)-N3-methylmalonamide (Compound 207); N1-hydroxy-2-(4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)benzamido)-N3-methylmalonamide (Compound 208); N1-hydroxy-2-(4-((2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)-N-methylbenzamido)-N3-methylmalonamide (Compound 209); N1-hydroxy-2-(4-(5-hydroxypenta-1,3-diynyl)-N-methylbenzamido)-N3-methylmalonamide (Compound 210); N1-hydroxy-2-(4-(6-hydroxyhexa-1,3-diynyl)-N-methylbenzamido)-N3-methylmalonamide (Compound 211); N1-hydroxy-2-(4-(5-hydroxyhexa-1,3-diynyl)-N-methylbenzamido)-N3-methylmalonamide (Compound 212); 2-(4-(5,6-dihydroxyhexa-1,3-diynyl)-N-methylbenzamido)-N1-hydroxy-N3-methylmalonamide (Compound 213); 2-(4-(6,7-dihydroxyhepta-1,3-diynyl)-N-methylbenzamido)-N1-hydroxy-N3-methylmalonamide (Compound 214); N1-hydroxy-2-(4-(6-hydroxy-5-methylhexa-1,3-diynyl)-N-methylbenzamido)-N3-methylmalonamide (Compound 215); N1-hydroxy-2-(4-((3-hydroxycyclobutyl)buta-1,3-diynyl)-N-methylbenzamido)-N3-methylmalonamide (Compound 216); N1-hydroxy-2-(4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)-N-methylbenzamido)-N3-methylmalonamide (Compound 217); N1-hydroxy-2-(4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)-N-methylbenzamido)-N3-methylmalonamide (Compound 218); N1-hydroxy-2-(4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)-N-methylbenzamido)-N3-methylmalonamide (Compound 219); N1-hydroxy-2-(4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)-N-methylbenzamido)-N3-methylmalonamide (Compound 220); N1-hydroxy-2-(4-((2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamido)-N3,2-dimethylmalonamide (Compound 221); N1-hydroxy-2-(4-(5-hydroxypenta-1,3-diynyl)benzamido)-N3,2-dimethylmalonamide (Compound 222); N1-hydroxy-2-(4-(6-hydroxyhexa-1,3-diynyl)benzamido)-N3,2-dimethylmalonamide (Compound 223); N1-hydroxy-2-(4-(5-hydroxyhexa-1,3-diynyl)benzamido)-N3,2-dimethylmalonamide (Compound 224); 2-(4-(5,6-dihydroxyhexa-1,3-diynyl)benzamido)-N1-hydroxy-N3,2-dimethylmalonamide (Compound 225); 2-(4-(6,7-dihydroxyhepta-1,3-diynyl)benzamido)-N1-hydroxy-N3,2-dimethylmalonamide (Compound 226); N1-hydroxy-2-(4-(6-hydroxy-5-methylhexa-1,3-diynyl)benzamido)-N3,2-dimethylmalonamide (Compound 227); N1-hydroxy-2-(4-((3-hydroxycyclobutyl)buta-1,3-diynyl)benzamido)-N3,2-dimethylmalonamide (Compound 228); N1-hydroxy-2-(4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)benzamido)-N3,2-dimethylmalonamide (Compound 229); N1-hydroxy-2-(4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)benzamido)-N3,2-dimethylmalonamide (Compound 230); N1-hydroxy-2-(4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)benzamido)-N3,2-dimethylmalonamide (Compound 231); N1-hydroxy-2-(4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)benzamido)-N3,2-dimethylmalonamide (Compound 232); N1-hydroxy-2-(4-((2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)-N-methylbenzamido)-N3,2-dimethylmalonamide (Compound 233); N1-hydroxy-2-(4-(5-hydroxypenta-1,3-diynyl)-N-methylbenzamido)-N3,2-dimethylmalonamide (Compound 234); N1-hydroxy-2-(4-(6-hydroxyhexa-1,3-diynyl)-N-methylbenzamido)-N3,2-dimethylmalonamide (Compound 235); N1-hydroxy-2-(4-(5-hydroxyhexa-1,3-diynyl)-N-methylbenzamido)-N3,2-dimethylmalonamide (Compound 236); 2-(4-(5,6-dihydroxyhexa-1,3-diynyl)-N-methylbenzamido)-N1-hydroxy-N3,2-dimethylmalonamide (Compound 237); 2-(4-(6,7-dihydroxyhepta-1,3-diynyl)-N-methylbenzamido)-N1-hydroxy-N3,2-dimethylmalonamide (Compound 238); N1-hydroxy-2-(4-(6-hydroxy-5-methylhexa-1,3-diynyl)-N-methylbenzamido)-N3,2-dimethylmalonamide (Compound 239); N1-hydroxy-2-(4-((3-hydroxycyclobutyl)buta-1,3-diynyl)-N-methylbenzamido)-N3,2-dimethylmalonamide (Compound 240); N1-hydroxy-2-(4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)-N-methylbenzamido)-N3,2-dimethylmalonamide (Compound 241); N1-hydroxy-2-(4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)-N-methylbenzamido)-N3,2-dimethylmalonamide (Compound 242); N1-hydroxy-2-(4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)-N-methylbenzamido)-N3,2-dimethylmalonamide (Compound 243); and N1-hydroxy-2-(4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)-N-methylbenzamido)-N3,2-dimethylmalonamide (Compound 244).

20. A compound having the following structure: ##STR00312## or a stereoisomer or pharmaceutically acceptable salt thereof.

Description

V. EXAMPLES

(1) HPLC: Angilent 1200; Mobile Phase: A: water (0.01% TFA) B:ACN (0.01% TFA); Column: ZORBAX SB-C18, 5 um, 4.6*150 mm; Oven Temperature: 50 C.

(2) LCMS: Angilent 1200; Mobile Phase: A: water (0.01% TFA) B:ACN (0.01% TFA), Column: SunFire C18 3.5 um, 4.6*50 mm; Oven Temperature: 50 C.

(3) GCMS: Agilent instrument (7890A Series gas chromatograph with a Mass Selective Detector 5975C; injector volume: 1 mL; initial column temperature: 40 C.; final column temperature: 250 C; ramp time: 8.4 min; gas flow rate: 1.2 mL/min; column: 5% phenyl methyl silox, Model:Agilent 19091s-433:325C, dimensions: 30.0 m250u m0.25 um)
NMR: Bruker AVANCE III 400 MHz, UltraShield-Plus Digital NMR

(4) A. Compound Synthesis

(5) Referring to the examples that follow, compounds of the present invention were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a 2690 Separation Module (Milford, Mass.) or an Agilent 1200; Mobile Phase: A: water (0.01% TFA) B:ACN (0.01% TFA); Column: ZORBAX SB-C18, 5 um, 4.6*150 mm; Oven Temperature: 50 C. or an Agilent 1100 series chromatography system (Santa Clara, Ca). The analytical columns were Phenomenex Luna C18(2) reversed phase, 10 m, 100 , axia packed, 2.050 mm and the preparative columns were Phenomenex Luna C18(2) reversed phase, 10 m, 100 , axia packed, 21.2250 or 50250 mm. A gradient elution was used, typically starting with 100% water and progressing to 100% acetonitrile over a varying lengths of time All solvents contained 0.1% acetic acid (AcOH). Compounds were detected by ultraviolet light (UV) absorption at either 220 or 254 nm. In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as, for example, Baker-Flex Silica Gel 1 B2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques

(6) Mass spectrometric analysis was performed on one of three LCMS instruments: a Waters System. (Alliance HT HPLC and a Micromass ZQ mass spectrometer; Column: Eclipse XDB-C-18, 2.150 mm; solvent system: 5-95% (or 35-95%, or 65-95% or 95-95%) acetonitrile in water with 0.05% TFA; flow rate 0.8 mL/min; molecular weight range 500-1500; cone Voltage 20 V; column temperature 40 C.) or a Hewlett Packard System (Series 1100 HPLC; Column: Eclipse XDB-C18, 2.150 mm; solvent system: 1-95% acetonitrile in water with 0.05% TFA; flow rate 0.4 mL/min; molecular weight range 150-850; cone Voltage 50 V; column temperature 30 C.). or an Agilent System (Series 1100 HPLC; Column: Waters Sunfire C18 reversed phase, 2.5 m, 100 , 2.150 mm; solvent system: 1-95% acetonitrile in water with 0.1% TFA; flow rate 0.5 mL/min; molecular weight range 150-1500; cone Voltage 70 V; column temperature 35 C.), or an Agilent 1200; Mobile Phase: A:water (0.01% TFA) B:ACN (0.01% TFA), Column: SunFire C18 3.5 um, 4.6*50 mm; Oven Temperature: 50 C. All masses are reported as those of the protonated parent ions.

(7) GCMS analysis was performed on a Hewlet Packard instrument (HP6890 Series gas chromatograph with a Mass Selective Detector 5973; injector volume: 1 L; initial column temperature: 50 C.; final column temperature: 250 C; ramp time: 20 min; gas flow rate: 1 mL/min; column: 5% phenyl methyl siloxane, Model #HP 190915-443, dimensions: 30.0 m25 m0.25 m); or Agilent instrument (7890A Series gas chromatograph with a Mass Selective Detector 5975C; injector volume: 1 mL; initial column temperature: 40 C.; final column temperature: 250 C; ramp time: 8.4 min; gas flow rate: 1.2 mL/min; column: 5% phenyl methyl silox, Model:Agilent 19091s-433:325C, dimensions: 30.0 m250u m0.25 um).

(8) Nuclear magnetic resonance (NMR) analysis was performed with a Varian 300 MHz NMR (Palo Alto, Calif.). and a Varian Unity Enova 400 MHz NMR spectrometer (Palo Alto, Calif.), or Bruker AVANCE III 400 MHz, UltraShield-Plus Digital NMR. The spectral reference was either TMS or the known chemical shift of the solvent. Some compound samples were run at elevated temperatures (e.g. 75 C.) to promote increased sample solubility.

(9) Procedure 1 (CC coupling reaction using CuCl-Cadiot): Hydroxylamine hydrochloride (0.23 mmol, 0.06 eq) and CuCl (0.08, 0.02 eq) were dissolved in 23% aqueous n-butylamine (1 mL) and the resulting solution was cooled to 0 C. A solution of the alkyne (4.3 mmol, 1.1 eq) in 23% aqueous n-butylamine (2 mL) was then added. The bromo-alkyne (3.92 mmol) and hydroxylamine hydrochloride (0.23 mmol, 0.06 eq) were dissolved in 23% aqueous n-butylamine (2 mL) and THF (3 mL), and they were slowly added to the reaction mixture. The reaction was stirred for 1 hr, followed by quenching with EtOAc and water. The organic layer was separated and washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to yield the desired coupled product.

(10) Procedure 2 (Boc deprotection using TFA): To the Boc-protected compound (3.39 mmol) at 0 C. was added a TFA:DCM solution (9 mL, 2:1) and the reaction was stirred for 1 hr. The reaction was concentrated under reduced pressure to yield a crude residue, which was azeotroped with IPA twice to yield the desired deprotected product.

(11) Procedure 3 (Hydroxamate formation): To a stirring solution of the ester (3.38 mmol) in IPA (4 mL) at 0 C. was slowly added 50% aqueous hydroxylamine (40 eq), and the reaction was stirred overnight. The reaction was quenched with AcOH (0.12 mol, 20 eq) or until the pH was 6. The volatiles were removed under reduced pressure, and the resulting solution was purified by RP HPLC.

(12) Procedure 4A (formation of imine in reductive amination to NHMe): To a stirring solution of the amine (2.37 g, 7.20 mmol) in DMF (14.39 mL) was added DIPEA (1.88 mL, 10.79 mmol) followed by formaldehyde (37% in water) (1.07 mL, 14.39 mmol) and the reaction was stirred for 2 hr. The excess aldehyde was quenched with n-butylamine (30% in water) (2.63 g, 10.79 mmol) and stirred for 1 hr. The reaction mixture was diluted with water, and lyophilized to yield the desired imine.

(13) Procedure 4B (reduction to amine in reductive amination to NHMe): To a stirring solution of the imine (3.96 g, 11.60 mmol) in THF (23.17 mL) and MeOH (2.439 mL) was added acetic acid (1.33 mL, 23.20 mmol) followed by sodium cyanoborohydride (10.94 g, 174 mmol) and the reaction was stirred for 1 hr. The reaction mixture was diluted with water (7 mL) and concentrated under reduced pressure to yield the amine.

(14) ##STR00264##

(15) Ethynyltrimethylsilane (82.4 g, 0.84 mol) was added dropwise over 10 min under a nitrogen atmosphere to a solution of methyl 4-bromobenzoate (150 g, 0.7 mol), PdCl.sub.2 (PPh.sub.3).sub.2 (15 g, 0.021 mol) and CuI (13 g, 0.07 mol) in TEA (1.5 L) and the reaction was stirred at 90 C. for 30 minutes. Solids were collected by filtration and washed with EtOAc (5500 mL). The filtrate was concentrated under reduced pressure to give a residue, which was distilled under reduced pressure to yield methyl 4-((trimethylsilyl) ethynyl) benzoate (INT-1.2) as an off-white solid (156 g, 96%).

(16) To a solution of methyl 4-((trimethylsilyl) ethynyl)benzoate (156 g, 0.67 mol) in methanol (800 mL) was added dropwise KOH/methanol (18 g/250 mL) keeping the temperature below 10 C. The reaction mixture was allowed to warm to room temperature for 5 min and was then neutralized with 2M HCl. Methyl 4-ethynylbenzoate (INT-1.3) was collected by filtration as a white solid (97 g, 90%). MS: m/z calcd for C.sub.10H.sub.8O.sub.2160.0. found [M+H].sup.+ 161.

(17) ##STR00265##

(18) To a solution of methyl 4-ethynylbenzoate (50 g, 0.31 mol) in acetone (750 mL) was added AgNO.sub.3 (5 g, 29.7 mmol) and the reaction mixture was stirred for 1 hr. NBS (61.2 g, 0.34 mol) was added and the reaction mixture was stirred at room temperature for 20 hr, filtered and concentrated under reduced pressure. The residue was diluted in EA, and washed with iced 20% H.sub.2SO.sub.4. The organic layer was washed with water and brine, dried (Na.sub.2SO.sub.4), filtered, concentrated under reduced pressure to give a residue, which was recrystallized from MeOH (1 mL/4 g) to yield methyl 4-(bromoethynyl) benzoate (INT-1.4) as an off-yellow solid (67 g, 90%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.98 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 3.92 (s, 3H).

(19) To a solution of methyl 4-(bromoethynyl) benzoate (67 g, 280 mmol) in CH.sub.3OH/THF/H.sub.2O=5/5/1 (1100 mL) was added NaOH (44.84 g) and the reaction mixture was stirred at 25 C. for 3 hr. The volatiles were removed under reduced pressure and the resulting solution was neutralized with 1N HCl to pH 3-5. Solids were collected by filtration, washed with water and dried at 50 C. for 5 hr to yield 4-(bromoethynyl) benzoic acid (INT-1) (61 g, 96%).

1. N-hydroxy-2-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carboxamide (1)

(20) ##STR00266##

(21) To a stirring solution of 4-amino-3-bromopyridine (1.1, 173 mg, 1 mmol) and Et.sub.3N (132 mg, 1.3 mmol) in DCM (5 mL) was added dropwise pivaloyl chloride (133 mg, 1.1 mmol), and the reaction was stirred at room temperature for 3 hr. The mixture was washed with water (2), NaHCO.sub.3, brine, dried and concentrated under reduced pressure to give the product 1.2 as a solid. MS: m/z calcd for C.sub.10H.sub.13BrN.sub.2O, 256.02/258.02. found [M+H].sup.+ 257/259.

(22) ##STR00267##

(23) A mixture of compound 1.2 (5 g, 19.4 mmol) and 10% Pd/C (500 mg) in MeOH (70 mL) was stirred under H.sub.2 (1 atm) at room temperature overnight. The Pd/C was removed by filtration and the solvent was concentrated under reduced pressure to yield a crude, which was dissolved in EtOAc. The organic layer was washed with NaHCO.sub.3, brine, dried and concentrated under reduced pressure to give the product 1.3 as a solid. MS: m/z calcd for C.sub.10H.sub.14N.sub.2O, 178.11. found [M+H].sup.+ 179.

(24) ##STR00268##

(25) To a solution of compound 1.3 (5.34 g, 30 mmol) in THF (200 mL) at 78 C. was added dropwise n-BuLi (47 mL, 75 mmol) and the reaction was stirred for 3 hr at 10 C. The reaction was cooled to 78 C. and a solution of diethyl oxalate (22 g, 150 mmol) in THF (20 mL) was added dropwise and the mixture was stirred overnight at room temperature. NH.sub.4Cl was added, and the reaction was extracted with EtOAc, washed with brine, dried, concentrated under reduced pressure and purified by flash chromatography (silica gel/EtOAc/PE 1:10-1:8) to give the product 1.4 as a solid. MS: m/z calcd for C.sub.14H.sub.18N.sub.2O.sub.4, 278.13. found [M+H].sup.+ 279.

(26) ##STR00269##

(27) Compound 1.7 was synthesized according to the procedure described in International PCT Patent Application Publication No. WO2012/154204.

(28) ##STR00270##

(29) TABLE-US-00002 1-(4-((trimethylsilyl)ethynyl)phenyl)ethanone (1.9) Reagent MW Eq. mmol g, mL Compound 1.8 198 1.0 101 20 g ethynyl(trimethyl)silane 98 1.4 141 13.8 g Pd(PPh.sub.3).sub.2Cl.sub.2 701 0.05 5.1 3.6 g Cul 190 0.1 10 1.9 TEA 300 mL

(30) To a stirring solution of compound 1.8 (20 g, 101 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (3.6 g, 141 mmol), CuI (1.9 g, 10 mmol) in TEA (300 mL) under argon was added ethynyl(trimethyl)silane (13.8 g, 141 mmol) at 90 C. and the reaction mixture was stirred at 90 C. for 4 hr. The solids were removed by filtration, and rinsed with ethyl acetate (380 mL). The filtrate was concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/ethyl acetate in petroleum ether 5%-10% v/v) to give compound 1.9 as a yellow oil (19 g, 90%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.92 (d, J=8, 2H), 7.56 (d, J=8, 2H), 2.56 (s, 3H), 0.23 (s, 9H).

(31) TABLE-US-00003 1-(4-ethynylphenyl)ethanone (1.10) Reagent MW Eq. mmol g, mL Compound 1.9 216 1.0 88 19 g KOH 56 0.5 44 2.46 g MeOH 200 mL

(32) To a stirring solution of compound 1.9 (19 g, 88 mmol) in MeOH (200 mL) was added a solution of KOH (2.46 g, 44 mmol) in MeOH (20 mL) at 10 C. and the mixture was stirred at room temperature for 1 hr. AcOH was added until the pH was 7, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with 5% aqueous NaHCO.sub.3 (100 mL), brine (100 mL), dried, and concentrated under reduced pressure to give compound 1.10 as a white solid (12 g, 95%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (d, J=8, 2H), 7.62 (d, J=8, 2H), 4.49 (s, 1H), 2.59 (s, 3H).

(33) TABLE-US-00004 1-(4-(bromoethynyl)phenyl)ethanone (1.11) Reagent MW Eq. Mmol g, mL Compound 1.11 144 1.0 83.3 12 g NBS 177 1.2 99.96 17.7 g AgNO.sub.3 169 0.095 7.9 1.34 g Acetone 200 mL

(34) To a stirring solution of compound 1.10 (12 g, 83.3 mmol) in acetone (200 mL) was added AgNO.sub.3 (1.34 g, 7.9 mmol) and the the reaction was stirred for 30 min. NBS (17.7 g, 99.96 mmol) was then added and the reaction mixture was stirred at 20 C. for 14 hr. Solids were removed by filtration and the filtrate was concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/ethyl acetate in petroleum ether 5%-10% v/v) to give compound 1.11 as a white solid (14 g, 76%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (d, J=8, 2H), 7.62 (d, J=8, 2H), 2.58 (s, 3H).

(35) TABLE-US-00005 1-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3- diyn-1-yl)phenyl)ethanone (1.12) Reagent MW Eq. mmol g, mL Compound 1.11 198 1.0 4.5 1.0 g Compound 1.7 96 1.5 6.75 648 mg Pd(PPh.sub.3).sub.2Cl.sub.2 701 0.05 0.225 158 mg Cul 190 0.1 0.45 90 mg TEA 101 2 9 1.16 g THF 30 mL

(36) To a stirring solution of compound 1.11 (1.0 g, 4.5 mmol), compound 1.7 (648 mg, 6.75 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (158 mg, 0.22 mmol), and CuI (90 mg, 0.45 mmol) in THF (30 mL) under argon was added TEA (1.16 g, 9 mmol) and the mixture was stirred at 20 C. for 14 hr. Solids were removed by filtration and rinsed with ethyl acetate (380 mL), the filtrate was concentrated under reduced pressure to yield a crude, which was purified by flash chromatography (silica gel/ethyl acetate in petroleum ether 15%-50% v/v) to give compound 1.12 as a yellow solid (450 mg, 42%). MS: m/z calcd for C.sub.16H.sub.14O.sub.2, 238.1. found [M+H].sup.+ 239. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (d, J=8.4, 2H), 7.53 (d, J=8.4, 2H), 3.61 (dd, J=6, 11.6, 1H), 3.51 (dd, J=6.8, 11.6, 1H), 2.59 (s, 3H), 1.57-1.62 (m, 1H), 1.49 (brs, 1H), 1.37-1.41 (m, 1H), 1.06-1.10 (m, 1H), 0.88-0.93 (m, 1H).

(37) ##STR00271##

(38) To a stirring solution of compound 1.4 (139 mg, 0.5 mmol) in EtOH (10 mL) was added KOH (112 mg, 2.0 mmol, 4M), and the reaction was heated at 100 C. for 3 hr. Racemic compound 1.12 (178.5 mg, 0.75 mmol) was added and the mixture was stirred overnight at 100 C. The solvent was concentrated under reduced pressure. Water was added, and the reaction was washed with Et.sub.2O. The reaction mixture was adjusted to pH 1-2 with acetic acid, and the resulting solids were collected by filtration and dried to yield the desired product 1.13. MS: m/z calcd for C.sub.23H.sub.16N.sub.2O.sub.3, 68.12. found [M+H].sup.+ 369.

(39) ##STR00272##

(40) To a stirring solution of compound 1.13 (184 mg, 0.5 mmol) in DMF (10 mL) was added K.sub.2CO.sub.3 (138 mg, 1.0 mmol), followed by iodomethane (74.55 mg, 0.52 mmol) and the reaction was stirred overnight at room temperature. The reaction was quenched with water, extracted with EtOAc, washed with brine, dried, concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/PE:EtOAc 1.5:1-1:1.5) to yield a solid, which was recrystallized from EA/PE (1:5) to give the desired product 1.14. MS: m/z calcd for C.sub.24H.sub.18N.sub.2O.sub.3, 382.13. found [M+H].sup.+ 383.

(41) ##STR00273##

(42) Compound 1.14 (500 mg) was converted to N-hydroxy-2-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)-1,6-naphthyridine-4-carboxamide (1, 339 mg, 68%) using Procedure 3: MS: m/z calcd for C.sub.23H.sub.17N.sub.3O.sub.3, 383.13. found [M+H].sup.+ 384.

2. N-hydroxy-4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)picolinamide (2)

(43) ##STR00274##

(44) To a stirring solution of compound 2.1 (27.8 g, 0.15 mol), compound 2.2 (45.7 g, 0.18 mol) and PdCl.sub.2(PPh.sub.3).sub.2 (5.26 g, 7.5 mmol) in 1,4-dioxane (500 mL), was added KOAc (22.0 g, 0.225 mol) under an argon atmosphere and the mixture was stirred at 80 C. for 15 hr. The solvent was removed under reduced pressure, and the residue was diluted with PE (500 mL). Solids were removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/PE:EA 10:1) to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.3, 32.5 g, 95%) as a white solid.

(45) ##STR00275##

(46) To a stirring solution of compound 2.3 (32.4 g, 0.14 mol), compound 2.4 (32.2 g, 0.17 mol) and Pd(PPh.sub.3).sub.4 (8.08 g, 7 mmol) in 1,4-dioxane/methanol (800 mL, 1:1) was added Na.sub.2CO.sub.3 (22.3 g, 0.21 mol) under an argon atmosphere and the mixture was stirred at 80 C. for 15 hr. The solvent was removed under reduced pressure and the resulting residue was diluted with water (500 mL) and extracted with EtOAc (3500 mL). The combined organic layers were dried and concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/PE:EA 2:1) to give ethyl 4-(4-formylphenyl)picolinate (2.5, 14.2 g, 40%) as a yellow solid.

(47) ##STR00276##

(48) To a stirring solution of compound 2.5 (12.7 g, 50 mmol) in CH.sub.3OH (300 mL) was added the Bestmann reagent (14.4 g, 75 mmol) followed by K.sub.2CO.sub.3 (20.8 g, 150 mmol) and the reaction was stirred for 5 hr. The reaction mixture was diluted with water (500 mL) and extracted with Et.sub.2O (3300 mL). The combined organic layers were dried and concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/PE:Et.sub.2O 10:1-5:1) to give methyl 4-(4-ethynylphenyl)picolinate (2.6, 4.0 g, 33.9%) as a white solid.

(49) ##STR00277##

(50) To a stirring solution of racemic compound 2.7 (4.8 g, 50 mmol) and AgNO.sub.3 (0.85 g, 5 mmol) in acetone (200 mL) was added NBS (10.7 g, 60 mmol) under an argon atmosphere and the mixture was stirred at room temperature for 15 hr. The mixture was filtered and the residue was taken up with acetone, the combined organic layers were concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/PE:EA 5:1) to give (2-trans-(bromoethynyl)cyclopropyl)methanol (2.8, 5.2 g, 60%) as a colorless oil.

(51) ##STR00278##

(52) To a stirring solution of compound 2.6 (1.77 g, 7.5 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (262 mg, 0.37 mmol), CuI (143 mg, 0.75 mmol), and DIPEA (2.9 g, 22.5 mmol) in THF (50 mL) was added compound 2.8 (1.84 g, 10.5 mmol) under an argon atmosphere, and the mixture was stirred at room temperature for 5 hr. The solvent was removed under reduced pressure, and the resulting residue was diluted with water (100 mL) and extracted with EtOAc (3150 mL). The combined organic layers were dried and concentrated under reduced pressure to give a red oil, which was purified by flash chromatography (silica gel/PE:EA 5:13:1) to yield methyl 4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)picolinate (2.9, 570 mg, 23%): MS: m/z calcd for C.sub.21H.sub.17NO.sub.3, 331.12. found [M+H].sup.+ 332; .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) 8.77 (d, J=5.6 Hz, 1H), 8.30 (s, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 4.72 (t, J=5.6 Hz, 1H), 3.91 (s, 3H), 3.44 (m, 1H), 3.24 (m, 1H), 1.45 (m, 2H), 0.88 (m, 2H).

(53) ##STR00279##

(54) Methyl 4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)picolinate (2.9, 500 mg) was treated according to Procedure 3 to give N-hydroxy-4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)picolinamide (2, 157 mg, 31%). MS: m/z calcd for C.sub.20H.sub.16N.sub.2O.sub.3, 332.12. found [M+H].sup.+ 333.1.

3. N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide (3)

(55) ##STR00280##

(56) To a stirring suspension of (R)-2-amino-3-mercapto-3-methylbutanoic acid (3.1, 9 g, 60.3 mmol) in DMF (20 mL) was added BOC-anhydride (14.0 mL, 60.3 mmol) followed by TEA (8.41 mL, 63.3 mmol) and the reaction mixture was stirred for 18 hr. Excess solvent was removed under reduced pressure. The crude product was treated with methyl iodide (18.83 g, 133 mmol) in DMF (20 mL) and Cs.sub.2CO.sub.3 (43.2 g, 133 mmol) at room temperature for 18 hr. Water (100 mL) was added and the product was extracted with ethyl acetate (2200 mL), dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to give compound 3.2 (12.62 g) as a white solid. Subsequent BOC deprotection was achieved by treatment with TFA (20 mL) in CH.sub.2Cl.sub.2 (20 mL) for 5 hr. The solvent was removed under reduced pressure to give the desired product 3.3 (8.2 g).

(57) ##STR00281##

(58) A stirring solution of racemic ((trans)-2-ethynylcyclopropyl)methanol (1.7, 11 g, 106 mmol), copper(I) chloride (0.20 g, 2.03 mmol), and hydroxylamine hydrochloride (0.42 g, 6.08 mmol) in 30% aqueous butylamine (156 mL) was poured into a 1 L jacketed reactor and cooled to 0 C. A solution of 4-(bromoethynyl)benzoic acid (INT-1, 22.81 g, 101 mmol) and hydroxylamine hydrochloride (0.42 g, 6.08 mmol) in 30% aqueous butylamine (111 mL) was then added dropwise and the reaction was stirred for 2 hr. The reaction mixture was washed with MTBE (2230 mL) and the aqueous layer was diluted with methyl THF (460 mL). The solution was cooled to 0 C. and acidified by dropwise addition of 6M HCl (100 ml) to pH 1. The reaction mixture was filtered through Celite, and washed with methyl-THF (230 ml). The two layers were partitioned and the aqueous layer was back-extracted with methyl-THF (230 mL). The organic layers were washed with 2M HCl (2230 mL), water (230 ml), and brine (230 ml), dried over Na.sub.2SO.sub.4 and filtered. The organic layer was concentrated under reduced pressure until the solution turned cloudy, then heptane (230 mL) was added. The resulting solution was concentrated under reduced pressure to 5 volumes and then additional heptane (230 mL) was added. The resulting solution was concentrated to 5 volumes to give a slurry. The solids were collected by filtration, washed with heptane (50 mL), and dried under reduced pressure to yield 4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzoic acid (3.4, 3.96 g). MS: m/z calcd for C.sub.16H.sub.12O.sub.3, 240.08. found [MH].sup.+239.1. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 13.18 (s, 1H), 7.85 (d, 2H), 7.61 (d, 2H), 4.72 (t, 1H), 3.39-3.52 (m, 1H), 3.21-3.32 (m, 1H), 1.41-1.51 (m, 2H), 0.81-0.99 (m, 2H).

(59) ##STR00282##

(60) To a stirring solution of triethylamine (1.06 g, 10.52 mmol), and (R)-methyl 2-amino-3-methyl-3-(methylthio)butanoate (3.3, 1.86 g, 10.52 mmol) was added a solution of racemic 4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzoic acid (3.4, 2.5 g, 10.52 mmol) in DMF (40 mL), followed by 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (4 g, 10.52 mmol) and the reaction was stirred for 2 hr. Water (100 mL) was added and the mixture was extracted with ethyl acetate (2100 mL), dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to yield a crude, which was purified by flash chromatography (silica gel/ethyl acetate 10-40% in hexanes) to yield the corresponding ester 3.5 (2.6 g), which was converted to N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide (3) using Procedure 3. MS: m/z calcd for C.sub.21H.sub.24N.sub.2O.sub.4S, 400.15. found [M+H].sup.+ 401.

4. N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide (4)

(61) ##STR00283##

(62) To a stirring solution of N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide (3, 0.2 g, 0.50 mmol) in acetonitrile/water (20 mL) was added 30% aqueous hydrogen peroxide (0.015 mL, 0.50 mmol) and the reaction mixture was stirred at room temperature for 18 hr. The reaction mixture was lyophylized to afford N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide (4, 200 mg, 449 mmol, 90%). MS: m/z calcd for C.sub.21H.sub.24N.sub.2O.sub.5S, 416.14. found [M+H].sup.+ 417.

5. N((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide (5)

(63) ##STR00284##

(64) N((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide (3, 120 mg, 0.3 mmol) in 22% acetonitrile-water (100 mL) was treated with 30% peracetic acid (1 mL) overnight at room temperature. The reaction was lyophilized to afford N((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide (5, 130 mg). MS: m/z calcd for C.sub.21H.sub.24N.sub.2O.sub.6S, 432.14. found [M+H].sup.+ 433.

6. N((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamide (6)

(65) ##STR00285##

(66) To a stirring solution of 6-bromo-2-naphthoic acid (6.1, 1.0 g, 4.0 mmol), racemic ((trans)-2-ethynylcyclopropyl)methanol (1.7, 0.5 g, 5.2 mmol), copper(I) iodide (30 mg, 0.16 mmol) and palladium(II) bis(triphenylphosphine) dichloride (56 mg, 0.08 mmol) in tetrahydrofuran (7.5 mL) under a nitrogen atmosphere was added triethylamine (2.5 mL) and the reaction was stirred for 1 week. The reaction was partitioned between 2N aqueous sodium hydroxide and ethyl acetate. The aqueous layer was acidified with conc HCl and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium chloride and dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthoic acid (6.2, 1.0 g, 94%).

(67) ##STR00286##

(68) To a stirring suspension of (S)-methyl-2-amino-3-((tert-butoxycarbonyl)amino)-3-methylbutanoate oxalate (6.3, 1.6 g, 4.9 mmol) and 6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthoic acid (6.2, 1.0 g, 3.8 mmol) in ACN (10 mL) at 0 C. was added triethylamine (2.1 mL, 15 mmol), followed by the portionwise addition of a solution of HATU (3.0 g, 7.9 mmol) in ACN (10 mL) and the reaction mixture was stirred at 0 C. for 75 min. The reaction was concentrated under reduced pressure to yield a residue, which was partitioned between MTBE and water. The organic layer was washed with 1M citric acid, water, saturated sodium bicarbonate (2), saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamido)-3-methylbutanoate (6.4), which was carried through to the next step without further purification.

(69) ##STR00287##

(70) To a stirring solution of (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamido)-3-methylbutanoate (6.4) in methanol (10 mL) was added 4N HCl in dioxane (10 mL) and the reaction mixture was stirred at rt for 2 hr, then at 4 C. overnight. The mixture was concentrated under reduced pressure to give a residue, which was partitioned between water and MTBE. The aqueous layer was basified with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-amino-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamido)-3-methylbutanoate (6.5, 1.2 g, 3.0 mmol, 79%).

(71) ##STR00288##

(72) Compound 6.5 (1.2 g) was treated according to Procedure 3 to yield the desired compound N((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamide (6, 400 mg, 1.01 mmol, 33.3% yield). MS: m/z calcd for C.sub.22H.sub.25N.sub.3O.sub.4, 395.18. found [M+H].sup.+ 396.2.

7. N((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamide (7)

(73) ##STR00289##

(74) To a stirring solution of 6-bromobenzo[b]thiophene-2-carboxylic acid (7.1, 1.0 g, 3.9 mmol) in DMF (7.5 mL) under a nitrogen atmosphere were added racemic ((trans)-2-ethynylcyclopropyl)methanol (1.7, 935 mg, 9.7 mmol), copper(I) iodide (30 mg, 0.16 mmol) and palladium(II) bis(triphenylphosphine) dichloride (56 mg, 0.08 mmol), followed by triethylamine (2.5 mL) and the reaction was stirred at room temperature for 1 hr, and then at 40 C. for 20 hr. The reaction mixture was partitioned between 2N aqueous sodium hydroxide and ethyl acetate. The aqueous layer was acidified with conc HCl and extracted with ethyl acetate. The resulting organic layer was washed with water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxylic acid (7.2, 900 mg, 3.3 mmol, 85%).

(75) ##STR00290##

(76) To a stirring solution of (S)-methyl 2-amino-3-((tert-butoxycarbonyl)amino)-3-methylbutanoate oxalate 6.3 (1.4 g, 4.3 mmol), 6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxylic acid (7.2, 900 mg, 3.3 mmol) in ACN (10 mL) at 0 C. was added triethylamine (1.8 mL, 13 mmol), followed by the portionwise addition of a suspension of HATU (2.6 g, 6.9 mmol) in ACN (10 mL), and the reaction mixture was stirred at 0 C. for 105 min. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between MTBE and water. The organic layer was washed with 1M citric acid, water, saturated sodium bicarbonate (2), saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamido)-3-methylbutanoate (7.3), which was carried through to the next step without further purification.

(77) ##STR00291##

(78) To a stirring solution of (S)-methyl 3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamido)-3-methylbutanoate (7.3) in methanol (10 mL) was added 4N HCl in dioxane (10 mL) and the reaction was stirred at room temperature for 2 hr, then at 4 C. overnight. The reaction mixture was concentrated under reduced pressure to yield a residue, which was partitioned between water and MTBE. The aqueous layer was basified with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (S)-methyl 3-amino-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamido)-3-methylbutanoate (7.4, 880 mg, 2.2 mmol, 67%).

(79) ##STR00292##

(80) Compound 7.4 (0.88 g) was treated according to Procedure 3 to yield the desired compound N((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamide (7, 16.3 mg, 0.041 mmol, 1.85% yield). MS: m/z calcd for C.sub.20H.sub.23N.sub.3O.sub.4S, 401.14. found [M+H].sup.+ 402.2.

8. N1-hydroxy-2-(4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamido)-N3-methylmalonamide (8)

(81) ##STR00293##

(82) To a stirring solution of diethyl 2-((tert-butoxycarbonyl)amino)malonate (8.1, 0.93 mL, 3.63 mmol) in methanol (10 mL) was added 40% methanamine in water (0.32 mL, 3.63 mmol) and the reaction was stirred at room temperature for 27 days. The reaction was concentrated under reduced pressure to give an oil, which was purified by flash chromatography (silica gel/10% MeOH/DCM) to provide compound 8.2 (592 mg, 66.2% yield). MS: m/z calcd for C.sub.10H.sub.18N.sub.2O.sub.5, 246.12. found [M+Na].sup.+269.1.

(83) ##STR00294##

(84) Compound 8.2 (0.59 g, 2.40 mmol) was dissolved in DCM (3 mL) and TFA (3 mL) and the reaction was stirred for 30 min. The reaction mixture was concentrated under reduced pressure to give compound 8.3 (0.88 g), which was carried through to the next step without further purification. MS: m/z calcd for C.sub.5H.sub.10N.sub.2O.sub.3, 146.07. found [M+H].sup.+ 147.1.

(85) ##STR00295## ##STR00296##

(86) The synthesis of compound 8.14 was carried out as described in International PCT Patent Application Publication No. WO2012/154204.

(87) ##STR00297##

(88) To a stirring solution of compound 8.3 (375 mg, 1.44 mmol) in ACN (3 mL) was added compound 8.14 (315 mg, 1.31 mmol), followed by DIPEA (1.01 mL, 5.77 mmol) and the reaction mixture was cooled to 0 C. HATU (548 mg, 1.44 mmol) was added and the reaction was allowed to warm to room temperature. After 1 hr solids were collected by filtration, and washed with ACN to yield compound 8.15 (200 mg, 41.4% yield). MS: m/z calcd for C.sub.20H.sub.20N.sub.2O.sub.5, 368.14. found [M+H].sup.+ 369.1.

(89) ##STR00298##

(90) To a stirring solution of compound 8.15 (200 mg, 0.54 mmol) in THF (1.0 mL) and methanol (1 mL) was added dropwise over 1 min a solution of 50% hydroxamic acid in water (1 mL) and the reaction was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure to give a crude, which was purified by RP HPLC (0.1% AcOH in water and ACN) to give N1-hydroxy-2-(4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamido)-N3-methylmalonamide (8, 47.7 mg, 23.8% yield). MS: m/z calcd for C.sub.19H.sub.19N.sub.3O.sub.6 369.13. found [M+H].sup.+ 370.1. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 10.84 (br, 1H), 9.06 (s, 1H), 8.57 (d, 1H), 8.02 (d, 1H), 7.89 (d, 2H), 7.60 (d, 2H), 4.99 (d, 1H), 4.70 (t, 1H), 3.43-3.37 (m, 1H), 3.29-3.22 (m, 1H), 2.60 (d, 3H), 1.46-1.41 (m, 2H), 0.94-0.86 (m, 2H).

9. N-hydroxy-4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (9)

(91) ##STR00299##

(92) A solution of 2-(4-bromophenyl)ethanol (20.0 g, 100 mol) in CH.sub.2Cl.sub.2 (10 mL) was added dropwise to a solution of imidazole (22.4 mg, 0.33 mmol), PPh.sub.3 (33.3 g, 127 mmol), and I.sub.2 (32.5 g, 130 mmol) in CH.sub.2Cl.sub.2 (50 mL) at 0 C., and the reaction was warmed to room temperature and stirred overnight. The reaction mixture was washed with saturated aqueous sodium thiosulfate (250 mL), brine, dried over Na.sub.2SO4, filtered and concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/PE) to yield 1-bromo-4-(2-iodoethyl)benzene (9.2, 22.7 g, 73%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 3.13 (t, J=7.6 Hz, 2H), 3.32 (t, J=7.6 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H).

Methyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate

(93) ##STR00300##

(94) Compound 9.3 was synthesized according to the procedure described in WO 2011045703.

(95) ##STR00301##

(96) To a stirring suspension of methyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.3, 6.36 g, 18.23 mmol), bis(triphenylphosphine)palladium(II) chloride (1.28 mg, 1.82 mmol) and copper(I) iodide (347 mg, 1.82 mmol) in triethylamine (30 mL) was added ethynyltrimethylsilane (0.92 mL, 6.49 mmol) and the reaction mixture was heated to 80 C. briefly, and then allowed to stir at room temperature for 18 hr. Volatiles were removed under reduced pressure and the resulting residue was purified by flash chromatography (silica gel/15-50% EtOAc/hexanes) to yield methyl 2-methyl-2-(methylsulfonyl)-4-(4-((trimethylsilyl)ethynyl)phenyl)butanoate (9.4, 4.0 g, 59.9% yield). MS: m/z calcd for C.sub.18H.sub.26O.sub.4SSi, 366.13. found [M+H].sup.+ 367.2.

(97) ##STR00302##

(98) To a stirring solution of methyl 2-methyl-2-(methylsulfonyl)-4-(4-((trimethylsilyl)ethynyl)phenyl)butanoate (9.4, 4.4 g, 12.0 mmol) in methanol (80 mL) was added K.sub.2CO.sub.3 (100 mg, 0.720 mmol) and the reaction was stirred at room temperature for 3 hr. The reaction mixture was filtered through celite, concentrated under reduced pressure to give a residue, which was dissolved in DCM, filtered and concentrated under reduced pressure to yield methyl 4-(4-ethynylphenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.5, 2.49 g, 70.5%). MS: m/z calcd for C.sub.15H.sub.18O.sub.4S, 294.09. found [M+H].sup.+ 295.2.

(99) ##STR00303##

(100) To a stirring solution of methyl 4-(4-ethynylphenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.5, 2.49 g, 8.46 mmol) and silver nitrate (144 mg, 0.85 mmol) in acetone (24 mL) was added NBS (2.5 g, 14.33 mmol) and the reaction was stirred at room temperature for 1.5 hr. Solvent was removed under reduced pressure to give a residue, which was purified by flash chromatography (silica gel/30-50% EtOAc/hexanes) to yield methyl 4-(4-(bromoethynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.6, 150 mg, 0.40 mmol, 4.75%). MS: m/z calcd for C.sub.15H.sub.17BrO.sub.4S, 372.0/374.0. found [M+H].sup.+ 373.0/375.0.

(101) ##STR00304##

(102) To a stirring solution of racemic ((trans)-2-ethynylcyclopropyl)methanol (1.7) in n-butylamine (750 L, 30% in 1:1 water/THF) at 10 C. was added a solution of copper chloride (4 mg) in n-butylamine (300 L, 30% in 1:1 water/THF) and NH.sub.2OH (12 L of 50% in water) and the reaction was stirred for 10 min. A solution of methyl 4-(4-(bromoethynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.6) in n-butylamine (750 L, 30% in 1:1 water/THF) and NH.sub.2OH (12 L of 50% in water, 0.201 mmol) at 10 C. was then added dropwise over 10 min and the reaction was stirred at 10 C. for 10 min. The reaction mixture was diluted with EtOAc (10 mL) and washed with 1M citric acid (5 mL). The organic layer was washed with water (25 mL), sodium bicarbonate (5 mL), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give a thick oil (9.7), which was carried through to the next step without further purification. MS: m/z calcd for C.sub.21H.sub.24O.sub.5S, 388.13. found [M+H].sup.+ 389.2.

(103) ##STR00305##

(104) To a stirring solution of methyl 4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)-2-methyl-2-(methylsulfonyl) butanoate (9.7) in isopropanol (1.3 mL) at 0 C. was added hydroxylamine (946 L, 15.44 mmol, 50% in water) and the reaction was stirred at room temperature overnight. The reaction mixture was neutralized with AcOH (884 L, 15.44 mmol) and concentrated under reduced pressure to give a crude, which was purified by RP-HPLC (0-30% ACN in water) to yield N-hydroxy-4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl) buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (9, 22.6 mg, 22.6% yield). MS: m/z calcd for C.sub.20H.sub.23NO.sub.5S, 389.13. found [M+H].sup.+ 390.2.

(105) B. Antimicrobial Activity

(106) 1. Bacterial Screens and Cultures

(107) Bacterial isolates were cultivated from 70 C. frozen stocks by overnight passages at 35 C. in ambient air on Mueller-Hinton agar (Beckton Dickinson, Franklin Lakes, N.J.). Clinical isolates tested were obtained from various geographically diverse hospitals in the US and abroad (Focus Diagnostics, Herndon, Va. and JMI, North Liberty, Iowa). Quality control strains were from the American Type Culture Collection (ATCC; Rockville, Md.).

(108) 2. Susceptibility Testing

(109) Minimum Inhibitory Concentrations (MICs) were determined by the broth microdilution method in accordance with the Clinical and Laboratory Standards Institute (CLSI) guidelines. In brief, organism suspensions were adjusted to a 0.5 McFarland standard to yield a final inoculum between 310.sup.5 and 710.sup.5 colony-forming units (CFU)/mL. Drug dilutions and inocula were made in sterile, cation adjusted Mueller-Hinton Broth (Beckton Dickinson). An inoculum volume of 100 L was added to wells containing 100 L of broth with 2-fold serial dilutions of drug. All inoculated microdilution trays were incubated in ambient air at 35 C. for 18-24 hr. Following incubation, the lowest concentration of the drug that prevented visible growth (OD600 nm<0.05) was recorded as the MIC. Performance of the assay was monitored by the use of laboratory quality-control strains and levofloxacin, a compound with a defined MIC spectrum, in accordance with CLSI guidelines. Typically, compounds of the present invention have MIC values of 0.03-32 g/mL. To this end, data for certain representative compounds is shown in Table II below.

(110) TABLE-US-00006 TABLE II Minimum Inhibitory Concentrations (MICs) cmpd. AECO AKPN APAE 1 A A C 2 A C C 3 A A A 4 A C A 5 A A A 6 B C A 7 B C B 8 A A A 9 A B A MIC Key: A = MIC's of 1.0 g/mL or less B = MIC's of greater than 1.0 g/mL to 8.0 g/mL C = MIC's of greater than 8.0 g/mL to 16.0 g/mL D = MIC's of greater than 16.0 g/mL * AECO is Escherichia coli ATCC25922. AKPN is Klebsiella pneumonia ATCC43816. APAE is Pseudomonas aeruginosa ATCC27853.

(111) It should be understood that the organic compounds according to the invention may exhibit the phenomenon of tautomerism. As the chemical structures within this specification can only represent one of the possible tautomeric forms, it should be understood that the invention encompasses any tautomeric form of the drawn structure.

(112) Furthermore, while particular embodiments of the present invention have been shown and described herein for purposes of illustration, it will be understood, of course, that the invention is not limited thereto since modifications may be made by persons skilled in the art, particularly in light of the foregoing teachings, without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

(113) All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are incorporated herein by reference, in their entirety to the extent not inconsistent with the present description.