U.S. patent application number 11/417346 was filed with the patent office on 2007-10-18 for antibacterial agents.
This patent application is currently assigned to University of Washington. Invention is credited to Niels H. Andersen, Jason Bowman, Alice Erwin, Eric Harwood, Toni Kline, Khisimuzi Mdluli, Simon Ng, Keith B. Pfister, Ribhi Shawar, Allan S. Wagman, Asha Yabannavar.
Application Number | 20070244197 11/417346 |
Document ID | / |
Family ID | 32719190 |
Filed Date | 2007-10-18 |
United States Patent
Application |
20070244197 |
Kind Code |
A1 |
Andersen; Niels H. ; et
al. |
October 18, 2007 |
Antibacterial agents
Abstract
Antibacterial compounds of formula I are provided: ##STR1## As
well as stereoisomers, pharmaceutically acceptable salts, esters,
and prodrugs thereof; pharmaceutical compositions comprising such
compounds; methods of treating bacterial infections by the
administration of such compounds; and processes for the preparation
of the compounds.
Inventors: |
Andersen; Niels H.;
(Seattle, WA) ; Bowman; Jason; (Quincy, IL)
; Erwin; Alice; (Seattle, WA) ; Harwood; Eric;
(Seattle, WA) ; Kline; Toni; (Seattle, WA)
; Mdluli; Khisimuzi; (Coppell, TX) ; Ng;
Simon; (Walnut Creek, CA) ; Pfister; Keith B.;
(San Ramon, CA) ; Shawar; Ribhi; (Bellevue,
WA) ; Wagman; Allan S.; (Belmont, CA) ;
Yabannavar; Asha; (Lafayette, CA) |
Correspondence
Address: |
NIXON PEABODY LLP - PATENT GROUP
CLINTON SQUARE
P.O. BOX 31051
ROCHESTER
NY
14603-1051
US
|
Assignee: |
University of Washington
Seattle
WA
|
Family ID: |
32719190 |
Appl. No.: |
11/417346 |
Filed: |
May 3, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10754928 |
Jan 8, 2004 |
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11417346 |
May 3, 2006 |
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60438523 |
Jan 8, 2003 |
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60466974 |
Apr 30, 2003 |
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60520211 |
Nov 13, 2003 |
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Current U.S.
Class: |
514/575 ;
562/623 |
Current CPC
Class: |
C07C 251/40 20130101;
C07C 275/16 20130101; C07C 2601/04 20170501; A61P 31/04 20180101;
A61P 43/00 20180101; C07C 323/62 20130101; C07D 213/80 20130101;
C07D 239/26 20130101; C07D 207/27 20130101; C07D 211/26 20130101;
C07D 213/38 20130101; C07C 311/19 20130101; C07C 311/06 20130101;
C07D 233/56 20130101; C07C 259/06 20130101; C07D 211/56 20130101;
C07D 207/16 20130101; C07D 295/13 20130101; A61P 29/00 20180101;
C07D 213/54 20130101; C07C 233/83 20130101; C07C 323/41 20130101;
C07D 207/327 20130101; C07C 2601/18 20170501; C07C 275/26 20130101;
C07D 211/58 20130101; C07D 295/192 20130101; C07C 335/08 20130101;
C07D 213/61 20130101; C07D 213/56 20130101; C07D 213/74 20130101;
C07C 381/00 20130101; C07C 255/57 20130101; C07D 207/09 20130101;
C07D 213/40 20130101; C07D 295/155 20130101; C07D 333/20 20130101;
C07D 211/42 20130101; C07C 255/24 20130101; C07D 241/04 20130101;
C07D 333/58 20130101; C07D 211/62 20130101; C07C 311/21 20130101;
C07C 311/08 20130101; C07C 255/25 20130101; C07C 337/08 20130101;
C07D 231/12 20130101; C07D 241/12 20130101; C07D 285/01 20130101;
C07D 213/82 20130101; C07C 275/14 20130101; C07D 295/215 20130101;
C07D 307/68 20130101; C07C 323/25 20130101; C07C 239/16 20130101;
C07D 207/14 20130101; C07D 215/48 20130101; C07D 239/42 20130101;
A61P 31/00 20180101; C07C 255/44 20130101; C07C 2603/74 20170501;
C07D 233/64 20130101; C07D 317/68 20130101; C07D 317/60 20130101;
C07D 263/34 20130101; C07D 333/32 20130101; A61P 11/00 20180101;
C07C 2602/42 20170501; C07D 213/81 20130101; C07D 235/14 20130101;
C07C 279/14 20130101; C07D 241/18 20130101; C07D 333/24 20130101;
C07D 311/24 20130101; C07D 217/26 20130101; C07D 453/00 20130101;
C07D 295/135 20130101; C07C 2601/14 20170501; C07C 2601/02
20170501; C07D 207/08 20130101; C07C 317/32 20130101; C07C 323/60
20130101; C07D 333/36 20130101 |
Class at
Publication: |
514/575 ;
562/623 |
International
Class: |
A61K 31/19 20060101
A61K031/19; C07C 259/04 20060101 C07C259/04 |
Claims
1. A compound according to the formula IA: ##STR1484## or a
stereoisomer, pharmaceutically acceptable salt, ester, or prodrug
thereof, wherein D is absent or selected from the group consisting
of (1) substituted or unsubstituted C.sub.3-C.sub.8-cycloalkyl; (2)
substituted or unsubstituted aryl; (3) substituted or unsubstituted
heterocyclyl; and (4) substituted or unsubstituted heteroaryl; Y is
selected from the group consisting of (1) substituted or
unsubstituted C.sub.3-C.sub.8-cycloalkyl; (2) substituted or
unsubstituted aryl; (3) substituted or unsubstituted heterocyclyl;
and (4) substituted or unsubstituted heteroaryl; R.sub.4 is H or
substituted or unsubstituted C.sub.1-C.sub.6-alkyl; A is selected
from the group consisting of (1) --C(R.sup.1a,R.sup.2a)OR.sup.3a;
and (2) --C(R.sup.1a,R.sup.2a)N(R.sup.4a,R.sup.5a); wherein
R.sup.1a, R.sup.2a, R.sup.4a, and R.sup.5a are independently
selected from the group consisting of (1) H; and (2) substituted
and unsubstituted C.sub.1-C.sub.6-alkyl.
2. The compound of claim 1, wherein A is
--C(R.sup.1a,R.sup.2a)OR.sup.3a.
3. The compound of claim 2, wherein A is --CH.sub.2OH.
4. The compound of claim 2, wherein A is --CH(CH.sub.3)OH.
5. The compound of claim 1, wherein A is
--C(R.sup.1a,R.sup.2a)N(R.sup.4a,R.sup.5a).
6. The compound of claim 5, wherein A is
--CH(CH.sub.3)NH.sub.2.
7. The compound of claim 1, wherein D is absent and Y is a
substituted or unsubstituted aryl.
8. The compound of claim 1, wherein D is a substituted or
unsubstituted aryl and Y is a substituted or unsubstituted
aryl.
9. A compound according to the formula IB: ##STR1485## or a
stereoisomer, pharmaceutically acceptable salt, ester, or prodrug
thereof, wherein D is absent or selected from the group consisting
of (1) substituted or unsubstituted C.sub.3-C.sub.8-cycloalkyl; (2)
substituted or unsubstituted aryl; (3) substituted or unsubstituted
heterocyclyl; and (4) substituted or unsubstituted heteroaryl; G is
--C.ident.C--C.ident.C--; Y is selected from the group consisting
of (1) substituted or unsubstituted C.sub.3-C.sub.8-cycloalkyl; (2)
substituted or unsubstituted aryl; (3) substituted or unsubstituted
heterocyclyl; and (4) substituted or unsubstituted heteroaryl;
R.sub.4 is H or substituted or unsubstituted C.sub.1-C.sub.6-alkyl;
A is --C(R.sup.1a,R.sup.2a)N(R.sup.4a,R.sup.5a), wherein R.sup.1a,
R.sup.2a, R.sup.4a, and R.sup.5a are independently selected from
the group consisting of (1) H; and (2) substituted and
unsubstituted C.sub.1-C.sub.6-alkyl.
10. A pharmaceutical composition comprising the compound of claim 1
and a pharmaceutically acceptable excipient.
11. A pharmaceutical composition comprising the compound of claim 9
and a pharmaceutically acceptable excipient.
12. A pharmaceutical composition comprising a compound of claim 1,
a second agent, and a pharmaceutically acceptable excipient,
wherein the second agent is an antibacterial agent, and
antiendotoxin agent or an inhaled non-antibacterial agent for the
treatment of respiratory tract infection.
13. A pharmaceutical composition comprising a compound of claim 9,
a second agent, and a pharmaceutically acceptable excipient,
wherein the second agent is an antibacterial agent, and
antiendotoxin agent or an inhaled non-antibacterial agent for the
treatment of respiratory tract infection.
14. A method of inhibiting LpxC comprising administering to a
patient in need thereof, an effective amount of the compound of
claim 1.
15. A method of inhibiting LpxC comprising administering to a
patient in need thereof, an effective amount of the compound of
claim 9.
16. A method of inhibiting LpxC comprising administering to a
patient in need thereof, an effective amount of the compound of
claim 1 and an effective amount of a second agent, wherein the
second agent is an antibacterial agent, an antiendotoxin agent or
an inhaled non-antibacterial agent for the treatment of respiratory
tract infection.
17. A method of inhibiting LpxC comprising administering to a
patient in need thereof, an effective amount of the compound of
claim 9 and an effective amount of a second agent, wherein the
second agent is an antibacterial agent, an antiendotoxin agent or
an inhaled non-antibacterial agent for the treatment of respiratory
tract infection.
18. A method of treating an infection comprising administering to a
patient in need thereof, an effective amount of the compound of
claim 1.
19. A method of treating an infection comprising administering to a
patient in need thereof, an effective amount of the compound of
claim 9.
20. A method of treating an infection comprising administering to a
patient in need thereof, an effective amount of the compound of
claim 1 and an effective amount of a second agent, wherein the
second agent is an antibacterial agent, an antiendotoxin agent or
an inhaled non-antibacterial agent for the treatment of respiratory
tract infection.
21. A method of treating an infection comprising administering to a
patient in need thereof, an effective amount of the compound of
claim 9 and an effective amount of a second agent, wherein the
second agent is an antibacterial agent, an antiendotoxin agent or
an inhaled non-antibacterial agent for the treatment of respiratory
tract infection.
Description
[0001] This application claims benefit of priority to the following
U.S. Provisional Patent Applications, Ser. No. 60/438,523, filed
Jan. 8, 2003; Ser. No. 60/466,974, filed Apr. 30, 2003; and Ser.
No. 60/520,211 filed Nov. 13, 2003; each of which is incorporated
herein by reference in its entirety for any purpose.
FIELD OF THE INVENTION
[0002] This invention pertains generally to treating infections
caused by gram-negative bacteria. More specifically, the invention
described herein pertains to treating gram-negative infections by
inhibiting activity of
UDP-3-O--(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase
(LpxC). The present invention provides small molecule inhibitors of
LpxC, pharmaceutical formulations containing such inhibitors,
methods of treating patients with such pharmaceutical formulations,
and to methods of preparing such pharmaceutical formulations and
inhibitors. The inhibitors can be used to treat Gram-negative
infections of patients alone and in combination with other
antibacterials.
BACKGROUND OF THE INVENTION
[0003] Over the past several decades, the frequency of
antimicrobial resistance and its association with serious
infectious diseases have increased at alarming rates. The
increasing prevalence of resistance among nosocomial pathogens is
particularly disconcerting. Of the over 2 million nosocomial
infections occurring each year in the United States, 50 to 60% are
caused by antimicrobial-resistant strains of bacteria. This high
rate of resistance increases the morbidity, mortality, and costs
associated with nosocomial infections. In the United States,
nosocomial infections are thought to contribute to or cause more
than 77,000 deaths per year and cost approximately $5 to $10
billion annually. Among Gram-positive organisms, the most important
resistant pathogens are methicillin-(oxacillin-) resistant
Staphylococcus aureus, .beta.-lactam-resistant and
multidrug-resistant pneumococci, and vancomycin-resistant
enterococci. Important causes of Gram-negative resistance include
extended-spectrum .beta.-lactamases (ESBLs) in Klebsiella
pneumoniae, Escherichia coli, and Proteus mirabilis, high-level
third-generation cephalosporin (Amp C) .beta.-lactamase resistance
among Enterobacter species and Citrobacter freundii, and
multidrug-resistance genes observed in Pseudomonas aeruginosa,
Acinetobacter, and Stenotrophomonas maltophilia. (Jones RN 2001
Chest 119 (supplement), 397S-404S: Resistance patterns among
nosocomial pathogens: Trends over the past few years.)
[0004] The problem of antibacterial resistance is compounded by the
existence of bacterial strains resistant to multiple
antibacterials. For example, Pseudomonas aeruginosa isolates
resistant to fluoroquinolones are virtually all resistant to
additional antibacterials (Sahm D F et al 2001 Antimicrobial Agents
and Chemotherapy 45, 267-274: Evaluation of current activities of
fluoroquinolones against gram-negative bacilli using centralized in
vitro testing and electronic surveillance.)
[0005] Thus there is a need for new antibacterials, particularly
antibacterials with novel mechanisms of action. Most of the
antibacterial discovery effort in the pharmaceutical industry is
aimed at development of drugs effective against gram-positive
bacteria. However, there is also a need for new gram-negative
antibacterials. Gram-negative bacteria are in general more
resistant to a large number of antibacterials and chemotherapeutic
agents than are gram-positive bacteria. A survey of recently
reported antibacterials of natural origin showed that over 90%
lacked activity against Escherichia coli, although they were active
against gram-positive bacteria. The outer membrane of gram-negative
bacteria contributes to this intrinsic resistance by acting as an
efficient permeability barrier, because the narrow porin channels
limit the penetration of hydrophilic solutes and the low fluidity
of the lipopolysaccharide leaflet slows down the inward diffusion
of lipophilic solutes. A second mechanism contributes to the
intrinsic resistance of gram-negative bacteria. Recent studies
showed that multiple drug efflux pumps, sometimes with unusually
broad specificity, act as this second factor to create the general
intrinsic resistance of gram-negative bacteria. When their
expression levels are elevated as a consequence of physiological
regulation or genetic alteration, they can frequently produce
impressive levels of resistance to a wide variety of antimicrobial
agents. (Nikaido H 1998 Clinical Infectious Diseases 27(Suppl 1),
S32-41: Antibacterial resistance caused by gram-negative multidrug
efflux pumps.)
[0006] Historically, most development of antimicrobial agents has
been relatively empirical. Active compounds have generally been
found via screening soil, sewage, water, and other natural
substances to detect antimicrobial-producing organisms, or by
screening various chemical compounds. Once a leading candidate has
been found and its chemical structure determined, a series of
analogs is made to identify an optimal compound for further
clinical development. A more rational approach involves the
defining of new targets, such as genes or enzymatic functions,
responsible for a crucial cellular essential activity. Once this
has been done, inhibitors or blockers of the function or gene
product can be developed.
[0007] In order to identify potential targets for novel
gram-negative antibacterial agents, studies aimed at identifying
all essential and important genes in Pseudomonas aeruginosa have
been performed. Among the essential genes identified was lpxC, that
encodes the enzyme
uridyldiphospho-3-O--(R-hydroxydecanoyl)-N-acetylglucosamine
deacetylase (LpxC). This enzyme is the first committed step in the
synthesis of lipid A, the lipid moiety of lipopolysaccharide, that
is an essential component of all gram-negative bacteria. It
therefore is an attractive target for novel antibacterials. In
order to be useful as antibacterial agents, LpxC inhibitors would
not only have to inhibit the enzymatic activity of LpxC from a
variety of bacteria, but would have to defeat the intrinsic
resistance mechanisms of gram-negative bacteria, as described
above: they would have to penetrate the outer membrane and be
relatively unsusceptible to multidrug efflux pumps.
[0008] Researchers have identified a few compounds with
antibacterial activity that target lipid A biosynthesis. WO
97/42179 to Patchett et al. discloses compounds of the formula:
##STR2##
[0009] The compounds possess activity against certain gram-negative
organisms, for example Escherichia coli, but are not active against
other medically important gram-negative bacteria, for example
Pseudomonas aeruginosa. Subsequent studies have found that the
primary reason for their inactivity against particular, medically
important gram-negative bacteria is their poor ability to inhibit
P. aeruginosa LpxC; efflux by the major multidrug efflux pump or
inability to penetrate the outer membrane were not the critical
factors.
[0010] Jackman et al., in J. Biol. Chem. (vol. 275, no. 15, Apr.
14, 2000, pps. 11002-11009), discuss the mechanism of lipid A
biosynthesis in the context of gram-negative bacteria and discloses
a new class of hydroxamate-containing inhibitors of LpxC. Wyckoff
et al., in Trends in Microbiology (vol. 6, no. 4, April 1998, pps.
154-159), discuss the role of LpxC in lipid A biosynthesis and its
role in regulation. Wyckoff et al. disclose a few oxazoline
hydroxamic acids that inhibit bacterial growth. However, Wyckoff et
al. also discuss the shortcomings of the available deacetylase
inhibitors as bactericidal agents against Pseudomonas and that more
work is needed to be done in the area.
[0011] Thus, an increasing need exists for LpxC inhibitors that
have activity as bactericidal agents against gram-negative
bacteria. It is, accordingly, an object of this invention to
provide compounds and combinations of such compounds for use in the
preparation of antibacterials and other pharmaceuticals capable of
inhibiting Gram-negative bacterial infections.
[0012] U.S. Patent Publication No. 2001/0053555 (U.S. patent
application Ser. No. 08/958,638) published Dec. 20, 2001,
corresponding to WO 98/18754 published May 7, 1998 discloses a
combinatorial library of hydroxylamine, hydroxamic acid,
hydroxyurea and hydroxylsulfonamide compounds purported to be
potentially useful as inhibitors of metalloproteases. U.S. Pat. No.
6,281,245, a continuation in part of U.S. Ser. No. 08/958,638
claims a method of inhibiting a deformylase enzyme by administering
one of the hydroxylamine compounds from the combinatorial library
as disclosed in U.S. Patent Publication No. 2001/0053555 and the
corresponding WO 98/18754. Related to the above disclosed patent
publications is WO 99/57097, published Nov. 11, 1999, that
discloses a method of solid phase synthesis of the hydroxylamine
library of compounds. WO 00/61134 (to British Biotech
Pharmaceuticals Limited), published Oct. 19, 2000, discloses
compounds of the formula below: ##STR3##
[0013] The compounds are useful as antimicrobial agents that are
believed to have bactericidal activity at least in part to
intracellular inhibition of bacterial polypeptide deformylase.
[0014] In an earlier to British Biotech Pharmaceuticals Limited, WO
99/39704, published Aug. 12, 1999, compounds of the formula below
are disclosed: ##STR4## The compounds are useful as antimicrobial
agents useful against gram-negative and gram positive bacteria.
[0015] Recently, De Novo Pharmaceuticals LTD disclosed in WO
02/50081, published Jun. 27, 2002, antibacterial and antiprotozoal
agents having the formulae shown below: ##STR5## The patent
publication discusses that the antibacterial activity is due, at
least in part, to intracellular inhibition of bacterial polypeptide
deformylase.
SUMMARY OF THE INVENTION
[0016] The present invention provides novel compounds,
pharmaceutical formulations including the compounds, methods of
inhibiting UDP-3-O--(R-3-hydroxydecanoyl)-N-acetylglucosamine
deacetylase (LpxC), and methods of treating gram-negative bacterial
infections.
[0017] In one embodiment, the present invention provides compounds
of formula I: ##STR6## or stereoisomers, pharmaceutically
acceptable salts, esters, and prodrugs thereof, wherein [0018] E is
absent or selected from the group consisting of
[0019] (1) H,
[0020] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0021] (3) substituted or unsubstituted
C.sub.2-C.sub.6-alkenyl,
[0022] (4) substituted or unsubstituted
C.sub.2-C.sub.6-alkynyl,
[0023] (5) substituted or unsubstituted aryl,
[0024] (6) substituted or unsubstituted heterocyclyl, and
[0025] (7) substituted or unsubstituted heteroaryl; [0026] L is
absent or selected from the group consisting of
[0027] (1) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0028] (2)
--(NH).sub.0-1--(CH.sub.2).sub.j--NR.sup.3L--(CH.sub.2).sub.k--,
[0029] (3) --(NH).sub.0-1--C(R.sup.1L,
R.sup.2L)--NR.sup.3L--C(R.sup.1L, R.sup.2L)--,
[0030] (4) --C(R.sup.1L, R.sup.2L)--O--C(R.sup.1L, R.sup.2L)--,
[0031] (5) --(CH.sub.2).sub.j--NR.sup.3L--C(R.sup.1L,
R.sup.2L)--CONH--(CH.sub.2).sub.k--,
[0032] (6) --CO--C(R.sup.1L, R.sup.2L)--NHCO--,
[0033] (7) --CONH--,
[0034] (8) --NHCO--,
[0035] wherein
[0036] R.sup.1L, R.sup.2L, and R.sup.3L are independently selected
from the group consisting of [0037] (a) H, [0038] (b) substituted
or unsubstituted C.sub.1-C.sub.6-alkyl, [0039] (c)
C.sub.1-C.sub.6-alkyl substituted with aryl, [0040] (d)
C.sub.1-C.sub.6-alkyl substituted with heterocyclyl, and [0041] (e)
C.sub.1-C.sub.6-alkyl substituted with heteroaryl
[0042] or R.sup.1L and R.sup.3L, together with the atoms to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring
atoms of the heterocyclic ring system are selected from N, O and
S;
[0043] j is an integer of 0-4;
[0044] k is an integer of 0-4; [0045] D is absent or selected from
the group consisting of
[0046] (1) substituted or unsubstituted
C.sub.3-C.sub.8-cycloalkyl,
[0047] (2) substituted or unsubstituted aryl,
[0048] (3) substituted or unsubstituted heterocyclyl, and
[0049] (4) substituted or unsubstituted heteroaryl; [0050] G is
absent or selected from the group consisting of
[0051] (1) --(CH.sub.2).sub.i--O--(CH.sub.2).sub.i--,
[0052] (2) --(CH.sub.2).sub.i--S--(CH.sub.2).sub.i--,
[0053] (3) --(CH.sub.2).sub.i--NR.sup.g--(CH.sub.2).sub.i--,
[0054] (4) --C(.dbd.O)--,
[0055] (5) --NHC(.dbd.O)--,
[0056] (6) --C(.dbd.O)NH--,
[0057] (7) --(CH.sub.2).sub.iNHCH.sub.2C(.dbd.O)NH--,
[0058] (8) --C.ident.C--,
[0059] (9) --C.ident.C--C.ident.C--, and
[0060] (10) --C.dbd.C--;
[0061] wherein
[0062] Rg is H or substituted or unsubstituted
C.sub.1-C.sub.6-alkyl;
[0063] i is an interger of 0-4; [0064] Y is selected from the group
consisting of
[0065] (1) substituted or unsubstituted
C.sub.3-C.sub.8-cycloalkyl,
[0066] (2) substituted or unsubstituted aryl,
[0067] (3) substituted or unsubstituted heterocyclyl, and
[0068] (4) substituted or unsubstituted heteroaryl; [0069] X is
selected from the group consisting of
[0070] (1) --(C.dbd.O)--,
[0071] (2) --C.sub.1-C.sub.6-alkyl-(C.dbd.O)--,
[0072] (3) --C.sub.2-C.sub.6-alkenyl-(C.dbd.O)--,
[0073] (4) --C.sub.2-C.sub.6-alkynyl-(C.dbd.O)--, and
[0074] (5) --CH.sub.2--;
[0075] or when B is absent, X and A, together with the atoms to
which they are attached can form a heterocyclic ring, having from 5
to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring
system are selected from N, O and S; [0076] B is a absent or
##STR7##
[0077] wherein R.sup.1b and R.sup.2b, are independently selected
from the group consisting of [0078] (a) H, [0079] (b) substituted
or unsubstituted C.sub.1-C.sub.6-alkyl, [0080] (c) substituted or
unsubstituted C.sub.2-C.sub.6-alkenyl, [0081] (d) substituted or
unsubstituted C.sub.2-C.sub.6-alkynyl, [0082] (e) substituted or
unsubstituted aryl, [0083] (f) substituted or unsubstituted
heterocyclyl, [0084] (g) substituted or unsubstituted heteroaryl,
[0085] (h) C.sub.1-C.sub.6-alkyl substituted with aryl, [0086] (i)
C.sub.1-C.sub.6-alkyl substituted with heterocyclyl, and [0087] (j)
C.sub.1-C.sub.6-alkyl substituted with heteroaryl,
[0088] or R.sup.1b and R.sup.2b, together with the atoms to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 5 to 8 ring atoms, wherein 1-2 ring
atoms of the heterocyclic ring system are selected from N, O and
S;
[0089] q is an integer of 0-4; [0090] R.sub.3 is H or substituted
or unsubstituted C.sub.1-C.sub.6-alkyl,
[0091] or R.sub.3 and A, together with the atoms to which they are
attached can form a substituted or unsubstituted 3-10 membered
cycloalkyl or a heterocyclic ring system, wherein the heterocyclic
ring system may have from 3 to 10 ring atoms, with 1 to 2 rings
being in the ring system and contain from 1-4 heteroatoms selected
from N, O and S; [0092] R.sub.4 is H or substituted or
unsubstituted C.sub.1-C.sub.6-alkyl,
[0093] or R.sub.4 and A, together with the atoms to which they are
attached can form a substituted or unsubstituted heterocyclic ring,
having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the
heterocyclic ring system are selected from N, O and S; [0094] n is
an integer of 0-6; [0095] A is selected from the group consisting
of
[0096] (1) H,
[0097] (2) --(CH.sub.2).sub.rC(R.sup.1a,
R.sup.2a)(CH.sub.2).sub.sOR.sup.3a,
[0098] (3) --(CH.sub.2).sub.rC(R.sup.1a, R.sup.2a)N(R.sup.4a,
R.sup.5a),
[0099] (4) --(CH.sub.2).sub.rC(R.sup.1a,
R.sup.2a)N(R.sup.4a)COR.sup.3a,
[0100] (5) --(CH.sub.2).sub.rC(R.sup.1a, R.sup.2a)NHCON(R.sup.4a,
R.sup.5a),
[0101] (6) --(CH.sub.2).sub.rC(R.sup.1a,
R.sup.2a)NHC(.dbd.NH)N(R.sup.4a, R.sup.5a),
[0102] (7) --CH(R.sup.1a, R.sup.2a),
[0103] (8) --C.ident.CH,
[0104] (9) --(CH.sub.2).sub.rC(R.sup.1a, R.sup.2a)CN,
[0105] (10) --(CH.sub.2).sub.rC(R.sup.1a,
R.sup.2a)CO.sub.2R.sup.3a, and
[0106] (11) --(CH.sub.2).sub.rC(R.sup.1a, R.sup.2a)CON(R.sup.4a,
R.sup.5a),
[0107] wherein R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4a, and R.sup.5a
are independently selected from the group consisting of [0108] (a)
H, [0109] (b) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0110] (c) substituted or unsubstituted aryl, [0111] (d)
substituted or unsubstituted heterocyclyl, [0112] (e) substituted
or unsubstituted heteroaryl, [0113] (f) C.sub.1-C.sub.6-alkyl
substituted with aryl, [0114] (g) C.sub.1-C.sub.6-alkyl substituted
with heterocyclyl, and [0115] (h) C.sub.1-C.sub.6-alkyl
substituted-with heteroaryl, [0116] or R.sup.4a and R.sup.5a
together with the N atom to which they are attached can form a
substituted or unsubstituted heterocyclic ring, having from 5 to 8
ring atoms, wherein 1-2 ring atoms of the heterocyclic ring system
are selected from N, O and S;
[0117] r is an integer of 0-4;
[0118] s is an integer of 0-4; [0119] Q is absent or selected from
the group consisting of
[0120] (1) --C(.dbd.O)N(R.sub.1, R.sub.2),
[0121] (2) --NHC(.dbd.O)N(R.sub.1, R.sub.2),
[0122] (3) --N(OH)C(.dbd.O)N(R.sub.1, R.sub.2).
[0123] (4) --CH(OH)C(.dbd.O)N(R.sub.1, R.sub.2),
[0124] (5) --CH[N(R.sup.2q, R.sup.3q)]C(.dbd.O)N(R.sub.1,
R.sub.2),
[0125] (6) --CHR.sub.1qC(.dbd.O)N(R.sub.1, R.sub.2),
[0126] (7) --CO.sub.2H,
[0127] (8) --C(.dbd.O)NHSO.sub.2R.sup.4q,
[0128] (9) --SO.sub.2NH.sub.2,
[0129] (10) --N(OH)C(.dbd.O)R.sup.1q,
[0130] (11) --N(OH)SO.sub.2R.sup.4q,
[0131] (12) --NHSO.sub.2R.sup.4q,
[0132] (13) --SH,
[0133] (14) --CH(SH)(CH.sub.2).sub.0-1C(.dbd.O)N(R.sub.1,
R.sub.2),
[0134] (15) --CH(SH)(CH.sub.2).sub.0-1CO.sub.2H,
[0135] (16) --CH(OH)(CH.sub.2).sub.0-1CO.sub.2H,
[0136] (17) --CH(SH)CH.sub.2CO.sub.2R.sup.1q,
[0137] (18) --CH(OH)(CH.sub.2)SO.sub.2NH.sub.2,
[0138] (19) --CH(CH.sub.2SH)NHCOR.sup.1q,
[0139] (20) --CH(CH.sub.2SH)NHSO.sub.2R.sup.4q,
[0140] (21) --CH(CH.sub.2SR.sup.5q)CO.sub.2H,
[0141] (22) --CH(CH.sub.2SH)NHSO.sub.2NH.sub.2,
[0142] (23) --CH(CH.sub.2OH)CO.sub.2H,
[0143] (24) --H(CH.sub.2OH)NHSO.sub.2NH.sub.2,
[0144] (25) --C(.dbd.O)CH.sub.2CO.sub.2H,
[0145] (26) --C(.dbd.O)(CH.sub.2).sub.0-1CONH.sub.2,
[0146] (27) --OSO.sub.2NHR.sup.5q,
[0147] (28) --SO.sub.2NHNH.sub.2,
[0148] (29) --P(.dbd.O)(OH).sub.2, ##STR8##
[0149] wherein
[0150] R.sub.1 is selected from the group consisting of [0151] (1)
H, [0152] (2) --OH, [0153] (3) --OC.sub.1-6-alkyl, [0154] (4)
--N(R.sup.2q, R.sup.3q), and [0155] (5) substituted or
unsubstituted C.sub.1-6-alkyl;
[0156] R.sub.2 is selected from the group consisting of [0157] (1)
H, [0158] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0159] (3) substituted or unsubstituted C.sub.2-C.sub.6-alkenyl,
[0160] (4) substituted or unsubstituted C.sub.2-C.sub.6-alkenyl,
[0161] (5) substituted or unsubstituted aryl, [0162] (6)
substituted or unsubstituted heterocyclyl, [0163] (7) substituted
or unsubstituted heteroaryl, [0164] (8) C.sub.1-C.sub.6-alkyl
substituted with aryl, [0165] (9) C.sub.1-C.sub.6-alkyl substituted
with heterocyclyl, and [0166] (10) C.sub.1-C.sub.6-alkyl
substituted with heteroaryl, [0167] or R.sup.1 and R.sup.2,
together with the N atom to which they are attached can form a
substituted or unsubstituted heterocyclic ring, having from 3 to 10
ring atoms, wherein 1-4 ring atoms of the heterocyclic ring system
are selected from N, O and S, [0168] or R.sup.2 and R.sup.4,
together with the N atoms to which they are attached can form a
substituted or unsubstituted heterocyclic ring, having from 3 to 10
ring atoms, wherein 1-4 ring atoms of the heterocyclic ring system
are selected from N, O and S;
[0169] R.sup.1q, R.sup.2q, R.sup.3q, R.sup.4q, and R.sup.5q are
selected from H or C.sub.1-C.sub.6 alkyl,
wherein B is absent, or E, L, G, and B are absent, or E, L, and G
are absent, or E, L, and B are absent, or E, L, D, G, and B are
absent.
[0170] In one aspect, the invention provides a method of inhibiting
a deacetylase enzyme in a gram-negative bacteria, thereby affecting
bacterial growth, comprising administering to a patient in need of
such inhibition a compound of formula I.
[0171] In another aspect, the invention provides a method of
inhibiting LpxC, thereby modulating the virulence of a bacterial
infection, comprising administering to a patient in need of such
inhibition a compound of formula I.
[0172] In another aspect, the invention provides a method for
treating a subject with a gram-negative bacterial infection
comprising administering to the subject in need thereof an
antibacterially effective amount of a compound of formula I with a
pharmaceutically acceptable carrier. In a preferred embodiment of
the method of treatment, the subject is a mammal and in some
embodiments, a human.
[0173] In another aspect, the invention provides a method of
administering an inhibitory amount of a compound of formula I to
fermentative or non-fermentative gram-negative bacteria. In a
preferred embodiment of the method of administering an inhibitory
amount of a compound of formula I to fermentative or
non-fermentative gram-negative bacteria, the gram-negative bacteria
are selected from the group consisting of Pseudomonas aeruginosa,
Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes
xylosoxidans, Acinetobacter, Enterobacteriaceae, Haemophilus, and
Neisseria species.
[0174] In another embodiment, the invention provides a method of
administering an inhibitory amount of a compound of formula I to
gram-negative bacteria, such as Enterobacteriaceae which is
selected from the group consisting of organisms such as Serratia,
Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella,
Providencia, Morganella, Cedecea, and Edwardsiella species and
Escherichia coli.
[0175] Another embodiment of the invention provides a
pharmaceutical composition comprising an effective amount of a
compound of Formula I with a pharmaceutically acceptable carrier
thereof.
[0176] Pharmaceutical formulations according to the present
invention are provided which include any of the compounds described
above in combination with a pharmaceutically acceptable
carrier.
[0177] Another embodiment of the invention provides a method of
co-administering the compound of formula I with other therapeutic
agents that are selected for their particular usefulness against
the condition that is being treated.
[0178] For example, the compound of formula I is useful in
combination with other anti-bacterial agents. The compound of
formula I augments the sensitivity of gram-negative bacteria to
existing classes of antibacterials. Combinations of the presently
disclosed compounds with other anti-bacterial agents are within the
scope of the invention. Such anti-bacterial agents include, but are
not limited to, erythromycin, rifampicin, Nalidixic acid,
carbenicillin, bacitracin, cycloserine, fosfomycin, and
vancomycin.
DETAILED DESCRIPTION
[0179] The present invention provides novel compounds, methods for
inhibiting LpxC in gram-negative bacteria, and novel methods for
treating bacterial infections. The compounds provided herein can be
formulated into pharmaceutical formulations and medicaments that
are useful in the methods of the invention. The invention also
provides for the use of the compounds in preparing medicaments and
pharmaceutical formulations, for use of the compounds in inhibiting
LpxC, and for use of the compounds in treating bacterial infections
in a subject.
[0180] The following abbreviations and definitions are used
throughout this application:
[0181] "LpxC" is an abbreviation that stands for
UDP-3-O--(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase.
[0182] Generally, reference to a certain element such as hydrogen
or H is meant to include all isotopes of that element. For example,
if an R group is defined to include hydrogen or H, it also includes
deuterium and tritium.
[0183] The phrase "alkyl" refers to alkyl groups that do not
contain heteroatoms. Thus the phrase includes straight chain alkyl
groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also
includes branched chain isomers of straight chain alkyl groups,
including but not limited to, the following that are provided by
way of example: --CH(CH.sub.3).sub.2,
--CH(CH.sub.3)(CH.sub.2CH.sub.3), --CH(CH.sub.2CH.sub.3).sub.2,
--C(CH.sub.3).sub.3, --C(CH.sub.2CH.sub.3).sub.3,
--CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2, --CH.sub.2C(CH.sub.3).sub.3,
--CH.sub.2C(CH.sub.2CH.sub.3).sub.3,
--CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH.sub.2CH.sub.2CH(CH.sub.2CH.sub.3).sub.2,
--CH.sub.2CH.sub.2C(CH.sub.3).sub.3,
--CH.sub.2CH.sub.2C(CH.sub.2CH.sub.3).sub.3,
--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2,
--CH(CH.sub.3)CH(CH.sub.3)CH(CH.sub.3).sub.2,
--CH(CH.sub.2CH.sub.3)CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2CH.sub.3),
and others. The phrase also includes cyclic alkyl groups such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl and such rings substituted with straight and branched
chain alkyl groups as defined above. Thus the phrase alkyl groups
includes primary alkyl groups, secondary alkyl groups, and tertiary
alkyl groups. Preferred alkyl groups include straight and branched
chain alkyl groups and cyclic alkyl groups having 1 to 12 carbon
atoms.
[0184] The phrase "substituted alkyl" refers to an alkyl group as
defined above in which one or more bonds to a carbon(s) or
hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon
atoms such as, but not limited to, a halogen atom such as F, Cl,
Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy
groups, aryloxy groups, and ester groups; a sulfur atom in groups
such as thiol groups, alkyl and aryl sulfide groups, sulfone
groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in
groups such as amines, amides, alkylamines, dialkylamines,
arylamines, alkylarylamines, diarylamines, N-oxides, imides, and
enamines; a silicon atom in groups such as in trialkylsilyl groups,
dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl
groups; and other heteroatoms in various other groups. Substituted
alkyl groups also include groups in which one or more bonds to a
carbon(s) or hydrogen(s) atom is replaced by a higher-order bond
(e.g., a double- or triple-bond) to a heteroatom such as oxygen in
oxo, carbonyl, carboxyl, and ester groups; nitrogen in groups such
as imines, oximes, hydrazones, and nitriles. Substituted alkyl
groups further include alkyl groups in which one or more bonds to a
carbon(s) or hydrogen(s) atoms is replaced by a bond to an aryl,
heterocyclyl group, or cycloalkyl group. Preferred substituted
alkyl groups include, among others, alkyl groups in which one or
more bonds to a carbon or hydrogen atom is/are replaced by one or
more bonds to fluorine atoms. Another preferred substituted alkyl
group is the trifluoromethyl group and other alkyl groups that
contain the trifluoromethyl group. Other preferred substituted
alkyl groups include those in which one or more bonds to a carbon
or hydrogen atom is replaced by a bond to an oxygen atom such that
the substituted alkyl group contains a hydroxyl, alkoxy, or aryloxy
group. Still other preferred substituted alkyl groups include alkyl
groups that have an amine, or a substituted or unsubstituted
alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine,
diarylamine, heterocyclylamine, diheterocyclylamine,
(alkyl)(heterocyclyl)amine, or (aryl)(heterocyclyl)amine group.
[0185] The phrase "alkenyl" refers to straight and branched chain
and cyclic groups such as those described with respect to alkyl
groups as defined above, except that at least one double bond
exists between two carbon atoms. Examples include, but are not
limited to vinyl, --CH.dbd.C(H)(CH.sub.3),
--CH.dbd.C(CH.sub.3).sub.2, --C(CH.sub.3).dbd.C(H).sub.2,
--C(CH.sub.3).dbd.C(H)(CH.sub.3),
--C(CH.sub.2CH.sub.3).dbd.CH.sub.2, cyclohexenyl, cyclopentenyl,
cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among
others. The phrase "substituted alkenyl" has the same meaning with
respect to alkenyl groups that substituted alkyl groups had with
respect to unsubstituted alkyl groups. A substituted alkenyl group
includes alkenyl groups in which a non-carbon or non-hydrogen atom
is bonded to a carbon double bonded to another carbon and those in
which one of the non-carbon or non-hydrogen atoms is bonded to a
carbon not involved in a double bond to another carbon.
[0186] The phrase "alkynyl" refers to straight and branched chain
groups such as those described with respect to alkyl groups as
defined above, except that at least one triple bond exists between
two carbon atoms. Examples include, but are not limited to
--C.ident.C(H), --C.ident.C(CH.sub.3),
--C.ident.C(CH.sub.2CH.sub.3), --C(H.sub.2)C.ident.C(H),
--C(H).sub.2C.ident.C(CH.sub.3), and
--C(H).sub.2C.dbd.C(CH.sub.2CH.sub.3) among others. The phrase
"substituted alkynyl" has the same meaning with respect to alkynyl
groups that substituted alkyl groups had with respect to
unsubstituted alkyl groups. A substituted alkynyl group includes
alkynyl groups in which a non-carbon or non-hydrogen atom is bonded
to a carbon triple bonded to another carbon and those in which a
non-carbon or non-hydrogen atom is bonded to a carbon not involved
in a triple bond to another carbon.
[0187] The phrase "heterocyclyl" refers to both aromatic and
nonaromatic ring compounds including monocyclic, bicyclic, and
polycyclic ring compounds such as, but not limited to,
quinuclidinyl, containing 3 or more ring members of which one or
more is a heteroatom such as, but not limited to, N, O, and S.
Although the phrase "unsubstituted heterocyclyl" includes condensed
heterocyclic rings such as benzimidazolyl, it does not include
heterocyclyl groups that have other groups such as alkyl or halo
groups bonded to one of the ring members as compounds such as
2-methylbenzimidazolyl are substituted heterocyclyl groups.
Examples of heterocyclyl groups include, but are not limited to:
unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms
such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl,
pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl,
1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazolyl, (e.g.
1H-tetrazolyl, 2H tetrazolyl, etc.); saturated 3 to 8 membered
rings containing 1 to 4 nitrogen atoms such as, but not limited to,
pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; condensed
unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms
such as, but not limited to, indolyl, isoindolyl, indolinyl,
indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,
benzotriazolyl; unsaturated 3 to 8 membered rings containing 1 to 2
oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to,
oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); saturated 3 to 8
membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen
atoms such as, but not limited to, morpholinyl; unsaturated
condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1
to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl,
benzoxazinyl (e.g. 2H-1,4-benzoxazinyl etc.); unsaturated 3 to 8
membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen
atoms such as, but not limited to, thiazolyl, isothiazolyl,
thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4thiadiazolyl, 1,2,5-thiadiazolyl, etc.); saturated 3 to 8
membered rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen
atoms such as, but not limited to, thiazolodinyl; saturated and
unsaturated 3 to 8 membered rings containing 1 to 2 sulfur atoms
such as, but not limited to, thienyl, dihydrodithiinyl,
dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran;
unsaturated condensed heterocyclic rings containing 1 to 2 sulfur
atoms and 1 to 3 nitrogen atoms such as, but not limited to,
benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g.
2H-1,4benzothiazinyl, etc.), dihydrobenzothiazinyl (e.g.
2H-3,4-dihydrobenzothiazinyl, etc.), unsaturated 3 to 8 membered
rings containing oxygen atoms such as, but not limited to furyl;
unsaturated condensed heterocyclic rings containing 1 to 2 oxygen
atoms such as benzodioxolyl (e.g. 1,3-benzodioxoyl, etc.);
unsaturated 3 to 8 membered rings containing an oxygen atom and 1
to 2 sulfur atoms such as, but not limited to, dihydrooxathiinyl,
saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and
1 to 2 sulfur atoms such as 1,4-oxathiane; unsaturated condensed
rings containing 1 to 2 sulfur atoms such as benzothienyl,
benzodithiinyl; and unsaturated condensed heterocyclic rings
containing an oxygen atom and 1 to 2 oxygen atoms such as
benzoxathiinyl. Heterocyclyl group also include those described
above in which one or more S atoms in the ring is double-bonded to
one or two oxygen atoms (sulfoxides and sulfones). For example,
heterocyclyl groups include tetrahydrothiophene,
tetrahydrothiophene oxide, and tetrahydrothiophene 1,1-dioxide.
Preferred heterocyclyl groups contain 5 or 6 ring members. More
preferred heterocyclyl groups include morpholine, piperazine,
piperidine, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole,
1,2,4-triazole, tetrazole, thiomorpholine, thiomorpholine in which
the S atom of the thiomorpholine is bonded to one or more O atoms,
pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one,
oxazole, quinuclidine, thiazole, isoxazole, furan, and
tetrahydrofuran.
[0188] The phrase "substituted heterocyclyl" refers to a
heterocyclyl group as defined above in which one of the ring
members is bonded to a non-hydrogen atom such as described above
with respect to substituted alkyl groups and substituted aryl
groups. Examples, include, but are not limited to,
2-methylbenzimidazolyl, 5-methylbenzimidazolyl,
5-chlorobenzthiazolyl, 1-methyl piperazinyl, and 2-chloropyridyl
among others.
[0189] The phrase "aryl" refers to aryl groups that do not contain
heteroatoms. Thus the phrase includes, but is not limited to,
groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way of
example. Although the phrase "unsubstituted aryl" includes groups
containing condensed rings such as naphthalene, it does not include
aryl groups that have other groups such as alkyl or halo groups
bonded to one of the ring members, as aryl groups such as tolyl are
considered herein to be substituted aryl groups as described below.
A preferred unsubstituted aryl group is phenyl. Unsubstituted aryl
groups may be bonded to one or more carbon atom(s), oxygen atom(s),
nitrogen atom(s), and/or sulfur atom(s) in the parent compound,
however.
[0190] The phrase "substituted aryl group" has the same meaning
with respect to unsubstituted aryl groups that substituted alkyl
groups had with respect to unsubstituted alkyl groups. However, a
substituted aryl group also includes aryl groups in which one of
the aromatic carbons is bonded to one of the non-carbon or
non-hydrogen atoms described above and also includes aryl groups in
which one or more aromatic carbons of the aryl group is bonded to a
substituted and/or unsubstituted alkyl, alkenyl, or alkynyl group
as defined herein. This includes bonding arrangements in which two
carbon atoms of an aryl group are bonded to two atoms of an alkyl,
alkenyl, or alkynyl group to define a fused ring system (e.g.
dihydronaphthyl or tetrahydronaphthyl). Thus, the phrase
"substituted aryl" includes, but is not limited to tolyl, and
hydroxyphenyl among others. Preferred substituents include straight
and branched chain alkyl groups, --CH.sub.3, --C.sub.2H.sub.5,
--CH.sub.2OH, --OH, --OCH.sub.3, --OC.sub.2H.sub.5, --OCF.sub.3,
--CN, --NO.sub.2, --CO.sub.2H, --CO.sub.2CH.sub.3, --CONH.sub.2,
--NH.sub.2, --F, --Cl, Br, --CF.sub.3, --N(CH.sub.3).sub.2,
--NHSO.sub.2CH.sub.3, --NHCOCH.sub.3.
[0191] The term "heteroaryl", as used herein, refers to a cyclic or
bicyclic aromatic radical having from five to ten ring atoms in
each ring of which one atom of the cyclic or bicyclic ring is
selected from S, O and N; zero, one or two ring atoms are
additional heteroatoms independently selected from S, O and N; and
the remaining ring atoms are carbon, the radical being joined to
the rest of the molecule via any of the ring atoms, such as, for
example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,
oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and
naphthyridinyl, and the like.
[0192] The term "substituted heteroaryl" as used herein refers to a
heteroaryl group as defined herein substituted by independent
replacement of one, two or three of the hydrogen atoms thereon with
Cl, Br, F, I, OH, CN, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy substituted with
aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino,
mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and
carboxamide. In addition, any one substituent may be an aryl,
heteroaryl, or heterocycloalkyl group. Preferred substituents
include straight and branched chain alkyl groups, --CH.sub.3,
--C.sub.2H.sub.5, --CH.sub.2OH, --OH, --OCH.sub.3,
--OC.sub.2H.sub.5, --OCF.sub.3, --CN, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CONH.sub.2, --NH.sub.2, --F, --Cl, Br,
--CF.sub.3, --N(CH.sub.3).sub.2, --NHSO.sub.2CH.sub.3,
--NHCOCH.sub.3.
[0193] The term "biaryl" refers to a group or substituent to which
two aryl groups, which are not condensed to each other, are bound.
Exemplary biaryl compounds include, for example, phenylbenzene,
diphenyldiazene, 4-methylthio-1-phenylbenzene, phenoxybenzene,
(2-phenylethynyl)benzene, diphenyl ketone,
(4-phenylbuta-1,3-diynyl)benzene, phenylbenzylamine,
(phenylmethoxy)benzene, and the like. Preferred optionally
substituted biaryl groups include:
2-(phenylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,
1,4-diphenylbenzene,
N-[4-(2-phenylethynyl)phenyl]-2-[benzylamino]acetamide,
2-amino-N-[4-(2-phenylethynyl)phenyl]propanamide,
2-amino-N-[4-(2-phenylethynyl)phenyl]acetamide,
2-(cyclopropylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,
2-(ethylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,
2-[(2-methylpropyl)amino]-N-[4-(2-phenylethynyl)phenyl]acetamide,
5-phenyl-2H-benzo[d]1,3-dioxolene,
2-chloro-1-methoxy-4-phenylbenzene,
2-[(imidazolylmethyl)amino]-N-[4-(2-phenylethynyl)phenyl]acetamide,
4-phenyl-1-phenoxybenzene,
N-(2-aminoethyl)[4-(2-phenylethynyl)phenyl]carboxamide,
2-{[(4-fluorophenyl)methyl]amino}-N-[4-(2-phenylethynyl)phenyl]acetamide,
2-{[(4-methylphenyl)methyl]amino}-N-[4-(2-phenylethynyl)phenyl]acetamide,
4-phenyl-1-(trifluoromethyl)benzene, 1-butyl-4-phenylbenzene,
2-(cyclohexylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,
2-(ethylmethylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,
2-(butylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide,
N-[4-(2-phenylethynyl)phenyl]-2-(4-pyridylamino)acetamide,
N-[4-(2-phenylethynyl)phenyl]-2-(quinuclidin-3-ylamino)acetamide,
N-[4-(2-phenylethynyl)phenyl]pyrrolidin-2-ylcarboxamide,
2-amino-3-methyl-N-[4-(2-phenylethynyl)phenyl]butanamide,
4-(4-phenylbuta-1,3-diynyl)phenylamine,
2-(dimethylamino)-N-[4-(4-phenylbuta-1,3-diynyl)phenyl]acetamide,
2-(ethylamino)-N-[4-(4-phenylbuta-1,3-diynyl)phenyl]acetamide,
4-ethyl-1-phenylbenzene, 1-[4-(2-phenylethynyl)phenyl]ethan-1-one,
N-(1-carbamoyl-2-hydroxypropyl)[4-(4-phenylbuta-1,3-diynyl)phenyl]carboxa-
mide, N-[4-(2-phenylethynyl)phenyl]propanamide, 4-methoxyphenyl
phenyl ketone, phenyl-N-benzamide,
(tert-butoxy)-N-[(4-phenylphenyl)methyl]carboxamide,
2-(3-phenylphenoxy)ethanehydroxamic acid, 3-phenylphenyl
propanoate, 1-(4-ethoxyphenyl)-4-methoxybenzene, and
[4-(2-phenylethynyl)phenyl]pyrrole.
[0194] The term "heteroarylaryl" refers to a biaryl group where one
of the aryl groups is a heteroaryl group. Exemplary heteroarylaryl
groups include, for example, 2-phenylpyridine, phenylpyrrole,
3-(2-phenylethynyl)pyridine, phenylpyrazole,
5-(2-phenylethynyl)-1,3-dihydropyrimidine-2,4-dione,
4-phenyl-1,2,3-thiadiazole, 2-(2-phenylethynyl)pyrazine,
2-phenylthiophene, phenylimidazole, 3-(2-piperazinylphenyl)furan,
3-(2,4-dichlorophenyl)-4-methylpyrrole, and the like. Preferred
optionally substituted heteroarylaryl groups include:
5-(2-phenylethynyl)pyrimidine-2-ylamine,
1-methoxy-4-(2-thienyl)benzene, 1-methoxy-3-(2-thienyl)benzene,
5-methyl-2-phenylpyridine, 5-methyl-3-phenylisoxazole,
2-[3-(trifluoromethyl)phenyl]furan,
3-fluoro-5-(2-furyl)-2-methoxy-1-prop-2-enylbenzene,
(hydroxyimino)(5-phenyl(2-thienyl))methane,
5-[(4-methylpiperazinyl)methyl]-2-phenylthiophene,
2-(4-ethylphenyl)thiophene, 4-methylthio-1-(2-thienyl)benzene,
2-(3-nitrophenyl)thiophene,
(tert-butoxy)-N-[(5-phenyl(3-pyridyl))methyl]carboxamide,
hydroxy-N-[(5-phenyl(3-pyridyl))methyl]amide,
2-(phenylmethylthio)pyridine, and benzylimidazole.
[0195] The term "heteroarylheteroaryl" refers to a biaryl group
where both of the aryl groups is a heteroaryl group. Exemplary
heteroarylheteroaryl groups include, for example,
3-pyridylimidazole, 2-imidazolylpyrazine, and the like. Preferred
optionally substituted heteroarylheteroaryl groups include:
2-(4-piperazinyl-3-pyridyl)furan,
diethyl(3-pyrazin-2-yl(4-pyridyl))amine, and
dimethyl{2-[2-(5-methylpyrazin-2-yl)ethynyl](4-pyridyl))amine.
[0196] "Optionally substituted" refers to the optional replacement
of hydrogen with one or more monovalent or divalent radicals.
Optionally substituted groups include those described herein, for
each group in which a distinct definition for substitution is
supplied. Additionally, suitable substitution groups include, for
example, hydroxyl, nitro, amino, imino, cyano, halo, thio,
thioamido, amidino, imidino, oxo, oxamidino, methoxamidino,
imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl,
substituted alkyl, haloloweralkyl, loweralkoxy, haloloweralkoxy,
loweralkoxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,
heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl,
cyanoalkyl, benzyl, pyridyl, pyrazolyl, pyrrole, thiophene,
imidazolyl, and the like.
[0197] Representative substituted amidino and heterocycloamidino
groups include, for example, those shown below. These amidino and
heterocycloamidino groups can be further substituted as will be
apparent to those having skill in the organic and medicinal
chemistry arts in conjunction with the disclosure herein.
##STR9##
[0198] Representative substituted alkylcarbonylamino,
alkyloxycarbonylamino, aminoalkyloxycarbonylamino, and
arylcarbonylamino groups include, for example, those shown below.
These groups can be further substituted as will be apparent to
those having skill in the organic and medicinal chemistry arts in
conjunction with the disclosure herein. ##STR10##
[0199] Representative substituted aminocarbonyl groups include, for
example, those shown below. These can be further substituted by
heterocyclo groups and heteroaryl groups as will be apparent to
those having skill in the organic and medicinal chemistry arts in
conjunction with the disclosure herein. Prefered aminocarbonyl
groups include: N-(2-cyanoethyl)carboxamide,
N-(3-methoxypropyl)carboxamide, N-cyclopropylcarboxamide,
N-(2-hydroxy-isopropyl)carboxamide, methyl
2-carbonylamino-3-hydroxypropanoate,
N-(2-hydroxypropyl)carboxamide, N-(2-hydroxy-isopropyl)carboxamide,
N-[2-hydroxy-1-hydroxymethyl)ethyl]carboxamide,
N-(2-carbonylaminoethyl)acetamide,
N-(2-(2-pyridyl)ethyl)carboxamide, N-(2-pyridylmethyl)carboxamide,
N-(oxolan-2-ylmethyl)carboxamide,
N-(4-hydroxypyrrolidin-2-yl)carboxamide,
N-[2-(2-hydroxyethoxy)ethyl]carboxamide,
N-(4-hydroxycyclohexyl)carboxamide,
N-[2-(2-oxo-4-imidazolinyl)ethyl]carboxamide,
N-(carbonylaminomethyl)acetamide,
N-(3-pyrrolidinylpropyl)carboxamide,
N-[1-(carbonylaminomethyl)pyrrolidin-3-yl]acetamide,
N-(2-morpholin-4-ylethyl)carboxamide,
N-[3-(2-oxopyrrolidinyl)propyl]carboxamide,
4-methyl-2-oxopiperazinecarbaldehyde,
N-(2-hydroxy-3-pyrrolidinylpropyl)carboxamide,
N-(2-hydroxy-3-morpholin-4-ylpropyl)carboxamide,
N-{2-[(5-cyano-2-pyridyl)amino]ethyl}carboxamide,
3-(dimethylamino)pyrrolidinecarbaldehyde,
N-[(5-methylpyrazin-2-yl)methyl]carboxamide,
2,2,2-trifluoro-N-(1-formylpyrrolidin-3-yl)acetamide, ##STR11##
[0200] Representative substituted alkoxycarbonyl groups include,
for example, those shown below. These alkoxycarbonyl groups can be
further substituted as will be apparent to those having skill in
the organic and medicinal chemistry arts in conjunction with the
disclosure herein. ##STR12##
[0201] The term "protected" with respect to hydroxyl groups, amine
groups, and sulfhydryl groups refers to forms of these
functionalities that are protected from undesirable reaction with a
protecting group known to those skilled in the art such as those
set forth in Protective Groups in Organic Synthesis, Greene, T. W.;
Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd
Edition, 1999) that can be added or removed using the procedures
set forth therein. Examples of protected hydroxyl groups include,
but are not limited to, silyl ethers such as those obtained by
reaction of a hydroxyl group with a reagent such as, but not
limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane,
triisopropylchlorosilane, triethylchlorosilane; substituted methyl
and ethyl ethers such as, but not limited to methoxymethyl ether,
methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether,
2-methoxyethoxymethyl ether, tetrahydropyranyl ethers,
1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but
not limited to, benzoylformate, formate, acetate, trichloroacetate,
and trifluoracetate. Examples of protected amine groups include,
but are not limited to, amides such as, formamide, acetamide,
trifluoroacetamide, and benzamide; imides, such as phthalimide, and
dithiosuccinimide; and others. Examples of protected sulfhydryl
groups include, but are not limited to, thioethers such as S-benzyl
thioether, and S-4-picolyl thioether; substituted S-methyl
derivatives such as hemithio, dithio and aminothio acetals; and
others.
[0202] A "pharmaceutically acceptable salt" includes a salt with an
inorganic base, organic base, inorganic acid, organic acid, or
basic or acidic amino acid. As salts of inorganic bases, the
invention includes, for example, alkali metals such as sodium or
potassium; alkaline earth metals such as calcium and magnesium or
aluminum; and ammonia. As salts of organic bases, the invention
includes, for example, trimethylamine, triethylamine, pyridine,
picoline, ethanolamine, diethanolamine, and triethanolamine. As
salts of inorganic acids, the instant invention includes, for
example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric
acid, and phosphoric acid. As salts of organic acids, the instant
invention includes, for example, formic acid, acetic acid,
trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid,
maleic acid, citric acid, succinic acid, malic acid,
methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic
acid. As salts of basic amino acids, the instant invention
includes, for example, arginine, lysine and ornithine. Acidic amino
acids include, for example, aspartic acid and glutamic acid.
[0203] As used herein, the term "pharmaceutically acceptable ester"
refers to esters that hydrolyze in vivo and include those that
break down readily in the human body to leave the parent compound
or a salt thereof. Suitable ester groups include, for example,
those derived from pharmaceutically acceptable aliphatic carboxylic
acids, particularly alkanoic, alkenoic, cycloalkanoic and
alkanedioic acids, in which each alkyl or alkenyl moiety
advantageously has not more than 6 carbon atoms. Representative
examples of particular esters include, but are not limited to,
formates, acetates, propionates, butyrates, acrylates and
ethylsuccinates.
[0204] The term "pharmaceutically acceptable prodrugs" as used
herein refers to those prodrugs of the compounds of the present
invention that are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the invention. The term
"prodrug" refers to compounds that are rapidly transformed in vivo
to yield the parent compound of the above formula, for example by
hydrolysis in blood. A thorough discussion is provided in T.
Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14
of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,
Bioreversible Carriers in Drug Design, American Pharmaceutical
Association and Pergamon Press, 1987, both of which are
incorporated herein by reference.
[0205] The term "antibacterial agent" refers to agents synthesized
or modified in the laboratory that have either bactericidal or
bacteriostatic activity. An "active" agent in this context will
inhibit the growth of P. aeruginosa and other gram-negative
bacteria. The term "inhibiting the growth" indicates that the rate
of increase in the numbers of a population of a particular
bacterium is reduced. Thus, the term includes situations in which
the bacterial population increases but at a reduced rate, as well
as situations where the growth of the population is stopped, as
well as situations where the numbers of the bacteria in the
population are reduced or the population even eliminated. If an
enzyme activity assay is used to screen for inhibitors, one can
make modifications in uptake/efflux, solubility, half-life, etc. to
compounds in order to correlate enzyme inhibition with growth
inhibition. The activity of antibacterial agents is not necessarily
limited to bacteria but may also encompass activity against
parasites, virus, and fungi.
[0206] The subject invention also includes isotopically-labeled
LpxC inhibitors, that are structurally identical to those disclosed
above, but for the fact that one or more atoms are replaced by an
atom having an atomic mass or mass number different from the atomic
mass or mass number usually found in nature. Examples of isotopes
that can be incorporated into compounds of the invention include
isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,
sulfur, fluorine and chlorine, such as .sup.2H, .sup.3H, .sup.13C,
.sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P, .sup.32P,
.sup.35S, .sup.18F and .sup.36Cl, respectively. Compounds of the
present invention, prodrugs thereof, and pharmaceutically
acceptable salts of said compounds and of said prodrugs that
contain the aforementioned isotopes and/or other isotopes of other
atoms are within the scope of this invention. Certain isotopically
labeled compounds of the present invention, for example those into
which radioactive isotopes such as .sup.3H and .sup.14C are
incorporated, are useful in drug and/or substrate tissue
distribution assays. Tritiated, i.e., .sup.3H, and carbon-14, i.e.,
.sup.14C, isotopes are particularly preferred for their ease of
preparation and detectability. Further, substitution with heavier
isotopes such as deuterium, i.e., .sup.2H, may afford certain
therapeutic advantages resulting from greater metabolic stability,
for example increased in vivo half-life or reduced dosage
requirements and, hence, may be preferred in some circumstances.
Isotopically labeled compounds of this invention and prodrugs
thereof can generally be prepared by carrying out known or
referenced procedures and by substituting a readily available
isotopically labeled reagent for a non-isotopically labeled
reagent.
[0207] The present invention provides novel compounds,
pharmaceutical formulations including the compounds, methods of
inhibiting UDP-3-O--(R-3-hydroxydecanoyl)-N-acetylglucosamine
deacetylase (LpxC), and methods of treating gram-negative bacterial
infections. [0208] In one embodiment, the present invention
provides compounds of formula I: ##STR13## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0209] E is absent or selected from the group consisting
of
[0210] (1) H,
[0211] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0212] (3) substituted or unsubstituted
C.sub.2-C.sub.6-alkenyl,
[0213] (4) substituted or unsubstituted
C.sub.2-C.sub.6-alkynyl,
[0214] (5) substituted or unsubstituted aryl,
[0215] (6) substituted or unsubstituted heterocyclyl, and
[0216] (7) substituted or unsubstituted heteroaryl; [0217] L is
absent or selected from the group consisting of
[0218] (1) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0219] (2)
--(NH).sub.0-1--(CH.sub.2).sub.j--NR.sup.3L--(CH.sub.2).sub.k--,
[0220] (3) --(NH).sub.0-1--C(R.sup.1L,
R.sup.2L)--NR.sup.3L--C(R.sup.1L, R.sup.2L)--,
[0221] (4) --C(R.sup.1L, R.sup.2L)--O--C(R.sup.1L, R.sup.2L)--,
[0222] (5) --(CH.sub.2).sub.j--NR.sup.3L--C(R.sup.1L,
R.sup.2L)--CONH--(CH.sub.2).sub.k--,
[0223] (6) --CO--C(R.sup.1L, R.sup.2L)--NHCO--,
[0224] (7) --CONH--,
[0225] (8) --NHCO--,
[0226] wherein
[0227] R.sup.1L, R.sup.2L, and R.sup.3L are independently selected
from the group consisting of [0228] (a) H, [0229] (b) substituted
or unsubstituted C.sub.1-C.sub.6-alkyl, [0230] (c)
C.sub.1-C.sub.6-alkyl substituted with aryl, [0231] (d)
C.sub.1-C.sub.6-alkyl substituted with heterocyclyl, and [0232] (e)
C.sub.1-C.sub.6-alkyl substituted with heteroaryl,
[0233] or R.sup.1L and R.sup.3L, together with the atoms to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring
atoms of the heterocyclic ring system are selected from N, O and
S,
[0234] j is an integer of 0-4;
[0235] k is an integer of 0-4; [0236] D is absent or selected from
the group consisting of
[0237] (1) substituted or unsubstituted
C.sub.3-C.sub.8-cycloalkyl,
[0238] (2) substituted or unsubstituted aryl,
[0239] (3) substituted or unsubstituted heterocyclyl, and
[0240] (4) substituted or unsubstituted heteroaryl; [0241] G is
absent or selected from the group consisting of
[0242] (1) --(CH.sub.2).sub.i--O--(CH.sub.2).sub.i--,
[0243] (2) --(CH.sub.2).sub.i--S--(CH.sub.2).sub.i--,
[0244] (3) --(CH.sub.2).sub.i--NR.sup.g--(CH.sub.2).sub.i--,
[0245] (4) --C(.dbd.O)--,
[0246] (5) --NHC(.dbd.O)--,
[0247] (6) --C(.dbd.O)NH--,
[0248] (7) --(CH.sub.2).sub.iNHCH.sub.2C(.dbd.O)NH--,
[0249] (8) --C.ident.C--,
[0250] (9) --C.ident.C--C.ident.--, and
[0251] (10) --C.dbd.C--;
[0252] wherein
[0253] Rg is H or substituted or unsubstituted
C.sub.1-C.sub.6-alkyl;
[0254] i is an interger of 0-4; [0255] Y is selected from the group
consisting of
[0256] (1) substituted or unsubstituted
C.sub.3-C.sub.8-cycloalkyl,
[0257] (2) substituted or unsubstituted aryl,
[0258] (3) substituted or unsubstituted heterocyclyl, and
[0259] (4) substituted or unsubstituted heteroaryl; [0260] X is
selected from the group consisting of
[0261] (1) --(C.dbd.O)--,
[0262] (2) --C.sub.1-C.sub.6-alkyl-(C.dbd.O)--,
[0263] (3) --C.sub.2-C.sub.6-alkenyl-(C.dbd.O)--,
[0264] (4) --C.sub.2-C.sub.6-alkynyl-(C.dbd.O)--, and
[0265] (5) --CH.sub.2--;
[0266] or when B is absent, X and A, together with the atoms to
which they are attached can form a heterocyclic ring, having from 5
to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring
system are selected from N, O and S; [0267] B is a absent or
##STR14##
[0268] wherein R.sup.1b and R.sup.2b, are independently selected
from the group consisting of [0269] (a) H, [0270] (b) substituted
or unsubstituted C.sub.1-C.sub.6-alkyl, [0271] (c) substituted or
unsubstituted C.sub.2-C.sub.6-alkenyl, [0272] (d) substituted or
unsubstituted C.sub.2-C.sub.6-alkynyl, [0273] (e) substituted or
unsubstituted aryl, [0274] (f) substituted or unsubstituted
heterocyclyl, [0275] (g) substituted or unsubstituted heteroaryl,
[0276] (h) C.sub.1-C.sub.6-alkyl substituted with aryl, [0277] (i)
C.sub.1-C.sub.6-alkyl substituted with heterocyclyl, and [0278] (j)
C.sub.1-C.sub.6-alkyl substituted with heteroaryl,
[0279] or R.sup.1b and R.sup.2b, together with the atoms to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring
atoms of the heterocyclic: ring system are selected from N, O and
S;
[0280] q is an integer of 0-4; [0281] R.sub.3 is H or substituted
or unsubstituted C.sub.1-C.sub.6-alkyl,
[0282] or R.sub.3 and A, together with the atoms to which they are
attached can form a substituted or unsubstituted 3-10 membered
cycloalkyl or a heterocyclic ring system, wherein the heterocyclic
ring system may have from 3 to 10 ring atoms, with 1 to 2 rings
being in the ring system and contain from 1-4 heteroatoms selected
from N, O and S; [0283] R.sub.4 is H or substituted or
unsubstituted C.sub.1-C.sub.6-alkyl,
[0284] or R.sub.4 and A, together with the atoms to which they are
attached can form a substituted or unsubstituted heterocyclic ring,
having from 3 to 8 ring atoms, wherein 1-2 ring atoms of the
heterocyclic ring system are selected from N, O and S; [0285] n is
an integer of 0-2; [0286] A is selected from the group consisting
of
[0287] (1) H,
[0288] (2) --(CH.sub.2).sub.rC(R.sup.1a,
R.sup.2a)(CH.sub.2).sub.sOR.sup.3a,
[0289] (3) --(CH.sub.2).sub.rC(R.sup.1a, R.sup.2a)N(R.sup.4a,
R.sup.5a),
[0290] (4) --(CH.sub.2).sub.rC(R.sup.1a,
R.sup.2a)N(R.sup.4a)COR.sup.3a,
[0291] (5) --(CH.sub.2).sub.rC(R.sup.1a, R.sup.2a)NHCON(R.sup.4a,
R.sup.5a),
[0292] (6) --(CH.sub.2).sub.rC(R.sup.1a,
R.sup.2a)NHC(.dbd.NH)N(R.sup.4a, R.sup.5a),
[0293] (7) --CH(R.sup.1a, R.sup.2a),
[0294] (8) --C.ident.CH,
[0295] (9) --(CH.sub.2).sub.rC(R.sup.1a, R.sup.2a)CN,
[0296] (10) --(CH.sub.2).sub.rC(R.sup.1a,
R.sup.2a)CO.sub.2R.sup.3a, and
[0297] (11) --(CH.sub.2).sub.rC(R.sup.1a, R.sup.2a)CN(R.sup.4a,
R.sup.5a),
[0298] wherein R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4a, and R.sup.5a
are independently selected from the group consisting of [0299] (a)
H, [0300] (b) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0301] (c) substituted or unsubstituted aryl, [0302] (d)
substituted or unsubstituted heterocyclyl, [0303] (e) substituted
or unsubstituted heteroaryl, [0304] (f) C.sub.1-C.sub.6-alkyl
substituted with aryl, [0305] (g) C.sub.1-C.sub.6-alkyl substituted
with heterocyclyl, and [0306] (h) C.sub.1-C.sub.6-alkyl substituted
with heteroaryl, [0307] or R.sup.4a and R.sup.5a together with the
N atom to which they are attached can form a substituted or
unsubstituted heterocyclic ring, having from 3 to 8 ring atoms,
wherein 1-2 ring atoms of the heterocyclic ring system are selected
from N, O and S;
[0308] r is an integer of 0-4;
[0309] s is an integer of 0-4; [0310] Q is absent or selected from
the group consisting of
[0311] (1) --C(.dbd.O)N(R.sub.1, R.sub.2),
[0312] (2) --NHC(.dbd.O)N(R.sub.1, R.sub.2),
[0313] (3) --N(OH)C(.dbd.O)N(R.sub.1, R.sub.2),
[0314] (4) --CH(OH)C(.dbd.O)N(R.sub.1, R.sub.2),
[0315] (5) --CH[N(R.sup.2q, R.sup.3q)]C(.dbd.O)N(R.sub.1,
R.sub.2),
[0316] (6) --CHR.sup.1qC(.dbd.O)N(R.sub.1, R.sub.2),
[0317] (7) --CO.sub.2H,
[0318] (8) --C(.dbd.O)NHSO.sub.2R.sup.4q,
[0319] (9) --SO.sub.2NH.sub.2,
[0320] (10) --N(OH)C(.dbd.O)R.sup.1q,
[0321] (11) --N(OH)SO.sub.2R.sup.4q,
[0322] (12) --NHSO.sub.2R.sup.4q,
[0323] (13) --SH,
[0324] (14) --CH(SH)(CH.sub.2).sub.0-1C(.dbd.O)N(R.sub.1,
R.sub.2),
[0325] (15) --CH(SH)(CH.sub.2).sub.0-1CO.sub.2H,
[0326] (16) --CH(OH)(CH.sub.2).sub.0-1CO.sub.2H,
[0327] (17) --CH(SH)CH.sub.2CO.sub.2R.sup.1q,
[0328] (18) --CH(OH)(CH.sub.2)SO.sub.2NH.sub.2,
[0329] (19) --CH(CH.sub.2SH)NHCOR.sup.1q,
[0330] (20) --CH(CH.sub.2SH)NHSO.sub.2R.sup.4q,
[0331] (21) --CH(CH.sub.2SR.sup.5q)CO.sub.2H,
[0332] (22) --CH(CH.sub.2SH)NHSO.sub.2NH.sub.2,
[0333] (23) --CH(CH.sub.2OH)CO.sub.2H,
[0334] (24) --CH(CH.sub.2OH)NHSO.sub.2NH.sub.2,
[0335] (25) --C(.dbd.O)CH.sub.2CO.sub.2H,
[0336] (26) --C(.dbd.O)(CH.sub.2).sub.0-1CONH.sub.2,
[0337] (27) --OSO.sub.2NHR.sup.5q,
[0338] (28) --SO.sub.2NHNH.sub.2,
[0339] (29) --P(.dbd.O)(OH).sub.2, ##STR15## [0340] R.sub.1 is
selected from the group consisting of
[0341] (1) --H,
[0342] (2) --OH,
[0343] (3) --OC.sub.1-6-alkyl,
[0344] (4) --N(R.sup.2q, R.sup.3q), and
[0345] (5) substituted or unsubstituted C.sub.1-6-alkyl; [0346]
R.sub.2 is selected from the group consisting of
[0347] (1) H,
[0348] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0349] (3) substituted or unsubstituted
C.sub.2-C.sub.6-alkenyl,
[0350] (4) substituted or unsubstituted
C.sub.2-C.sub.6-alkenyl,
[0351] (5) substituted or unsubstituted aryl,
[0352] (6) substituted or unsubstituted heterocyclyl,
[0353] (7) substituted or unsubstituted heteroaryl,
[0354] (8) C.sub.1-C.sub.6alkyl substituted with aryl,
[0355] (9) C.sub.1-C.sub.6-alkyl substituted with heterocyclyl,
and
[0356] (10) C.sub.1-C.sub.6-alkyl substituted with heteroaryl,
[0357] or R.sup.1 and R.sup.2, together with the N atom to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 3 to 10 ring atoms, wherein 1-4 ring
atoms of the heterocyclic ring system are selected from N, O and
S,
[0358] R.sup.1q, R.sup.2q, R.sup.3q, R.sup.4q, and R.sup.5q are
selected from H or C.sub.1-C.sub.6 alkyl,
wherein B is absent, or E, L, G, and B are absent, or E, L, and G
are absent, or E, L, and B are absent, or E, L, D, G, and B are
absent.
[0359] In another embodiment, the present invention provides
compounds of formula I: ##STR16## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0360] E is absent or selected from the group consisting
of
[0361] (1) H,
[0362] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0363] (3) substituted or unsubstituted aryl,
[0364] (4) substituted or unsubstituted heterocyclyl, and
[0365] (5) substituted or unsubstituted heteroaryl; [0366] L is
absent or selected from the group consisting of
[0367] (1) --(CH.sub.2).sub.j--NR.sup.3L--(CH.sub.2).sub.k--,
[0368] (2) --C(R.sup.1L, R.sup.2L).sub.j--NR.sup.3L--C(R.sup.1L,
R.sup.2L).sub.k--,
[0369] (3) --C(R.sup.1L, R.sup.2L).sub.j--O--C(R.sup.1L,
R.sup.2L).sub.k--,
[0370] (4) --(CH.sub.2).sub.j--NR.sup.3L--C(R.sup.1L,
R.sup.2L).sub.k--CONH--(CH.sub.2).sub.k--,
[0371] (5) --CO--C(R.sup.1L, R.sup.2L)--NHCO--,
[0372] (6) --CONH--, and
[0373] (7) --NHCO--,
[0374] wherein
[0375] R.sup.1L, R.sup.2L, R.sup.3L are independently selected from
the group consisting of [0376] (a) H, [0377] (b) substituted or
unsubstituted C.sub.1-C.sub.6-alkyl, [0378] (c)
C.sub.1-C.sub.6-alkyl substituted with aryl, [0379] (d)
C.sub.1-C.sub.6-alkyl substituted with heterocyclyl, [0380] (e)
C.sub.1-C.sub.6-alkyl substituted with heteroaryl,
[0381] or R.sup.1L and R.sup.3L, together with the atoms to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 5 to 8 ring atoms, wherein 1-2 ring
atoms of the heterocyclic ring system are selected from N, O and
S;
[0382] j is an integer of 0-4;
[0383] k is an integer of 0-4; [0384] D is absent or selected from
the group consisting of
[0385] (1) substituted or unsubstituted
C.sub.3-C.sub.8-cycloalkyl,
[0386] (2) substituted or unsubstituted aryl,
[0387] (3) substituted or unsubstituted heterocyclyl,
[0388] (4) substituted or unsubstituted heteroaryl, and [0389] G is
absent or selected from the group consisting of
[0390] (1) --C(.dbd.O)--,
[0391] (2) --NHC(.dbd.O)--,
[0392] (3) --C(.dbd.O)NH--,
[0393] (4) --(CH.sub.2).sub.iNHCH.sub.2C(.dbd.O)NH--,
[0394] (5) --C.ident.C--, and
[0395] (6) --C.ident.C--C.ident.C--,
[0396] wherein i is an interger of 0-4; [0397] Y is selected from
the group consisting of
[0398] (1) substituted or unsubstituted
C.sub.3-C.sub.8-cycloalkyl,
[0399] (2) substituted or unsubstituted aryl,
[0400] (3) substituted or unsubstituted heterocyclyl, and
[0401] (4) substituted or unsubstituted heteroaryl; [0402] X is
selected from the group consisting of
[0403] (1) --(C.dbd.O)--,
[0404] (2) --C.sub.1-C.sub.6-alkyl-(C.dbd.O)--,
[0405] (3) --C.sub.2-C.sub.6-alkenyl-(C.dbd.O)--,
[0406] (4) --C.sub.2-C.sub.6-alkynyl-(C.dbd.O)--, and
[0407] (5) --CH.sub.2--;
[0408] or when B is absent, X and A together with the atoms to
which they are attached can form a heterocyclic ring, having from 5
to 8 ring atoms, wherein 1-2 ring atoms of the heterocyclic ring
system are selected from N, O and S; [0409] B is absent or
##STR17##
[0410] wherein R.sup.1b and R.sup.2b are independently selected
from the group consisting of [0411] (a) H [0412] (b) substituted or
unsubstituted C.sub.1-C.sub.6-alkyl, [0413] (c) substituted or
unsubstituted C.sub.2-C.sub.6-alkenyl, [0414] (d) substituted or
unsubstituted C.sub.2-C.sub.6-alkenyl, [0415] (e) substituted or
unsubstituted aryl, [0416] (f) substituted or unsubstituted
heterocyclyl, [0417] (g) substituted or unsubstituted heteroaryl,
[0418] (h) C.sub.1-C.sub.6-alkyl substituted with aryl, [0419] (i)
C.sub.1-C.sub.6-alkyl substituted with heterocyclyl, and [0420] (j)
C.sub.1-C.sub.6-alkyl substituted with heteroaryl, [0421] or
R.sup.1b and R.sup.2b, together with the atoms to which they are
attached can form a substituted or unsubstituted heterocyclic ring,
having from 5 to 8 ring atoms, wherein 1-2 ring atoms of the
heterocyclic ring system are selected from N, O and S;
[0422] q is an integer of 0-2; [0423] R.sub.3 is H or substituted
or unsubstituted C.sub.1-C.sub.6-alkyl,
[0424] or R.sub.3 and A, together with the atoms to which they are
attached can form a substituted or unsubstituted 3-10 membered
cycloalkyl or a heterocyclic ring system, wherein the heterocyclic
ring system may have from 3 to 10 ring atoms, with 1 to 2 rings
being in the ring system and contain from 1-4 heteroatoms selected
from N, O and S; [0425] R.sub.4 is H or substituted or
unsubstituted C.sub.1-C.sub.6-alkyl,
[0426] or R.sub.4 and A, together with the atoms to which they are
attached can form a substituted or unsubstituted heterocyclic ring,
having from 5 to 8 ring atoms, wherein 1-2 ring atoms of the
heterocyclic ring system are selected from N, O and S; [0427] A is
selected from the group consisting of
[0428] (1) H,
[0429] (2) --(CH.sub.2).sub.rC(R.sup.1a,
R.sup.2a)(CH.sub.2).sub.sOR.sup.3a,
[0430] (3) --(CH.sub.2).sub.rC(R.sup.1a, R.sup.2a)N(R.sup.4a,
R.sup.5a),
[0431] (4) --(CH.sub.2).sub.rC(R.sup.1a,
R.sup.2a)N(R.sup.4a)COR.sup.3a,
[0432] (5) --(CH.sub.2).sub.rC(R.sup.1a, R.sup.2a)NHCON(R.sup.4a,
R.sup.5a),
[0433] (6) --(CH.sub.2).sub.rC(R.sup.1a,
R.sup.2a)NHC(.dbd.NH)N(R.sup.4a, R.sup.5a),
[0434] (7) --CH(R.sup.1a, R.sup.2a),
[0435] (8) --C.ident.CH,
[0436] (9) --(CH.sub.2).sub.rC(R.sup.1a, R.sup.2a)CN, and
[0437] (10) --(CH.sub.2).sub.rC(R.sup.1a,
R.sup.2a)CO.sub.2R.sup.3a,
[0438] wherein R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4a, and
R.sup.5a, are independently selected from the group consisting of
[0439] (a) H, [0440] (b) substituted or unsubstituted
C.sub.1-C.sub.6-alkyl, [0441] (c) C.sub.1-C.sub.6-alkyl substituted
with aryl, [0442] (d) C.sub.1-C.sub.6-alkyl substituted with
heterocyclyl, and [0443] (e) C.sub.1-C.sub.6-alkyl substituted with
heteroaryl, [0444] or R.sup.4a and R.sup.5a, together with the N
atom to which they are attached can form a substituted or
unsubstituted heterocyclic ring, having from 5 to 8 ring atoms,
wherein 1-2 ring atoms of the heterocyclic ring system are selected
from N, O and S;
[0445] r is an integer of 0-4; [0446] Q is absent or selected from
the group consisting of
[0447] (1) --C(.dbd.O)N(R.sub.1, R.sub.2),
[0448] (2) --NHC(.dbd.O)N(R.sub.1, R.sub.2),
[0449] (3) --N(OH)C(.dbd.O)N(R.sub.1, R.sub.2),
[0450] (4) --CH(OH)C(.dbd.O)N(R.sub.1, R.sub.2),
[0451] (5) --CH]N(R.sup.2q, R.sup.3q)C(.dbd.O)N(R.sub.1, R.sub.2),
and
[0452] (6) --CHR.sup.1qC(.dbd.O)N(R.sub.1, R.sub.2), [0453] R.sub.1
is selected from the group consisting of
[0454] (1) H,
[0455] (2) OH,
[0456] (3) OC.sub.1-6-alkyl,
[0457] (4) N(R.sup.2q, R.sup.3q), and
[0458] (5) substituted or unsubstituted C.sub.1-6-alkyl; [0459]
R.sub.2 is selected from the group consisting of
[0460] (1) H,
[0461] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0462] (3) substituted or unsubstituted aryl,
[0463] (4) substituted or unsubstituted heterocyclyl,
[0464] (5) substituted or unsubstituted heteroaryl,
[0465] (6) C.sub.1-C.sub.6-alkyl substituted with aryl,
[0466] (7) C.sub.1-C.sub.6-alkyl substituted with heterocyclyl,
and
[0467] (8) C.sub.1-C.sub.6-alkyl substituted with heteroaryl,
[0468] or R.sup.1 and R.sup.2, together with the N atom to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 3 to 10 ring atoms, wherein 1-4 ring
atoms of the heterocyclic ring system are selected from N, O and
S,
[0469] R.sup.1q, R.sup.2q, and R.sup.3q are selected from H or
C.sub.1-C.sub.6 alkyl,
wherein B is absent, or E, L, G, and B are absent, or E, L, and G
are absent, or E, L, and B are absent, or E, L, D, G, and B are
absent.
[0470] In another embodiment, the present invention provides
compounds of formula II: ##STR18## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0471] D-G-Y taken together, is selected from the group
consisting of ##STR19## ##STR20## ##STR21## ##STR22## ##STR23##
[0472] Wherein
[0473] R is selected from the group consisting of --CH.sub.3,
--C.sub.2H.sub.5, --CH.sub.2OH, --OH, --OCH.sub.3,
--OC.sub.2H.sub.5, --OCF.sub.3, --CN, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CONH.sub.2, --NH.sub.2, --F, --Cl, --Br,
--CF.sub.3, --N(CH.sub.3).sub.2, --NHSO.sub.2CH.sub.3, and
--NHCOCH.sub.3;
[0474] X is selected from the group consisting of
[0475] (1) --(C.dbd.O)--,
[0476] (2) --C.sub.1-C.sub.6-alkyl-(C.dbd.O)--, and
[0477] (3) --C.sub.2-C.sub.6-alkenyl-(C.dbd.O)--. [0478] In another
embodiment, the present invention provides compounds of formula
III: ##STR24## or stereoisomers, pharmaceutically acceptable salts,
esters, and prodrugs thereof, wherein [0479] D-G-Y taken together,
is selected from the group consisting of ##STR25## ##STR26##
##STR27## ##STR28## ##STR29##
[0480] Wherein
[0481] R is selected from the group consisting of --CH.sub.3,
--C.sub.2H.sub.5, --CH.sub.2OH, --OH, --OCH.sub.3,
--OC.sub.2H.sub.5, --OCF.sub.3, --CN, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CONH.sub.2, --NH.sub.2, --F, --Cl, --Br,
--CF.sub.3, --N(CH.sub.3).sub.2, --NHSO.sub.2CH.sub.3, and
--NHCOCH.sub.3; [0482] X is selected from the groups consisting
of
[0483] (1) --(C.dbd.O)--,
[0484] (2) --C.sub.1-C.sub.6-alkyl-(C.dbd.O)--, and
[0485] (3) --C.sub.2-C.sub.6-alkenyl-(C.dbd.O)--. [0486] In another
embodiment, the present invention provides compounds of formula IV:
##STR30## or stereoisomers, pharmaceutically acceptable salts,
esters, and prodrugs thereof, wherein [0487] D-G-Y taken together,
is selected from the group consisting of ##STR31## ##STR32##
##STR33## ##STR34## ##STR35##
[0488] Wherein
[0489] R is selected from the group consisting of --CH.sub.3,
--C.sub.2H.sub.5, --CH.sub.2OH, --OH, --OCH.sub.3,
--OC.sub.2H.sub.5, --OCF.sub.3, --CN, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CONH.sub.2, --NH.sub.2, --F, --Cl, --Br,
--CF.sub.3, --N(CH.sub.3).sub.2, --NHSO.sub.2CH.sub.3, and
--NHCOCH.sub.3; [0490] X is selected from the groups consisting
of
[0491] (1) --(C.dbd.O)--,
[0492] (2) --C.sub.1-C.sub.6-alkyl-(C.dbd.O)--, and
[0493] (3) --C.sub.2-C.sub.6-alkenyl-(C.dbd.O)--. [0494] In another
embodiment, the present invention provides compounds of formula V:
##STR36## or stereoisomers, pharmaceutically acceptable salts,
esters, and prodrugs thereof, wherein [0495] D-G-Y taken together,
is selected from the group consisting of ##STR37## ##STR38##
##STR39## ##STR40## ##STR41##
[0496] Wherein
[0497] R is selected from the group consisting of --CH.sub.3,
--C.sub.2H.sub.5, --CH.sub.2OH, --OH, --OCH.sub.3,
--OC.sub.2H.sub.5, --OCF.sub.3, --CN, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CONH.sub.2, --NH.sub.2, --F, --Cl, --Br,
--CF.sub.3, --N(CH.sub.3).sub.2, --NHSO.sub.2CH.sub.3, and
--NHCOCH.sub.3; [0498] X is selected from the groups consisting
of
[0499] (1) --(C.dbd.O)--,
[0500] (2) --C.sub.1-C.sub.6-alkyl-(C.dbd.O)--, and
[0501] (3) --C.sub.2-C.sub.6-alkenyl-(C.dbd.O)--. [0502] In another
embodiment, the present invention provides compounds of formula VI:
##STR42## or stereoisomers, pharmaceutically acceptable salts,
esters, and prodrugs thereof, wherein [0503] E is absent or
selected from the group consisting of
[0504] (1) H,
[0505] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0506] (3) substituted or unsubstituted aryl,
[0507] (4) substituted or unsubstituted heterocyclyl, and
[0508] (5) substituted or unsubstituted heteroaryl,
[0509] or E and R.sup.3L, together with the atoms to which they are
attached can form a substituted or unsubstituted heterocyclic ring,
having from 3 to 10 ring atoms, wherein 1-4 ring atoms of the
heterocyclic ring system are selected from N, O and S, [0510]
R.sup.1L, R.sup.3L are independently selected from the group
consisting of
[0511] (1) H,
[0512] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0513] (3) C.sub.1-C.sub.6-alkyl substituted with aryl,
[0514] (4) C.sub.1-C.sub.6-alkyl substituted with heterocyclyl,
and
[0515] (5) C.sub.1-C.sub.6-alkyl substituted with heteroaryl,
[0516] or R.sup.1L and R.sup.3L, together with the atoms to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring
atoms of the heterocyclic ring system are selected from N, O and S.
[0517] In another embodiment, the present invention provides
compounds of formula VII: ##STR43## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0518] E is absent or selected from the group consisting
of
[0519] (1) H,
[0520] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0521] (3) substituted or unsubstituted aryl,
[0522] (4) substituted or unsubstituted heterocyclyl, and
[0523] (5) substituted or unsubstituted heteroaryl,
[0524] or E and R.sup.3L, together with the atoms to which they are
attached can form a substituted or unsubstituted heterocyclic ring,
having from 3 to 10 ring atoms, wherein 1-4 ring atoms of the
heterocyclic ring system are selected from N, O and S; [0525]
R.sup.1L, R.sup.3L are independently selected from the group
consisting of
[0526] (1) H,
[0527] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0528] (3) C.sub.1-C.sub.6-alkyl substituted with aryl,
[0529] (4) C.sub.1-C.sub.6-alkyl substituted with heterocyclyl,
and
[0530] (5) C.sub.1-C.sub.6-alkyl substituted with heteroaryl,
[0531] or R.sup.1L and R.sup.3L, together with the atoms to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring
atoms of the heterocyclic ring system are selected from N, O and S.
[0532] In another embodiment, the present invention provides
compounds of formula VIII: ##STR44## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0533] E is absent or selected from the group consisting
of
[0534] (1) H,
[0535] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0536] (3) substituted or unsubstituted aryl,
[0537] (4) substituted or unsubstituted heterocyclyl, and
[0538] (5) substituted or unsubstituted heteroaryl,
[0539] or E and R.sup.3L, together with the atoms to which they are
attached can form a substituted or unsubstituted heterocyclic ring,
having from 3 to 10 ring atoms, wherein 1-4 ring atoms of the
heterocyclic ring system are selected from N, O and S; [0540]
R.sup.1L, R.sup.3L are independently selected from the group
consisting of
[0541] (1) H,
[0542] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0543] (3) C.sub.1-C.sub.6-alkyl substituted with aryl,
[0544] (4) C.sub.1-C.sub.6-alkyl substituted with heterocyclyl,
and
[0545] (5) C.sub.1-C.sub.6-alkyl substituted with heteroaryl,
[0546] or R.sup.1L and R.sup.3L, together with the atoms to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring
atoms of the heterocyclic ring system are selected from N, O and S.
[0547] In another embodiment, the present invention provides
compounds of formula IX: ##STR45## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0548] E is absent or selected from the group consisting
of
[0549] (1) H,
[0550] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0551] (3) substituted or unsubstituted aryl,
[0552] (4) substituted or unsubstituted heterocyclyl, and
[0553] (5) substituted or unsubstituted heteroaryl,
[0554] or E and R.sup.3L, together with the atoms to which they are
attached can form a substituted or unsubstituted heterocyclic ring,
having from 3 to 10 ring atoms, wherein 1-4 ring atoms of the
heterocyclic ring system are selected from N, O and S; [0555]
R.sup.1L, R.sup.3L are independently selected from the group
consisting of
[0556] (1) H,
[0557] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0558] (3) C.sub.1-C.sub.6-alkyl substituted with aryl,
[0559] (4) C.sub.1-C.sub.6-alkyl substituted with heterocyclyl,
and
[0560] (5) C.sub.1-C.sub.6-alkyl substituted with heteroaryl,
[0561] or R.sup.1L and R.sup.3L, together with the atoms to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring
atoms of the heterocyclic ring system are selected from N, O and S.
[0562] In another embodiment, the present invention provides
compounds of formula X: ##STR46## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0563] E is absent or selected from the group consisting
of
[0564] (1) H,
[0565] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0566] (3) substituted or unsubstituted aryl,
[0567] (4) substituted or unsubstituted heterocyclyl, and
[0568] (5) substituted or unsubstituted heteroaryl,
[0569] or E and R.sup.3L, together with the atoms to which they are
attached can form a substituted or unsubstituted heterocyclic ring,
having from 3 to 10 ring atoms, wherein 1-4 ring atoms of the
heterocyclic ring system are selected from N, O and S; [0570]
R.sup.1L, R.sup.3L are independently selected from the group
consisting of
[0571] (1) H,
[0572] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0573] (3) C.sub.1-C.sub.6-alkyl substituted with aryl,
[0574] (4) C.sub.1-C.sub.6-alkyl substituted with heterocyclyl,
and
[0575] (5) C.sub.1-C.sub.6-alkyl substituted with heteroaryl,
[0576] or R.sup.1L and R.sup.3L, together with the atoms to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 3 to 8 ring atoms, wherein 1-2 ring
atoms of the heterocyclic ring system are selected from N, O and S.
[0577] In another embodiment, the present invention provides
compounds of formula XI: ##STR47## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0578] Y--X taken together, is selected from the group
consisting of ##STR48## ##STR49## [0579] In another embodiment, the
present invention provides compounds of formula XII: ##STR50## or
stereoisomers, pharmaceutically acceptable salts, esters, and
prodrugs thereof, wherein [0580] R.sup.1b and R.sup.2b are
independently selected from the group consisting of
[0581] (1) H,
[0582] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0583] (3) substituted or unsubstituted
C.sub.2-C.sub.6-alkenyl,
[0584] (4) substituted or unsubstituted
C.sub.2-C.sub.6-alkenyl,
[0585] (5) substituted or unsubstituted aryl,
[0586] (6) substituted or unsubstituted heterocyclyl,
[0587] (7) substituted or unsubstituted heteroaryl,
[0588] (8) C.sub.1-C.sub.6-alkyl substituted with aryl,
[0589] (9) C.sub.1-C.sub.6-alkyl substituted with heterocyclyl,
and
[0590] (10) C.sub.1-C.sub.6-alkyl substituted with heteroaryl;
q is an integer of 0-2;
[0591] In another embodiment, the present invention provides
compounds of formula XIII: ##STR51## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0592] R.sub.4 is selected from the group consisting of
[0593] (1) H,
[0594] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0595] (3) C.sub.1-C.sub.6-alkyl substituted with aryl,
[0596] (4) C.sub.1-C.sub.6-alkyl substituted with heterocyclyl,
and
[0597] (5) C.sub.1-C.sub.6-alkyl substituted with heteroaryl;
[0598] A is H or --CH(CH.sub.3)OH--; [0599] R.sub.1 is H or
substituted or unsubstituted C.sub.1-6-alkyl; [0600] R.sub.2 is
selected from the group consisting of
[0601] (1) H,
[0602] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0603] (3) substituted or unsubstituted aryl,
[0604] (4) substituted or unsubstituted heterocyclyl,
[0605] (5) substituted or unsubstituted heteroaryl,
[0606] (6) C.sub.1-C.sub.6-alkyl substituted with aryl,
[0607] (7) C.sub.1-C.sub.6-alkyl substituted with heterocyclyl,
[0608] (8) C.sub.1-C.sub.6-alkyl substituted with heteroaryl,
[0609] or R.sup.1 and R.sup.2 together with the N atom to which
they are attached can form a substituted or unsubstituted
heterocyclic ring, having from 3 to 10 ring atoms, wherein 1-2 ring
atoms of the heterocyclic ring system are selected from N, O and S.
[0610] In another embodiment, the present invention provides
compounds of formula XIV: ##STR52## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0611] D-G-Y taken together is selected from the group
consisting of ##STR53## ##STR54## ##STR55## ##STR56## ##STR57##
[0612] Wherein
[0613] R is selected from the group consisting of --CH.sub.3,
--C.sub.2H.sub.5, --CH.sub.2OH, --OH, --OCH.sub.3,
--OC.sub.2H.sub.5, --OCF.sub.3, --CN, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CONH.sub.2, --NH.sub.2, --F, --Cl, --Br,
--CF.sub.3, --N(CH.sub.3).sub.2, --NHSO.sub.2CH.sub.3, and
--NHCOCH.sub.3; [0614] R.sub.4 is selected from the group
consisting of
[0615] (1) H,
[0616] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0617] (3) C.sub.1-C.sub.6-alkyl substituted with aryl,
[0618] (4) C.sub.1-C.sub.6-alkyl substituted with heterocyclyl,
and
[0619] (5) C.sub.1-C.sub.6-alkyl substituted with heteroaryl.
[0620] In another embodiment, the present invention provides
compounds of formula XV: ##STR58## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0621] D-G-Y taken together, is selected from the group
consisting of ##STR59## ##STR60## ##STR61## ##STR62## ##STR63##
[0622] Wherein
[0623] R is selected from the group consisting of --CH.sub.3,
--C.sub.2H.sub.5, --CH.sub.2OH, --OH, --OCH.sub.3,
--OC.sub.2H.sub.5, --OCF.sub.3, --CN, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CONH.sub.2, --NH.sub.2, --F, --Cl, --Br,
--CF.sub.3, --N(CH.sub.3).sub.2, --NHSO.sub.2CH.sub.3, and
--NHCOCH.sub.3; [0624] In another embodiment, the present invention
provides compounds of formula XVI: ##STR64## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0625] D-G-Y taken together, is selected from the group
consisting of ##STR65## ##STR66## ##STR67## ##STR68## ##STR69##
[0626] Wherein
[0627] R is selected from the group consisting of --CH.sub.3,
--C.sub.2H.sub.5, --CH.sub.2OH, --OH, --OCH.sub.3,
--OC.sub.2H.sub.5, --OCF.sub.3, --CN, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CONH.sub.2, --NH.sub.2, --F, --Cl, --Br,
--CF.sub.3, --N(CH.sub.3).sub.2, --NHSO.sub.2CH.sub.3, and
--NHCOCH.sub.3; [0628] R.sub.4 is selected from the group
consisting of
[0629] (1) H,
[0630] (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl,
[0631] (3) C.sub.1-C.sub.6-alkyl substituted with aryl,
[0632] (4) C.sub.1-C.sub.6-alkyl substituted with heterocyclyl,
and
[0633] (5) C.sub.1-C.sub.6-alkyl substituted with heteroaryl;
[0634] In another embodiment, the present invention provides
compounds of formula XVII: ##STR70## or stereoisomers,
pharmaceutically acceptable salts, esters, and prodrugs thereof,
wherein [0635] D-G-Y taken together, is selected from the group
consisting of ##STR71## ##STR72## ##STR73## ##STR74## ##STR75##
[0636] Wherein
[0637] R is selected from the group consisting of --CH.sub.3,
--C.sub.2H.sub.5, --CH.sub.2OH, --OH, --OCH.sub.3,
--OC.sub.2H.sub.5, --OCF.sub.3, --CN, --NO.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CONH.sub.2, --NH.sub.2, --F, --Cl, --Br,
--CF.sub.3, --N(CH.sub.3).sub.2, --NHSO.sub.2CH.sub.3, and
--NHCOCH.sub.3;
[0638] In one aspect, the invention provides a method of inhibiting
a deacetylase enzyme in a gram-negative bacteria, thereby affecting
bacterial growth, comprising administering to a patient in need of
such inhibition a compound of formula I.
[0639] In another aspect, the invention provides a method of
inhibiting LpxC, thereby modulating the virulence of a bacterial
infection, comprising administering to a patient in need of such
inhibition a compound of formula I.
[0640] In some embodiments of the method of inhibiting LpxC using a
compound of formula I, the IC.sub.50 value of the compound is less
than or equal to 10 .mu.M with respect to LpxC. In other such
embodiments, the IC.sub.50 value is less than or equal to 1 .mu.M,
is less than or equal to 0.1 .mu.M, is less than or equal to 0.050
.mu.M, is less than or equal to 0.030 .mu.M, is less than or equal
to 0.025 .mu.M, or is less than or equal to 0.010 .mu.M.
[0641] In one aspect of the invention, methods for treating a
subject comprising administering to the subject an antibacterially
effective amount of a compound of formula I, together with a
pharmaceutically acceptable carrier is provided. In a preferred
embodiment of the method of treatment, the subject is a mammal and
some embodiments, a human.
[0642] In another aspect, the invention provides a method of
administering an inhibitory amount of a compound of formula I to
fermentative or non-fermentative gram-negative bacteria. In a
preferred embodiment of the method of administering an inhibitory
amount of a compound of formula I to fermentative or
non-fermentative gram-negative bacteria, the gram-negative bacteria
are selected from the group consisting of Pseudomonas aeruginosa,
Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes
xylosoxidans, Acinetobacter, Enterobacteriaceae, Haemophilus,
Neisseria species.
[0643] In another embodiment, the invention provides a method of
administering an inhibitory amount of a compound of formula I to
gram-negative bacteria, such as Enterobacteriaceae that is selected
from the group consisting of organisms such as Serratia, Proteus,
Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia,
Morganella, Cedecea, and Edwardsiella species and Escherichia
coli.
[0644] Another embodiment of the invention provides a
pharmaceutical composition comprising an effective amount of a
compound of Formula I with a pharmaceutically acceptable carrier
thereof.
[0645] Pharmaceutical formulations according to the present
invention are provided which include any of the compounds described
above in combination with a pharmaceutically acceptable
carrier.
[0646] Another embodiment of the invention provides a method of
co-administering the compound of formula I with other therapeutic
agents that are selected for their particular usefulness against
the condition that is being treated.
[0647] For example, the compound of formula I is useful in
combination with other anti-bacterial agents. The compound of
formula I augments the sensitivity of gram-negative bacteria to
existing classes of antibacterials. Combinations of the presently
disclosed compounds with other anti-bacterial agents are within the
scope of the invention. Such anti-bacterial agents include, but are
not limited to, erythromycin, rifampicin, Nalidixic acid,
carbenicillin, bacitracin, cycloserine, fosfomycin, and
vancomycin.
[0648] A further aspect of the invention is the use of LpxC
inhibitors for the treatment of an infection, particularly a
bacterial infection. A bacterial infection treated with the
compounds of the invention can be a primary infection or a
co-infection caused by a species of bacteria and one or more
additional infectious agents selected from the group consisting of
bacteria, virus, parasite and fungus.
[0649] The term "treating", as used herein, refers to reversing,
alleviating, inhibiting the progress of, or preventing the disorder
or condition to which such term applies, or one or more symptoms of
such disorder or condition. The term "treatment", as used herein,
refers to the act of treating, as "treating" is defined immediately
above.
[0650] The compounds of the invention can be used for treating
conditions caused by the bacterial production of endotoxin and, in
particular, by gram-negative bacteria and bacteria that use LpxC in
the biosynthesis of lipopolysaccharide (LPS) or endotoxin.
[0651] The compounds of the invention also are useful in the
conditions that are caused or exacerbated by the bacterial
production of lipid A and LPS or endotoxin, such as sepsis, septic
shock, systemic inflammation, localized inflammation, chronic
obstructive pulmonary disease (COPD) and acute exacerbations of
chronic bronchitis (AECB). For these conditions, treatment includes
the administration of a compound of the invention, or a combination
of compounds of the invention, optionally with a second agent
wherein the second agent is a second antibacterial agent or a
second non-antibacterial agent.
[0652] For sepsis, septic shock, systemic inflammation, localized
inflammation, chronic obstructive pulmonary disease (COPD) and
acute exacerbations of chronic bronchitis (AECB), preferred second
non-antibacterial agents include antiendotoxins including endotoxin
receptor-binding antibodies, endotoxin-binding antibodies,
antiCD14-binding protein antibodies antilipopolysaccharide-binding
protein antibodies and tyrosine kinase inhibitors.
[0653] In treatment of serious or chronic respiratory tract
infections, the compounds of the present invention may also be used
with second non-antibacterial agents administered via inhalation.
Preferred non-antibacterial agents used in this treatment include
anti-inflammatory steroids, non-steroidal anti-inflammatory agents,
bronchiodilators, mucolytics, anti-asthma therapeutics and lung
fluid surfactants. In particular, the non-antibacterial agent may
be selected from a group consisting of albuterol, salbuterol,
budesonide, beclomethasone, dexamethasone, nedocromil,
beclomethasone, fluticasone, flunisolide, triamcinolone, ibuprofin,
rofecoxib, naproxen, celecoxib, nedocromil, ipratropium,
metaproterenol, pirbuterol, salmeterol, bronchiodilators,
mucolytics, calfactant, beractant, poractant alfa, surfaxin and
pulmozyme (also called dornase alfa).
[0654] The compounds of the invention can be used, alone or in
combination with a second antibacterial agent for the treatment of
a serious or chronic respiratory tract infection including serious
lung and nosocomial infections such as those caused by Enterobacter
aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella
pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Serratia
marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa,
Burkholderia cepacia, Acinetobacter calcoaceticus, Alcaligenes
xylosoxidans, Flavobacterium meningosepticum, Providencia stuartii
and Citrobacter freundi, community lung infections such as those
caused by Haemophilus Influenzae, Legionella species, Moraxella
catarrhalis, Branhamella catarrhalis, Enterobacter species,
Acinetobacter species, Klebsiella species, and Proteus species, and
infections caused by other bacterial species such as Neisseria
species, Shigella species, Salmonella species, Helicobacter pylori,
Vibrionaceae and Bordetella species as well as the infections is
caused by a Brucella species, Francisella tularensis and/or
Yersinia Pestis.
[0655] When used for treating Gram-negative bacteria, the compounds
of the present invention can be used to sensitize gram-negative
bacteria to the effects of a second agent.
[0656] When the compounds of the present invention are used in
combination with a second antibacterial agent, non-limiting
examples of antibacterial agents may be selected from the following
groups: [0657] (1) Macrolides or ketolides such as erythromycin,
azithromycin, clarithromycin and telithromycin; [0658] (2)
Beta-lactams including penicillin, cephalosporin, and carbapenems
such as carbapenem, imipenem, and meropenem; [0659] (3) Monobactams
such as penicillin G, penicillin V, methicillin, oxacillin,
cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin,
carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin,
temocillin, cepalothin, cephapirin, cephradine, cephaloridine,
cefazolin, cefamandole, cefuroxime, cephalexin, cefprozil,
cefaclor, loracarbef, cefoxitin, cefinetazole, cefotaxime,
ceftizoxime, ceftriaxone, cefoperzone, ceftazidime, cefixime,
cefpodoxime, ceftibuten, cefdinir, cefpirome, cefepime, and
astreonam; [0660] (4) Quinolones such as nalidixic acid, oxolinic
acid, norfloxacin, pefloxacin, enoxacin, ofloxacin, levofloxacin,
ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin,
grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin,
gatifloxacin, moxifloxacin, sitafloxacin, ganefloxacin,
gemifloxacin and pazufloxacin; [0661] (5) Antibacterial
sulfonamides and antibacterial sulphanilamides, including
para-aminobenzoic acid, sulfadiazine, sulfisoxazole,
sulfamethoxazole and sulfathalidine; [0662] (6) Aminoglycosides
such as streptomycin, neomycin, kanamycin, paromycin, gentamicin,
tobramycin, amikacin, netilmicin, spectinomycin, sisomicin,
dibekalin and isepamicin; [0663] (7) Tetracyclines such as
tetracycline, chlortetracycline, demeclocycline, minocycline,
oxytetracycline, methacycline, doxycycline; [0664] (8) Rifamycins
such as rifampicin (also called rifampin), rifapentine, rifabutin,
bezoxazinorifamycin and rifaximin; [0665] (9) Lincosamides such as
lincomycin and clindamycin; [0666] (10) Glycopeptides such as
vancomycin and teicoplanin; [0667] (11) Streptogramins such as
quinupristin and daflopristin; [0668] (12) Oxazolidinones such as
linezolid; [0669] (13) Polymyxin, colistin and colymycin; [0670]
(14) Trimethoprim and bacitracin.
[0671] The second antibacterial agent may be administered in
combination with the compounds of the present inventions wherein
the second antibacterial agent is administered prior to,
simultaneously, or after the compound or compounds of the present
invention. When simultaneous administration of a compound of the
invention with a second agent is desired and the route of
administration is the same, then a compound of the invention may be
formulated with a second agent into the same dosage form. An
example of a dosage form containing a compound of the invention and
a second agent is a tablet or a capsule.
[0672] When used for treating a serious or chronic respiratory
tract infections, the compounds of the invention may be used alone
or in combination with a second antibacterial agent administered
via inhalation. In the case of inhalation, a preferred second
antibacterial agent is selected from a group consisting of
tobramycin, gentamicin, aztreonam, ciprofloxacin, polymyxin,
colistin, colymycin, azithromycin and clarithromycin.
Pharmaceutical Compositions
[0673] Pharmaceutical compositions of the present invention
comprise a therapeutically effective amount of a compound of the
present invention formulated together with one or more
pharmaceutically acceptable carriers. As used herein, the term
"pharmaceutically acceptable carrier" means a non-toxic, inert
solid, semi-solid or liquid filler, diluent, encapsulating material
or formulation auxiliary of any type. Some examples of materials
that can serve as pharmaceutically acceptable carriers are sugars
such as lactose, glucose and sucrose; starches such as corn starch
and potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol; esters such as ethyl oleate
and ethyl laurate; agar; buffering agents such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate
buffer solutions, as well as other non-toxic compatible lubricants
such as sodium lauryl sulfate and magnesium stearate, as well as
coloring agents, releasing agents, coating agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can
also be present in the composition, according to the judgment of
the formulator. The pharmaceutical compositions of this invention
can be administered to humans and other animals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments, or drops), bucally, or as an
oral or nasal spray, or a liquid aerosol or dry powder formulation
for inhalation.
[0674] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof. Besides inert diluents,
the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
[0675] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0676] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions that can be dissolved or dispersed in sterile water or
other sterile injectable medium prior to use.
[0677] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution that, in turn, may depend upon crystal
size and crystalline form. Alternatively, delayed absorption of a
parenterally administered drug form may be accomplished by
dissolving or suspending the drug in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the drug
in biodegradable polymers such as polylactide-polyglycolide.
Depending upon the ratio of drug to polymer and the nature of the
particular polymer employed, the rate of drug release can be
controlled. Examples of other biodegradable polymers include
poly(orthoesters) and poly(anhydrides). Depot injectable
formulations may also be prepared by entrapping the drug in
liposomes or microemulsions that are compatible with body
tissues.
[0678] Compositions for rectal or vaginal administration are
preferably suppositories that can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0679] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, acetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0680] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0681] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions that can be used include
polymeric substances and waxes.
[0682] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0683] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0684] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulations, ear drops, and
the like are also contemplated as being within the scope of this
invention.
[0685] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0686] Compositions of the invention may also be formulated for
delivery as a liquid aerosol or inhalable dry powder. Liquid
aerosol formulations may be nebulized predominantly into particle
sizes that can be delivered to the terminal and respiratory
bronchioles where bacteria reside in patients with bronchial
infections, such as chronic bronchitis and pneumonia. Pathogenic
bacteria are commonly present throughout airways down to bronchi,
bronchioli and lung parenchema, particularly in terminal and
respiratory bronchioles. During exacerbation of infection, bacteria
can also be present in alveoli. Liquid aerosol and inhalable dry
powder formulations are preferably delivered throughout the
endobronchial tree to the terminal bronchioles and eventually to
the parenchymal tissue.
[0687] Aerosolized formulations of the invention may be delivered
using an aerosol forming device, such as a jet, vibrating porous
plate or ultrasonic nebulizer, preferably selected to allow the
formation of a aerosol particles having with a mass medium average
diameter predominantly between 1 to 5 .mu.m. Further, the
formulation preferably has balanced osmolarity ionic strength and
chloride concentration, and the smallest aerosolizable volume able
to deliver effective dose of the compounds of the invention to the
site of the infection. Additionally, the aerosolized formulation
preferably does not impair negatively the functionality of the
airways and does not cause undesirable side effects.
[0688] Aerosolization devices suitable for administration of
aerosol formulations of the invention include, for example, jet,
vibrating porous plate, ultrasonic nebulizers and energized dry
powder inhalers, that are able to nebulize the formulation of the
invention into aerosol particle size predominantly in the size
range from 1-5 .mu.m. Predominantly in this application means that
at least 70% but preferably more than 90% of all generated aerosol
particles are 1 to 5 .mu.m range. A jet nebulizer works by air
pressure to break a liquid solution into aerosol droplets.
Vibrating porous plate nebulizers work by using a sonic vacuum
produced by a rapidly vibrating porous plate to extrude a solvent
droplet through a porous plate. An ultrasonic nebulizer works by a
piezoelectric crystal that shears a liquid into small aerosol
droplets. A variety of suitable devices are available, including,
for example, AeroNeb and AeroDose vibrating porous plate nebulizers
(AeroGen, Inc., Sunnyvale, Calif.), Sidestream7 nebulizers
(Medic-Aid Ltd., West Sussex, England), Pari LC7 and Pari LC Star7
jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Va.),
and Aerosonic (DeVilbiss Medizinische Produkte (Deutschland) GmbH,
Heiden, Germany) and UltraAire7 (Omron Healthcare, Inc., Vernon
Hills, Ill.) ultrasonic nebulizers.
[0689] Compounds of the invention may also be formulated for use as
topical powders and sprays that can contain, in addition to the
compounds of this invention, excipients such as lactose, talc,
silicic acid, aluminum hydroxide, calcium silicates and polyamide
powder, or mixtures of these substances. Sprays can additionally
contain customary propellants such as chlorofluorohydrocarbons.
[0690] Transdermal patches have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0691] According to the methods of treatment of the present
invention, bacterial infections are treated or prevented in a
patient such as a human or lower mammal by administering to the
patient a therapeutically effective amount of a compound of the
invention, in such amounts and for such time as is necessary to
achieve the desired result. By a "therapeutically effective amount"
of a compound of the invention is meant a sufficient amount of the
compound to treat bacterial infections, at a reasonable
benefit/risk ratio applicable to any medical treatment. It will be
understood, however, that the total daily usage of the compounds
and compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
patient will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed; and like
factors well known in the medical arts.
[0692] The total daily dose of the compounds of this invention
administered to a human or other mammal in single or in divided
doses can be in amounts, for example, from 0.01 to 50 mg/kg body
weight or more usually from 0.1 to 25 mg/kg body weight. Single
dose compositions may contain such amounts or submultiples thereof
to make up the daily dose. In general, treatment regimens according
to the present invention comprise administration to a patient in
need of such treatment from about 10 mg to about 2000 mg of the
compound(s) of this invention per day in single or multiple
doses.
[0693] Methods of formulation are well known in the art and are
disclosed, for example, in Remington: The Science and Practice of
Pharmacy, Mack Publishing Company, Easton, Pa., 19th Edition
(1995). Pharmaceutical compositions for use in the present
invention can be in the form of sterile, non-pyrogenic liquid
solutions or suspensions, coated capsules, suppositories,
lyophilized powders, transdermal patches or other forms known in
the art.
[0694] A "kit" as used in the instant application includes a
container for containing the pharmaceutical compositions and may
also include divided containers such as a divided bottle or a
divided foil packet. The container can be in any conventional shape
or form as known in the art that is made of a pharmaceutically
acceptable material, for example a paper or cardboard box, a glass
or plastic bottle or jar, a resealable bag (for example, to hold a
"refill" of tablets for placement into a different container), or a
blister pack with individual doses for pressing out of the pack
according to a therapeutic schedule. The container employed can
depend on the exact dosage form involved, for example a
conventional cardboard box would not generally be used to hold a
liquid suspension. It is feasible that more than one container can
be used together in a single package to market a single dosage
form. For example, tablets may be contained in a bottle that is in
turn contained within a box.
[0695] An example of such a kit is a so-called blister pack.
Blister packs are well known in the packaging industry and are
being widely used for the packaging of pharmaceutical unit dosage
forms (tablets, capsules, and the like). Blister packs generally
consist of a sheet of relatively stiff material covered with a foil
of a preferably transparent plastic material. During the packaging
process, recesses are formed in the plastic foil. The recesses have
the size and shape of individual tablets or capsules to be packed
or may have the size and shape to accommodate multiple tablets
and/or capsules to be packed. Next, the tablets or capsules are
placed in the recesses accordingly and the sheet of relatively
stiff material is sealed against the plastic foil at the face of
the foil that is opposite from the direction in which the recesses
were formed. As a result, the tablets or capsules are individually
sealed or collectively sealed, as desired, in the recesses between
the plastic foil and the sheet. Preferably the strength of the
sheet is such that the tablets or capsules can be removed from the
blister pack by manually applying pressure on the recesses whereby
an opening is formed in the sheet at the place of the recess. The
tablet or capsule can then be removed via said opening.
[0696] It maybe desirable to provide a written memory aid, where
the written memory aid is of the type containing information and/or
instructions for the physician, pharmacist or other health care
provider, or subject, e.g., in the form of numbers next to the
tablets or capsules whereby the numbers correspond with the days of
the regimen that the tablets or capsules so specified should be
ingested or a card that contains the same type of information.
Another example of such a memory aid is a calendar printed on the
card e.g., as follows "First Week, Monday, Tuesday," . . . etc. . .
. "Second Week, Monday, Tuesday, . . . " etc. Other variations of
memory aids will be readily apparent. A "daily dose" can be a
single tablet or capsule or several tablets or capsules to be taken
on a given day. When the kit contains separate compositions, a
daily dose of one or more compositions of the kit can consist of
one tablet or capsule while a daily dose of another one or more
compositions of the kit can consist of several tablets or
capsules.
[0697] Another specific embodiment of a kit is a dispenser designed
to dispense the daily doses one at a time in the order of their
intended use. Preferably, the dispenser is equipped with a
memory-aid, so as to further facilitate compliance with the
regimen. An example of such a memory-aid is a mechanical counter,
that indicates the number of daily doses that has been dispensed.
Another example of such a memory-aid is a battery-powered
micro-chip memory coupled with a liquid crystal readout, or audible
reminder signal that, for example, reads out the date that the last
daily dose has been taken and/or reminds one when the next dose is
to be taken.
[0698] The kits of the present invention may also include, in
addition to LpxC inhibitors, one or more additional
pharmaceutically active compounds. Preferably, the additional
compound is another LpxC inhibitor or another compound useful to
bacterial infections. The additional compounds may be administered
in the same dosage form as the LpxC inhibitor or in different
dosage forms. Likewise, the additional compounds can be
administered at the same time as the LpxC inhibitor or at different
times.
[0699] Compositions of the present compounds may also be used in
combination with other known antibacterial agents of similar
spectrum to (1) synergistically enhance treatment of severe
Gram-negative infections covered by the spectrum of this compound
or (2) add coverage in severe infections in which multiple
organisms are suspected in which another agent of a different
spectrum may be required in addition to this compound. Potential
agents include members of the aminoglycosides, penicillins,
cephalosporins, fluoroquinolones, macrolides, glycopeptides,
lipopeptides and oxazolidinones. The treatment can involve
administering a composition having both active agents or
administration of the inventive compounds followed by or preceded
by administration of an additional active antibacterial agent.
Characterization and Purification Methods
[0700] 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.). The
analytical columns were Alltima C-18 reversed phase, 4.6.times.250
mm from Alltech (Deerfield, Ill.). A gradient elution was used,
typically starting with 5% acetonitrile/95% water and progressing
to 100% acetonitrile over a period of 40 minutes. All solvents
contained 0.1% trifluoroacetic acid (TFA). Compounds were detected
by ultraviolet light (UV) absorption at either 220 or 254 nm. HPLC
solvents were from Burdick and Jackson (Muskegan, Mich.), or Fisher
Scientific (Pittsburg, Pa.). 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
1B2-F flexible sheets. TLC results were readily detected visually
under ultraviolet light, or by employing well known iodine vapor
and other various staining techniques.
[0701] Mass spectrometric analysis was performed on one of two LCMS
instruments: a Waters System (Alliance HT HPLC and a Micromass ZQ
mass spectrometer; Column: Eclipse XDB-C18, 2.1.times.50 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.degree.
C.) or a Hewlett Packard System (Series 1100 HPLC; Column: Eclipse
XDB-C18, 2.1.times.50 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.degree. C.). All
masses are reported as those of the protonated parent ions.
[0702] GCMS analysis was performed on a Hewlet Packard instrument
(HP6890 Series gas chromatograph with a Mass Selective Detector
5973; injector volume: 1 .mu.L; initial column temperature:
50.degree. C.; final column temperature: 250 C; ramp time: 20
minutes; gas flow rate: 1 mL/min; column: 5% phenyl methyl
siloxane, Model #HP 190915-443, dimensions: 30.0 m.times.25
m.times.0.25 m).
[0703] Nuclear magnetic resonance (NMR) analysis was performed with
a Varian 300 Mhz NMR (Palo Alto, Calif.). 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.degree.
C.) to promote increased sample solubility.
[0704] The purity of some of the invention compounds was assessed
by elemental analysis (Desert Analytics, Tuscon, Ariz.)
[0705] Melting points were determined on a laboratory Devices
Mel-Temp apparatus (Holliston, Mass.).
[0706] Preparative separations were carried out using a Flash 40
chromatography system and KP-Sil, 60A (Biotage, Charlottesville,
Va.), or by flash column chromatography using silica gel (230-400
mesh) packing material, or by HPLC using a C-18 reversed phase
column. Typical solvents employed for the Flash 40 Biotage system
and flash column chromatography were dichloromethane, methanol,
ethyl acetate, hexane, acetone, aqueous hydroxyamine and triethyl
amine. Typical solvents employed for the reverse phase HPLC were
varying concentrations of acetonitrile and water with 0.1%
trifluoroacetic acid.
[0707] Compounds of the present invention can be readily
synthesized using the methods described herein, or other methods,
that are well known in the art. For example, the synthesis of
hxdroxamic acids or similar scaffolds having a wide variety of
substituents are comprehensively reviewed in Kline T, Andersen N H,
Harwood E A, Bowman J, Malanda A, Endsley S, Erwin A L, Doyle M,
Fong S, Harris A L, Mendelsohn B, Mdluli K, Raetz C R, Stover C K,
Witte P R, Yabannavar A, Zhu S., "Potent, novel in vitro inhibitors
of the Pseudomonas aeruginosa deacetylase LpxC," J Med Chem 2002
July 4;45(14):3112-29; Patchett, A. A., Nargund, R., Chen, M.-H.,
Nishi, H. R., U.S. Pat. No. 5,925,659, 1999; Pirrung, M. C., Chau,
J. H., "A Convenient Procedure for the Preparation of Amino Acid
Hydroxamates from Esters," J. Org. Chem. 1995, 60, 8084-8085; Nhu,
K., Patel, D. V., "A New and Efficient Solid Phase Synthesis of
Hydroxamic Acids," J. Org. Chem. 1997, 62, 7088-7089; Patel, D.,
Nhu, K., "Methods for Solid-phase Synthesis of Hydroxylamine
Compounds and Derivatives, and Combinatorial Libraries Thereof,"
PCT WO 98/18754, 1998, Mellor, S. L., McGuire, C., Chan, W. C.,
"N-Fmoc-aminoxy-2-chlortrityl Polystyrene Resin: A Facile
Solid-phase Methodology for the Synthesis of Hydroxamic Acids,"
Tetrahedron Lett., 1997, 38, 3311-3314; Khan, S. I., Grinstaff, M.
W., "A Facile and Convenient Solid-phase Procedure for Synthesizing
Nucleoside Hydroxamic Acids," Terahedron. Lett., 1998, 39,
8031-8034; Zhang, Y., Li, D., Houtman, J. C., Witiak, D. T.,
Seltzer, J., Bertics, P. J., Lauhon, C. T., "Design, Combinatorial
Chemical Synthesis, and in vitro Characterization of Novel Urea
Based Gelatinase Inhibitors," Bioorg. Med. Chem. Lett., 1999, 9,
2823-2826, Ito, Y., Inubushi, Y., Zenbayashi, M., Tomita, S.,
Saegusa, T., "Synthetic Reactions by Complex Catalysts. XXXI, A
Novel and Versatile Method of Heterocycle Synthesis," J. Am Chem.
Soc., 1973, 95, 4447-4448; Ito, Y., Ito, I., Hirao, T., Saegus, T.,
"Synthetic Reactions by Complex Catalysts XXXV," Syn. Commun. 1974,
4, 97-103; Witte, H., Seliger, W., "Cyclische Imidsaurester aus
Nitrilen und Aminoalkoholen," Liebigs Ann. Chem, 1974, 996-1009;
Pattenden, G., Thom. S. M., "Naturally Occurring Linear Fused
Thiazoline-Thiazole Containing Metabolites: Total Synthesis of (-)
Didehydromirabazole A, a Cytotoxic Alkaloid from Blue-Green Algae,"
J. Chem. Soc. Perkin Trans 1, 1993, 1629-1636; Boyce, R. J.,
Mulqueen, G. C., Pattenden, G., "Total Synthesis of Thiangazole, A
Novel Naturally Occurring HIV-1 Inhibitor from Polyangium sp."
Tetrahedron, 1995, 51, 7321-7330; Galeotti, N., Plagnes, E., Jouin,
P., "Synthesis of Peptidyl Aldehydes from Thiazolines,"
Tetrahedron. Lett. 1997, 38, 2459-2462; Charette, A. B., Chua, P.,
"Mild Method for the Synthesis of Thiazolines from Secondary and
Tertiary Amides," J. Org. Chem., 1998, 63, 908-909; Bergeron, R.
J., Wiegand, J., McManis, J. S., McCosar, B. H., Weimar, W. R.,
Brittenham, G. M., Smith, R. E., "Effects of C-4 Stereochemistry
and C-4' Hydroxylation on the Iron Clearing Efficiency and Toxicity
of Desferrithiocin Analogues," J. Med. Chem. 1999, 42, 2432-2440;
Raman, P., Razavik H., Kelly, J. W., "Titanium (IV)-mediated Tandem
Deprotection-cyclodehydration of Protected Cysteine N-Amides:
Biomimetic Synthesis of Thiazoline- and Thiazole-containing
Heterocycles," Org. Lett., 2000, 2, 3289-3292; Fernandez, X.,
Fellous, R., Dunach, E., "Novel Synthesis of 2-Thioazolines,"
Tetrahedron Lett., 2000, 41, 3381-3384. Wipf, P., Miller, C. P.,
Venkatraman, S., Fritch, P., "C. Thiolysis of Oxazolinenes: A New,
Selective Method for the Direct Conversion of Peptide Oxazolines
into Thiazolines," Tetrahedron Lett., 1995, 36, 6395-6398, which
are incorporated herein by reference.
[0708] The synthesis of other non-hydroxamates compounds or more
generally zinc binding groups are reviewed in Pirrung, M. C.,
Tumey, L. N., Raetz, C. R. H., Jackman, J. E., Snehalatha, K.,
McClerren, A. L., Fierke, C. A., Gantt, S. L., Rusche, K. M.,
"Inhibition of the Antibacterial Target
UDP-(3-O-acyl)-N-acetylglucosamine Deacetylase (LpxC): Isoxazoline
Zinc Amidase Inhibitors Bearing Diverse Metal Binding Groups,"
Journal of Medicinal Chemistry (2002), 45(19), 4359-4370; Jackman,
J. E., Fierke, C. A., Tumey, L. N., Pirrung, M., Uchiyama, T.,
Tahir, S. H., Hindsgaul, O., Raetz, C. R. H., "Antibacterial agents
that target lipid A biosynthesis in gram-negative bacteria:
inhibition of diverse
UDP-3-O--(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylases by
substrate analogs containing zinc binding motifs," Journal of
Biological Chemistry (2000), 275(15), 11002-11009; Brooks, C. D.
W., Summers, J. B., "Modulators of Leukotriene Biosynthesis and
Receptor Activation," Journal of Medicinal Chemistry (1996),
39(14), 2629-2654; Jeng, A. Y., De Lombaert, S., "Endothelin
converting enzyme inhibitors," Current Pharmaceutical Design
(1997), 3(6), 597-614; Zask, A., Levin, J. I., Killar, L. M.,
Skotnicki, J. S., "Inhibition of matrix metalloproteinases:
structure based design," Current Pharmaceutical Design (1996),
2(6), 624-661; Skotnicki, J. S., DiGrandi, M. J., Levin, J. I.,
Chemical and Screening Sciences, Wyeth Research, New York, N.Y.,
USA. Current Opinion in Drug Discovery & Development (2003),
6(5), 742-759.
[0709] The foregoing may be better understood by reference to the
following examples, that are presented for illustration and not to
limit the scope of the inventive concepts.
EXAMPLES
[0710] The following are abbreviations used in the examples: [0711]
AcOH: Acetic acid [0712] aq: Aqueous [0713] ATP: Adenosine
triphosphate [0714] Boc: tert-butoxycarbonyl [0715] Boc-Thr(OBn)-OH
3-(R)-Benzyloxy-2-(S)-tert-butoxycarbonylamino-butyric acid. [0716]
DAP or Dap: Diaminopropionate [0717] DCM:
4-(Dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran
[0718] DEAD: Diethyl azodicarboxylate [0719] DIEA:
Diisopropylethylamine [0720] DME: 1,2-dimethoxyethane [0721] DMF:
N,N-Dimethylformamide [0722] DMSO: Dimethyl sulfoxide [0723] DPPA:
Diphenyl phosphoryl azide [0724] Et.sub.3N: Triethylamine [0725]
EDC: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide [0726] EDCI:
1-(3-dimethylaminopropyl)3-ethylcarbodiimide [0727] EtOAc: Ethyl
acetate [0728] EtOH: Ethanol [0729] Fmoc:
9-fluorenylmethoxycarbonyl [0730] Gly-OH: glycine [0731] HATU:
O-(7-azabenzotriaazol-1-yl)-N,N,N'N'=tetramethyluronium
hexafluorophophate [0732] HBTU:
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0733] Hex: hexane [0734] HOBt: butyl alcohol
[0735] HOBT: 1-Hydroxybenzotriazole [0736] HPLC: High Pressure
Liquid Chromatography [0737] IC.sub.50 value: The concentration of
an inhibitor that causes a 50% reduction in a measured activity.
[0738] iPrOH: Isopropanol [0739] LC/MS: Liquid Chromatography/Mass
Spectrometry [0740] LRMS: Low Resolution Mass Spectrometry [0741]
MeOH: Methanol [0742] NaOMe: sodium methoxide [0743] nm: Nanometer
[0744] NMP: N-Methylpyrrolidone [0745] PPh.sub.3: triphenyl
phosphine [0746] RP-HPLC: Reversed-phase high-pressure liquid
chromatography [0747] RT: Room temperature [0748] sat: Saturated
[0749] TEA: Triethylamine [0750] TFA: Trifluoroacetic acid [0751]
THF: Tetrahydrofuran [0752] Thr: Threonine [0753] TLC: Thin Layer
Chromatography [0754] Trt-Br: Tert-butyl bromide
[0755] Nomenclature for the Example compounds was provided using
ACD Name version 5.07 software (Nov. 14, 2001) available from
Advanced Chemistry Development, Inc. Some of the compounds and
starting materials were named using standard IUPAC
nomenclature.
Synthesis of N-Aroyl Threonine Analogues and Formation of
Hydroxamate
Example 1
Synthesis of
3-bromo-4-fluoro-N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}be-
nzamide (3)
[0756] TABLE-US-00001 ##STR76## ##STR77## ##STR78## Reagent MW Eq.
g/ml mmol Benzoicacid (1) 219.02 1.0 2.152 g 9.83 L-Thr-OMe--HCl
169.61 1.2 1.968 g 11.6 EDCI 191.71 1.2 2.218 g 11.6 HOBt 135.13
1.1 1.410 g 10.4 DIEA 129.25 4.0 6.8 mL 39.0 DMF 60 mL
Preparation of
(2S,3R)-2-(3-bromo-4-fluoro-benzoylamino)-3-hydroxy-butyric acid
methyl ester (2)
[0757] Diisopropylethylamine (6.8 mL, 39.0 mmol) was added to a
stirred solution of 3-bromo-4-fluorobenzoic acid 1 (2.152 g, 9.83
mmol), L-threonine methyl ester hydrochloride (1.968 g, 11.6 mmol),
EDCI (2.218 g, 11.6 mmol) and HOBt (1.410 g, 10.4 mmol) in
anhydrous DMF (60 mL) at 0.degree. C. under N.sub.2. The solution
was stirred at 0.degree. C. for 1 h and at room temperature for 20
h. The solution was diluted with EtOAc (300 mL) and washed with 1.0
M HCl (2.times.80 mL), saturated NaHCO.sub.3 (2.times.80 mL),
H.sub.2O (4.times.80 mL), dried over MgSO.sub.4, filtered and
concentrated in vacuo to give a colorless syrup which solidified on
standing to afford 3.280 g (100%) of
(2S,3R)-2-(3-bromo-4-fluoro-benzoylamino)-3-hydroxy-butyric acid
methyl ester 2 as a white solid, mp 73-74.degree. C. MS(ES+) m/z
333.9 (C.sub.12H.sub.13BrFNO.sub.4+H requires 334.00).
Preparation of
3-bromo-4-fluoro-N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}be-
nzamide (3)
[0758] ##STR79##
[0759] To a solution of hydroxylamine hydrochloride (66 mg, 0.95
mmol) in anhydrous MeOH (2.0 mL) at 0.degree. C. under N.sub.2
atmosphere was added sodium methoxide (25 wt % in MeOH, 360 mg,
1.67 mmol). A precipitate formed immediately and the cloudy white
solution was stirred for 10 minutes at 0.degree. C. A solution of
methyl
(2S,3R)-2-[(3-bromo-4-fluorophenyl)carbonylamino]-3-hydroxybutanoate
(2) (284 mg, 0.850 mmol) in MeOH (2.0 mL) was added and the
reaction stirred 2 h at 0.degree. C. and then warmed gradually to
room temperature overnight (17 h total). Aqueous 1.0 M HCl (10 mL)
was added and the solution extracted with 4:1 chloroform/isopropyl
alcohol (4.times.20 mL). The organic layers were combined, dried
over Na.sub.2SO.sub.4 and concentrated to give a pink foam. The
crude solid was triturated with diethyl ether (2.times.8 mL) and
dried in vacuo to give
3-bromo-4-fluoro-N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}be-
nzamide 3 as a white foam: mp 152-153.degree. C. Rf (10:1
CH.sub.2Cl.sub.2/MeOH on silica gel)=0.53.
Preparation of Hydroxamates
Example 2
Synthesis of
4-benzoyl-N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}benzamide
[0760] ##STR80## Procedure:
[0761] To a solution of hydroxylamine hydrochloride (121 mg, 1.74
mmol) in anhydrous MeOH (2.0 mL) at 0.degree. C. under N2
atmosphere was added sodium methoxide (25 wt % in MeOH, 680 mg,
3.14 mmol). A precipitate was immediately observed and the cloudy
white solution was stirred for 10 minutes at 0.degree. C. A
solution of methyl
(2S,3R)-3-hydroxy-2-{[4-(phenylcarbonyl)phenyl]carbonylamino}butanoate
(1) (534 mg, 1.56 mmol) in MeOH (3.0 mL) was added and the reaction
stirred 3 h at 0.degree. C., then warmed gradually to ambient
temperature overnight (18 h total). Aqueous 0.5 M HCl (20 mL) was
added and the solution extracted with 5:1 chloroform/isopropyl
alcohol (4.times.40 mL). The organic layers were combined, dried
over Na.sub.2SO.sub.4 and concentrated to give an orange foam.
Purification by silica gel chromatography (increasing eluant
polarity from 30:1 CH.sub.2Cl.sub.2/MeOH to 15:1
CH.sub.2Cl.sub.2/MeOH) afforded 228 mg (43%) of
4-benzoyl-N-}(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}-
benzamide.
Example 3
Synthesis of
(2R,3R)-3-hydroxy-1-{[4-(trifluoromethoxy)phenyl]carbonyl}pyrrolidine-2-c-
arbohydroxamic acid
Preparation of
((2R,3R)-3-hydroxy-1-{[4-(trifluoromethoxy)phenyl]carbonyl}pyrrolidin-2-y-
l)-N-(phenylmethoxy)carboxamide (2)
[0762] ##STR81## Procedure:
[0763] To a solution of
(2R,3R)-3-hydroxy-1-{[4-(trifluoromethoxy)phenyl]carbonyl}pyrrolidine-2-c-
arboxylic acid (1) (405 mg, 1.27 mmol), benzylhydroxylamine
hydrochloride (243 mg, 1.52 mmol), HATU (556 mg, 1.46 mmol), and
HOBt (178 mg, 1.32 mmol) in DMF (10 mL) at 0.degree. C. was added
diisopropylethylamine (710 .mu.L, 4.07 mmol) with stirring. The
cooling bath was removed after one hour and the reaction mixture
stirred at ambient temperature for 18 h and then diluted with EtOAc
(200 mL). The organic layer was washed with 1.0 M HCl (2.times.60
mL), sat. NaHCO.sub.3 (2.times.60 mL) and H.sub.2O (5.times.60 mL),
dried over MgSO.sub.4 and concentrated to give 493 mg (92%) of
((2R,3R)-3-hydroxy-1-{[4-(trifluoromethoxy)phenyl]carbonyl}pyrro-
lidin-2-yl)-N-(phenylmethoxy)carboxamide (2), a colorless oil that
slowly crystallized upon standing. Rf (25:1
CH.sub.2Cl.sub.2/MeOH)=0.35.
Prepartion of
(2R,3R)-3-hydroxy-1-{[4-(trifluoromethoxy)phenyl]carbonyl}pyrrolidine-2-c-
arbohydroxamic acid (2)
[0764] ##STR82## Procedure:
[0765] To a solution of
((2R,3R)-3-hydroxy-1-{[4-(trifluoromethoxy)phenyl]carbonyl}pyrrolidin-2-y-
l)-N-(phenylmethoxy)carboxamide (1) (143 mg, 0.337 mmol) in EtOH
(10 mL) was added 20% Pd(OH).sub.2/C (50 mg). The solution was
purged with hydrogen gas (approx. 0.5 L from a 1 L balloon) and
then stirred under an atmosphere of H.sub.2 (balloon pressure). TLC
analysis showed no starting material after one hour. The solution
was diluted with EtOAc (10 mL) and filtered through celite, washing
with 20:1 EtOAc/EtOH (50 mL). The solution was concentrated and
dried in vacuo to afford 90 mg (80%) of
(2R,3R)-3-hydroxy-1-{[4-(trifluoromethoxy)phenyl]carbonyl}pyrrolidine-2-c-
arbohydroxamic acid (2) as a sticky white foam: mp 64-65.degree. C.
Rf (10:1 CH.sub.2Cl.sub.2/MeOH)=0.29.
Synthesis of N-Benzyl Threonine Analogues by Reductive
Amination
Example 4
Synthesis of
(2S,3R)-3-hydroxy-2-{[(4-phenylphenyl)methyl]amino}butanehydroxamic
acid (3)
[0766] TABLE-US-00002 ##STR83## ##STR84## ##STR85## Reagent MW Eq.
g/ml mmol 4-biphenylcarboxaldehyde 182.22 1.0 1.104 g 6.06
L-Thr-OMe--HCl 169.61 1.0 1.030 g 6.07 NaBH(OAc).sub.3 211.94 1.4
1.800 g 8.49 Et.sub.3N 101.19 2.0 1.70 mL 12.1 THF 25 mL
[0767] Triethylamine (1.70 mL, 12.1 mmol) was added to a stirred
suspension of L-threonine methyl ester hydrochloride (1.030 g, 6.07
mmol) and 4-biphenylcarboxaldehyde (1.104 g, 6.06 mmol) in THF (25
mL). After 20 min, NaBH(OAc).sub.3 was added and the suspension
stirred for 20 h. The reaction was monitored by TLC (50:1 DCM/MeOH,
R.sub.f=0.4). The reaction mixture was quenched with saturated
NaHCO.sub.3 (50 mL), extracted with EtOAc (2.times.120 mL), dried
over MgSO.sub.4, filtered and concentrated to give a yellow oil.
Purification by silica gel chromatography (150:1 DCM/MeOH) afforded
1.220 g (67% yield, 98% pure) of (2S,
3R)-2-[(biphenyl-4-ylmethyl)-amino]-3-hydroxy-butyric acid methyl
ester 2 as a pale yellow oil.
[0768] HPLC (260 nm, 34 min run) 14.2 min; LRMS(ES+) m/z 299.9
(C.sub.18H.sub.21NO.sub.3+H requires 300.10). Compound 3 was then
formed by the addition of NH.sub.2OH in MeOH/NaOMe at 0.degree. C.,
warming to ambient temparture of the period of several hours. LCMS
MH+301.15.
General Methods for Making Phenyl-benzoic acids and Phenyl-benzoate
esters (see Example 5 below)
[0769] ##STR86##
Suzuki Procedures Using Pd(dppf)Cl.sub.2-DCM Catalyst and a
THF/H.sub.2O Mixture
[0770] TABLE-US-00003 ##STR87## Reagent MW EQ g/ml mmol Bromo Arene
#1 .about.300 1 100 mg .about.0.33 Boronic Acid #2 -- 1.2 --
.about.0.40 Na.sub.2CO.sub.3 105.99 3 104 m .about.0.99
Pd(dppf)Cl.sub.2 816.63 0.1-0.2 27-54 mg .about.0.033-0.066 THF (3)
(sparged with 0.75 ml argon for 5 min.) water (1) (sparged 0.25 ml
with argon for 5 min.)
Standard Procedure
[0771] 1 eq aryl halide (1) was added to 1.2 eq. (2) and
Pd(dppf)Cl.sub.2 in THF, followed by addition of water and stirred
8 hours at RT. Upon completion (usually over night), the reactions
are diluted with ethyl acetate (5-10 ml) and water (1 ml). The
organic layer is separated and washed with NaHCO.sub.3 (2.times.3
ml), water (1.times.3 ml), brine (1.times.3 ml), dried with
Na.sub.2SO.sub.4, filtered and concentrated in an 8 ml glass vial.
The residue is dissolved in DMSO and injected on a preparatory HPLC
reverse phase column to afford >80% yield.
Suzuki Procedures Using Pd(dppf)Cl.sub.2-DCM Catalyst and DMF
Solvent
[0772] TABLE-US-00004 ##STR88## Reagent MW EQ g/ml mmol Bromo Arene
#1 .about.500 1 20 mg .about.0.04 Boronic Acid #2 .about.200 2
.about.14 mg .about.0.08 Pd(dppf)Cl.sub.2 816.63 0.25 10 mg
.about.0.01-0.02 TEA 101.19 5 28 .mu.L .about.0.2 DMF (dry &
sparged with argon 0.5 ml for 5 min.)
Standard Procedure
[0773] The haloarene 1 and boronic acid 2 were weighed out and
placed in the reaction flask. The DMF was sparged with argon for
5-10 minutes, followed by TEA addition, and the reaction was
lightly bubbled with argon. The solid Pd(dppf)Cl.sub.2 catalyst was
added in one portion. The vial was flushed with argon, capped tight
and stirred or shaken at .about.80.degree. C. Upon reaching
completion (over night), the reaction was filtered and injected on
a preparatory HPLC reverse phase column (80% yield).
Synthesis of Methyl DAP Analogues
Example 5
3-(R)-Amino-2-(S)-[(4'-ethyl-biphenyl-4-carbonyl)-amino]-butyl-hydroxamic
acid (8)
[0774] ##STR89##
Preparation of N-triphenylmethyl allo-threonine methyl ester
(2)
[0775] TABLE-US-00005 ##STR90## Reagent MW EQ g/ml mmol
H-allo-Thr-OMe.HCl (1) 169.7 1.2 2.0 g 12.0 Trt-Br 323.24 1.0 3.23
g 10.0 DIEA 129.25 3.0 5.2 ml 30.0 CHCl.sub.3 (dry) 100 ml
[0776] For similar procedures see: Righi, P.; Scardovi, N.;
Marotta, E.; ten Holte, P.; Zwanenburg, B. Organic Letters 2002,
4(4), 497-500.
[0777] A solution of trityl bromide (3.2 g, 10.0 mmol) in
CHCl.sub.3 (40 ml) was added dropwise to a stirred solution of
allo-threonine methyl ester HCl salt (1) (2.0 g, 12.0 mmol) and
DIEA (5.2 ml, 30.0 mmol) in CHCl.sub.3 (60 ml) at rt under N.sub.2.
The reaction could be followed by TLC eluting with EtOAc/Hex
(40:60) (Rf=0.3). After stirring 12 h, the reaction was
concentrated to a brown oil. The crude product was diluted with
EtOAc (170 ml) and washed with 0.2 N citric acid (2.times.50 ml),
water (2.times.50 ml), brine (50 ml), dried (Na.sub.2SO.sub.4),
filtered and concentrated under reduced pressure to yield 3.73 g
(85% yield, 95% pure) of a yellow solid.
[0778] HPLC(220 nm, 41 min. run) 30.90 min.; HPLC(220 nm, 17 min.
run) 14.86 min.; LCMS: LC(214 nm) 3.06 min., MS(ES+) m/z 376.2
(C.sub.24H.sub.25NO.sub.3+H requires 376.18).
Preparation of 3-(R)-Azido-2-(S)-(trityl-amino)-butyric acid methyl
ester (3)
[0779] TABLE-US-00006 ##STR91## Reagent MW Eq. g/ml mmol
Trt-allo-Thr-OMe (2) 375.46 1.0 4.08 g 10.88 PPh.sub.3 262.29 1.0
2.85 g 10.88 DEAD (neat) 174.16 1.6 2.93 m1 17.82 DPPA 275.7 2.7
6.40 ml 29.7 THF (dry) 50 ml
[0780] For similar procedures see: Matsuda, A.; Yasuoka, J.;
Sasaki, T.; Ueda, T. J. Med. Chem. 1991, 34, 999-1002.
[0781] A solution of pure DEAD (2.9 ml, 17.8 mmol) in THF (5 ml)
was added slowly dropwise to a stirred solution of
trt-allo-threonine methyl ester (2) (4.1 g, 10.9 mmol) and
PPh.sub.3 (2.9 g, 10.9 mmol) in THF (40 ml) at 0.degree. C. under
N.sub.2. After 3 min., a solution of DPPA (6.4 ml, 29.7 mmol) in
THF (5 ml) was added to the orange-yellow reaction solution at
0.degree. C. After 1 h, the reaction was allowed to warm to rt.
After 40 h, the reaction had reached completion by TLC
(Hexane/DCM/EtOAc (64:20:16) (Rf=0.6)) and LCMS. The yellow
solution was concentrated to give 18 g of crude material that was
purified by column chromatography eluting with Hexane/EtOAc (88:12)
giving 3.5 g of 70% pure product after evaporation. The product was
purified again (to remove trityl alcohol and a crotyl side-product
formed during the reaction by elimination) by column chromatography
eluting with Hexane/DCM/EtOAc (76:20:4) giving 1.65 g (38% yield)
of a pale yellow oil after concentration and drying in vacuo. Note
that the trityl protecting group would hydrolyze when exposed to
TFA while running the sample on HPLC.
[0782] Alternately, the reaction could be carried out in dry DCM. A
reaction using 5.44 g (14.5 mmol) of trt-allo-threonine methyl
ester (2) in DCM (100 ml) with PPh.sub.3 (3.8 g, 14.5 mmol), pure
DEAD (3.4 ml, 21.8 mmol) in DCM (5 ml) and DPPA (6.3 ml, 24.0 mmol)
in DCM (10 ml) were combined following the procedure above. After 3
days, the reaction did not progress further by TLC and LCMS. After
the same work up, 2.97 g of the product was obtained in 51%
yield.
[0783] HPLC(220 nm, 41 min. run) 40.5 min.; HPLC(220 nm, 17 min.
run) 16.32 min.; LCMS: LC(214 nm) 3.7 min., MS(ES+) m/z 401.2
(C.sub.24H.sub.25N.sub.3O.sub.2+H requires 401.15).
Preparation of 2-(S)-Amino-3-(R)-azido-butyric acid methyl ester
HCl Salt (4)
[0784] TABLE-US-00007 ##STR92## Reagent MW EQ g/ml mmol
Trt-Azido-Thr-OMe (3) 400.47 1.0 4.79 g 11.98 TFA 57 ml CHCl.sub.3
(dry) 3 ml
[0785] A solution of Trt-Azido-Thr-OMe (3) (4.8 g, 12.0 mmol) was
dissolved in a 95% TFA/DCM solution (60 ml) at rt with stirring.
After 2.5 h, the reaction was complete by LCMS. The bright yellow
solution was diluted with 0.5 N aq. HCl (300 ml). The aqueous layer
was extracted with DCM (2.times.30 ml) and then lyophilized to
dryness. The white solid was dissolved in AcCN/water (50:50) (100
ml) and again lyophilized to dryness to produce a consistent powder
and remove as much of the TFA as possible. The azido-Thr product
(4), 2.26 g (97% yield, 95% pure) of a white solid, was obtained as
the HCl salt.
[0786] HPLC(220 nm, 41 min. run) 7.91 min.; HPLC(220 nm, 17
min.run) 3.36 min; LCMS: LC(214 nm) 0.48 min., MS(ES+) m/z 159.3
(C.sub.5H.sub.10N.sub.4O.sub.2+H requires 159.08).
Preparation of
3-(R)-Azido-2-(S)-[(4'-ethyl-biphenyl-4-carbonyl)-amino]-butyric
acid methyl ester (6)
[0787] TABLE-US-00008 ##STR93## ##STR94## Reagent MW EQ g/ml mmol
Azido-Thr-OMe.HCl (4) 194.62 1.0 195 mg 1.0 Biphenyl Acid (5)
226.27 1.0 226 mg 1.0 HOBT 153 1.0 158 mg 1.0 EDC.HCl 191.17 1.3
249 mg 1.3 DIEA 129.25 2.5 0.44 ml 2.5 DCM (dry) 10 ml
[0788] A EDC.HCl (249 mg, 1.3 mmol) was added to a stirred
colorless solution of azido-Thr-OMe.HCl (4) (195 mg, 1.0 mmol),
HOBT (158 mg, 1.0 mmol), 4'-Ethyl-biphenyl-4-carboxylic acid (5)
(226 mg, 1.0 mmol) and DIEA (0.44 ml, 2.5 mmol) in DCM (10 ml) at
rt under N.sub.2. After 24 h, the reaction had reached completion
by TLC (Hexane/EtOAc (60:40) (Rf=0.3)) and LCMS. The reaction was
evaporated under reduced pressure to a brown tar. The crude product
was dissolved in EtOAc (100 ml) and washed with 0.2N aq. HCl
(2.times.50 ml), aq. sat. NaHCO.sub.3 (50 ml), brine (50 ml), dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure to yield a crude brown solid. The crude material was
further purified by column chromatography eluting with Hexane/EtOAc
(70:30) giving 245 mg (67% yield) of pure product after evaporation
and drying in vacuo.
[0789] HPLC(220 nm, 41 min. run) 33.87 min.; HPLC(220 nm, 17 min.
run) 15.61 min; LCMS: LC(214 nm) 3.25 min., MS(+) m/z
367.2(C.sub.20H.sub.22N.sub.4O.sub.3+H requires 367.17).
Preparation of
3-(R)-Amino-2-(S)-[(4'-ethyl-biphenyl-4-carbonyl)-amino]-butyric
acid methyl ester (7)
[0790] TABLE-US-00009 ##STR95## ##STR96## Reagent MW EQ g/ml mmol
Biphenyl Azido-Thr (6) 366.41 1.0 244 mg 0.67 1O% Pd/C 200 mg
H.sub.2 (gas) 12''balloon MeOH (dry) 10 ml
[0791] A solution of biphenyl azido-Thr methyl ester (6) (244 mg,
0.67 mmol) in MeOH (10 ml) was made by sonicating until the milky
precipitate cleared. After bubbling nitrogen through the reaction
solution for 30 sec., 10% Pd/C was added in one portion. The
reaction was stirred under nitrogen at RT. The reaction was exposed
to aspirator vacuum to remove the nitrogen and then opened to the
hydrogen gas at balloon pressure (.about.1 atm). The reaction
stirred for 3 h at which time the hydrogen was exchanged for
nitrogen. The reaction was filtered through a pad of celite to
remove the palladium. The celite pad was washed with MeOH (30 ml).
The combined fractions of MeOH were evaporated under reduced
pressure and dried in vacuo to give 225 mg (99% yield) of pure
produce (7) as a white solid.
[0792] HPLC(220 nm, 17 min. run) 10.79 min.; LCMS: LC(214 nm) 2.21
min., MS(ES+) m/z 341.2 (C.sub.20H.sub.24N.sub.2O.sub.2+H requires
341.18).
Preparation of
3-(R)-Amino-2-(S)-[(4'-ethyl-biphenyl-4-carbonyl)-amino]-butyl-hydroxamic
acid (8)
[0793] TABLE-US-00010 ##STR97## ##STR98## Reagent MW EQ g/ml mmol
Amino-Thr-OMe (7) 340.42 1.0 225 mg 0.66 H.sub.2NOH.HCl 69.49 10.0
460 mg 6.6 NaOMe 54.02 .about.12.0 .about.430 mg 7.92 MeOH (dry) 7
ml DCM (dry) 5 ml
[0794] To a stirred suspension of biphenyl-amino-Thr methyl ester
(7) (225 mg, 0.6 mmol) and hydroxylamine HCl salt (460 mg, 6.6
mmol) in MeOH (7 ml) and DCM (5 ml) was added fresh solid NaOMe
powder (430 mg, 7.92 mmol) in one portion. After stirring for 2
min. at rt under nitrogen, the pH of the reaction on wet pH paper
was approximately 7-8. The suspension had change from larger
particles of white solid to a finely-divided milky consistency. The
pH of the reaction was checked after adding small portions of NaOMe
(50-100 mg) and allowing 2 min. for the reaction to equilibrate.
The pH of the reaction reached a stable 11-12 after the final
portion of NaOMe was added (250 mg total). The reaction was
initiated at pH 11 and proceeded quickly. After 30 min., the
reaction reached 85% completion as determined by LCMS, and the
reaction was placed in a -10.degree. C. bath. The cold mixture
filtered over fine filter paper on a Buchner funnel. The white
residue was washed with MeOH (15 ml). The organic fractions were
collected and concentrated under reduced pressure to give crude
product (750 mg). The crude product (only one 150 mg portion) was
dissolved in DMSO (1 ml), AcCN (100 .mu.l) and water (100 .mu.l),
passed through a Teflon syringe filter, and the clear filtrate was
injected on a preparative HPLC. The purification used a 20.times.50
mm Ultro 120 C18 column running a 22 ml/min 2% gradient
(AcCN/water, 0.1% TFA) for 16 min. The purified fractions were
lyophilized to dryness. The product as the TFA salt was dissolved
in AcCN/water (50:50) (5 ml), 1N aq. HCl (1 equivalent) and
lyophilized again to give 11.5 mg of white powder as an HCl salt
(23% yield).
[0795] HPLC(220 nm, 41 min. run) 19.31 min.; HPLC(220 nm, 17 min.
run) 9.39 min; LCMS: LC(214 nm) 1.98 min., MS(ES+) m/z 342.2
(C.sub.19H.sub.23N.sub.3O.sub.3+H requires 342.17).
Synthesis of 4'Benzamide Biphenyl Threonine Hydroxamic Acid
Example 6
Biphenyl-4,4'-dicarboxylic acid 4'-[(3-Boc-amino-propyl)-amide]
4-[((2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)amide] (6), and
Example 7
Biphenyl-4,4'-dicarboxylic acid 4'-[(3-amino-propyl)-amide]
4-[((2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)-amide] (7)
[0796] ##STR99##
Synthesis of
(2S,3R)-2-amino-3-(phenylmethoxy)-N-(phenylmethoxy)butanamide
(1)
[0797] ##STR100## Procedure:
[0798] To a suspension of benzylhydroxylamine hydrochloride (8.310
g, 52.06 mmol), Boc-Thr(OBn)-OH (14.01 g, 45.28 mmol), EDCI (10.01
g, 52.21 mmol), and HOBt (6.90 g, 51.06 mmol) in CH.sub.2Cl.sub.2
(300 mL) at 0.degree. C. was added diisopropylethylamine (28.3 mL,
162 mmol) with stirring. The cooling bath was removed after one
hour and the reaction mixture stirred at ambient temperature for 20
h and was then diluted with CH.sub.2Cl.sub.2 (300 mL). The organic
layer was washed with 1.0 M HCl (2.times.200 mL), sat. NaHCO.sub.3
(2.times.200 mL) and brine (200 mL), dried over MgSO.sub.4 and
concentrated to give 14.5 g of a white solid. The crude solid was
treated with a solution of trifluoroacetic acid (90 mL) in
CH.sub.2Cl.sub.2 (90 mL) and stirred for 2.5 h. The reaction
mixture was concentrated by rotary evaporation and then diluted
with CH.sub.2Cl.sub.2 (600 mL). The organic layer was washed with
sat. NaHCO.sub.3 (2.times.200 mL), dried over MgSO.sub.4 and
concentrated to give a dark orange oil. Purification by silica gel
chromatography (50:1 CH.sub.2Cl.sub.2/MeOH) afforded
(2S,3R)-2-amino-3-(phenylmethoxy)-N-phenylmethoxy)butanamide (A)
(8.9 g,) as a pale yellow oil. Rf (50:1 CH.sub.2Cl.sub.2/MeOH on
silica gel)=0.2.
Preparation of
(1S,2R)-4'-(2-benzyloxy-1-benzyloxycarbamoyl-propylcarbamoyl)-biphenyl-4--
carboxylic acid (3)
[0799] TABLE-US-00011 Reagent MW Eq. g/mL mmol Amine (1) 314.38 1.0
0.944 g 3.00 Dicarboxylic acid (2) 242.23 1.9 1.360 g 5.61 BOP
442.3 1.5 2.007 g 4.54 DIEA 129.25 3.3 1.7 mL 9.76 DMF 200 mL
[0800] To a suspension of 4,4'-biphenyldicarboxylic acid 2 (1.360
g, 5.61 mmol) in DMF (180 mL) was added BOP (2.007 g, 4.54 mmol)
and DIEA (1.7 mL, 9.8 mmol). A solution of
(1S,2R)-2-amino-3,N-bis-benzyloxy-butyramide 1 (944 mg, 3.00 mmol)
in DMF (20 mL) was added and the reaction stirred for 18 h. The
solution was diluted with EtOAc (250 mL) and washed with 1.0 M HCl
(500 mL). The aqueous layer was extracted with EtOAc (250 mL) and
the organic layers combined. The organic layer was washed with 1.0
M HCl (250 mL), dried over MgSO.sub.4, and concentrated to give a
crude yellow solid. Purification by silica gel chromatography (60:1
CH.sub.2Cl.sub.2/MeOH) gave 210 mg
(1S,2R)-4'-(2-benzyloxy-1-benzyloxycarbamoyl-propylcarbamoyl)-biphenyl-4--
carboxylic acid 3. (13% yield) as a yellow solid. R.sub.f=0.80
(10:1 CH.sub.2Cl.sub.2/MeOH); LRMS (ES+) m/z 539.1
(C.sub.32H.sub.30N.sub.2O.sub.6+H requires 539.22).
Preparation of biphenyl-4,4'-dicarboxylic acid
4'-[(3-(Boc)-amino-propyl)-amide]-4-[(2R)-benzyloxy-(1S)-benzyloxycarbamo-
yl-propyl)amide] (5)
[0801] TABLE-US-00012 Reagent MW Eq. g/mL mmol Biphenylcarboxylic
acid (3) 538.59 1.0 0.200 g 0.371 Amine (4) 174.24 1.1 0.071 g
0.407 EDCI 191.71 1.1 0.078 g 0.407 HOBt 135.13 1.0 0.052 g 0.385
DIEA 129.25 2.7 180 .mu.L 1.0 DMF 2 mL
[0802] To a solution of biphenylcarboxylic acid 3 (200 mg, 0.371
mmol), EDCI (78 mg, 0.407 mmol), and HOBt (52 mg, 0.385 mmol) in
DMF (2 mL) was added t-Butyl N-(3-aminopropyl)carbamate 4 (71 mg,
0.407 mmol) and DIEA (180 .mu.L, 1.0 mmol). The reaction mixture
was stirred 24 h, diluted with EtOAc (150 mL), washed with 1.0 M
HCl (2.times.60 mL), saturated NaHCO.sub.3 (2.times.60 mL),
H.sub.2O (3.times.60 mL), dried over MgSO.sub.4 and concentrated to
give a crude white solid. Purification by silica gel chromatography
(25:1 CH.sub.2Cl.sub.2/MeOH) afforded 194 mg (75% yield) of
biphenyl-4,4'-dicarboxylic acid
4'-[(3-(Boc)-amino-propyl)-amide]-4-[(2R)-benzyloxy-1S)-benzyloxycarbamoy-
l-propyl)-amide] 5 as a white solid. R.sub.f=0.15 (50:1
CH.sub.2Cl.sub.2/MeOH); LRMS (ES+) m/z 695.2
(C.sub.40H.sub.46N.sub.4O.sub.7+H requires 695.35).
Preparation of Biphenyl-4,4'-dicarboxylic acid
4'-[(3-Boc-amino-propyl)-amide]
4-[((2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)-amide] (6)
[0803] TABLE-US-00013 Reagent MW Eq. g/mL mmol Biphenyl diamide (5)
694.82 1.00 0.190 g 0.273 Pd(OH).sub.2 (20%/C) 106.42 0.15 0.020 g
0.040 H.sub.2 (g) balloon THF 5.0 mL MeOH 3.0 mL
[0804] A solution of dibenzyl-protected threonine hydroxamic acid 5
(190 mg, 0.273 mmol) in THF (5 mL) and MeOH (3 mL) was charged with
Pd(OH).sub.2 (20%/C, 20 mg, 0.04 mmol) and stirred under a hydrogen
atmosphere (balloon pressure) for 16 h. The crude mixture was
filtered through a plug of celite eluting with 2:1 MeO (15 mL) and
concentrated to give an orange syrup. Purification by silica gel
chromatography (5:1:1 THF/MeOH/CH.sub.2Cl.sub.2 afforded 110 mg
(78% yield) of biphenyl-4,4'-dicarboxylic acid
4'-[(3-Boc-amino-propyl)-amide]
4-[((2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)-amide] as a white
foam, mp 75-77.degree. C. R.sub.f=0.20 (10:1
CH.sub.2Cl.sub.2/MeOH); LRMS (ES+) m/z 515.4
(C.sub.26H.sub.34N.sub.4O.sub.7+H requires 515.26).
Preparation of Biphenyl-4,4'-dicarboxylic acid
4'-[(3-amino-propyl)-amide]
4-[((2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)-amide] (7)
[0805] TABLE-US-00014 Reagent MW Eq. g/mL mmol Boc-protected amine
(6) 514.57 1.00 0.080 g 0.155 TFA 3.0 mL CH.sub.2Cl.sub.2 3.0
mL
[0806] A flask containing Boc-protected amine 6 (80 mg, 0.155 mmol)
was treated with 50% TFA/CH.sub.2Cl.sub.2 (6.0 mL) and stirred for
2.5 h. The reaction mixture was concentrated by rotary evaporation
to give a brown syrup. Purification by RP-HPLC (C.sub.18 column,
CH.sub.3CN gradient 5-70%, 0.1% TFA, UV analysis 300 nm, 36 min)
and lyophilization of the collected fractions afforded 14 mg (21%
yield) of biphenyl-4,4'-dicarboxylic acid
4'-[(3-amino-propyl)-amide]
4-[((2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)-amide] as a white
solid. LRMS (ES+) m/z 415.3 (C.sub.21H.sub.26N.sub.4O.sub.5+H
requires 415.20); RP-HPLC (300 nm, 36 min run) 18.2 min.
Example 8
Synthesis of
N-(2-(N-hydroxycarbamoyl)(2S)-2-{[4-(4-ethylphenyl)phenyl]carbonylamino}e-
thyl)acetamide (4)
[0807] ##STR101##
Preparation of
3-Acetylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic
acid (2)
[0808] TABLE-US-00015 ##STR102## ##STR103## Reagent MW EQ g/ml mmol
Fmoc-DAP-H (1) 326.4 1.0 980 mg 3.0 Acetic anhydride 102.09 1.5 425
uL 4.5 Pyridine 79.1 2.0 483 uL 6.0 THF 20 ml
[0809] Acetic anhydride in THF (5 ml) was added to a cloudy mixture
of Fmoc-DAP-H (1) (980 mg, 3.0 mmol) and pyridine (483 uL, 6.0
mmol) in THF (15 ml) with stirring at rt. After 4 hours, the clear
pale yellow solution had reacted completely by LCMS. The reaction
was evaporated under reduced pressure. The residue was dissolved in
EtOAc (150 ml) and washed with 0.1M NaHSO.sub.4 (50 ml), water (50
ml), sat. brine (50 ml), dried with Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give 1.1 g of crude product
as a white solid. The crude product was purified by prep. HPLC to
give 0.99 g (90% yield) of acyl-DAP (2).
Preparation of (2-Acetylamino-1-hydroxycarbamoyl-ethyl)-carbamic
acid 9H-fluoren-9-ylmethyl ester trityl resin (3)
[0810] TABLE-US-00016 ##STR104## ##STR105## Reagent MW EQ g/ml mmol
H.sub.2N--O-Trt Resin 1.0 120 mg 0.113 Fmoc-DAP(Ac)-H (1) 368.4 5.0
980 mg 0.564 HATU 380 5.0 0.146 g 0.564 DIEA 129.25 10.0 196 ul
1.13 NMP 1.7 ml
[0811] A solution of Fmoc-DAP(Ac)-H (1) (980 mg, 0.56 mmol), HATU
(0.146 g, 0.56 mmol) in NMP (1.7 ml) was made. After 2 min. of
shaking, the activated acid was added to the deprotected
H.sub.2N--O-Trt Resin (120 mg, 0.113 mmol) at rt with shaking.
[Deprotection of the Fmoc group from the resin was accomplished
using 20% piperizine in DMF (4 ml) for 2 hours twice. The resin was
drained and washed with DMF (2.times.5 ml) and DCM (2.times.5 ml).]
After shaking for 20 hours, the reaction was drained and washed
with DMF (2.times.5 ml) and DCM (2.times.5 ml). The resin was dried
and used as is in the next reaction.
Preparation of
N-(2-(N-hydroxycarbamoyl)(2S)-2-{[4-(4-ethylphenyl)phenyl]carbonylamino}e-
thyl)acetamide (4)
Preparation of (2-Acetylamino-1-hydroxycarbamoyl-ethyl)-carbamic
acid 9H-fluoren-9-ylmethyl ester trityl resin (3)
[0812] TABLE-US-00017 ##STR106## ##STR107## Reagent MW EQ g/ml mmol
Fmoc-DAP(Ac)-Trt Resin (3) 1.0 120 mg 0.113 4'-Etbiphenyl 4-carboxy
acid 226.3 5.0 91 mg 0.4 HATU 380 5.0 152 mg 0.4 DIEA 129.25 10.0
140 ul 0.8 NMP 1.0 ml
[0813] The resin was treated with 20% piperizine in DMF (4 ml) for
2 hours twice. The resin was drained and washed with DMF (2.times.5
ml) and DCM (2.times.5 ml). The resin was dried in vacuo. A
solution of 4'-Ethyl-biphenyl-4-carboxylic acid (91 mg, 0.4 mmol),
HATU (152 g, 0.4 mmol) in NMP (1.0 ml) was made. After 2 min. of
shaking, the activated acid was added to the deprotected
H-DAP(Ac)-Trt resin (120 mg, 0.113 mmol) at rt with shaking. After
shaking for 18 hours, the reaction was drained and washed with DMF
(2.times.5 ml) and DCM (2.times.5 ml). The resin was dried in
vacuo. The product was cleaved from the resin through treatment
with a solution of TFA (500 uL), DCM (500 uL) and water (50 uL) for
25 min. The resin was filtered and washed with fresh DCM (2 ml).
The combined TFA and DCM fractions are evaporated under reduced
pressure. The residue was diluted with CH.sub.3CN/water (1:1) (10
ml) and lyophilized. The crude product was purified by prep. HPLC.
The crude product was dissolved in DMSO (1 ml), passed through a
Teflon syringe filter, and the clear filtrate was injected on a
preparative HPLC. The purification used a 20.times.50 mm Ultro 120
C18 column running a 22 ml/min 2% gradient (AcCN/water, 0.1% TFA)
for 16 min. The purified fractions were lyophilized to dryness. The
solid residue was lyophilized again from CH.sub.3CN/water (1:1) (5
ml) give 8.6 mg of pure product (4) (.about.21% yield).
Example 9
Synthesis of 4'-Ethyl-biphenyl-4-carboxylic acid
(1-hydroxycarbamoyl-2-methanesulfonylamino-ethyl)-amide (3)
Preparation of 4'-Ethyl-biphenyl-4-carboxylic acid
(2-amino-1-hydroxycarbamoyl-ethyl)-amide trityl resin (2)
[0814] TABLE-US-00018 ##STR108## ##STR109## Reagent MW EQ g/ml mmol
Biphenyl-DAP(Alloc)-Trt Resin (1) 1.0 500 mg 0.35 Dimethyl
barbituric acid 156.14 10.0 600 mg 3.5 Pd(PPh.sub.3).sub.4 1135.6
1.0 438 mg 0.35 PPh.sub.3 262.3 2.0 202 mg 0.7 DCM 11.0 ml
[0815] Pd(PPh.sub.3).sub.4 (438 mg, 0.35 mmol) was added to a vial
containing biphenyl-DAP(Alloc)-Trt Resin (1) (500 mg, 0.35 mmol),
Dimethyl barbituric acid (600 mg, 3.5 mmol) and PPh.sub.3 (438 mg,
0.35 mmol) in DCM (11 ml) at rt under argon. The mixture was
sparged with argon and shaken for 16 hours. The bright yellow
mixture was drained and washed with DMF (8.times.10 ml) and DCM
(8.times.10 ml). The resin was dried in vacuo to give the
deprotected DAP resin 2.
Preparation of 4'-Ethyl-biphenyl-4-carboxylic acid
(1-hydroxycarbamoyl-2-methane sulfonylamino-ethyl)-amide (3)
[0816] TABLE-US-00019 ##STR110## ##STR111## Reagent MW EQ g/ml mmol
Biphenyl-DAP-Trt Resin (2) 1.0 160 mg 0.11 Methanesulfonyl chloride
114.55 10.0 85 uL 1.1 Lutidine 107.16 15.0 190 uL 1.6 DCM 1.5
ml
[0817] Methanesulfonyl chloride (85 uL, 1.1 mmol) was added to a
mixture of deprotected DAP resin (2) (160 mg, 0.11 mmol) and
lutidine (190 uL, 1.6 mmol) in DCM (1.5 ml). After shaking for 16
hours, the mixture was drained and washed with DMF (10.times.2 ml)
and DCM (5.times.2 ml). The product was cleaved from the resin
through treatment with TFA/water (4:1) (1.5 ml). After shaking for
45 min., the TFA solution was collected from the resin by
filtration, and the resin was washed with TFA (1 ml) and TFA/water
(1:1) (10 ml). The combined TFA fractions were concentrated under
reduced pressure to a reddish-brown solid The product, identified
by LCMS, was purified by prep. HPLC using a 20.times.50 mm Ultro
120 C18 column running a 22 ml/min 4% gradient (AcCN/water, 0.1%
TFA) for 16 min. The purified fractions were lyophilized to
dryness. The solid residue was lyophilized again from
CH.sub.3CN/water (1:1) (5 ml) give 4 mg of pure product as a white
solid (3) (.about.9% yield).
Example 10
Synthesis of 4'-Ethyl-biphenyl-4-carboxylic add
[2-(3,3-dimethyl-ureido)-1-hydroxycarbamoyl-ethyl]-amide (3)
(Continued from compound 2 of Example 9 above)
[0818] TABLE-US-00020 ##STR112## ##STR113## Reagent MW EQ g/ml mmol
Biphenyl-DAP-Trt Resin (2) 1.0 125 mg 0.096 Dimethylcarbamyl
chloride 107.5 10.0 103 mg 0.96 Lutidine 107.16 20.0 225 uL 1.92
DCM 1.5 ml
[0819] Dimethylcarbamyl chloride (103 mg, 0.96 mmol) was added to a
mixture of deprotected DAP resin (2) (125 mg, 0.096 mmol) and
lutidine (225 uL, 1.92 mmol) in DCM (1.5 ml). After shaking at rt
for 5 hours, the mixture was drained and washed with DCM (5.times.2
ml), DMF (5.times.2 ml) and DCM (5.times.2 ml). The product was
cleaved from the resin through treatment with TFA/water (4:1) (1.5
ml). After shaking for 45 min., the TFA solution was collected from
the resin by filtration, and the resin was washed with TFA/water
(1:1) (2 ml). The combined TFA fractions were concentrated under
reduced pressure to a reddish-brown solid. The product, identified
by LCMS, was purified by prep. HPLC using a 20.times.50 mm Ultro
120 C18 column running a 22 ml/min 4% gradient (AcCN/water, 0.1%
TFA) for 16 min. The purified fractions were lyophilized to
dryness. The solid residue was lyophilized again from
CH.sub.3CN/water (1:1) (5 ml) give 5 mg of pure product as a white
solid (3) (.about.13% yield).
Example 11
Synthesis of 4'-Ethyl-biphenyl-4-carboxylic acid
[2-(2-amino-ethylamino)-1-hydroxycarbamoyl-ethyl]-amide (2)
[0820] TABLE-US-00021 ##STR114## ##STR115## Reagent MW EQ g/ml mmol
Biphenyl-DAP-hydroxamate (1) 327.4 1.0 20 mg 0.096
Boc-amino-acetaldehyde 159.19 4.0 6.4 mg 0.4 NaBH.sub.3CN 62.84
10.0 3.1 mg 0.05 Acetic acid 60.05 20.0 6 uL 1.00 DCM 1.5 ml
[0821] NaBH.sub.3CN (3.1 mg, 0.05 mmol) followed by acetic acid (6
uL, 1.0 mmol) were sequentially added to a stirred suspension of
biphenyl-DAP-hydroxamate (1) (20 mg, 0.096 mmol) and
Boc-amino-acetaldehyde (6.4 mg, 0.4 mmol) in MeOH (1.5 ml) in a 4
ml vial. The reaction was followed by LCMS. After stirring 12
hours, the cloudy reaction was only 50% complete. The reaction was
concentrated under reduced pressure to a thick slurry that was
dissolved in DMSO. The product was purified by prep. HPLC using a
20.times.50 mm Ultro 120 C18 column running a 22 ml/min 3% gradient
(AcCN/water, 0.1% TFA) for 16 min. The purified fractions were
lyophilized to dryness. The dried powder was dissolved in
CH.sub.3CN/water (1:1) (1 ml) and 1M HCl (700 uL). After heating at
50.degree. C. for 75 min., the reaction mixture was again
lyophilized to dryness to produce 7.1 mg of product (2) as a
2.times.HCl salt white powder (.about.17% yield).
Example 12
Synthesis of
N-(1-(N-hydroxycarbamoyl)(1S,2R)-2-hydroxypropyl)[4-(2-phenylethynyl)phen-
yl]carboxamide
[0822] ##STR116##
Preparation of 4-Phenylethynyl-benzoic acid (3)
[0823] TABLE-US-00022 ##STR117## ##STR118## Reagent MW EQ g/ml mmol
Iodo-beazoate 1 262 1.0 20.0 g 76.34 Ethynyl-benzene 2 102 1.1 8.56
g 83.96 PdCl.sub.2(PPh.sub.3).sub.2 702 0.012 0.65 g 0.92 CuI 190
0.024 0.35 g 1.83 TEA 101 1.5 16 ml 114.5 d = 0.726 THF (dry &
sparged with 110 ml argon for 5 min.)
[0824] The 4-iodo-benzoic acid methyl ester 1 (20.0 g, 76.34 mmol),
ethynyl-benzene 2 (8.56 g, 83.96 mmol), PdCl.sub.2(PPh.sub.3).sub.2
(0.65 g, 0.92 mmol), and CuI (0.35 g, 1.83 mmol) were mixed with
THF (110 ml) in a round bottom under argon. The dry THF was sparged
with dry, oxygen-free argon for at least 5 min. immediately before
use. The reaction was cooled to 10.degree. C. and TEA (16 ml) was
added. The cooling bath was removed and the reaction was stirred at
RT under argon. After 2.5 h, the reaction was diluted with EtOAc
(400 ml) and the solids were filtered off through a pad of celite.
The organic filtrate was washed with 1M HCl (60 ml), sat. aq.
NaHCO.sub.3 (60 ml), water (60 ml), brine (60 ml), dried with
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude solid methyl ester was dissolved in MeOH (400 ml), 6M
NaOH (30 ml) and water (50 ml). The reaction was stirred at
70.degree. C. until a clear solution was formed (about 1 h). The
reaction could be followed by LCMS. The reaction was cooled and
diluted with water (500 ml) and hexane (100 ml). The pH was
adjusted to pH 6-7. The white solid that formed was collected and
washed with water (3.times.60 ml) and hexane (3.times.60 ml). The
solid 3 was dried in vacuo yielding 17.3 g (approximately
quantitative yield in 99% purity).
Preperation of 3-Hydroxy-2-(4-phenylethynyl-benzoylamino)-butyric
acid methyl ester (4)
[0825] TABLE-US-00023 ##STR119## ##STR120## Reagent MW EQ g/ml mmol
4-Phenylethynyl-benzoic acid (3) 222 1.0 1.55 g 7.0 Threonine
methyl ester.HCl 169.65 1.4 1.66 g 9.8 HBTU 380 1.0 2.66 g 7.0 DIBA
125.28 2.5 3.05 ml 17.5 DMF 21 ml
[0826] A solution of threonine (1.66 g, 9.8 mmol) and DIEA (1.53
ml, 8.8 mmol) in DMF (10 ml) was added to a stirred solution of
4-phenylethynyl-benzoic acid 3 (1.55 g, 7.0 mmol) and DIEA (1.53
ml, 8.8 mmol) in DMF (11 ml) at rt. After 12 h, the reaction was
diluted with EtOAc (300 ml) and washed with 0.5M HCl (2.times.60
ml), sat. aq. NaHCO.sub.3 (60 ml), 50% diluted brine (60 ml), sat.
brine (60 ml), dried with Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. Upon drying in vacuo, 2.34 g
of white solid was obtained (approximately quantitative yield in
99% purity).
Preperation of
N-(2-Hydroxy-1-hydroxycarbamoyl-propyl)-4-phenylethynyl-benzamide
(5)
[0827] TABLE-US-00024 ##STR121## ##STR122## Reagent MW EQ g/ml mmol
Tolanoic-Tbr-OMe (4) 340.42 1.0 2.34 g 7.0 H.sub.2NOH.HCl 69.49
10.0 4.81 g 70.0 NaOMe 54.02 >11.0 >4.16 g >77.0 MeOH
(dry) 50 ml DCM (dry) 30 ml
[0828] A solution of tolanoic-Thr methyl ester (4) (2.34 g, 7.0
mmol) in MeOH (20 ml) and DCM (30 ml) was added to a cooled
(-10.degree. C. bath) suspension of hydroxylamine HCl salt (4.81 g,
70.0 mmol) and NaOMe (4.16 g, 77.0 mmol) in MeOH (30 ml). Follow
reaction by LCMS. After stirring for 2 hours, the reaction seems to
stall at 50% completion. Add an additional 1 equivalent of NaOMe
(0.416 g). After 3 hours, the reaction was 75% complete. Add an
additional 0.5 equivalent of NaOMe (0.21 g). After 4 hours, the
reaction was 90% complete. Add an additional 0.15 equivalent of
NaOMe (0.064 g) for a total of 12.65 equivalents of NaOMe. The pH
of the reaction was between 11-12 and had reacted about 95%
completion. The reaction was diluted with EtOAc (500 ml) and washed
with sat. aq. NaHCO.sub.3 (2.times.60 ml), 50% diluted brine (60
ml), sat. brine (60 ml), dried with Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was dissolved in
minimal DMA. The product was purified by prep. HPLC using a reverse
phase Ultro 120 C18 column running a 2% gradient (AcCN/water, 0.1%
TFA). The purified fractions were lyophilized to dryness. The
product as the TFA salt was dissolved in AcCN/water (50:50) (80
ml), 1N aq. HCl (13 equivalent) and lyophilized again to give 1.3 g
of white powder in 55% yield and >97% purity.
Example 13
Synthesis of
3-(R)-Amino-2-(S)-(3-phenylethynyl-benzoylamino)-butyl-hydroxamic
acid (10)
Preparation of
3-(R)-Azido-2-(S)-(3-phenylethynl-benzoylamino)-butyric acid methyl
ester (9)
[0829] ##STR123##
[0830] The synthesis of compound 4 is described above. The tolanyl
compound (9) was made by the same procedures as for compound (6).
The product (9) was obtained in 92% yield (952 mg).
[0831] HPLC(220 nm, 41 min. run) 32.64 min.; HPLC(220 nm, 17 min.
run) 15.08 min LCMS: LC(214 nm) 3.16 min., MS(ES+) m/z 363.1
(C.sub.20H.sub.18N.sub.4O.sub.3+H requires 363.14).
Preparation of
3-(R)-Amino-2-(S)-(3-phenylethynyl-benzoylamino)-butyl-hydroxamic
acid (10)
[0832] TABLE-US-00025 ##STR124## ##STR125## Reagent MW Eq. g/ml
mmol Amino-Thr-OMe (9) 362.38 1.0 726 mg 2.0 PPh.sub.3 262.29 1.0
526 mg 2.0 H.sub.2NOH.HCl 69.49 10.0 1.4 g 20.0 NaOMe 54.02
.about.12.0 1.3 g 24.0 THF (dry) 20 ml MeOH (dry) 20 ml
[0833] Triphenylphosphine (526 mg, 2.0 mmol) was added to a stirred
solution of tolanyl-azido-Thr methyl ester (9) (726 mg, 2.0 mmol)
at rt. After 3 days the reaction reached completion as judged by
TLC (EtOAc/Hex (2:1)) and LCMS. The reaction was concentrated under
reduced pressure to give an ivory colored solid. The crude
amino-phosphine was dissolved in MeOH (20 ml) to give a pale yellow
solution. To the solution of amino-phosphine was added sequentially
hydroxylamine HCl salt (1.4 g, 20.0 mmol) followed by fresh solid
NaOMe powder (1.3 g, 24.0 mmol) to make a milky pH 10 suspension.
After 36 h, the reaction was complete by LCMS. The reaction was
evaporated under reduced pressure to give a yellow solid that was
dried in vacuo. The crude product (2.75 g) was triturated with
ether (3.times.50 ml) to remove impurities (P(O)Ph.sub.3) and then
was dissolved in abs. EtOH (120 ml) with sonication for 15 min. A
fine white powder was suction filtered off, and the clear yellow
ethanolic portion was concentrated to a small volume. The crude
product was dissolved in DMSO (8 ml) and purified by preparative
HPLC (Ultro 120 C18 75.times.300 mm column) running a gradient
(AcCN/water, 0.1% TFA) from 5 to 70% for 55 min. The purified
fractions were pooled together and lyophilized to dryness. The
product as the TFA salt was dissolved in AcCN/water (50:50) (100
ml), 1N aq. HCl (1 equivalent) and lyophilized again to give 325 mg
of light yellow powder as the HCl salt (43% yield).
[0834] HPLC(220 nm, 41 min.run) 18.31 min.; HPLC(220 nm, 17
min.run) 9.11 min; LCMS: LC(214 nm) 1.91 min., MS(ES+) m/z 338.1
(C.sub.19H.sub.19N.sub.3O.sub.3+H requires 338.14).
Synthesis of 4'-(N-Acylamino)-Tolan Dap Analogs
Example 14
Synthesis of
4-({4-[(aminoacetyl)amino]phenyl}ethynyl)-N-[(1S)-1-(aminomethyl)-2-(hydr-
oxyamino)-2-oxoethyl]benzamide
[0835] ##STR126##
Preparation of 2-N-Boc-amino-N-(4-iodo-phenyl)-acetamide (2)
[0836] TABLE-US-00026 ##STR127## ##STR128## Reagent MW Eq. g/ml
mmol Boc-Gly-OH 175.19 1.00 1.752 g 10.0 4-Iodoaniline (1) 219.03
1.04 2.290 g 10.4 EDCI 191.71 1.04 1.994 g 10.4 HOBt 135.13 1.00
1.351 g 10.0 DCM 18 mL DMF 1 mL
[0837] A solution of Boc-Gly-OH (1.752 g, 10.0 mmol) in DCM (18 mL)
and DMF (1 mL) was treated with EDCI (1.994 g, 10.4 mmol) and HOBt
(1.351 g, 10.0 mmol). After stirring 15 min, 4-iodoaniline 1 (2.290
g, 10.4 mmol) was added and the reaction monitored by TLC (25:1
DCM/MeOH (R.sub.f=0.6)). After 24 h the solution was diluted with
EtOAc (250 mL), washed with 1.0 M HCl (3.times.100 mL), sat.
NaHCO.sub.3 (3.times.100 mL), brine (3.times.100 mL), dried over
MgSO.sub.4, filtered and concentrate in vacuo to afford 2.900 g
(77% yield) of a white solid.
Preparation of
(2S)-3-N-Boc-amino-(4-ethynyl-benzoylamino)-propionic acid methyl
ester (4)
[0838] TABLE-US-00027 ##STR129## ##STR130## Reagent MW Eq. g/mL
mmol 4-Ethynylbenzoic acid (3) 146.14 1.0 0.910 g 6.22
H-Dap(Boc)-OMe--HCl 254.71 1.2 1.903 g 7.47 EDCI 191.71 1.2 1.432 g
7.47 HOBt 135.13 1.1 0.910 g 6.73 DIEA 129.25 3.2 3.5 mL 20.0 DMF
50 mL
[0839] Triethylamine (3.5 mL, 20.0 mmol) was added to a stirred
solution of 4-ethynylbenzoic acid 3 (910 mg, 6.22 mmol),
H-Dap(Boc)-OMe hydrochloride (1.903 g, 7.47 mmol), EDCI (1.432 g,
7.47 mmol), and HOBt (910 mg, 6.73 mmol) in DMF (50.0 mL). After
stirring 20 h, the reaction mixture was diluted with EtOAc (400
mL), washed with 1.0 M HCl (2.times.100 mL), saturated NaHCO.sub.3
(2.times.100 mL), H.sub.2O (4.times.100 mL), dried over MgSO.sub.4,
filtered and concentrated in vacuo to give 2.140 g (99% yield) of a
tan solid, mp=110-111.degree. C. LRMS (ES+) m/z 346.9
(C.sub.18H.sub.22N.sub.2O.sub.5+H requires 347.10). ##STR131##
[0840] To a suspension of methyl
(2S)-3-[(tert-butoxy)carbonylamino]-2-[(4-ethynylphenyl)carbonylamino]pro-
panoate (4) (200 mg, 0.577 mmol) and
2-[(tert-butoxy)carbonylamino]-N-(4-iodophenyl)acetamide (2) (476
mg, 1.26 mmol) was added Et.sub.3N (350 .mu.L, 2.5 mmol). The
solution was purged with a stream of N.sub.2 for several minutes
and PdCl.sub.2(PPh.sub.3)2 (20 mg, 0.028 mmol) and CuI (10.6 mg,
0.055 mmol) were added. The reaction mixture was stirred at ambient
temperature for 22 h and then concentrated by rotary evaporation.
The crude black residue was chromatographed twice by silica gel
chromatography (30:1 CH.sub.2Cl.sub.2/MeOH) to give 285 mg (83%) of
methyl
(2S)-3-[(tert-butoxy)carbonylamino]-2-({4-[2-(4-{2-[(tert-butoxy)carbonyl-
amino]acetylamino}phenyl)ethynyl]phenyl}carbonylamino)propanoate
(5) as a yellow foam. ##STR132##
[0841] To a solution of hydroxylamine hydrochloride (98 mg, 1.41
mmol) in MeOH (1.3 mL) at 0.degree. C. was added 25 wt % NaOMe (460
mg, 2.13 mmol). The solution was stirred at 0.degree. C. for 15 min
and then charged with a solution of methyl
(2S)-3-[(tert-butoxy)carbonylamino]-2-({4-[2-(4-{2-[(tert-butoxy)carbonyl-
amino]acetylamino}phenyl)ethynyl]phenyl}carbonylamino)propanoate
(4) (279 mg, 0.469 mmol) in THF (1.5 mL) and MeOH (0.6 mL). The
reaction was stirred at 0.degree. C. for 30 min and at room
temperature for 2.5 h. The reaction mixture was diluted with 4:1
CHCl.sub.3/iPrOH (50 ml) and washed with 0.1 M HCl (30 mL). The
layers were separated and the aqueous layer extracted once more
with 4:1 CHCl.sub.3/iPrOH (30 ml). The organic layers were
combined, dried over Na.sub.2SO.sub.4, filtered and concentrated.
The crude residue was suspended in 10:1 CH.sub.2Cl.sub.2/MeOH (4
mL), filtered, and washed with 50:1 CH.sub.2Cl.sub.2/MeOH (2 mL)
and Et.sub.2O (10 mL) to afford 180 mg (64%) of
N-(4-{2-[4-(N-{1-(N-hydroxycarbamoyl)(1S)-2-[(tert-butoxy)carbonylamino]e-
thyl}carbamoyl)phenyl]ethynyl}phenyl)-2-[(tert-butoxy)carbonylamino]acetam-
ide (6) as a white powder.
[0842] To an oven-dried flask containing
N-(4-{2-[4-(N-{1-(N-hydroxycarbamoyl)(1S)-2-[(tert-butoxy)carbonylamino]e-
thyl}carbamoyl)phenyl]ethynyl}phenyl)-2-[(tert-butoxy)carbonylamino]acetam-
ide (6) (130 mg, 0.218 mmol) was added 1:1 TFA/CH.sub.2Cl.sub.2
(2.5 mL). The resulting pink solution was stirred for 2 h and
concentrated to give a pink gum. The crude residue was rinsed with
CH.sub.2Cl.sub.2 (4 mL), concentrated by rotary evaporation and
dissolved in THF (2 mL) and MeOH (0.4 mL). A solution of 4 M HCl in
dioxane (200 .mu.L) was added and the resulting precipitate
filtered and washed with Et.sub.2O (10 mL) to afford 90 mg of
4-({4-[(aminoacetyl)amino]phenyl}ethynyl)-N-[(1S)-1-(aminomethyl)-2-(hydr-
oxyamino)-2-oxoethyl]benzamide as a pale tan powder. Reaction of
Iodoaniline with Bromoacetyl Bromide ##STR133##
[0843] Bromoacetyl bromide (175 .mu.L, 2.00 mmol) was added
dropwise over 5 minutes to a solution of 4-iodoaniline (438 mg,
2.00 mmol) and Et.sub.3N (280 .mu.L, 2.00 mmol) in benzene (5 mL).
The reaction was stirred 1 hour, treated with morpholine (1.0 mL,
11.5 mmol) and stirred overnight. The reaction mixture was diluted
with EtOAc (200 mL), washed with aqueous 0.1 M KOH (50 mL),
H.sub.2O (50 mL), dried over MgSO.sub.4 and concentrated to give a
yellow oil. Purification by silica gel chromatography (100:1
CH.sub.2Cl.sub.2/MeOH) afforded 630 mg (91%) of
N-(4-iodophenyl)-2-morpholin-4-ylacetamide as a waxy tan solid.
This product was converted to analogues in a similar manner as
Example 14.
Example A
Preparation of
4-[4-(6-Chloro-pyridin-3-yl)-buta-1,3-diynyl]-benzoic acid methyl
ester
[0844] TABLE-US-00028 ##STR134## ##STR135## ##STR136## Reagent MW
EQ g/ml mmol H-DAP(Boc)-OMe (1) 254 1.05 5.93 g 23.3 4-Iodo-beazoic
acid 248 1.0 5.49 g 22.2 HOAT 136.1 1.02 3.08 g 22.6 EDC 191.71
1.02 4.33 g 22.6 DIBA 129.25 2.5 9.7 ml 55.1 DMF 85 ml
[0845] DIEA (9.7 ml, 55.1 mmol) was added to a stirred solution of
4-iodo-benzoic acid (5.49 g, 22.2 mmol), HOAT (3.08 g, 22.6 mmol),
EDC (4.33 g, 22.6 mmol) in DMF (85 ml). After 2 min., the
H-DAP(Boc)-OMe (1) was added in one portion. After 12 hours, the
reaction was found complete by LCMS. The reaction was diluted with
EtOAc/hexane (1:1) (500 ml). The organic phase was washed with 1N
HCl (2.times.80 ml), 1N NaOH (2.times.80 ml), water (2.times.80
ml), sat. brine (80 ml), dried with Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to give crude product. The
residue was filtered through a filter plug of silica eluting with
EtOAc/hexane (1:1). The fractions with product were evaporated to
give 9.3 g of product
(3-tert-Butoxycarbonylamino-2-(4-iodo-benzoylamino)-propionic acid
methyl ester) in 93% yield. This product was converted to analogues
in a similar manner as the aforementioned Examples.
Example 15
N-(1-(N-hydroxycarbamoyl)(1S,2R)-2-hydroxypropyl)(4-{2-[4-morpholin-4-ylme-
thyl)phenyl]ethynyl}phenyl)carboxamide (5)
[0846] ##STR137##
Preparation of (2S,
3R)-2-[4-(4-formyl-phenylethynyl)-benzoylamino]-3-hydroxy-butyric
acid methyl ester (3)
[0847] TABLE-US-00029 ##STR138## ##STR139## ##STR140## Reagent MW
Eq. g/ml mmol Ethynylbenzene (1) 261.27 1.0 0.745 g 2.85
4-Iodobenzaldehyde (2) 232.00 1.4 0.902 g 3.89
PdCl.sub.2(PPh.sub.3).sub.2 701.89 0.03 0.070 g 0.10 Cul 190.44
0.06 0.034 g 0.18 Et.sub.3N 101.19 2.3 0.90 mL 6.5 THF 50 mL
[0848] A solution of alkyne 1 (745 mg, 2.85 mmol),
4-iodobenzaldehyde 2 (902 mg; 3.89 mmol), and Et.sub.3N (900 .mu.L,
6.5 mmol) in THF (50 mL) was purged with a stream of N.sub.2 for
two minutes and then treated with PdCl.sub.2(Ph.sub.3).sub.2 (70
mg, 0.10 mmol) and CuI (34 mg, 0.18 mmol). The reaction mixture was
stirred 40 h, concentrated by rotary evaporation and purified by
silica gel chromatography (40:1 DCM/MeOH) to give 0.833 g (80%
yield) of (2S,
3R)-2-[4-(4-formyl-phenylethynyl)-benzoylamino]-3-hydroxy-butyric
acid methyl ester 3 as a pale yellow powder, mp=143-144.degree. C.
R.sub.f=0.3 (25:1 DCM/MeOH); LRMS (ES+) m/z 366.1
(C.sub.21H.sub.19NO.sub.5+H requires 366.13); HPLC (300 nm, 47 min)
15.3 min.
Preparation of (2S,
3R)-3-Hydroxy-2-[4-(4-morpholin-4-ylmethyl-phenylethynyl)-benzoylamino]-b-
utyric acid methyl ester (4)
[0849] TABLE-US-00030 ##STR141## ##STR142## ##STR143## Reagent MW
Eq. g/ml mmol Tolanylaldehyde (3) 365.38 1.0 0.822 g 2.25
Morpholine 87.12 1.3 0.260 mL 2.97 NaBH(OAc).sub.3 211.94 1.4 0.670
g 3.16 THF 15 ml
[0850] Sodium triacetoxyborohydride (0.670 g, 3.16 mmol) was added
to a solution of benzaldehyde 3 (0.822 g, 2.25 mmol) and morpholine
(260 .mu.L, 2.97 mmol) in THF (15 mL) under N.sub.2 atmosphere and
the reaction monitored by TLC (25:1 DCM/MeOH, R.sub.f=0.2). After
stirring 4 h, the reaction mixture was quenched with saturated
NaHCO.sub.3 (150 mL), extracted with EtOAc (3.times.100 mL), dried
over MgSO.sub.4, filtered and concentrated to give a yellow syrup.
Purification by silica gel chromatography (35:1 DCM/MeOH) afforded
0.844 g (86% yield) of 4 as a sticky white foam.
Preparation of (2S,
3R)-N-(2-Hydroxy-1-hydroxycarbamoyl-propyl)-4-(4-morpholin-4-ylmethyl-phe-
nylethynyl)-benzamide (5)
[0851] TABLE-US-00031 ##STR144## ##STR145## Reagent MW Eq. g/ml
mmol Methyl ester (4) 436.50 1.0 0.829 g 1.90 NH.sub.2OH--HCl 69.49
3.0 0.400 g 5.76 NaOMe (25 wt %) 54.02 4.5 1.860 g 8.60 MeOH 8 mL
THF 3 mL
[0852] Sodium methoxide (25 wt % in MeOH, 1.860 g, 8.60 mmol) was
added to a stirred solution of hydroxylamine hydrochloride (400 mg,
5.76 mmol) in anhydrous MeOH (5 mL) at 0.degree. C. under N.sub.2
atmosphere. After stirring 20 min, a solution of methyl ester 4
(829 mg, 1.90 mmol) in 1:1 MeOH/THF (6 mL) was added and the
reaction mixture stirred at 0.degree. C. for 1 h and at room
temperature for 4 h. The reaction was quenched with 1.0 M HCl (6
mL), concentrated by rotary evaporation to remove organic solvents,
and diluted with DMSO (4 mL). Analytical RP-HPLC (C.sub.18 column,
CH.sub.3CN gradient 5-35%, 0.1% TFA, UV analysis 300 nm, 16 min)
indicated a purity of 85% for the crude product mixture.
Purification by preparative RP-HPLC and lyophilization of the
collected fractions gave 701 mg (81%) of 5 as a fluffy white solid.
LRMS (ES+) m/z 438.1 (C.sub.24H.sub.27N.sub.3O.sub.5+H requires
438.20); RP-HPLC (300 nm, 16 min run) 8.7 min.
Resin Procedures for Synthesizing Tolanyl Hydroxamates
Example 16
Synthesis of
4-[(4-{[(benzylamino)acetyl]amino}phenyl)ethynyl]-N-{(1S,2R)-2-hydroxy-1--
[(hydroxyamino)carbonyl]propyl}benzamide
[0853] ##STR146##
[0854] 1. Coupling to Fmoc Hydroxylamine Resin
[0855] The resin was pre-swelled by adding DCM and shaking for 30
min. The resin was drained, 20% piperdine was added in DMF, the
resin was shaken 1.25 hours, and finally drained and washed in
2.times.DMF and 2.times.DCM. After draining completely, 20%
piperdine in DMF was added to attain cleavage in 1.25 hours. The
resin was washed 4.times.DMF, 4.times.DCM and drained completely.
In a separate flask, the amino acid (Fmoc-Thr tBu-OH, or Fmoc-DAP
Boc-OH, 4 eq) was mixed, HATU (4 eq), DMF (60 ml) and Hunig's (8
eq) base were added and stirred for 2-3 min. The mixture was added
to the resin and shaken 20-24 hours. Subsequently, the resin was
drained and run with a standard wash (1.times.DCM, 4.times.DMF and
4.times.DCM). The Fmoc was removed from the amino acid by adding
20% piperdine in DMF and shaken 1.25 hours, drained, and given the
standard wash (1.times.DCM, 4.times.DMF and 4.times.DCM).
[0856] 2. Coupling of 4-iodobenzoic Acid to Amino Acid Resin
[0857] A mixture of 4-iodobenzoic acid (4 eq), HBTU (4 eq), DMF (60
ml) was shaken for several minutes. Hunig's base (8 eq) was
subsequently added and the mixture was shaken further for 2-3 min.
The pre-activated mixture was then added to the prepared Thr or DAP
resin (Fmoc removed, 7.5 g, 5.775 mmol). The reaction is shaken
12-16 hours followed by the standard wash (1.times.DCM, 4.times.DMF
and 4.times.DCM).
[0858] 3. Alkyne Coupling on Resin
[0859] To the 4-iodobenzoic resin (4 g, 3.08 mmol) was added
4-aminophenylacetylene (3 eq), Pd(PPh.sub.3).sub.2Cl.sub.2 (0.04
eq), CuI (0.08 eq) and THF (urged with Argon). After mixing for 1
min., TEA (4.5 eq) was added and the reaction was shaken 12 hours
at RT under argon.
[0860] 4. Aniline Coupling with Bromoacetyl Chloride on Resin
[0861] To aniline resin (4 g, 3.08 mmol) was added DCM (30 ml)
lutidine (10 eq) and shaken for 1 min. Bromoacetyl chloride (8 eq)
in DCM (5 ml) was added slowly. After the addition, the slurry was
shaken for 1.5 to 1.75 hours. Subsequent draining and a wash with
2.times.DCM, 4.times.DMF and 4.times.DCM was then performed.
[0862] 5. Displacement with Amines on Resin
[0863] To the bromoacetyl resin (125 mg), was added NMP (1.5 ml)
followed by amine (0.2 g or ml, ie excess) and the slurry was
shaken for 12-16 hours at RT. To neutralize the salt, TEA was
added. The imidazole was heated at 38.degree. C. for 24 h (in the
case of anilines, they were heated at 38.degree. C. for 48 h). The
reaction mixture was drained and washed 4.times.DMF and
4.times.DCM.
[0864] 6. Cleavage from Resin and Deprotection of Thr tBu and DAP
Boc
[0865] The resin (125 mg) was soaked in TFA/water (80:20 v/v) (1.5
ml) at RT for 45 min. Upon cleavage the solution was collected and
the resin was washed with more TFA/water mixture (0.75 ml). To the
TFA/product solution was added acetonitrile/water solution (1:1
v/v, 10 ml) and pure water (2.5 ml). The mixture was frozen in
liquid nitrogen for .about.15 min and lyophilized. The dry residue
was dissolved in the acetonitrile/water solution (1:1 v/v, 10 ml)
again followed by addition of 1M aq. HCl (1.2 eq per basic
nitrogen), frozen, and lyophilized to a powder.
Synthesis of 3'-Nitro-Tolan Threonine Hydroxamic Acid
Example 17
(1S,2R)-N-(2-hydroxy-1-hydroxycarbamoyl-propyl)-4-(3-nitro-phenylethynyl)--
benzamide
[0866] ##STR147##
Preparation of
(1S,2R)-N-(2-tert-butoxy-1-hydroxycarbamoyl-propyl)-4-ethynyl-benzamide
on hydroxylamine 2-chlorotrityl resin (3)
[0867] TABLE-US-00032 Reagent MW Eq. g/mL mmol Fmoc-threonine/resin
(1) 0.70 mmol/g 1.0 0.522 g 0.365 4-Ethynylbenzoic acid (2) 146.14
3.0 0.160 g 1.10 DIC 126.20 4.9 0.28 mL 1.79 HOBt 135.13 3.0 0.148
g 1.10 DIEA 129.25 6.3 0.40 mL 2.30 DCM 1.0 mL DMF 3.0 mL
[0868] The resin 1 (0.522 g, 0.365 mmol, 0.70 mmol/g) was swelled
in DCM (5 mL) for 2 h and drained. The resin was treated with 20%
piperidine in DMF (6 mL) for 1 hour, washed with DMF (4.times.6 mL)
and DCM (4.times.6 mL) and drained completely. In a separate flask,
4-ethynylbenzoic acid 2 (0.160 g, 1.10 mmol), DIC (0.280 mL, 1.79
mmol), HOBt (0.148 g, 1.10 mmol) and DIEA (0.4 mL, 2.30 mmol) were
dissolved in DCM (1 mL) and DMF (4 mL), stirred 15 min and added to
the resin. After shaking for 36 h, the mixture was drained, washed
with DMF (4.times.6 mL) and DCM (4.times.6 mL) and dried in vacuo
to give 0.495 g of a yellow resin.
Preparation of
(1S,2R)-N-(2-hydroxy-1-hydroxycarbamoyl-propyl)-4-(3-nitro-phenylethynyl)-
-benzamide (5)
[0869] TABLE-US-00033 Reagent MW Eq. g/mL mmol Alkyne on resin (3)
0.70 mmol/g 1.0 100 mg 0.070 1-Iodo-3-nitrobenzene (4) 249.01 5.0
87.1 mg 0.350 PdCl.sub.2(PPh.sub.3).sub.2 701.89 0.2 10.0 mg 0.014
CuI 190.44 0.5 7.0 mg 0.036 Et.sub.3N 101.19 15 150 .mu.L 1.10 DMF
1.5 mL
[0870] Resin 3 (100 mg, 0.070 mmol) was swelled in DCM (2 mL) for 1
h and drained. A solution of 1-iodo-3-nitrobenzene 4 (87.1 mg,
0.350 mmol) and Et.sub.3N (150 .mu.L, 1.10 mmol) in DMF (1.5 mL)
was purged with a stream of N.sub.2 bubbles for two minutes and
added to the resin. After mixing for 5 min,
PdCl.sub.2(PPh.sub.3).sub.2 (10.0 mg, 0.014 mmol) and CuI (7.0 mg,
0.036 mmol) were added and the mixture shaken for 26 h. The resin
was drained, washed with DMF (3.times.2 mL), DCM (3.times.2 mL) and
cleaved with 10% TFA/DCM (1.5 mL) for 20 min. The solution was
collected and the resin was rinsed with additional 10% TFA/DCM (1.0
mL). The cleavage fractions were combined, treated with neat TFA
(2.0 mL), stirred for 1 h at rt and concentrated by rotary
evaporation to give a crude brown residue. Purification by RP-HPLC
(C.sub.18 column, CH.sub.3CN gradient 5-65%, 0.1% TFA, UV analysis
300 nm, 28 min) and lyophilization of the collected fractions
afforded 6.0 mg (22% yield) of
(1S,2R)-N-(2-hydroxy-1-hydroxycarbamoyl-propyl)-4-(3-nitro-phenylethynyl)-
-benzamide as a white foam. LRMS (ES+) m/z 384.2
(C.sub.19H.sub.17N.sub.3O.sub.6+H requires 384.15); RP-HPLC (300
nm, 28 min run) 15.2 min.
Synthesis of 4'-Trifluoromethoxy-Tolan Dap Hydroxamic Acid
Example 18
(1S)-N-(2-amino-1-hydroxycarbamoyl-ethyl)-4-(4-trifluoromethoxy-phenylethy-
nyl)-benzamide (5)
[0871] ##STR148##
Preparation of
(1S)-N-(2-(Boc)-amino-1-hydroxycarbamoyl-ethyl)-4-ethynyl-benz-amide
on hydroxylamine 2-chlorotrityl resin (3)
[0872] TABLE-US-00034 Reagent MW Eq. g/mL mmol Fmoc-Dap/resin (1)
0.70 mmol/g 1.0 1.330 g 0.931 4-Ethynylbenzoic acid (2) 146.14 3.0
0.408 g 2.793 DIC 126.20 4.8 0.70 mL 4.470 HOBt 135.13 3.0 0.377 g
2.793 DIEA 129.25 6.2 1.0 mL 5.7 DCM 10.0 mL DMF 2.0 mL
[0873] The resin 1 (1.330 g, 0.931 mmol, 0.70 mmol/g) was swelled
in DCM (15 mL) for 2 h and drained. The resin was treated with 20%
piperidine in DMF (20 mL) for 1 hour, washed with DMF (3.times.15
mL) and DCM (3.times.15 mL) and drained completely. In a separate
flask, 4-ethynylbenzoic acid 2 (0.408 g, 2.793 mmol), DIC (0.70 mL,
4.470 mmol), HOBt (0.377 g, 2.793 mmol) and DIEA (1.0 mL, 5.7 mmol)
were dissolved in DCM (10 mL) and DMF (2 mL), stirred 15 min and
added to the resin. After shaking for 36 h, the mixture was
drained, washed with DMF (3.times.15 mL) and DCM (3.times.15 mL)
and dried in vacuo to give 1.290 g of a yellow resin.
Preparation of
(1S)-N-(2-amino-1-hydroxycarbamoyl-ethyl)-4-(4-trifluoromethoxy-phenyleth-
ynyl)-benzamide (5)
[0874] TABLE-US-00035 Reagent MW Eq. g/mL mmol Alkyne on resin (3)
0.70 mmol/g 1.0 120 mg 0.084 4-CF.sub.3O-iodobenzene (4) 287.99 4.0
96.8 mg 0.336 PdCl.sub.2(PPh.sub.3).sub.2 701.89 0.3 18.0 mg 0.025
CuI 190.44 0.5 8.0 mg 0.042 Et.sub.3N 101.19 13 150 .mu.L 1.10 DMF
2.0 mL
[0875] Resin 3 (120 mg, 0.084 mmol) was swelled in DCM (2 mL) for 1
h and drained. A solution of 4-trifluoromethoxy)iodobenzene 4 (96.8
mg, 0.336 mmol) and Et.sub.3N (150 .mu.L, 1.10 mmol) in DMF (2.0
mL) was purged with a stream of N.sub.2 bubbles for two minutes and
added to the resin. After mixing for 5 min,
PdCl.sub.2(PPh.sub.3).sub.2 (18.0 mg, 0.025 mmol) and CuI (8.0 mg,
0.042 mmol) were added and the mixture shaken for 24 h. The resin
was drained, washed with DMF (3.times.2 mL), DCM (3.times.2 mL) and
cleaved with 10% TFA/DCM (2.0 mL) for 20 min. The solution was
collected and the resin was rinsed with additional 10% TFA/DCM (1.0
mL). The cleavage fractions were combined, treated with neat TFA
(3.0 mL), stirred for 1 h at rt and concentrated by rotary
evaporation to give a crude brown residue. Purification by RP-HPLC
(C.sub.18 column, CH.sub.3CN gradient 5-55%, 0.1% TFA, U analysis
300 nm, 28 min) and lyophilization of the collected fractions
afforded 9.0 mg (25% yield) of
(1S)-N-(2-amino-1-hydroxycarbamoyl-ethyl)-4-(4-trifluoromethoxy-phenyleth-
ynyl)-benzamide as a white solid. LRMS (ES+) m/z 408.0
(C.sub.19H.sub.16F.sub.3N.sub.3O.sub.4+H requires408.11); RP-HPLC
(300 nm, 28 min run) 18.0 min.
Example 19
Synthesis of
N-(1-(N-hydroxycarbamoyl)(1S,2R)-2-hydroxypropyl)[4-(4-phenylbuta-1,3-diy-
nyl)phenyl]carboxamide
[0876] TABLE-US-00036 ##STR149## ##STR150## ##STR151## ##STR152##
##STR153## ##STR154## Reagent MW EQ g/ml mmol Dibromovinylbenzoic
acid (2) 320 1.0 5.76 g 18.0 Ethynyl-benzene 102 1.4 2.57 g 25.2
Pd.sub.2dba.sub.3 915 0.01 164 mg 0.18 (1% cat.) TMPP 352 0.04 253
mg 0.72 (4%) TEA 101 3.0 7.5 ml 54.0 DMF 60 ml degassed with
argon
[0877] The 4-(2,2-Dibromo-vinyl)-beizoic acid methyl ester (2) was
made by the method of Wang Shen and Le Wang in J. Org. Chem. 1999,
64, 8873-8879.
[0878] A solution of 4-(2,2-dibromo-vinyl)-benzoic acid methyl
ester (2) (5.76 g, 18.0 mmol), ethynyl-benzene (2.57 g, 25.2 mmol),
Pd.sub.2dba.sub.3 (164 mg, 0.18 mmol),
tris(4-methoxyphenyl)phosphine (TMPP) (253 mg, 0.72 mmol) were
dissolved in argon sparged (5 min.) DMF (60 ml). The reaction was
sparged with argon for 1 min. TEA (7.5 ml, 54.0 mmol) was added to
the stirred reaction mixture that was then heated under argon at
85.degree. C. for 3.5 hours. The reaction was found complete by
LCMS. The reaction was cooled to rt and diluted with EtOAc/hexane
(1:1) (300 ml). The organic phase was washed with 1M HCl
(2.times.50 ml), 1M NaOH (3.times.50 ml), water (2.times.50 ml),
sat. brine (50 ml), dried with Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to obtain 5.25 g of crude
product as an oil. The oil was treated with approximately 20 ml of
a solution of 20% EtOAc/hexane that was heated to dissolve the
residue. The walls of the flask were washed with the 20%
EtOAc/hexane solution (5 ml) that upon cooling gave 1.45 g of pure
product (31% yield) as a white solid. The balence of the crude
reaction product was purified by flash chromatography using EtOAc
(8%)/hexane as eluant The pure fractions were evaporated and dried
in vacuo to give addition product typically 25-30% addition
yield.
[0879] 4-(4-Phenyl-buta-1,3-diynyl)-benzoic acid methyl ester (4)
was made according to the method of Wang Shen and Sheela A. Thomas
in Org. Lett. 2000, 2(18), 2857-2860.
Preparation of 4-(4-Phenyl-buta-1,3-diynyl)-benzoic acid (5)
[0880] A 3M aq. solution of NaOH (20 ml) was added to a stirred
solution of methyl ester 4 (1.45 g, 5.6 mmol) in MeOH (100 ml) at
rt. The reaction solution was heated to reflux for 45 min. until
the reaction turned clear. All of the starting material was gone by
TLC and HPLC. The reaction was cooled to rt and some MeOH
(.about.50 ml) was removed by evaporation under reduced pressure.
Water (100 ml) was added to the mixture. Conc. HCl was added
dropwise to the stirred solution until acidic by pH paper (pH2).
The white precipitate that formed was collected by suction
filtration. The solid was washed with water (3.times.20 ml) and
hexane (2.times.20 ml) to give after drying 1.35 g of product acid
5 in 99% yield.
[0881] Subsequent conversion of compound 5 to compound 7 was
performed according to the method described in Example 12 for the
synthesis of
N-(2-Hydroxy-1-hydroxycarbamoyl-propyl)-4-phenylethynyl-benzamide
(compound 5). LCMS MH+363.13.
Example B
Synthesis of
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-oxoethyl]-4-[4-(4-aminophenyl)-
buta-1,3-diynyl]benzamide
Preparation of
2-{4-[4-(4-Amino-phenyl)-buta-1,3-diynyl]-benzoylamino}-3-tert-butoxycarb-
onylamino-propionic acid methyl ester (2)
[0882] TABLE-US-00037 ##STR155## ##STR156## Reagent MW EQ g/ml mmol
H-DAP(Boc)-OMe 254 1.05 5.12 g 20.1 1,3-diynyl benzoic acid (1)
261.3 1.0 5.0 g 19.1 HOBT 135.1 1.05 2.72 g 20.1 EDC 191.71 1.05
3.85 g 20.1 DIEA 129.25 3.0. 10.5 ml 60.3 DMF 80 ml
[0883] DIEA (10.5 ml, 60.3 mmol) was added to a stirred solution of
4-[4-(4-Amino-phenyl)-buta-1,3-diynyl]-benzoic acid (1) (5.0 g,
19.1 mmol), HOBT (2.72 g, 20.1 mmol), EDC (3.85 g, 20.1 mmol) in
DMF (80 ml). After 2 min., the H-DAP(Boc)-OMe was added in one
portion. After 12 hours at rt, the reaction was found complete by
LCMS. The reaction was diluted with EtOAc/hexane (4:1) (500 ml).
The organic phase was washed with 1N NaOH (2.times.80 ml), water
(2.times.80 ml), sat. brine (80 ml), dried with Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give crude
product. The residue was filtered through a filter plug of silica
eluting with EtOAc/hexane (4:1). The fractions with product were
evaporated to give 8.02 g of product in 91% yield.
[0884] Subsequent conversion of compound 2 to the final hydroxamic
acid (for example, Example 892) was performed according to the
method described in Example 12 for the synthesis of
N-(2-Hydroxy-1-hydroxycarbamoyl-propyl)-4-phenylethynyl-benzamide
(compound 5).
Synthesis of 4-(Buta-1,3-diynyl)-benzoic Acid (4) for making
1,3-diynyl analogues (such as Example 20 below)
[0885] ##STR157##
Preparation of 4-(4-trimethylsilanyl-buta-1,3-diynyl)-benzoic acid
methyl ester (3)
[0886] TABLE-US-00038 ##STR158## ##STR159## Reagent MW Eq. g/ml
mmol Methyl 4-iodobeuzoate (2) 262.04 1.0 4.510 g 17.2
Trimethylsilylbutadiyne (1) 122.24 2.5 5.240 g 42.8
PdCl.sub.2(PPh.sub.3).sub.2 701.89 0.04 0.483 g 0.690 CuI 190.44
0.08 0.262 g 1.37 Et.sub.3N 101.19 3.0 7.2 mL 52.0 CH.sub.3CN 50
mL
[0887] A solution of methyl 4-iodobenzoate 2 (4.510 g, 17.2 mmol),
PdCl.sub.2(PPh.sub.3).sub.2 (483 mg, 0.690 mmol), and CuI (262 mg,
1.37 mmol) in CH.sub.3CN (50 mL) was cooled to 0.degree. C. under
N.sub.2 atmosphere in the absence of light. Triethylamine (7.2 mL,
52.0 mmol) was added, followed by trimethylsilyl-1,3-butadiyne 1
(5.240 g, 42.8 mmol) and the reaction stirred 3 h at 0.degree. C.
and 30 h at ambient temperature. Removal of solvent by rotary
evaporation afforded a crude black residue that was purified by
silica gel chromatography (95:5 hexanes/EtOAc) to give 3.450 g (79%
yield) of 4-(4-trimethylsilanyl-buta-1,3-diynyl)-benzoic acid
methyl ester 3 as a brown solid, mp=67-68.degree. C.
Preparation of 4-(buta-1,3-diynyl)-benzoic acid (4)
[0888] TABLE-US-00039 ##STR160## ##STR161## Reagent MW Eq. g/ml
mmol Methyl ester (3) 252.34 1.0 3.420 g 13.5 KOH 56.11 4.9 3.700 g
65.9 H.sub.2O 10 mL THF 26 mL
[0889] Potassium hydroxide (3.700 g, 65.9 mmol) was dissolved in
H.sub.2O (10 mL) and added to a solution of
4-(4-trimethylsilanyl-buta-1,3-diynyl)-benzoic acid methyl ester 3
(3.420 g, 13.5 mmol) in THF (26 mL) in the absence of light. After
stirring 16 h, the reaction was quenched with 1.0 M HCl (120 mL)
and the resulting precipitate was filtered, washed with 1:1
hexanes/benzene (150 mL) and dried in vacuo to afford 2.100 g (91%
yield, 98% pure) of 4-(buta-1,3-diynyl)-benzoic acid 4 as a brown
solid, mp>230.degree. C. Although diyne 4 was found to be
unstable at room temperature it could be stored for several weeks
at 0.degree. C. with only small amounts of decomposition observed
by TLC. R.sub.f=0.2 (4:1 Hexanes/EtOAc); HPLC (300 nm, 28 min run)
16.0 min; LRMS (ES+) m/z 171.0 (C.sub.11H.sub.6O.sub.2+H requires
171.04).
Synthesis of a 3'-Nitrophenyl-Diacetylenic-Dap Hydroxamic Acid
Example 20
N-(1-(N-hydroxycarbamoyl)(1S)-2-aminoethyl){4-[4-(3-nitrophenyl)buta-1,3-d-
iynyl]phenyl}carboxamide (6)
[0890] ##STR162##
Preparation of Fmoc-Dap(Boc)-NHOH on hydroxylamine 2-chlorotrityl
resin (2)
[0891] TABLE-US-00040 ##STR163## ##STR164## Reagent MW Eq. g/mL
mmol Hydroxylamine resin (1) 0.77 mmol/g 1.0 3.288 g 2.53
Fmoc-Dap(Boc)-OH 426.47 3.0 3.175 g 7.44 HATU 380.25 3.0 2.829 g
7.44 DIEA 129.25 10.0 4.3 mL 24.7 DMF 35 mL
[0892] A suspension of N-Fmoc-hydroxylamine 2-chlorotrityl resin
(3.288 g, 2.53 mmol, 0.77 mmol/g, Novabiochem) in DCM (40 mL) was
shaken for 2 h and drained. The resin was treated with 20%
piperidine in DMF (40 mL) for 1 hour, washed with DMF (2.times.40
mL), treated a second time with 20% piperidine in DMF (40 mL),
washed with DMF (3.times.40 mL) and DCM (3.times.40 mL) and drained
completely. In a separate flask, Fmoc-Dap(Boc)-OH (3.175 g, 7.44
mmol), HATU (2.829 g, 7.44 mmol) and DIEA (4.3 mL, 24.7 mmol) were
dissolved in DMF (35 mL), stirred three minutes and added to the
resin. After shaking for 48 h, the mixture was drained, washed with
DMF (4.times.40 mL) and DCM (4.times.40 mL) and dried in vacuo to
give 3.530 g of a yellow resin.
Preparation of
(S)-N-(2-N-Fmoc-amino-1-hydroxycarbamoyl-ethyl)-4-buta-1,3-diynyl-benzami-
de on hydroxylamine 2-chlorotrityl resin (4)
[0893] TABLE-US-00041 ##STR165## ##STR166## Reagent MW Eq. g/mL
mmol Fmoc-Dap(Boc)/resin (2) 0.71 mmol/g 1.0 3.530 g 2.53
Butadiynyl benzoic acid (3) 170.16 2.5 1.076 g 6.32 EDCI 191.71 3.0
1.457 g 7.60 HOBt 135.13 3.0 1.048 g 7.75 DIEA 129.25 5.0 2.2 mL
12.6 DCM 25 mL DMF 5 mL
[0894] The resin 2 (3.530 g, 2.53 mmol, 0.71 mmol/g) was swelled in
DCM (40 mL) for 2 h and drained. The resin was treated with 20%
piperidine in DMF (40 mL) for 1 hour, washed with DMF (4.times.40
mL) and DCM (4.times.40 mL) and drained completely. In a separate
flask, 4-buta-1,3-diynyl-benzoic acid 3 (1.076 g, 6.32 mmol), EDCI
(1.457 g, 7.60 mmol), HOBt (1.048 g, 7.75 mmol) and DIEA (2.2 mL,
12.6 mmol) were dissolved in DCM (25 mL) and DMF (5 mL), stirred 45
min and added to the resin. After shaking for 48 h, the mixture was
drained, washed with DMF (4.times.40 mL) and DCM (4.times.40 mL)
and dried in vacuo to give 3.35 g of a pale brown resin.
Preparation of
(S)-N-(2-amino-1-hydroxycarbamoyl-ethyl)-4-[4-(3-nitro-phenyl)-buta-1,3-d-
iynyl]-benzamide (6)
[0895] TABLE-US-00042 ##STR167## ##STR168## Reagent MW Eq. g/mL
mmol Diacetylene on resin (4) 0.77 mmol/g 1.0 176 mg 0.135
1-Iodo-3-nitrobenzene (5) 249.01 3.5 118 mg 0.474
PdCl.sub.2(PPh.sub.3).sub.2 701.89 0.07 6.0 mg 0.009 CuI 190.44
0.38 10.0 mg 0.052 Et.sub.3N 101.19 10.6 200 .mu.L 1.43 DMF 3.0
mL
[0896] Resin 4 (176 mg, 0.135 mmol) was swelled in DCM (3 mL) for 1
h and drained. A solution of 1-iodo-3-nitrobenzene 5 (118 mg, 0.474
mmol) and Et.sub.3N (200 .mu.L, 1.43 mmol) in DMF (3.0 mL) was
purged with a stream of N.sub.2 bubbles for two minutes and added
to the resin. After mixing for 5 min, PdCl.sub.2(PPh.sub.3).sub.2
(6.0 mg, 0.009 mmol) and CuI (10.0 mg, 0.052 mmol) were added and
the mixture shaken for 36 h. The resin was drained, washed with DMF
(4.times.3 mL), DCM (4.times.3 mL) and cleaved with 10% TFA/DCM (2
mL) for 20 min. The solution was collected and the resin was rinsed
with additional 10% TFA/DCM (2 mL). The cleavage friactions were
combined, treated with neat TFA (4.0 mL), stirred for 1 h at rt and
concentrated by rotary evaporation to give a crude brown residue.
Purification by RP-HPLC (C.sub.18 column, CH.sub.3CN gradient
5-65%, 0.1% TFA, UV analysis 300 nm, 30 min) and lyophilization of
the collected fractions afforded 12.0 mg (22%) of 470 as a white
solid. LRMS (ES+) m/z 392.9 (C.sub.20H.sub.16N.sub.4O.sub.5+H
requires 393.11); RP-HPLC (300 nm, 30 min run) 14.9 min.
Synthesis of 4'-Benzamide Diacetylene Dap Hydroxamic Acid
Example 21
N-((2S)-amino-1-hydroxycarbamoyl-ethyl)-4-{4-[4-(2-amino-ethylcarbamoyl)-p-
henyl]-buta-1,3-diynyl}-benzamide (3)
[0897] ##STR169##
Preparation of
N-((2S)-amino-1-hydroxycarbamoyl-ethyl)-4-{4-[4-(2-amino-ethylcarbamoyl)--
phenyl]-buta-1,3-diynyl}-benzamide (3)
[0898] TABLE-US-00043 Reagent MW Eq. g/mL mmol Alkyne on resin (1)
0.77 mmol/g 1.0 145 mg 0.111 4-Ethynylbenzamide (2) 430.54 2.6 124
mg 0.288 PdCl.sub.2(PPh.sub.3).sub.2 701.89 0.3 21 mg 0.030 CuI
190.44 1.0 22 mg 0.110 Et.sub.3N 101.19 6.5 100 .mu.L 0.72 DMF 2.0
mL
[0899] Resin 1 (145 mg, 0.111 mmol) was swelled in DCM (2 mL) for 1
h and drained. A solution of 4-ethynylbenzamide 2 (124 mg, 0.288
mmol) and Et.sub.3N (100 .mu.L, 0.72 mmol) in DMF (2.0 mL) was
added and the resin agitated for 5 min. A mixture of
PdCl.sub.2(PPh.sub.3).sub.2 (21 mg, 0.030 mmol) and CuI (22 mg,
0.110 mmol) was added and the resin was agitated for 60 h. The
resin was drained, washed with DMF (3.times.2 mL), DCM (3.times.2
mL) and cleaved with 10% TFA/DCM (1.5 mL) for 20 min. The solution
was collected and the resin was rinsed with additional 10% TFA/DCM
(1.0 mL). The cleavage fractions were combined, treated with neat
TFA (2.0 mL), stirred for 1 h at rt and concentrated by rotary
evaporation to give a crude brown residue. Purification by RP-HPLC
(C.sub.18 column, CH.sub.3CN gradient 5-55%, 0.1% TFA, UV analysis
300 nm, 26 min) and lyophilization of the collected fractions
afforded 2.6 mg (5% yield) of
N-((2S)-amino-1-hydroxycarbainoyl-ethyl)-4-{4-[4-(2-amino-ethylcarbamoyl)-
-phenyl]-buta-1,3-diynyl}-benzamide. LRMS (ES+) m/z 434.0
(C.sub.23H.sub.23N.sub.5O.sub.4+H requires 434.19); RP-HPLC (300
nm, 26 min run) 15.3 min.
Synthesis of N-[4-Butadiynyl-benzoyl]-Thr(tBu) on Resin (Continued
to make Examples 22 and 23)
[0900] ##STR170##
Preparation of (2S,
3R)-2-N-Fmoc-amino-3-tert-butoxy-N-hydroxy-butyramide on
hydroxylamine 2-chlorotrityl resin (2)
[0901] TABLE-US-00044 ##STR171## ##STR172## Reagent MW Eq. g/mL
mmol Hydroxylamine resin (1) 0.77 mmol/g 1.0 3.188 g 2.45
Fmoc-Thr(tBu)-OH 397.50 3.0 2.927 g 7.36 HATU 380.25 3.0 2.798 g
7.36 DIEA 129.25 10.0 4.3 mL 24.6 DMF 40 mL
[0902] A suspension of N-Fmoc-hydroxylamine 2-chlorotrityl resin
(3.188 g, 2.45 mmol, 0.77 mmol/g, Novabiochem) in DCM (40 mL) was
shaken for 2 h and drained. The resin was treated with 20%
piperidine in DMF (40 mL) for 1 hour, washed with DMF (2.times.40
mL), treated a second time with 20% piperidine in DMF (40 mL),
washed with DMF (3.times.40 mL) and DCM (3.times.40 mL) and drained
completely. In a separate flask, Fmoc-Thr(tBu)-OH (2.927 g, 7.36
mmol), HATU (2.798 g, 7.36 mmol) and DIEA (4.3 mL, 24.6 mmol) were
dissolved in DMF (40 mL), stirred three minutes and added to the
resin. After shaking for 24 h, the mixture was drained, washed with
DMF (4.times.40 mL) and DCM (4.times.40 mL) and dried in vacuo to
give 3.500 g of a yellow resin.
Preparation of
4-buta-1,3-diynyl-N-(2-tert-butoxy-1-hydroxycarbamoyl-propyl)-benzamide
on hydroxylamine 2-chlorotrityl resin (4)
[0903] TABLE-US-00045 ##STR173## ##STR174## Reagent MW Eq. g/mL
mmol Fmoc-threonine/resin (2) 0.77 mmol/g 1.0 2.030 g 1.56
Butadiynyl benzoic acid (3) 170.16 2.3 0.617 g 3.63 EDcI 191.71 2.8
0.834 g 4.35 HOBt 135.13 2.8 0.588 g 4.35 DIEA 129.25 3.7 1.0 mL
5.7 DCM 15 mL DMF 4 mL
[0904] The resin 2 (2.030 g, 1.56 mmol, 0.77 mmol/g) was swelled in
DCM (20 mL) for 2 h and drained. The resin was treated with 20%
piperidine in DMF (20 mL) for 1 hour, washed with DMF (4.times.20
mL) and DCM (4.times.20 mL) and drained completely. In a separate
flask, 4-buta-1,3-diynyl-benzoic acid 3 (0.617 g, 3.63 mmol), EDCI
(0.834 g, 4.35 mmol), HOBt (0.588 g, 4.35 mmol) and DIEA (1.0 mL,
5.7 mmol) were dissolved in DCM (15 mL) and DMF (4 mL), stirred 45
min and added to the resin. After shaking for 36 h, the mixture was
drained, washed with DMF (4.times.20 mL) and DCM (4.times.20 mL)
and dried in vacuo to give 1.900 g of a pale brown resin.
Synthesis of Diacetylenic Threonine Hydroxamic Acids
Example 22
(2S,3R)-4-[4-(3-aminomethyl-phenyl)-buta-1,3-diynyl]-N-(2-hydroxy-1-hydrox-
ycarbamoyl-propyl)-benzamide (3)
[0905] TABLE-US-00046 ##STR175## ##STR176## Reagent MW Eq. g/mL
mmol Diacetylene on resin (1) 0.77 mmol/g 1.0 100 mg 0.077
3-Iodobenzylamine HCl (2) 269.51 4.0 83.0 mg 0.308
PdCl.sub.2(PPh.sub.3).sub.2 701.89 0.2 11.0 mg 0.016 CuI 190.44 0.5
7.0 mg 0.037 Et.sub.3N 101.19 23 250 .mu.L 1.80 DMF 1.5 mL
[0906] Resin 1 (obtained from previous synthesis) (100 mg, 0.077
mmol) was swelled in DCM (2 mL) for 1 h and drained. A solution of
3-iodobenzylamine hydrochloride 2 (83.0 mg, 0.308 mmol) and
Et.sub.3N (250 .mu.L, 1.80 mmol) in DMF (1.5 mL) was purged with a
stream of N.sub.2 bubbles for two minutes and added to the resin.
After mixing for 5 min, PdCl.sub.2(PPh.sub.3).sub.2 (11.0 mg, 0.016
mmol) and CuI (7.0 mg, 0.037 mmol) were added and the mixture
shaken for 36 h. The resin was drained, washed with DMF (4.times.2
mL), DCM (4.times.2 mL) and cleaved with 10% TFA/DCM (1.5 mL) for
20 min. The solution was collected and the resin was rinsed with
additional 10% TFA/DCM (1.5 mL). The cleavage fractions were
combined, treated with neat TFA (3.0 mL), stirred for 1 h at rt and
concentrated by rotary evaporation to give a crude brown residue.
Purification by RP-HPLC (C.sub.18 column, CH.sub.3CN gradient
5-65%, 0.1% TFA, UV analysis 300 nm, 28 min) and lyophilization of
the collected fractions afforded 4.3 mg (14%) of
(2S,3R)-4-[4-(3-aminomethyl-phenyl)-buta-1,3-diynyl]-N-(2-hydroxy-1-hydro-
xycarbamoyl-propyl)-benzamide as a white solid. LRMS (ES+) m/z
392.0 (C.sub.22H.sub.21N.sub.3O.sub.4+H requires 392.15); RP-HPLC
(300 nm, 28 min run) 10.0 min.
Synthesis of Diacetylenic Benzylamine Analogues
Example 23
(1S,
2R)-N-2-hydroxy-1-hydroxycarbamoyl-propyl)-4-[4-(4-morpholin-4-ylmeth-
yl-phenyl)-buta-1,3-diynyl]-benzamide (4)
[0907] ##STR177##
Preparation of threonine diacetylenic benzaldehyde on resin (3)
[0908] TABLE-US-00047 ##STR178## ##STR179## Reagent MW Eq. g/mL
mmol Diacetylene on resin (1) 0.77 mmol/g 1.0 1.00 g 0.770
4-Iodobenzaldehyde 232.00 4.0 715 mg 3.081
PdCl.sub.2(PPh.sub.3).sub.2 701.89 0.07 40.0 mg 0.057 CuI 190.44
0.13 19.0 mg 0.100 Et.sub.3N 101.19 9.3 1.00 mL 7.17 DMF 20.0
mL
[0909] Resin 1 (1.00 g, 0.77 mmol) was pre-swelled in DCM (25 mL)
for 14 h and drained. A solution of 4-iodobenzaldehyde 2 (715 mg,
3.08 mmol) and Et.sub.3N (1.00 mL, 7.17 mmol) in DMF (20 mL) was
purged with N.sub.2 for two minutes and added to the resin. After
mixing for 5 min, PdCl.sub.2(PPh.sub.3).sub.2 (40.0 mg, 0.057 mmol)
and CuI (19.0 mg, 0.100 mmol) were added and the reaction shaken
for 48 h. The resin was drained, washed with DMF (4.times.20 mL),
DCM (4.times.20 mL) and dried in vacuo to give 1.100 g of a dark
yellow resin.
Preparation of (1S,
2R)-N-2-hydroxy-1-hydroxycarbamoyl-propyl)-4-[4-(4-morpholin-4-ylmethyl-p-
henyl)-buta-1,3-diynyl]-benzamide (4)
[0910] TABLE-US-00048 ##STR180## ##STR181## Reagent MW Eq. mg/.mu.l
mmol Benzaldehyde on resin (3) 0.77 mmol/g 1.0 188 mg 0.141
Morpholine 87.12 6.0 75 .mu.L 0.860 NaCNBH.sub.3 62.84 4.5 40 mg
0.637 Trimethyl orthoformate 106.12 6.5 100 .mu.L 0.914 Acetic acid
60.05 12.3 100 .mu.L 1.750 THF 3.0 mL MeOH 1.0 mL
[0911] A solution of morpholine (75 .mu.L, 0.860 mmol) and
trimethyl orthoformate (100 .mu.L, 0.914 mmol) in THF (3.0 mL) was
added to a Teflon-lined screw-capped vial containing the
resin-bound diacetylenic benzaldehyde 3. The resin was agitated for
10 min, treated successively with acetic acid (100 .mu.L, 1.75
mmol) and a solution of NaCNBH.sub.3 (40.0 mg, 0.637 mmol) in MeOH
(1.0 mL) and shaken for 44 h. The resin was filtered, washed with
DMF (3.times.3 mL) and DCM (3.times.3 mL) and drained. Cleavage
from the resin was achieved by treatment with 10% TFA/DCM (2.0 mL)
and shaking 20 min. The solution was collected and the resin was
rinsed with additional 10% TFA/DCM (2.0 mL). The cleavage fractions
were combined, treated with neat TFA (3.0 mL), stirred for 1 h at
rt and concentrated by rotary evaporation to give a crude yellow
residue. Purification by RP-HPLC (C.sub.18 column, CH.sub.3CN
gradient 5-35%, 0.1% TFA, UV analysis 300 nm, 18 min) and
lyophilization of the collected fractions afforded 19.0 mg (29%) of
472 as a fluffy yellow solid. LRMS (ES+) m/z 462.0
(C.sub.26H.sub.27N.sub.3O.sub.5+H requires 462.10); HPLC (300 nm,
18 min run) 10.3 min.
Synthesis of 4'-Benzamide Diacetylene Threonine Hydroxamic Acid
Example 24
(1S,2R)-N-(2-hydroxy-1-hydroxycarbamoyl-propyl)-4-{4-[4-(2-amino-ethylcarb-
amoyl)-phenyl]-buta-1,3-diynyl}-benzamide (5)
[0912] ##STR182##
Preparation of N-(2-trityl-amino-ethyl)-4-ethynyl-benzamide (3)
[0913] TABLE-US-00049 Reagent MW Eq. g/mL mmol 4-Ethynylbenzoic
acid (1) 146.14 1.0 0.292 g 2.00 N-Trityl ethylenediamine 302.41
1.3 0.810 g 2.67 EDCI 191.71 1.0 0.382 g 2.00 HOBt 135.13 3.0 0.270
g 2.00 DIEA 129.25 4.0 1.40 mL 8.00 DMF 10.0 mL
[0914] To a solution of 4-ethynylbenzoic acid 1 (292 mg, 2.00
mmol), EDCI (382 mg, 2.00 mmol), and HOBt (270 mg, 2.00 mmol) in
DMF (10 mL) was added N-trityl ethylenediamine 2 (810 mg, 2.67
mmol) and DIEA (1.4 mL, 8.0 mmol). The reaction mixture was stirred
24 h, diluted with EtOAc (200 mL), washed with 0.5 M HCl (60 mL),
saturated NaHCO.sub.3 (2.times.60 mL), H.sub.2O (4.times.60 mL),
dried over MgSO.sub.4 and concentrated to give 836 mg (97% yield)
of N-(2-trityl-amino-ethyl)-4-ethynyl-benzamide 3 as a white solid,
mp 50-51.degree. C. R.sub.f.dbd.0.40 (1:1 Hexanes/EtOAc).
Preparation of
(1S,2R)-N-(2-hydroxy-1-hydroxycarbamoyl-propyl)-4-{4-[4-(2-amino-ethylcar-
bamoyl)-phenyl]-buta-1,3-diynyl}-benzamide (5)
[0915] TABLE-US-00050 Reagent MW Eq. g/mL mmol Alkyne on resin (4)
0.77 mmol/g 1.00 150 mg 0.116 4-Ethynylbenzamide (3) 430.54 3.00
151 mg 0.350 PdCl.sub.2(PPh.sub.3).sub.2 701.89 0.25 21 mg 0.030
CuI 190.44 1.25 28 mg 0.147 Et.sub.3N 101.19 9.50 150 .mu.L 1.10
DMF 2.0 mL
[0916] Resin 4 (150 mg, 0.116 mmol) was swelled in DCM (2 mL) for 1
h and drained. A solution of 4-ethynylbenzamide 3 (151 mg, 0.350
mmol) and Et.sub.3N (150 .mu.L, 1.10 mmol) in DMF (2.0 mL) was
added and the resin agitated for 5 min. A mixture of
PdCl.sub.2(Ph.sub.3).sub.2 (21 mg, 0.030 mmol) and CuI (28 mg,
0.147 mmol) was added and the resin was agitated for 60 h. The
resin was drained, washed with DMF (3.times.2 mL), DCM (3.times.2
mL) and cleaved with 10% TFA/DCM (1.5 mL) for 20 min. The solution
was collected and the resin was rinsed with additional 10% TFA/DCM
(1.0 mL). The cleavage fractions were combined, treated with neat
TFA (2.0 mL), stirred for 1 h at rt and concentrated by rotary
evaporation to give a crude brown residue. Purification by RP-HPLC
(C.sub.18 column, CH.sub.3CN gradient 5-65%, 0.1% TFA, UV analysis
300 nm, 26 min) and lyophilization of the collected fractions
afforded 2.0 mg (4% yield) of
(1S,2R)-N-(2-hydroxy-1-hydroxycarbamoyl-propyl)-4-{4-[4-(2-amino-ethylcar-
bamoyl)-phenyl]-buta-1,3-diynyl}-benzamide. LRMS (ES+) m/z 449.1
(C.sub.24H.sub.24N.sub.4O.sub.5+H requires 449.18); RP-HPLC (300
nm, 26 min run) 17.0 min.
Synthesis of 3'-Pyridine Diacetylene Threonine Hydroxamic Acid
Example 25
N-((2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)-4-(4-pyridin-3-yl-buta-1,3-d-
iynyl)-benzamide (3)
[0917] ##STR183##
Preparation of
N-((2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)-4-(4-pyridin-3-yl-buta-1,3--
diynyl)-benzamide (3)
[0918] TABLE-US-00051 Reagent MW Eq. g/mL mmol Alkyne on resin (1)
0.77 mmol/g 1.0 142 mg 0.109 3-Ethynylpyridine (2) 103.12 3.4 38 mg
0.368 PdCl.sub.2(PPh.sub.3).sub.2 701.89 0.3 22 mg 0.031 CuI 190.44
1.2 25 mg 0.131 Et.sub.3N 101.19 13 200 .mu.L 1.40 DMF 2.0 mL
[0919] Resin 1 (142 mg, 0.109 mmol) was swelled in DCM (2 mL) for 1
h and drained. A solution of 3-ethynylpyridine 2 (38 mg, 0.368
mmol) and Et.sub.3N (200 .mu.L 1.4 mmol) in DMF (2 mL) was added
and the resin agitated for 5 min. A mixture of
PdCl.sub.2(PPh.sub.3).sub.2 (22 mg, 0.031 mmol) and CuI (25 mg,
0.131 mmol) was added and the resin was agitated for 72 h. The
resin was drained, washed with DMF (3.times.2 mL), DCM (3.times.2
mL) and cleaved with 10% TFA/DCM (1.5 mL) for 20 min. The solution
was collected and the resin was rinsed with additional 10% TFA/DCM
(1.0 mL). The cleavage fractions were combined, treated with neat
TFA (2.0 mL), stirred for 1 h at rt and concentrated by rotary
evaporation to give a crude brown residue. Purification by RP-HPLC
(C.sub.18 column, CH.sub.3CN gradient 5-65%, 0.1% TFA, UV analysis
300 nm, 24 min) and lyophilization of the collected fractions
afforded 4.4 mg (11% yield) of
N-((2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)-4-(4-pyridin-3-yl-buta-1,3--
diynyl)-benzamide. LRMS (ES+) m/z 364.0
(C.sub.20H.sub.17N.sub.3O.sub.4+H requires 364.13); RP-HPLC (300
nm, 24 min run) 11.2 min.
Example 26
Synthesis of N-(1-(N-hydroxycarbamoyl)(1S,2R)-2-hydroxy
propyl){4-[4-(6-morpholin-4-yl(3-pyridyl))buta-1,3-diynyl]phenyl}carboxam-
ide (5)
[0920] TABLE-US-00052 ##STR184## ##STR185## ##STR186## ##STR187##
Reagent MW EQ g/ml mmol Dibromovinylbenzoic acid (1) 320 1.0 9.6 g
30.0 2-Chloro-5-ethynyl-pyridine 138 1.3 5.43 g 39.0
Pd.sub.2dba.sub.3 915 0.01 274 mg 0.3 (1% cat.) TMPP 352 0.04 422
mg 1.2 (4%) TEA 101 3.0 12.5 ml 90.0 DMF 90 ml degassed with
argon
Preparation of
4-[4-(6-Chloro-pyridin-3-yl)-buta-1,3-diynyl]-benzoic acid methyl
ester
[0921] ##STR188##
[0922] 4-[4-(6-Chloro-pyridin-3-yl)-buta-1,3-diynyl]-benzoic acid
was made according to the method of Wang Shen and Sheela A. Thomas
in Org. Lett. 2000, 2(18), 2857-2860.
[0923] A solution of 4-(2,2-dibromo-vinyl)-benzoic acid methyl
ester (1) (9.6 g, 30.0 mmol), ethynyl-pyridine (2) (5.43 g, 39.0
mmol), Pd.sub.2dba.sub.3 (274 mg, 0.3 mmol),
tris(4-methoxyphenyl)phosphine (TMPP) (422 mg, 1.2 mmol) were
dissolved in argon sparged (5 min.) DMF (60 ml). The reaction was
sparged with argon for 1 min. TEA (12.5 ml, 90.0 mmol) was added to
the stirred reaction mixture that was then heated under argon at
85.degree. C. for 3 hours. The reaction was found complete by LCMS.
The reaction was cooled to rt and diluted with EtOAc/hexane (1:1)
(500 ml). The organic phase was washed with 1M NaOH (2.times.80
ml), water (2.times.80 ml), sat. brine (80 ml), dried with
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give crude product. The residue was filtered through a filter
plug of silica eluting with EtOAc/hexane (1:1). The fractions with
product were evaporated to give 9.06 g of product in good purity
(.about.96% pure). The material was taken on without further
purification.
Preparation of
4-[4-(6-Chloro-pyridin-3-yl)-buta-1,3-diynyl]-benzoic acid (3)
[0924] A 6M aq. solution of NaOH (15 ml) was added to a stirred
solution of 4-[4-(6-Chloro-pyridin-3-yl)-buta-1,3-diynyl]-benzoic
acid methyl ester. (9.06 g, 30 mmol) in MeOH (350 ml) at rt. The
reaction solution was heated to reflux for 3 hours. The reaction
stayed a mixture and did not turn clear. HPLC and LCMS indicated
that the reaction was forming side products. The reaction was
cooled to rt and some MeOH (.about.200 ml) was removed by
evaporation under reduced pressure. Water (400 ml) was added to the
mixture. Conc. HCl was added dropwise to the stirred solution until
acidic by pH paper (pH2). The yellow precipitate that formed was
collected by suction filtration. The solid was washed with water
(3.times.20 ml) and hexane (2.times.20 ml) to give the crude
product. HPLC indicated that there was approximately 40% product in
the mixture. The crude reaction product was purified by flash
chromatography using EtOAc (8-10%)/hexane as eluant. The pure
fractions were evaporated and dried in vacuo to give 4.2 g of
product 3 in 50% yied.
Preparation of
[4-[4-(6-chloro-pyridin-3-yl)-buta-1,3-diynyl]-benzoyl]-HN-Thr(OtBu)-hydr-
oxamic acid trityl resin (4)
[0925] ##STR189##
[0926] 4-[4-(6-Chloro-pyridin-3-yl)-buta-1,3-diynyl]-benzoic acid
(3) was coupled to a tert-butyl protected threonine pre-loaded on
hydroxylamine 2-chlorotrityl resin following the same procedure as
used for Example 26. The coupling employed DIC and HOBT.
[N-Fmoc-hydroxylamine 2-chlorotrityl resin was purchased from
Novabiochem cat.#01-64-0165.]
Preparation of
N-(2-Hydroxy-1-hydroxycarbamoyl-propyl)-4-[4-(6-morpholin-4-yl-pyridin-3--
yl)-buta-1,3-diynyl]-benzamide (5)
[0927] ##STR190##
[0928] A solution of morpholine (300 uL) in NMP (1 ml) was added to
a vial containing the 2-cloropyridine resin (4) (150 mg, 0.12
mmol). The reaction mixture was purged with argon and heated to
85-90.degree. C. for 24 hours. The resin was drained and washed
with DMF and DCM alternately several times. The product was cleaved
from the resin through treatment with a TFA/water solution (80:20)
(1.5 ml) for 45 min. The resin was filtered and washed with fresh
TFA/water solution (80:20) (0.5 ml). The combined TFA and organic
fractions were diluted with CH3CN/water (1:1) (10 ml), water (2 ml)
and lyophilized. The crude product was purified by prep. HPLC. The
crude product was dissolved in DMSO (1 ml), passed through a Teflon
syringe filter, and the clear filtrate was injected on a
preparative HPLC. The purification used a 20.times.50 mm Ultro 120
C18 column running a 22 ml/min 2% gradient (AcCN/water, 0.1% TFA)
for 16 min. The purified fractions were lyophilized to dryness to
give 2.2 mg of pure product as the TFA salt (.about.32% yield).
Example 27
Synthesis of
4-[4-(4-Amino-phenyl)-buta-1,3-diynyl]-N-(2-hydroxy-1-hydroxycarbamoyl-pr-
opyl)-benzamide (4)
[0929] ##STR191##
Preparation of
2-{4-[4-(4-Amino-phenyl)-buta-1,3-diynyl]-benzoylamino}-3-tert-butoxycarb-
onyloxy-butyric hydroxamic acid trityl resin (3)
[0930] TABLE-US-00053 ##STR192## ##STR193## ##STR194## Reagent MW
EQ g/ml mmol H-Thr(Boc)-NHO-Trt Resin (1) 1.0 5.8 g 4.47 1,3-diynyl
benzoic acid (2) 261.3 1.4 1.64 g 6.25 HOBT 135.1 1.4 0.85 g 6.25
DIC 126.2 1.4 0.98 ml 6.25 DIEA 129.25 3.5 2.7 ml 15.6 DMF 50
ml
[0931] DIEA (2.7 ml, 15.6 mmol) was added to a stirred solution of
4-[4-(4-Amino-phenyl)-buta-1,3-diynyl]-benzoic acid (2) (1.64 g,
6.3 mmol), HOBT (0.85 g, 6.3 mmol), DIC (0.98 ml, 6.3 mmol) in DMF
(50 ml). After 2 min., the Thr hydroxylamine resin (5.8 g, 4.5
mmol) was added in one portion. [N-Fmoc-hydroxylamine
2-chlorotrityl resin was purchased from Novabiochem
cat#01-64-0165.] After 12 hours at rt, the reaction was found
complete by LCMS. The resin was drained and washed with DMF and DCM
alternately 3 times each. The product on resin 3 was used as is in
subsequent reactions without further treatment.
Preparation of
4-[4-(4-Amino-phenyl)-buta-1,3-diynyl]-N-(2-hydroxy-1-hydroxy
carbamoyl-propyl)-benzamide (4)
[0932] TABLE-US-00054 ##STR195## ##STR196## Reagent MW EQ g/ml mmol
1,3-diynyl benzoic Thr Resin (3) 1.0 120 mg 0.09 TFA/water (80:20)
1.5 ml
[0933] The product (4) (120 mg, 0.09 mmol) was cleaved from the
resin through treatment with a TFA/water solution (80:20) (1.5 ml)
for 45 min. The resin was filtered and washed with fresh TFA/water
solution (80:20) (0.5 ml). The combined TFA and organic fractions
were diluted with CH3CN/water (1:1) (10 ml), water (2 ml) and
lyophilized. The crude product was purified by prep. HPLC. The
crude product was dissolved in DMSO (1 ml), passed through a Teflon
syringe filter, and the clear filtrate was injected on a
preparative HPLC. The purification used a 20.times.50 mm Ultro 120
C18 column running a 22 ml/min 2% gradient (AcCN/water, 0.1% TFA)
for 16 min. The purified fractions were lyophilized to dryness to
give 2.2 mg of pure product as the TFA salt. The product (4) was
lyophilized again from CH.sub.3CN/water with 10 equivalents of HCl
to remove most of the TFA to yield 2 mg of product as the HCl salt
(.about.53% yeild).
Example 28
Synthesis of
4-{4-[4-(2-Dimethylamino-acetylamino)-phenyl]-buta-1,3-diynyl}-N-(2-hydro-
xy-1-hydroxycarbamoyl-propyl)benzamide (6) (Continued from compound
3 of Example 27 above)
[0934] ##STR197##
Preparation of
2-(4-{4-[4-(2-Bromo-acetylamino)-phenyl]-buta-1,3-diynyl}-benzoylamino)-3-
-tert-butoxycarbonyloxy-butyric acid hydroxamate trityl resin
(5)
[0935] TABLE-US-00055 ##STR198## ##STR199## Reagent MW EQ g/ml mmol
Amino 1,3-diynyl benzoic Thr Trt Resin (3) 1.0 0.75 g 0.578
Bromo-acetyl chloride 157.4 8.0 0.728 g 4.62 Lutidine 107 10.0 1.07
ml 9.24 DMF 6 ml
[0936] A solution of bromo-acetyl chloride (0.75 g, 0.58 mmol) in
DCM (2 ml) was added to a mixture of
2-{4-[4-(4-Amino-phenyl)-buta-1,3-diynyl]-benzoylamino}-3-tert-butoxycarb-
onyloxy-butyric acid hydroxamate Trt Resin (3) (0.75 g, 0.58 mmol),
lutidine (1.1 ml, 9.2 mmol) and DCM (4 ml) at rt with shaking.
After shaking for 1.5 hours, the reaction was found complete by
LCMS. The resin was drained and washed with DCM (2.times.10 ml),
DMF (3.times.10 ml) and DCM (3.times.10 ml) again. The resin was
drained and dried in vacuo. The product on resin 5 was used as is
in subsequent reactions without further treatment.
Preparation of
4-{4-[4-(2-Dimethylamino-acetylamino)-phenyl]-buta-1,3-diynyl}-N-(2-hydro-
xy-1-hydroxycarbamoyl-propyl)-benzamide (6)
[0937] TABLE-US-00056 ##STR200## ##STR201## Reagent MW EQ g/ml mmol
Bromo acetic Thr Trt Resin (5) 1.0 125 mg 0.093 Dimethyl amine
45.08 0.2 ml excess NMP 1.2 ml
[0938] A solution of dimethyl amine (0.2 ml) in NMP (1.2 ml) was
added to bromo acetic Thr Trt Resin (5) (125 mg, 0.09 mmol) at rt
with shaking. After shaking for 12 hours, the reaction was found
complete by LCMS. The resin was drained and washed with DCM
(2.times.10 ml), DMF (3.times.10 ml) and DCM (3.times.10 ml) again.
The product (6) was cleaved from the resin through treatment with a
TFA/water solution (80:20) (1.5 ml) for 45 min. The resin was
filtered and washed with fresh TFA/water solution (80:20) (0.5 ml).
The combined TFA and organic fractions were diluted with
CH3CN/water (1:1) (10 ml), water (2 ml) and lyophilized. The crude
product was purified by prep. HPLC. The crude product was dissolved
in DMSO (1 ml), passed through a Teflon syringe filter, and the
clear filtrate was injected on a preparative HPLC. The purification
used a 20.times.50 mm Ultro 120 C18 column running a 22 ml/min 2%
gradient (AcCN/water, 0.1% TFA) for 16 min. The purified fractions
were lyophilized to dryness to give 2 mg of pure product as the TFA
salt (.about.37% yeild).
Example 29
Synthesis of
4-{4-[4-(2-Amino-4-methyl-pentanoylamino)-phenyl]-buta-1,3-diynyl}-N-(2-h-
ydroxy-1-hydroxycarbamoyl-propyl)-benzamide (7) (Continued from
compound 3 of Example 27 above)
[0939] TABLE-US-00057 ##STR202## ##STR203## Reagent MW EQ g/ml mmol
Amino 1,3-diynyl benzoic Thr Trt Resin (3) 1.0 125 mg 0.093
Fmoc-L-leucine 353.42 4.0 0.135 g 0.384 HATU 380 4.0 0.146 g 0.384
DIEA 129.25 8.0 133 ul 0.768 DMF 1.5 ml
[0940] A solution of Fmoc-L-leucine (0.135 g, 0.38 mmol), HATU
(0.146 g, 0.38 mmol) in DMF (1.5 ml) was made. After 2 min. of
shaking, the activated acid was added to the amino 1,3-diynyl
benzoic Thr Trt Resin (3) (125 mg, 0.09 mmol) at rt with shaking.
After shaking for 36 hours, the reaction was drained and washed
with DCM (2.times.4 ml), DMF (3.times.4 ml) and DCM (3.times.4 ml)
again. The resin was treated with 20% piperizine in DMF (4 ml) for
2 hours twice. The resin was drained and washed with DMF and DCM
alternately several times. The product was cleaved from the resin
through treatment with a TFA/water solution (80:20) (1.5 ml) for 45
min. The resin was filtered and washed with fresh TFA/water
solution (80:20) (0.5 ml). The combined TFA and organic fractions
were diluted with CH3CN/water (1:1) (10 ml), water (2 ml) and
lyophilized. The crude product was purified by prep. HPLC. The
crude product was dissolved in DMSO (1 ml), passed through a Teflon
syringe filter, and the clear filtrate was injected on a
preparative HPLC. The purification used a 20.times.50 mm Ultro 120
C18 column running a 22 ml/min 2% gradient (AcCN/water, 0.1% TFA)
for 16 min. The purified fractions were lyophilized to dryness to
give 1.7 mg of pure product (7) as the TFA salt (.about.30%
yield).
Examples 30-1307
Of Table 1 were Synthesized According to the Synthetic Schemes
Described Above
Biological Protocols and Data
P. aeruginosa LpxC Inhibition Assay
[0941] The assay followed the general method of Hyland et al
(Journal of Bacteriology 1997 179, 2029-2037: Cloning, expression
and purification of UDP-3-O-acyl-GlcNAc deacetylase from
Pseudomonas aeruginosa: a metalloamidase of the lipid A
biosynthesis pathway) and the radiolabeling procedure is according
to Kline et al. supra. Briefly, samples were incubated with 2 nM P.
aeruginosa LpxC and 150 nM
[3H--Ac]--UDP-3-O--(R-3-hydroxydecanoyl)-GlcNAc in a total volume
of 50 uL for 90 min at room temperature. Reactions were carried out
in 96-well polypropylene plates in 50 mM sodium phosphate buffer,
pH 7.5, containing 1 mg/mL BSA. Reactions were stopped by the
addition of 180 uL of a 3% suspension of activated charcoal powder
in 100 mM sodium acetate, pH 7.5. Supernatants were clarified by
centrifugation. A portion of the clarified supernatant, containing
the enzymatically released [3H]-acetate, was transferred to opaque
white 96-well plates containing scintillation fluid. The
radioactivity was measured in a Perkin-Elmer/Wallac Trilux
Microbeta counter. Control reactions to which 5 mM EDTA had been
added were included with each run to determine nonspecific tritium
release.
Bacterial Screens and Cultures
[0942] Bacterial isolates were cultivated from -70.degree. C.
frozen stocks by two consecutive overnight passages at 35.degree.
C. in ambient air on 5% blood agar (Remel, Lenexa, Kans.). Clinical
isolates tested were from a collection composed of isolates
collected during clinical trials and recent clinical isolates
obtained from various geographically diverse hospitals in the US.
Quality control and primary panel strains were from the American
Type Culture Collection (ATCC; Rockville, Md.), with the exception
of P. aeruginosa PAO200, a strain with a deletion of the mexABoprM
genes that was received from Dr. H. Schweizer. This strain does not
express the principal multidrug efflux pump and is hypersusceptible
to many antibacterials. Strain Z61 (ATCC 35151) is also
hypersusceptible to antibacterials. It is thought that the
hypersusceptibility of this strain is the result of increased
permeability of its outer membrane (Angus B L et al, Antimicrobial
Agents and Chemotherapy 1982 21, 299-309: Outer membrane
permeability in Pseudomonas aeruginosa: Comparison of a wild-type
with an antibacterial-supersusceptible mutant).
Susceptibility Testing
[0943] Minimum Inhibitory Concentrations (MICs) were determined by
the broth microdilution method in accordance with the National
Committee for Clinical Laboratory Standards (NCCLS) guidelines. In
brief, organism suspensions were are adjusted to a 0.5 McFarland
standard to yield a final inoculum between 3.times.10.sup.5 and
7.times.10.sup.5 colony-forming units (CFU)/mL. Drug dilutions and
inocula were made in sterile, cation adjusted Mueller-Hinton Broth
(Remel). An inoculum volume of 100 .mu.l was added to wells
containing 100 .mu.l of broth with 2-fold serial dilutions of drug.
All inoculated microdilution trays were incubated in ambient air at
35.degree. C. for 18-24 hours. Following incubation, the lowest
concentration of the drug that prevented visible growth was
recorded as the MIC. Performance of the assay was monitored by the
use of laboratory quality-control strains against tobramycin, that
has a defined MIC spectrum, in accordance with NCCLS
guidelines.
Efficacy in Mouse Model of Systemic Pseudomonas aeruginosa
Infection
[0944] Female Balb/c mice were injected intraperitoneally with 0.5
ml of a bacterial suspension containing approximately 100 times the
dose that would kill 50% of animals (LD.sub.50) of P. aeruginosa
strain PAO1 or E. coli ATCC 25922. At one and five hours post
infection, the test compound was injected intravenously in doses
ranging from 5 mg/kg to 100 mg/kg, five mice per group. Mice were
observed for 5 days, and the dose of compound resulting in survival
of 50% of mice (ED.sub.50) was calculated.
Drug Combination (Synergy) Studies
I. Principle
[0945] Checkerboard experiments can be performed to assess
potential interactions between primary drug of interest (#1) and
other related antibacterials (#2). P. aeruginosa ATCC 27853, S.
aureus ATCC 29213 and other organisms can be used as challenge
strains as well as selected clinical isolates. Broth microdilution
format can be used to assess the activity of drug #1 and test
compound alone and in combination. Two-fold dilutions of the two
compounds to be tested (each bracketing the expected MIC value) are
used. The fractional inhibitory concentration (FIC) was calculated
as the MIC of compound #1 in combination with a second compound,
divided by the MIC of compound #1 alone. A summation FIC
(.SIGMA.FIC) was computed for each drug combination as the sum of
the individual FICs of compound #1 and #2. Synergy was defined as
an .SIGMA.FIC.ltoreq.0.5, indifference as an .SIGMA.FIC between 0.5
and 4, and antagonism as .SIGMA.FIC>4. The lowest .SIGMA.FIC was
used for the final interpretation of drug combination studies.
Interpretation of Summation (.SIGMA.FIC)
[0946] a) Synergism, x.ltoreq.0.5
[0947] b) Indifference, 0.5<x.ltoreq.4
[0948] c) Antagonism, x>4 TABLE-US-00058 TABLE 2 Demonstration
of Antibacterial activity of Select Compounds from Table 1 Enzyme
inhibitory activity Compound Example # IC.sub.50 (nM) 12 <100 nM
572 <100 nM 481 <100 nM 19 <100 nM 516 <100 nM 280
<100 nM 366 <100 nM 777 <100 nM 315 <100 nM 779 <100
nM 860 <100 nM 801 <100 nM 13 <100 nM
[0949] TABLE-US-00059 TABLE 3 Antibacterial activity vs standard
panel of organisms (MIC, .mu.g/ml). Bacterial strain: Compound P.
aeruginosa E. coli S. aureus hyper-permeable P. aeruginosa Example
# 27853 25922 29213 P. aerug. 35151 PAO200 mexAB 12 A A C A A 572 A
A C A A 481 A A C A A 19 A A B A A 516 A A C A A 280 A A C A A 366
A A C A A 777 A A C A A 315 A A C A A 779 A A C A A 860 A A C A A
801 A A C A A 13 A A C AA A MIC Key MIC's of 6.25 ug/ml or less = A
MIC's of greater than 6.25 ug/ml to 50 ug/ml = B MIC's of greater
than 50 ug/ml = C
[0950] TABLE-US-00060 TABLE 4 Antibacterial activity vs cystic
fibrosis isolates of Pseudomonas aeruginosa (MIC, .mu.g/ml).
Strains have the following phenotypes: 3198 and 3236, sensitive to
most antibacterials; 2196, resistant to ciprofloxacin; 3224,
resistant to ceftazidime; 3317, resistant to aztreonam; 1145 and
3206, multi-drug resistant. Strain number: 3198 3236 2196 3224 3232
3317 1145 3206 Phenotype: LpxC inhibitors Sensitive Sensitive Cipro
R Tobra R Ceftaz. R Aztr. R MDR MDR 12 A A B A A A A A 481 A A A A
A A A A 19 A A A A A A A A 516 A A A A A A A A 280 A A B A A A A A
366 A A A A A A A A 777 A A A A A A A A 315 A A A A A A A A 779 A A
A A A A A A 801 A A A A A A A A 13 A A A A A A A A Comparator
antibacterials Tobramycin 2 0.5 2 64 1 2 8-32 64 Aztreonam 1 0.5 1
1 1 64 >128 >128 Ceftazidime 2 0.25 2 2 64 4 >128 >128
Cefepime 4 2 2 8 2 8 >128 32 Ciprofloxacin 1 0.06 >8 2 2 0.5
4 >8 MIC Key MIC's of 6.25 ug/ml or less = A MIC's of greater
than 6.25 ug/ml to 50 ug/ml = B MIC's of greater than 50 ug/ml =
C
[0951] TABLE-US-00061 TABLE 5 Antibacterial activity vs non-CF
clinical isolates of P. aeruginosa and vs other gram- negative
pathogens. Set 1: non-fermenting organisms. P. aer., P. aeruginosa;
Acinet. calc., Acinetobacter calcoaceticus; Alcal. xyl.,
Alcaligenes xylosoxidans; B. cep., Burkholderia cepacia; S. malt.,
Stenotrophomonas maltophilia Species: LpxC inhibitors P. aer 27853
P. aer. PAO1 P. aer 12307 P. aer psa-6b Acinet. calc. Alcal. xyl B.
cepacia S. malt. 12 A A A A A A B A 481 A A A A C C B C 19 A A A A
A B B B 516 A A A C C C C 280 A A A A C B B B 366 A A A B C A B B
777 A A B A B A C 315 A A A A C B A A 779 A A A C A A B 801 A A A B
C B C 13 A A A C A A B Comparator antibacterials Tobramycin 8 2 2
64 64/>128 0.5 Aztreonam 16 32 32 32 64 >128/16 Ceftazidime 4
64 16 1 8/4 1 Cefepime 2 8 8 8 32/16 8/1 Meropenem 0.5 0.25 4 0.5 4
64 Pip/Tazo 4 >128 8 1 64 16 Ciprofloxacin 0.5 2 0.5 0.5 MIC Key
MIC's of 6.25 ug/ml or less = A MIC's of greater than 6.25 ug/ml to
50 ug/ml = B MIC's of greater than 50 ug/ml = C
[0952] TABLE-US-00062 TABLE 6 Antibacterial activity vs non-CF
clinical isolates of P. aeruginosa and vs other gram- negative
pathogens, continued. Set 2: enteric organisms. E. aer.,
Enterobacter aerogenes; E. clo., Enterobacter cloacae; E. coli,
Escherichia coli; K. pneu., Klebsiella pneumoniae; K. oxy.,
Klebsiella oxytoca; P. mir., Proteus mirabilis; S. marc., Serratia
marcescens. Species: LpxC inhibitors E. aer. E. clo. E. coli 1619
E. coli 2788 K. pneu. K. oxy. P. mir. S. marc. 12 C A A A A A A A
481 C A A A A A A A 19 A A A A A A A A 516 C B A B C C C A 280 C A
A A B C B B 366 C A A A B B A A 777 B A A A A A A A 315 C A A A C C
C B 779 C A A A B B B A 801 B A A A A A A A 13 C A A A A A A A
Comparator antibacterials Tobramycin 64 0.06 16/64 0.06/2 64 1 2 2
Aztreonam <=0.13 128/64 <=0.13/0.25 2 0.5 <=0.13 <=0.13
Ceftazidime 32 0.25 >128 0.25/<=0.13 8 0.25 <=0.13 0.25
Cefepime <=0.13 4/<=0.13 <=0.13 8 <=0.13 <=0.13
<=0.13 Meropenem 2 <=0.06 0.25/0.13 <=0.06 0.13 <=0.06
0.5 0.13 Pip/Tazo 2 >128 1 >128 2 0.25 1 Ciprofloxacin >8
0.015 2 0.03 0.06 0.03 0.03 0.25 MIC Key MIC's of 6.25 ug/ml or
less = A MIC's of greater than 6.25 ug/ml to 50 ug/ml = B MIC's of
greater than 50 ug/ml = C
[0953] TABLE-US-00063 TABLE 7 Drug Combination (Synergy) Studies
Result Minimum Concentration (mg/ml) required to inhibit grouth of
E. coli 25922 Erythromycin LpxC inhibitor 925 LpxC inhibitor 925
only -- 6.25 Erythromycin only 128 -- LpxC inhibitor 925 +
erythromycin 2 0.78
[0954] Each of the Example compounds of Table 1 was synthesized and
assayed as described above. Many of the Example compounds 1-1307
displayed an IC.sub.50 value of less than 10 .mu.M with respect to
LpxC. Many of these compounds displayed an IC.sub.50 value of less
than or equal to 1 .mu.M or less than or equal to 0.1 .mu.M. Many
of these compounds exhibited IC.sub.50 values of less than or equal
to 0.050 .mu.M, less than or equal to 0.030 .mu.M, less than or
equal to 0.025 .mu.M, or less than or equal to 0.010 .mu.M.
[0955] 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. TABLE-US-00064 TABLE 1 Example Structure Name MH+ 30
##STR204## 3,4-difluoro-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 275.2 31 ##STR205##
(2S,3R)-N,3-dihydroxy-2-[(4- phenylbutanoyl)amino]butanamide 281.3
32 ##STR206## (2S,3R)-N,3-dihydroxy-2-({4-[4-
(methyloxy)phenyl]butanoyl}amino)butanamide 311.3 33 ##STR207##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-5-
phenylpentanamide 295.3 34 ##STR208##
(2E,4E)-N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-5-
phenylpenta-2,4-dienamide 291.3 35 ##STR209##
(2E)-N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-3-
phenylprop-2-enamide 265.3 36 ##STR210##
(2S,3R)-3-hydroxy-2-({(2E)-3-[4- (methyloxy)phenyl]prop-2-
enoyl}amino)butanoic acid 280.3 37 ##STR211##
(3R)-3-amino-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-5- phenylpentanamide 310.4 38
##STR212## (2E)-3-(4-fluorophenyl)-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}prop-2- enamide 283.3 39 ##STR213##
(2E)-3-(3-bromophenyl)-N-{(1S,2R)-2- hydroxy-2-
[(hydroxyamino)carbonyl]propyl}prop-2- enamide 344.2 40 ##STR214##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[(2-
phenylethyl)amino]methyl}benzamide 372.4 41 ##STR215##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
{[(4-phenylbutyl)amino]methyl}benzamide 400.5 42 ##STR216##
4-[(cyclopropylamino)methyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 308.3 43 ##STR217##
4-[(hexylamino)methyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 352.4 44 ##STR218##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[(2-
pyridin-2-ylethyl)amino]methyl}benzamide 373.4 45 ##STR219##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-(4-
methylpiperazin-1-yl)benzamide 337.4 46 ##STR220##
N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(piperidin- 1-ylmethyl)benzamide
336.4 47 ##STR221## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4- (morpholin-4-ylmethyl)benzamide
338.4 48 ##STR222## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({[3-(2- oxopyrrolidin-1-
yl)propyl]amino}methyl)benzamide 393.5 49 ##STR223##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[(3-
phenylpropyl)amino]methyl}benzamide 386.5 50 ##STR224##
(2S,5R)-N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-5-
phenylpyrrolidine-2-carboxamide 308.3 51 ##STR225##
(2R,5S)-N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-5-
phenylpyrrolidine-2-carboxamide 308.3 52 ##STR226##
(2S,3R)-2-{[(3S)-3-amino-4- phenylbutanoyl]amino}-N,3-
dihydroxybutanamide 296.3 53 ##STR227## (2S,3R)-2-{[(2S)-2-amino-4-
phenylbutanoyl]amino}-N,3- dihydroxybutanamide 296.3 54 ##STR228##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-6-(2-
pyrrolidin-1-ylethyl)pyridine-3-carboxamide 337.4 55 ##STR229##
2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-3-hydroxy-3-methylbutanoic acid 342.4 56
##STR230## 2-{[4-(4-ethylphenyl]carbonylamino}-
3-hydroxy-4-methylpentanoic acid 356.4 57 ##STR231##
{[(4'-ethyl-1,1'-bephenyl-4- yl)carbonyl]amino}(thien-2-yl)acetic
acid 366.5 58 ##STR232##
N-(2-{[(1,1-dimethylethyl)oxy]amino}-2-oxo-
1-thien-2-ylethyl)-4'-ethyl-1,1'-biphenyl-4- carboxamide 437.6 59
##STR233## 3-(dimethylamino)-2-{[(4'-ethyl-1,1'-biphenyl-
4-yl)carbonyl]amino}propanoic acid 341.4 60 ##STR234##
4'-ethyl-N-{(1S)-1-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]-
3-methylbutyl}-1,1'-biphenyl-4- carboxamide 456.6 61 ##STR235##
4'-ethyl-N-[(1S)-2-({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino-2-
oxo-1-(phenylmethyl)ethyl]-1,1'-biphenyl-4-carboxamide 490.6 62
##STR236## (2S)-1-[(4'-ethyl-1,1'-biphenyl-4-yl)carbonyl]-
N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}pyrrolidine-2-carboxamide 440.5 63
##STR237## 4'-ethyl-N-[(1S)-2-({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)-1-
(1H-imidsazol-4-ylmethyl)-2-oxoethyl]-1,1'- biphenyl-4-carboxamide
480.5 64 ##STR238## (3S)-[(4'-ethyl-1,1'-biphenyl-4-yl)carbonyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-1,2,3,4-
tetrahydroisoquinoline-3-carboxamide 502.6 65 ##STR239##
(2S)-2-[(1,1'-biphenyl-4-ylacetyl)amino]-N-
{(hydroxyamino)carbonyl]propyl}-4- methylpentanamide 442.5 66
##STR240## (2S,3R)-2-({(2S)-2-[(1,1'-biphenyl-4-
ylacetyl)amino]-3-phenylpropanoyl}amino)-N,3-dihydroxybutanamide
476.5 67 ##STR241## (2S,3R)-2-{[(2S)-2-[(1,1'-biphenyl-4-
ylacetyl)amino]-3-(4- hydroxyphenyl)propanoyl]amino}-N,3-
dihydroxybutanamide 492.5 68 ##STR242##
(2S)-1-(1,1'-biphenyl-4-ylacetyl)-N-{(1S,2R)- 2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}pyrrolidine- 2-carboxamide 426.5 69
##STR243## (2S,3R)-2-{[(2S)-2-[(1,1'-biphenyl-4-
ylacetyl)amino]-3-(1H-imidazol-4- yl)propanoyl]amino}-N,3-
dihydroxybutanamide 466.5 70 ##STR244##
(2S)-2-[(1,1'-biphenyl-4-ylacetyl)amino]-
N.about.1.about..about.{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}pentanediamide 457.5 71 ##STR245##
(3S)-3-[(1,1'-biphenyl-4-ylacetyl)amino]-4- ({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)-4- oxobutanoic acid 444.5 72
##STR246## (2S,4R)-1-[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]-4-hydroxy-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}pyrrolidine- 2-carboxamide 456.5 73
##STR247## N-[(1S)-1-(aminomethyl)-2-({(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)-2-
oxoethyl]-4'-ethyl-1,1'-biphenyl-4- carboxamide 429.5 74 ##STR248##
4'-ethyl-N-{(1S)-1-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]but-
3-ynyl)-1,1'-biphenyl-4-carboxamide 438.5 75 ##STR249##
(2S,3R)-2-({(2S)-2-[(1,1'-biphenyl-4-
ylacetyl)amino]propanoyl}amino)-N,3-dihydroxybutanamide 400.4 76
##STR250## (2S,4R)-1-(1,1'-biphenyl-4-ylacetyl)-4-
hydroxy-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}pyrrolidine-2-carboxamide 442.5 77
##STR251## 4'-ethyl-N-{(1R,2R)-2-hydroxy-1- [(hydroxy{[(2-
hydroxyethyl)amino]carbonyl}amino)methyl]propyl}-
1,1'-biphenyl-4-carboxamide 416.5 78 ##STR252##
N-((2R,3R)-2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-3-hydroxybutyl)-N-
hydroxymorpholine-4-carboxamide 442.5 79 ##STR253##
N-((2R,3R)-2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-3-hydroxybutyl)-N-
hydroxy-4-methylpiperazine-1-carboxamide 455.6 80 ##STR254##
N-((1R,2R)-1- {[[(cyclopropylamino)carbonyl](hydroxy)amino]methyl}-
2-hydroxypropyl)-4'-ethyl-1,1'-biphenyl-4-carboxamide 412.5 81
##STR255## 4'-ethyl-N-{(1R,2R)-2-hydroxy-1- [(hydroxy{[(pyridin-3-
ylmethyl)amino]carbonyl}amino)methyl]propyl}-
1,1'-biphenyl-4-carboxamide 463.5 82 ##STR256##
4'-ethyl-N-{(1R,2R)-2-hydroxy-1- [(hydroxy{[(2-pyridin-2-
ylethyl)amino]carbonyl}amino)methyl]propyl}-
1,1'-biphenyl-4-carboxamide 477.6 83 ##STR257##
4'-ethyl-N-{(1R,2R)-2-hydroxy-1- [(hydroxy{[(4-morpholin-4-
ylphenyl)amino]carbonyl}amino)methyl]propyl}-
1,1'-biphenyl-4-carboxamide 533.6 84 ##STR258##
N.about.1.about..about.((2R,3R)-2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-3-hydroxybutyl)-N.about.1.about..about.hydroxypiperidi-
ne-1,4-dicarboxamide 483.6 85 ##STR259##
4'-ethyl-N-[2-(hydroxyamino)ethyl]-1,1'- biphenyl-4-carboxamide
285.4 86 ##STR260## N-{2-[(aminocarbonyl)(hydroxy)amino]ethyl}-
4'-ethyl-1,1'-biphenyl-4-carboxamide 328.4 87 ##STR261## N-{2-
[(aminocarbonothioyl)(hydroxy)amino]ethyl}-
4'-ethyl-1,1'-biphenyl-4-carboxamide 344.4 88 ##STR262##
N-{2-[({[2-
(dimethylamino)ethyl]amino)carbonyl)(hydroxy)amino]ethyl}-
4'-ethyl-1,1'-biphenyl-4- carboxamide 399.5 89 ##STR263##
N-{2-[{[(2- cyanoethyl)amino]carbonyl}(hydroxy)amino]ethyl}-
4'-ethyl-1,1'-biphenyl-4-carboxamide 381.4 90 ##STR264##
4'-ethyl-N-[2-(hydroxy{[(2-
hydroxyethyl)amino]carbonyl}amino)ethyl]-
1,1'-biphenyl-4-carboxamide 372.4 91 ##STR265##
N-(2-{[(4'-ethyl-1,1'-biphenyl-4- yl)carbonyl]amino}ethyl)-N-
hydroxymorpholine-4-carboxamide 398.5 92 ##STR266##
N-(2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}ethyl)-N-hydroxy-4-
methylpiperazine-1-carboxamide 411.5 93 ##STR267##
N.about.1.about..about.(2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}ethyl)-N.about.1.about..about.hydroxypiperidine-1,4-dic-
arboxamide 439.5 94 ##STR268## N-(2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}ethyl)-N- hydroxypyrrolidine-1-carboxamide 382.5
95 ##STR269## N-{2-
[[(cyclopropylamino)carbonyl](hydroxy)amino]ethyl}-
4'-ethyl-1,1'-biphenyl-4-carboxamide 368.4 96 ##STR270##
4'-ethyl-N-{2-[hydroxy({[2-
(methyloxy)ethyl]amino}carbonyl)amino]ethyl}-
1,1'-biphenyl-4-carboxamide 386.5 97 ##STR271## N-{2-[({[2-
(acetylamino)ethyl]amino}carbonyl)(hydroxy)amino]ethyl}-
4'-ethyl-1,1'-biphenyl-4- carboxamide 413.5
98 ##STR272## 4'-ethyl-N-{2-[hydroxy({[3-(2-oxopyrrolidin-1-
yl)propyl]amino}carbonyl)amino]ethyl}-1,1'- biphenyl-4-carboxamide
453.6 99 ##STR273## 4'-ethyl-N-[2-(hydroxy{[(3-
hydroxypropyl)amino]carbonyl}amino)ethyl]-
1,1'-biphenyl-4-carboxamide 386.5 100 ##STR274##
4'-ethyl-N-{2-[hydroxy({[3-
(methyloxy)propyl]amino}carbonyl)amino]ethyl}-
1,1'-biphenyl-4-carboxamide 400.5 101 ##STR275##
N-(2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}ethyl)-N-hydroxy-1,4'-
bipiperidine-1'-carboxamide 479.6 102 ##STR276##
4'-ethyl-N-[2-(hydroxy{[(2-pyridin-2-
ylethyl)amino]carbonyl}amino)ethyl]-1,1'- biphenyl-4-carboxamide
433.5 103 ##STR277## 4'-ethyl-N-[2-(hydroxy{[(pyridin-3-
ylmethyl)amino]carbonyl}amino)ethyl]-1,1'- biphenyl-4-carboxamide
419.5 104 ##STR278## 4'-ethyl-N-[2-(hydroxy{[(4-morpholin-4-
ylphenyl)amino]carbonyl}amino)ethyl]-1,1'- biphenyl-4-carboxamide
489.6 105 ##STR279## N-(2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}ethyl)-N,3- dihydroxypiperidine-1-carboxamide
412.5 106 ##STR280## N-{2-[{[(3-
aminocyclohexyl)amino]carbonyl}(hydroxy)amino]ethyl}-
4'-ethyl-1,1'-biphenyl-4- carboxamide 425.5 107 ##STR281##
N-{2-[{[(2- aminoethyl)amino]carbonyl}(hydroxy)amino]ethyl}-
4'-ethyl-1,1'-biphenyl-4-carboxamide 371.4 108 ##STR282##
N-{2-[{[(3- aminopropyl)amino]carbonyl}(hydroxy)amino]ethyl}-
4'-ethyl-1,1'-biphenyl-4-carboxamide 385.5 109 ##STR283##
1,1-dimethylethyl 3-({[(2-{[(4'-ethyl-1,1'- biphenyl-4-
yl)carbonyl]amino}ethyl)(hydroxy)amino]carbonyl}amino)propyl-
carbamate 485.6 110 ##STR284## 4'-ethyl-N-{2-[({[(4-
fluorophenyl)methyl]amino}carbonyl)(hydroxy)amino]ethyl}-
1,1'-biphenyl-4-carboxamide 436.5 111 ##STR285##
N-(2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}ethyl)-N-hydroxy-3-
[(trifluoroacetyl)amino]pyrrolidine-1- carboxamide 493.5 112
##STR286## N-{2-[{[(4-aminothien-3-
yl)amino]carbonyl}(hydroxy)amino]ethyl}-4'-
ethyl-1,1'-biphenyl-4-carboxamide 425.5 113 ##STR287##
4'-ethyl-N-(2-{hydroxy[(piperidin-3-
ylamino)carbonyl]amino}ethyl)-1,1'-biphenyl- 4-carboxamide 411.5
114 ##STR288## 4'-ethyl-N-(2-{hydroxy[(piperidin-4-
ylamino)carbonyl]amino}ethyl)-1,1'-biphenyl- 4-carboxamide 411.5
115 ##STR289## 4'-ethyl-N-[2-(hydroxy{[(piperidin-2-
ylmethyl)amino]carbonyl}amino)ethyl]-1,1'- biphenyl-4-carboxamide
425.5 116 ##STR290## 4'-ethyl-N-[2-(hydroxy{[(piperidin-3-
ylmethyl)amino]carbonyl}amino)ethyl]-1,1'- biphenyl-4-carboxamide
425.5 117 ##STR291## 3-amino-N-(2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}ethyl)-N- hydroxypyrrolidine-1-carboxamide 397.5
118 ##STR292## 1,1-dimethylethyl-3-[({[(2-{[(4'-ethyl-1,1'-
biphenyl-4-
yl)carbonyl]amino}ethyl)(hydroxy)amino]carbonyl}amino)meth-
yl]piperidine- 1-carboxylate 525.7 119 ##STR293## 1,1-dimethylethyl
1-{[(2-{[(4'-ethyl-1,1'- biphenyl-4-
yl)carbonyl]amino}ethyl)(hydroxy)amino]carbonyl}pyrrolidin-
3-ylcarbamate 497.6 120 ##STR294##
4'-ethyl-N-[(1S,2R)-2-hydroxy-1-({[2-
(hydroxyamino)ethyl]amino}carbonyl)propyl]-
1,1'-biphenyl-4-carboxamide 386.5 121 ##STR295## N-{(1S,2R)-1-[({2-
[(aminocarbonyl)(hydroxy)amino]ethyl}amino)carbonyl]-
2-hydroxypropyl}-4'-ethyl-1,1'- biphenyl-4-carboxamide 429.5 122
##STR296## N-{(1S,2R)-1-[({2-
[(aminocarbonathioyl)(hydroxy)amino]ethyl}amino)carbonyl]-
2-hydroxypropyl}-4'-ethyl-1,1'- biphenyl-4-carboxamide 445.6 123
##STR297## 4'-ethyl-N-[(1S,2R)-2-hydroxy-1-({[2- (hydroxy{[(2-
hydroxyethyl)amino]carbonyl}amino)ethyl]amino}carbonyl)propyl]-
1,1'-biphenyl-4- carboxamide 473.5 124 ##STR298##
4'-ethyl-N-{(1S)-6-hydroxy-1-[(1R)-1-
hydroxyethyl]-2,7-dioxo-11-oxa-3,6,8-
triazadodec-1-yl}-1,1'-biphenyl-4- carboxamide 487.6 125 ##STR299##
4'-ethyl-N-{(1S)-6-hydroxy-1-[(1R)-1-
hydroxyethyl]-11-methyl-2,7-dioxo-3,6,8,11-
tetraazadodec-1-yl}-1,1'-biphenyl-4- carboxamide 500.6 126
##STR300## 4'-ethyl-N-{(1S)-6-hydroxy-1-[(1R)-1-
hydroxyethyl]-2,7,12-trioxo-3,6,8,11-
tetraazatridec-1-yl}-1,1'-biphenyl-4- carboxamide 514.6 127
##STR301## 4'-ethyl-N-{(1S,2R)-2-hydroxy-1-[({2-
[hydroxy({[3-(2-oxopyrrolidin-1-
yl)propyl]amino}carbonyl)amino]ethyl}amino)carbonyl]propyl}-
1,1'-biphenyl-4-carboxamide 554.7 128 ##STR302##
N-{(1S,2R)-1-[({2-[{[(2-
cyanoethyl)amino]carbonyl}(hydroxy)amino]ethyl}amino)carbonyl]-
2-hydroxypropyl}-4'- ethyl-1,1'-biphenyl-4-carboxamide 482.6 129
##STR303## N-{(1S,2R)-1-[({2-
[[(cyclopropylamino)carbonyl](hydroxy)amino]ethyl}amino)carbonyl]-
2-hydroxypropyl}-4'- ethyl-1,1'-biphenyl-4-carboxamide 469.6 130
##STR304## N-{2-[((2S,3R)-2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-3- hydroxybutanoyl)amino]ethyl}-N-
hydroxypyrrolidine-1-carboxamide 483.6 131 ##STR305##
N-{2-[((2S,3R)-2-{[(4'-ethyl-1,1'-biphenyl-4- yl)carbonyl]amino}-3-
hydroxybutanoyl)amino]ethyl}-N- hydroxymorpholine-4-carboxamide
499.6 132 ##STR306## N-{2-[((2S,3R)-2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-3- hydroxybutanoyl)amino]ethyl}-N-hydroxy-4-
methylpiperazine-1-carboxamide 512.6 133 ##STR307##
4'-ethyl-N-[(1S,2R)-2-hydroxy-1-({[2- (hydroxy{[(pyridin-3-
ylmethyl)amino]carbonyl}amino)ethyl]amino}carbonyl)propyl]-
1,1'-biphenyl-4-carboxamide 520.6 134 ##STR308##
4'-ethyl-N-[(1S,2R)-2-hydroxy-1-({[2- (hydroxy{[(2-pyridin-2-
ylethyl)amino]carbonyl}amino)ethyl]amino}carbonyl)propyl]-
1,1'-biphenyl-4-carboxamide 534.6 135 ##STR309## ##STR310##
##STR311## 3-chloro-N-{(1S,2S)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(trifluoromethyl)oxy]benzamide
357.7 136 ##STR312## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[(3-
nitrophenyl)methyl]oxy}benzamide 390.4 137 ##STR313##
(4R)-2-(4-fluoro-3-prop-2-enylphenyl)-N-
hydroxy-4,5-dihydro-1,3-oxazole-4- carboxamide 265.3 138 ##STR314##
3-fluoro-N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
(methyloxy)benzamide 287.3 139 ##STR315##
4-(but-3-enyloxy)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 309.3 140 ##STR316##
3-bromo-5-fluoro-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(prop-2- enyloxy)benzamide 392.2
141 ##STR317## 4-fluoro-N-{(1S,2S)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-3-prop-2- enylbenzamide 297.3 142
##STR318## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(prop-2-
enyloxy)-3-(trifluoromethyl)benzamide 363.3 143 ##STR319##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
(methyloxy)benzamide 269.3 144 ##STR320## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-3- (phenyloxy)benzamide 331.3 145
##STR321## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4- (methyloxy)-3-
[(trifluoromethyl)oxy]benzamide 353.3 146 ##STR322##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
[(trifluoromethyl)oxy]benzamide 323.2 147 ##STR323##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
[(trifluoromethyl)oxy]benzamide 323.2 148 ##STR324##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
(trifluoromethyl)benzamide 307.2 149 ##STR325##
3,4-difluoro-N-{(2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 275.2 150 ##STR326##
N-{(1S,2S)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
(methyloxy)benzamide 269.3 151 ##STR327## N-{(1S,2S)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4'-propyl-
1,1'-biphenyl-4-carboxamide 357.4 152 ##STR328##
N-{(1S,2S)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4'-propyl-
1,1'-biphenyl-4-carboxamide 357.4 153 ##STR329##
N-{(1S,2S)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
[trifluoro(methylidene)-lambda.about.6.about..about.sulfanyl]benzamide
341.3 154 ##STR330## N-{(1S,2S)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 239.2 155 ##STR331##
N-{(1S,2S)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-1,1'-
biphenyl-4-carboxamide 315.3 156 ##STR332##
3-bromo-N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
(methyloxy)benzamide 348.2 157 ##STR333##
4-fluoro-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-3-(prop-2- enyloxy)benzamide 313.3
158 ##STR334## 2,3,5,6-tetrafluoro-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-prop-2- enylbenzamide 351.3 159
##STR335## 3-fluoro-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-5-(trifluoromethyl)benzamide 325.2
160 ##STR336## 4-bromo-2-fluoro-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 336.1 161 ##STR337##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
(phenyloxy)benzamide 331.3 162 ##STR338##
4-(dimethylamino)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 282.3 163 ##STR339##
2-[3-fluoro-4-(methyloxy)-5-prop-2-
enylphenyl]-N-hydroxy-4,5-dihydro-1,3- oxazole-4-carboxamide 295.3
164 ##STR340## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-5-[3-
(trifluoromethyl)phenyl]furan-2-carboxamide 373.3 165 ##STR341##
4-{[(1E)-1,2-difluorobuta-1,3-dienyl]oxy}-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 343.3 166 ##STR342##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}quinoline-2-
carboxamide 290.3 167 ##STR343##
N-[2-(hydroxyamino)-1-(hydroxymethyl)-2-
oxoethyl]-1,1'-biphenyl-4-carboxamide 301.3 168 ##STR344##
N-{(1S,2S)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-1,1'-
biphenyl-4-carboxamide 315.3
169 ##STR345## N-{(1S,2S)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-2'-methyl-
1,1'-biphenyl-4-carboxamide 329.4 170 ##STR346##
N-{(1S,2S)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
(trifluoromethyl)benzamide 307.2 171 ##STR347##
4-fluoro-N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-3-
(trifluoromethyl)benzamide 325.2 172 ##STR348##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[(3-
nitrophenyl)oxy]methyl}benzamide 390.4 173 ##STR349##
N-[(1R)-2-(hydroxyamino)-1- (mercaptomethyl)-2-oxoethyl]-4-
[(trifluoromethyl)oxo]benzamide 325.3 174 ##STR350##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-1,3-
benzodioxole-5-carboxamide 283.3 175 ##STR351##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-6-
(trifluoromethyl)pyridine-3-carboxamide 308.2 176 ##STR352##
N-{3-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
[(trifluoromethyl)oxy]benzamide 323.2 177 ##STR353##
N-{3-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-1,1'-
biphenyl-4-carboxamide 315.3 178 ##STR354## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4- [hydroxy(phenyl)methyl]benzamide
345.4 179 ##STR355## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[({4-
[(trifluoromethyl)oxy]phenyl}oxy)methyl]benzamide 429.4 180
##STR356## 4-[({4-bromo-2-
[(trifluoromethyl)oxy]phenyl}oxy)methyl]-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 508.3 181 ##STR357##
N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-3'-nitro-1,1'-
biphenyl-4-carboxamide 360.3 182 ##STR358##
4-bromo-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 318.1 183 ##STR359##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4'-
(methyloxy)-1,1'-biphenyl-4-carboxamide 345.4 184 ##STR360##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4'-
[(trifluoromethyl)oxy]-1,1'-biphenyl-4- carboxamide 399.3 185
##STR361## 4'-(ethyloxy)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 359.4
186 ##STR362## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{5-[(Z)-
(hydroxyimino)methyl]thien-2-yl}benzamide 364.4 187 ##STR363##
3'-(ethyloxy)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 359.4
188 ##STR364## (2R,3R)-N,3-dihydroxy-1-({4-
[(trifluoromethyl)oxy]phenyl}carbonyl)pyrrolidine- 2-carboxamide
335.2 189 ##STR365## N-[2-(hydroxamino)-1-(hydroxymethyl)-2-
oxoethyl]-3-(1-methylethyl)-4- (methyloxy)benzamide 297.3 190
##STR366## N-[2-(hydroxamino)-1-(hydroxymethyl)-2-
oxoethyl]-3-(1-methylethyl)-4-(prop-2- enyloxy)benzamide 323.4 191
##STR367## N-[2-(hydroxamino)-1-(hydroxymethyl)-2-
oxoethyl]-4-(methyloxy)-3-propylbenzamide 297.3 192 ##STR368##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4'-
(methylthio)-1,1'-biphenyl-4-carboxamide 361.4 193 ##STR369##
5-bromo-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}thiophene-2- carboxamide 324.2 194
##STR370## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-5-{4-
[(trifluoromethyl)oxy]phenyl}thiophene-2- carboxamide 405.4 195
##STR371## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1- benzofuran-2-carboxamide 279.3
196 ##STR372## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-5- phenylthiophene-2-carboxamide
321.4 197 ##STR373## 4'-(dimethylamino)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 358.4
198 ##STR374## (2S,3R)-N,3-dihydroxy-2-[({2-
[(trifluoromethyl)oxy]phenyl}acetyl)amino]butanamide 337.3 199
##STR375## 5-[4-(ethyloxy)phenyl]-N-{(1S,2R)-2-hydroxy-
1-[(hydroxyamino)carbonyl]propyl}thiophene- 2-carboxamide 365.4 200
##STR376## 5-[3-(ethyloxy)phenyl]-N-{(1S,2R)-2-hydroxy-
1-[(hydroxyamino)carbonyl]propyl}thiophene- 2-carboxamide 365.4 201
##STR377## (4R)-N-hydroxy-2-{2'-[(trifluoromethyl)oxy]-
1,1'-biphenyl-4-yl}-4,5-dihydro-1,3-oxazole-4- carboxamide 367.3
202 ##STR378## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4'-
(hydroxymethyl)-1,1'-biphenyl-4-carboxamide 345.4 203 ##STR379##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{5-[(4-
methylpiperazin-1-yl)methyl]thien-2- yl}benzamide 433.5 204
##STR380## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-
(methyloxy)phenyl]carbonyl}benzamide 373.4 205 ##STR381##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(E)-
phenyldiazenyl]benzamide 343.4 206 ##STR382##
(4R)-N-hydroxy-2-{4-(methyloxy)-3-
[(trifluoromethyl)oxy]phenyl}-4,5-dihydro-1,3-
oxazole-4-carboxamide 321.2 207 ##STR383##
4'-ethyl-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 343.4
208 ##STR384## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4'-
(trifluoromethyl)-1,1'-biphenyl-4-carboxamide 383.3 209 ##STR385##
5-(4-ethylphenyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}thiophene-2- carboxamide 349.4 210
##STR386## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-5-[4-
(methyloxy)phenyl]thiophene-2-carboxamide 351.4 211 ##STR387##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-5-[4-
(methylthio)phenyl]thiophene-2-carboxamide 367.5 212 ##STR388##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-5-(3-
nitrophenyl)thiophene-2-carboxamide 366.4 213 ##STR389##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-oxo-4H-
chromene-2-carboxamide 307.3 214 ##STR390##
N-[1-[(hydroxyamino)carbonyl]-1- (hydroxymethyl)-2-methylpropyl]-4-
[(trifluoromethyl)oxy]benzamide 351.3 215 ##STR391##
N-[2-hydroxy-3-(hydroxyamino)-3-oxopropyl]-
1,1'-biphenyl-4-carboxamide 301.3 216 ##STR392##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(E)-2-
phenylethenyl]benzamide 341.4 217 ##STR393##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-9H-
fluorene-2-carboxamide 327.4 218 ##STR394##
4'-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]-
1,1'-biphenyl-4-carboxylic acid 359.3 219 ##STR395##
N-[2-(hydroxyamino)-1-(hydroxymethyl)-2-
oxoethyl]-4-(prop-2-enyloxy)-3- propylbenzamide 323.4 220
##STR396## N-{(1S,2R)-2-hydroxy-1-
[(hydrxoyamino)carbonyl]propyl}-4- iodobenzamide 365.1 221
##STR397## 4'-hydroxy-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 331.3
222 ##STR398## 6-bromo-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}pyridine-2- carboxamide 319.1 223
##STR399## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-6- phenylpyridine-2-carboxamide
316.3 224 ##STR400## 4'-butyl-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 371.4
225 ##STR401## 4'-dimethylethyl)-N-{(1S,2R)-2-hydroxy-
1-[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide
371.4 226 ##STR402## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-5-[3-
(methyloxy)phenyl]thiophene-2-carboxamide 351.4 227 ##STR403##
4'-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]- 1,1'-biphenyl-4-yl
dihydrogen phosphate 411.3 228 ##STR404##
N-ethyl-N'-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4,4'-dicarboxamide
386.4 229 ##STR405## N-[(1S,2R)-1-(hydrozinocarbonyl)-2-
hydroxypropyl]-4'-propyl-1,1'-biphenyl-4- carboxamide 356.4 230
##STR406## N-{(1S,2R)-2-hydroxy-1-
[(methylamino)carbonyl]propyl}-4'-propyl-1,1'-
biphenyl-4-carboxamide 355.4 231 ##STR407##
N-[(1S,2R)-1-(hydrazinocarbonyl)-2-
hydroxypropyl]-4-(methyloxy)benzamide 268.3 232 ##STR408##
(2S,3R)-2-[(1,1'-biphenyl-4-ylsulfonyl)amino]-
N,3-dihydroxybutanamide 351.4 233 ##STR409##
4-hydroxy-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 255.2 234 ##STR410##
3'-cyano-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 340.3
235 ##STR411## 1,1-dimethylethyl ({4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}oxy)acetate
369.4 236 ##STR412## (2S,3R)-2-[(1,1'-biphenyl-4-
ylsulfonyl)(methyl)amino]-N,3- dihydroxybutanamide 365.4 237
##STR413## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-3'-[(Z)-
(hydroxyimino)methyl]-4'-(methyloxy)-1,1'- biphenyl-4-carboxamide
388.4 238 ##STR414## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4- [(phenylcarbonyl)amino]benzamide
358.4 239 ##STR415## N-hydroxy-2-[3-(1-methylethyl)-4-(prop-2-
enyloxy)phenyl]-4,5-dihydro-1,3-oxazole-4- carboxamide 305.3 240
##STR416## 4'-butyl-N-{(1S,2R)-2-hydroxy-1-
[(methylamino)propyl}-1,1'-biphenyl- 4-carboxamide 369.5 241
##STR417## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(5- methylpyridin-2-yl)benzamide
330.4 242 ##STR418## 5-bromo-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)-carbonyl]propyl}pyridine-3- carboxamide 319.1 243
##STR419## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-pyridin-3- ylbenzamide 316.3
244 ##STR420## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-N'- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4,4'-dicarboxamide
475.5 245 ##STR421## (2S,3R)-N,3-dihydroxy-2-[({4-[(E)-2-
phenylethenyl]phenyl}methyl)amino]butanamide 327.4 246 ##STR422##
4-{[(4-bromophenyl)sulfonyl]amino}-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 473.3 247 ##STR423##
1,1-dimethylethyl 4-({4-[({(1S,2R)-2-hydroxy- 1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}amino)-
4-oxobutylcarbamate 439.5 248 ##STR424##
4-[(4-aminobutanoyl)amino]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 339.4 249 ##STR425##
1,1-dimethylethyl {4'-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)methyl]-
1,1'-biphenyl-4-yl}methylcarbamate 430.5 250 ##STR426##
N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-pyrimidin- 5-ylbenzamide 317.3
251 ##STR427## 1,1-dimethylethyl 5-{4-[({(1S,2R)-2-hydroxy- 1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}pyridine-
3-carboxylate 416.4 252 ##STR428## 5-(4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}pyridine-
3-carboxylic acid 360.3 253 ##STR429##
(4S)-N-hydroxy-2-{4-(methyloxy)-3-
[(trifluoromethyl)oxy]phenyl}-4,5-dihydro-1,3-
oxazole-4-carboxamide 321.2 254 ##STR430##
(2S,3R)-2-({[4'-(aminomethyl)-1,1'-biphenyl-4-
yl]methyl}amino)-N,3-dihydroxybutanamide 330.4 255 ##STR431##
(3S)-1-hydroxy-3-[(1R)-1-hydroxyethyl]-4-({4- [(E)-2-
phenylethenyl]phenyl}methyl)piperazine-2,6- dione 367.4 256
##STR432## (2S,3R)-N,3-dihydroxy-2-({[4-
(phenylethynyl)phenyl]methyl}amino)butanamide 325.4 257 ##STR433##
N-(3-aminopropyl)-N'-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzene-1,4- dicarboxamide 339.4 258
##STR434## N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl}-4-
(propanoylamino)benzamide 310.3 259 ##STR435##
1,1-dimethylethyl-3-[({4-[({(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}carbon-
yl)amino]propylcarbamate 439.5 260 ##STR436##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4'-
(phenyloxy)-1,1'-biphenyl-4-carboxamide 407.4 261 ##STR437##
N-[(1S,2R)-1- ({[cyano(phenyl)methyl]amino}carbonyl)-2-
hydroxypropyl]-4'-hydroxy-1,1'-biphenyl-4- carboxamide 430.5 262
##STR438## 4'-{[2-(hydroxyamino)-2-oxoethyl]oxy}-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-1,1'-
biphenyl-4-carboxamide 404.4 263 ##STR439## 4'-({[(1S,2R)-1-
{[(cyanomethyl)amino]carbonyl}-2-
(propanoyloxy)propyl]amino}carbonyl)-1,1'- biphenyl-4-yl propanoate
466.5 264 ##STR440## 4'-({[(1S,2R)-1-
{[(cyanomethyl)(propanoyl)amino]carbonyl}-
2-(propanoyloxy)propyl]amino}carbonyl)-1,1'- biphenyl-4-yl
propanoate 522.6 265 ##STR441## N-((1S,2R)-1-
{[(cyanomethyl)amino]carbonyl}-2-
hydroxypropyl)-4'-hydroxy-1,1'-biphenyl-4- carboxamide 354.4 266
##STR442## (2S,3S)-2-[(1,1'-biphenyl-4-ylmethyl)amino]-
N,3-dihydroxybutanamide 301.4 267 ##STR443##
N-{2-hydroxy-1-[(hydroxyamino)carbonyl]-2-
phenylethyl}-1,1'-biphenyl-4-carboxamide 377.4 268 ##STR444##
(2S,3R)-2[(diphenylacetyl)amino]-N,3- dihydroxybutanamide 329.4 269
##STR445## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-6-
[(phenylmethyl)thio]pyridine-3-carboxamide 362.4 270 ##STR446##
N,3-dihydroxy-2-({[4- (phenyloxy)phenyl]methyl}amino)butanamide
317.4 271 ##STR447## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-2'-
[(trifluoromethyl)oxy]-1,1'-biphenyl-4- carboxamide 399.3 272
##STR448## (2R,3S)-2-[(1,1'-biphenyl-4-ylmethyl)amino]-
N,3-dihydroxybutanamide 301.4 273 ##STR449##
4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]benzoic acid 283.3
274 ##STR450## 1,1-dimethylethyl 4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]benzoate 339.4 275
##STR451## (4R)-4-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-5-(hydroxyamino)-5- oxopentanoic acid 371.4 276
##STR452## 4'-ethyl-N-[(1R)-2-(hydroxyamino)-1-
(hydroxymethyl)-2-oxoethyl]-1,1'-biphenyl-4- carboxamide 329.4 277
##STR453## 4'-ethyl-N-[(1S)-2-(hydroxyamino)-1-
(hydroxymethyl)-2-oxoethyl]-1,1'-biphenyl-4- carboxamide 329.4 278
##STR454## (2S)-1-[(4'-ethyl-1,1'-biphenyl-4-yl)carbonyl]-
N,4-dihydroxypyrrolidine-2-carboxamide 355.4 279 ##STR455##
4'-ethyl-N-{(1S)-1- [(hydroxyamino)carbonyl]but-3-ynyl}-1,1'-
biphenyl-4-carboxamide 337.4 280 ##STR456##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4'-ethyl-1,1'-biphenyl-4- carboxamide 328.4 281
##STR457## N-{(1S)-1-[(hydroxyamino)carbonyl]-2-
methylpropyl}-1,1'-biphenyl-4-carboxamide 313.4 282 ##STR458##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-N-methyl-
1,1'-biphenyl-4-carboxamide 329.4 283 ##STR459##
4-ethynyl-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 263.3 284 ##STR460##
4-(1,3-benzodioxol-5-yl)-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 359.3 285 ##STR461##
N-{(1R,2S)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4'-propyl-
1,1'-biphenyl-4-carboxamide 357.4 286 ##STR462##
2-({[3'-(ethyloxy)-1,1'-biphenyl-4-
yl]methyl}amino)-N,3-dihydroxybutanamide 345.4 287 ##STR463##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-3,4'-
bis(methyloxy)-1,1'-biphenyl-4-carboxamide 375.4 288 ##STR464##
3'-formyl-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4'-
(methyloxy)-1,1'-biphenyl-4-carboxamide 373.4 289 ##STR465##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-(4-{4-
[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}buta-
1,3-diynyl)benzamide 523.5 290 ##STR466##
(2S,3R)-2-({[4'-(ethyloxy)-1,1'-biphenyl-4-
yl]methyl}amino)-N,3-dihydroxybutanamide 345.4 291 ##STR467##
3'-chloro-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4'-
(methyloxy)-1,1'-biphenyl-4-carboxamide 379.8 292 ##STR468##
(1R,2R)-N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-2-
phenylcyclopropanecarboxamide 279.3 293 ##STR469##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-(1H-
pyrrol-1-yl)benzamide 304.3 294 ##STR470## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4- propylbenzamide 281.3 295
##STR471## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4- pentylbenzamide 309.4 296
##STR472## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4- octylbenzamide 351.5 297
##STR473## (2E)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-3-(4- methylphenyl)prop-2-enamide
279.3 298 ##STR474## (2E)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-3-(4-
(trifluoromethyl)phenyl]prop-2-enamide 333.3 299 ##STR475##
(2E)-3-(1,1'-biphenyl-4-yl)-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}prop-2- enamide 341.4 300 ##STR476##
(2S,3R)-2-[(1,1'-biphenyl-4-ylacetyl)amino]-
N,3-dihydroxybutanamide 329.4 301 ##STR477##
(2S,3R)-2-{[(2S)-2-amino-3-(1,1'-biphenyl-4-
yl)propanoyl]amino}-N,3- dihydroxybutanamide 358.4 302 ##STR478##
(2S,3R)-2-{[(2R)-2-amino-3-(1,1'-biphenyl-4-
yl)propanoyl]amino}-N,3- dihydroxybutanamide 358.4 303 ##STR479##
(3S)-3-amino-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-5- phenylpentanamide 310.4 304
##STR480## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4- [(phenylamino)methyl]benzamide
344.4 305 ##STR481## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-
[(phenylmethyl)amino]methyl}benzamide 358.4 306 ##STR482##
4'-ethyl-N-{(1S,2R)-2-hydroxy-1-[({(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]propyl}-
1,1'-biphenyl-4-carboxamide 444.5 307 ##STR483##
(2S,3R)-2-[(1,1'-biphneyl-4-ylacetyl)amino]-3-
hydroxy-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}butanamide 430.5 308 ##STR484##
4-(4-chlorophenyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}cyclohexanecarboxamide 355.8 309
##STR485## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(1H- pyrazol-1-yl)benzamide 305.3
310 ##STR486## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4- morpholin-4-ylbenzamide 324.3
311 ##STR487## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(1,2,3- thiadiazol-4-yl)benzamide
323.3 312 ##STR488## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-
methylpiperazin-1-yl)methyl]benzamide 351.4 313 ##STR489##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-(1H-
imidazol-1-ylmethyl)benzamide 319.3 314 ##STR490##
(2S,4S)-N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-
phenylpyrrolidine-2-carboxamide 308.3 315 ##STR491##
4'-bromo-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 394.2
316 ##STR492## 4'-bromo-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 394.2
317 ##STR493## 4'-bromo-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide
394.2
318 ##STR494## (2R)-2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-N.about.1.about..about.hydroxypentanediamide
370.4 319 ##STR495## (2S,3S)-1-[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]-3-hydroxypyrrolidine-2- carboxylic acid 340.4 320
##STR496## (2S,3S)-N-[(1,1-dimethylethyl)oxy]-1-[(4'-
ethyl-1,1'-biphenyl-4-yl)carbonyl]-3-
hydroxypyrrolidine-2-carboxamide 411.5 321 ##STR497##
(2S,3S)-1-[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]-N,3-dihydroxypyrrolidine-2- carboxamide 355.4 322
##STR498## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-
nitrophenyl)ethynyl]benzamide 384.4 323 ##STR499##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[4-(1H-
pyrrol-1-yl)phenyl]ethynyl}benzamide 404.4 324 ##STR500##
N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4'-nitro-1,1'-
biphenyl-4-carboxamide 360.3 325 ##STR501##
(2S,3R)-N,3-dihydroxy-2-({[4'-(methyloxy)-3+-
propyl-1,1'-biphenyl-4- yl]methyl}amino)butanamide 373.5 326
##STR502## 4'-cyano-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 340.3
327 ##STR503## (2S,3R)-2-({[4'-(ethyloxy)-4-(methyloxy)-1,1'-
biphenyl-3-yl]methyl}amino)-N,3- dihydroxybutanamide 375.4 328
##STR504## 2',5'-difluoro-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 351.3
329 ##STR505## N-[(1S)-1-[(acetylamino)methyl]-2-
(hydroxyamino)-2-oxoethyl]-4'-ethyl-1,1'- biphenyl-4-carboxamide
370.4 330 ##STR506## N-{(1S)-4-amino-1-
[(hydroxyamino)carbonyl]butyl}-4'-ethyl-1,1'-
biphenyl-4-carboxamide 356.4 331 ##STR507##
4'-ethyl-N-[(1S)-2-(hydroxyamino)-1-(1H-
imidazol-5-ylmethyl)-2-oxoethyl]-1,1'- biphenyl-4-carboxamide 379.4
332 ##STR508## (2S,3R)-2-{[1-(1,1'-biphenyl-4-
yl6)ethyl]amino}-N,3-dihydroxybutanamide 315.4 333 ##STR509##
(2S,3R)-2-{[1-(1,1'-biphenyl-4-
yl)propyl]amino}-N,3-dihydroxybutanamide 329.4 334 ##STR510##
(2S,3R)-2-{[1-(4'-bromo-1,1'-biphenyl-4-
yl)ethyl]amino}-N,3-dihydroxybutanamide 394.3 335 ##STR511##
(2S,3R)-N,3-dihydroxy-2-{[1-(4'-methyl-1,1'-
biphenyl-4-yl)ethyl]amino}butanamide 329.4 336 ##STR512##
N-[(1S))-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-1,1'-biphenyl-4-carboxamide 300.3 337 ##STR513##
N-[(1S))-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(1H-pyrrol-1-yl)benzamide 289.3 338 ##STR514##
N-[(1S))-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-(4-
chlorophenyl)cyclohexanecarboxamide 340.8 339 ##STR515##
N-[(1S))-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-pentylbenzamide 294.4 340 ##STR516##
(2E)-N-[(1S)-1-(aminomethyl)-2-
(hydroxyamino)-2-oxoethyl]-3-(1,1'-biphenyl- 4-yl)prop-2-enamide
326.4 341 ##STR517## (2S)-3-amino-2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)methyl]amino}-N-hydroxypropanamide 314.4 342 ##STR518##
(2S)-3-amino-2-[(1,1'-biphenyl-4-
ylmethyl)amino]-N-hydroxypropanamide 286.3 343 ##STR519##
(2S)-3-amino-2-{[1-(4'-bromo-1,1'-biphenyl-4-
yl)ethyl]amino}-N-hydroxypropanamide 379.3 344 ##STR520##
(2S)-3-amino-N-hydroxy-2-{[1-(4'-methyl-1,1'-
biphenyl-4-yl)ethyl]amino}propanamide 314.4 345 ##STR521##
4'-ethyl-N-[(1S)-2-({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)-1-
(hydroxymethyl)-2-oxoethyl]-1,1'-biphenyl-4- carboxamide 430.5 346
##STR522## 4'-ethyl-N-[(1S)-2-({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)-1-[(4-
hydroxyphenyl)methyl]-2-oxoethyl}-1,1.varies.-
biphenyl-4-carboxamide 506.6 347 ##STR523##
(2S)-2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-N.about.1.about..about.{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}pentanediamide 471.5 348 ##STR524##
(4S)-4-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-5-({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)-5- oxopentanoic acid 472.5
349 ##STR525## (3S)-3-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-4-({(1S,2R)-2-hydrxoy-1-
[(hydroxyamino)carbonyl]propyl}amino)-4- oxobutanoic acid 458.5 350
##STR526## (3S)-2-(1,1'-biphenyl-4-ylacetyl)-N-{(1S,2R)-
2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-1,2,3,4-
tetrahydroisoquinoline-3-carboxamide 488.6 351 ##STR527##
4'-ethyl-N-[(1S)-2-({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)-1-
methyl-2-oxoethyl]-1,1'-biphenyl-4- carboxamide 414.5 352
##STR528## (2S,3R)-2-({(2S)-3-amino-2-[(1,1'-biphenyl-4-
ylacetyl)amino]propanoyl}amino)-N,3- dihydroxybutanamide 415.5 353
##STR529## (2S)-2-[(1,1'-biphenyl-4-ylacetyl)amino]-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}pent-4-
ynamide 424.5 354 ##STR530##
(2S,3R)-2-{[(2S)-2-amino-2-(1,1'-biphenyl-4-
yl)ethanoyl]amino}-N,3-dihydroxybutanamide 344.4 355 ##STR531##
(2S,3R)-2-{[(2R)-2-amino-2-(1,1'-biphenyl-4-
yl)ethanoyl]amino}-N,3-dihydroxybutanamide 344.4 356 ##STR532##
N-(3-aminopropyl)-4'-ethyl-N-[2-
(hydroxyamino)-2-oxoethyl]-1,1'-biphenyl-4- carboxamide 356.4 357
##STR533## N-(2-cyanoethyl)-4'-ethyl-N-[2-
(hydroxyamino)-2-oxoethyl]-1,1'-biphenyl-4- carboxamide 352.4 358
##STR534## N-[2-(acetylamino)ethyl]-4'-ethyl-N-[2-
(hydroxyamino)-2-oxoethyl]-1,1'-biphenyl-4- carboxamide 384.4 359
##STR535## 4'-ethyl-N-[2-hydroxyamino)-2-oxoethyl]-N-
prop-2-ynyl-1,1'-biphenyl-4-carboxamide 337.4 360 ##STR536##
4-cyano-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 264.3 361 ##STR537##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-cyanobenzamide 249.2 362 ##STR538## 1,1-dimethylethyl
(2S)-2-{[(4- ethynylphenyl)carbonyl]amino}-3-
(hydroxyamino)-3-oxopropylcarbamate 348.4 363 ##STR539##
1,1-dimethylethyl (2S)-3-(hydroxyamino)-3- oxo-2-[({4-[(E)-2-
phenylethenyl]phenyl}methyl)amino]propylcarbamate 412.5 364
##STR540## N-{(1R,2S)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-3'-
(trifluoromethyl)-1,1'-biphenyl-4-carboxamide 383.3 365 ##STR541##
(2S,3R)-2-[(1,1'-biphenyl-4-ylmethyl)amino]-3- hydroxybutanoic acid
286.3 366 ##STR542## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(phenylethynyl)benzamide 324.4 367 ##STR543##
1,1-dimethylethyl (2S)-3-(hydroxyamino)-3- oxo-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)propylcarbamate 424.5 368
##STR544## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-ethynylbenzamide 248.3 369 ##STR545##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-ethynylbenzamide 248.3 370 ##STR546##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[4-
(methyloxy)phenyl}benzamide 369.4 371 ##STR547##
(2S)-3-amino-N-hydroxy-2-[({4-[(E)-2-
phenylethenyl]methyl)amino]propanamide 312.4 372 ##STR548##
1,1-dimethylethyl 2-{4'-[({(1S,2R)-2-hydroxy- 1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]-
1,1'-biphenyl-4-yl}ethylcarbamate 458.5 373 ##STR549##
(2S,3R)-N,3-dihydroxy-2-[({4'-[(2-pyrrolidin-
1-ylethyl)oxy]-1,1'-biphenyl-4- yl}methyl)amino]butanamide 414.5
374 ##STR550## 1,1-dimethylethyl (1S)-4-({[(1,1-
dimethylethyl)oxy]carbonyl}amino)-1-({[4-
({4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)phen-
yl]amino}carbonyl)butylcarbamate 668.8 375 ##STR551##
4-(4-chlorophenyl)-N-[(1S)-2-({(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)-1-
methyl-2-oxoethyl]cyclohexanecarboxamide 426.9 376 ##STR552##
4'-ethyl-N-[2-({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)-2-
oxoethyl]-1,1'-biphenyl-4-carboxamide 400.4 377 ##STR553##
4'-ethyl-N-[3-({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)-3-
oxopropyl]-1,1'-biphenyl-4-carboxamide 414.5 378 ##STR554##
4'-ethyl-N-[4-({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)-4-
oxobutyl]-1,1'-biphenyl-4-carboxamide 428.5 379 ##STR555##
N-((1S)-2-{[(1S)-1-(aminomethyl)-2-
(hydroxyamino)-2-oxoethyl]amino}-1-methyl-
2-oxoethyl)-4'-ethyl-1,1'-biphenyl-4- carboxamide 399.5 380
##STR556## N-(2-{[(1S)-1-(aminomethyl)-2-
(hydroxyamino)-2-oxoethyl]amino}-2-
oxoethyl)-4'-ethyl-1,1'-biphenyl-4- carboxamide 385.4 381
##STR557## N-(3-([(1S)-1-(aminomethyl)-2-
(hydroxyamino)-2-oxoethyl]amino}-3-
oxopropyl)-4'-ethyl-1,1'-biphenyl-4- carboxamide 399.5 382
##STR558## N-(4-{[(1S)-1-(aminomethyl)-2-
(hydroxyamino)-2-oxoethyl]amino}-4-oxobutyl)-4'-1,1'-biphenyl-4-
carboxamide 413.5 383 ##STR559##
4'-ethyl-N-[1-[(hydroxyamino)carbonyl]-2-
(methyloxy)propyl]-1,1'-biphenyl-4- carboxamide 357.4 384
##STR560## 4'-ethyl-N-[(1S,2R)-1- [(hydroxyamino)carbonyl]-2-
(methyloxy)propyl]-1,1'-biphenyl-4- carboxamide 357.4 385
##STR561## N-[1-[(dimethylamino)methyl]-2-
(hydroxyamino)-2-oxoethyl]-4'-ethyl-1,1'- biphenyl-4-carboxamide
356.4 386 ##STR562## N-{(1S)-3-cyano-1-
[(hydroxyamino)carbonyl]propyl}-4'-ethyl-1,1'-
biphenyl-4-carboxamide 352.4 387 ##STR563## N-{(1S)-5-amino-1-
[(hydroxyamino)carbonyl]pentyl}-4'-ethyl-1,1'-
biphenyl-4-carboxamide 370.5 388 ##STR564## N-{(1S)-3-amino-1-
[(hydroxyamino)carbonyl]propyl}-4'-ethyl-1,1'-
biphenyl-4-carboxamide 342.4 389 ##STR565##
4'-ethyl-N-hydroxy-1,1'-biphenyl-4- carboxamide 242.3 390
##STR566## 4'-ethyl-N-{2-hydroxy-1-
[(hydroxyamino)carbonyl]-2-methylpropyl}-
1,1'-biphenyl-4-carboxamide 357.4 391 ##STR567##
N-[(2S)-2-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-3-(hydroxyamino)-3-
oxopropyl]morpholine-4-carboxamide 441.5 392 ##STR568##
N-[(1S)-1-{[(aminocarbonyl)amino]methyl}-2-
(hydroxyamino)-2-oxoethyl]-4'-ethyl-1,1'- biphenyl-4-carboxamide
371.4 393 ##STR569## N-[(1S)-1-
({[amino(imino)methyl]amino}methyl)-2-
(hydroxyamino)-2-oxoethyl]-4'-ethyl-1,1'- biphenyl-4-carboxamide
370.4 394 ##STR570## N-[(2S)-2-amino-3-(hydroxyamino)-3-
oxopropyl]-4'-ethyl-1,1'-biphenyl-4- carboxamide 328.4 395
##STR571## 1-[(4'-ethyl-1,1'-biphenyl-4-yl)carbonyl]-N-
hydroxypiperazine-2-carboxamide 354.4 396 ##STR572##
N-[(2S)-2-amino-3-(hydroxyamino)-3-
oxopropyl]-4-(phenylethynyl)benzamide 324.4 397 ##STR573##
N-hydroxy-1-{[4- (phenylethynyl)phenyl]carbonyl}piperazine-2-
carboxamide 350.4 398 ##STR574## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-
pentylphenyl)ethynyl]benzamide 409.5 399 ##STR575##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[3-
(methyloxy)phenyl]ethynyl}benzamide 369.4 400 ##STR576##
4-[(3-fluoro-4-methylphenyl)ethynyl]-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 371.4 401 ##STR577##
4-[(2,4-difluorophenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 375.3 402 ##STR578##
methyl (2E)-3-(ethylamino)-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)but-2- enoate 363.4 403
##STR579## 1,1-dimethylethyl-4-{[(2S)-3-(hydroxyamino)-
3-oxo-2-({[4- (phenylethynyl)phenyl]carbonyl}amino)propyl]amino}-
4-oxobutylcarbamate 509.6 404 ##STR580##
N-(1-(N-hydroxycarbamoyl)-2-hydroxy-3- methylbutyl)[4-(4-
ethylphenyl)phenyl]carboxamide 371.4 405 ##STR581## N-((1R,2R)-1-
{[(aminocarbonyl)(hydroxy)amino]methyl}-2-
hydroxypropyl)-4'-ethyl-1,1'-biphenyl-4- carboxamide 372.4 406
##STR582## 4'-ethyl-N-((1R,2R)-1- {[formyl(hydroxy)amino]methyl}-2-
hydroxypropyl)-1,1'-biphenyl-4-carboxamide 357.4 407 ##STR583##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[4-
(trifluoromethyl)phenyl]ethynyl}benzamide 407.4 408 ##STR584##
1,1-dimethylethyl-2-{[(2S)-3-(hydroxyamino)- 3-oxo-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)propyl]amino}-
2-oxoethylcarbamate 481.5 409 ##STR585##
N-[(1S)-1-{[(aminoacetyl)amino]methyl}-2-
(hydroxyamino)-2-oxoethyl]-4- (phenylethynyl)benzamide 381.4 410
##STR586## N-[(1S)-1-{[(4-aminobutanoyl)amino]methyl}-
2-(hydroxyamino)-2-oxoethyl]-4-(phenylethynyl)benzamide 409.5 411
##STR587## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-pent-1- ynylbenzamide 305.3 412
##STR588## N-{(1S,2R)-2-[(1,1-dimethylethyl)oxy]-1-
[(hydroxyamino)carbonyl]propyl}-4'-propyl-
1,1'-biphenyl-4-carboxamide 413.5 413 ##STR589## 1,1-dimethylethyl
(1S)-4-({[(1,1- dimethylethyl)oxy]carbonyl}amino)-1-{[(2-{4'-
[({(1S,2R)-2-hydroxy-1-
[(hydrxoyamino)carbonyl]propyl}amino)carbonyl]-1,1'-biphenyl-4-
yl}ethyl)amino]carbonyl}butylcarbamate 672.8 414 ##STR590##
4'-(2-aminoethyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 358.4
415 ##STR591## 4'-(2-{[(2S)-2,5-
diaminopentanoyl]amino}-N-{(1S,2R)-2-
hydroxy-1-[(hydroxyamino)carbonyl]propyl}-
1,1'-biphenyl-4-carboxamide 472.6 416 ##STR592##
4-(cyclohex-1-en-1-ylethynyl)-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 343.4 417 ##STR593##
4-(3,3-dimethylbut-1-ynyl)-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 319.4 418 ##STR594##
N-{(1S)-1-{[(aminoacetyl)amino]methyl}-2-
[(2-{[(2S)-3-(hydroxyamino)-3-oxo-({[4-
(phenylethynyl)phenyl]carbonyl}amino)propyl]amino}-
2-oxoethyl)amino]-2-oxoethyl}-4- (phenylethynyl)benzamide 728.8 419
##STR595## 4-[(4-{[(2S)-2,5-
diaminopentanoyl]amino}phenyl)ethynyl]-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 468.5 420 ##STR596##
4'-(2-aminoethyl)-N-{(1E)-1-
[(hydroxyamino)carbonyl]prop-1-enyl}-1,1'- biphenyl-4-carboxamide
340.4 421 ##STR597## 2',4'-difluoro-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1'- biphenyl-4-carboxamide 351.3
422 ##STR598## N-[(1E)-1-formylprop-1-enyl]-4'-propyl-1,1'-
biphenyl-4-carboxamide 308.4 423 ##STR599##
N-hydroxy-4-(pyridin-3-ylethynyl)benzamide 239.2 424 ##STR600##
4-(3-hydroxy-3,5-dimethylhex-1-ynyl)-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 363.4 425 ##STR601##
4'-ethyl-N-{(1R,2R)-2-hydroxy-1-
[(hydroxyamino)methyl]propyl}-1,1'-biphenyl- 4-carboxamide 329.4
426 ##STR602## 4'-ethyl-N-{(1R,2R)-1- [(hydroxyamino)methyl]-2-
[(phenylmethyl)oxy]propyl}-1,1'-biphenyl-4- carboxamide 419.5 427
##STR603## 4'-ethyl-N-[(5R,6R)-3-hydroxy-6-methyl-2-
oxo-1,3,-oxazinan-5-yl]-1,1'-biphenyl-4- carboxamide 355.4 428
##STR604## N-((1R,2R)-1-{[({[2-
(dimethylamino)ethyl]amino}carbonyl)(hydroxy)amino]methyl}-
2-hydroxypropyl)-4'-ethyl- 1,1'-biphenyl-4-carboxamide 443.6 429
##STR605## N-((1R,2R)-1-{[{[(2-
cyanoethyl)amino]carbonyl}(hydroxy)amino]methyl}-
2-hydroxypropyl)-4'-ethyl-1,1'- biphenyl-4-carboxamide 425.5 430
##STR606## 4'-ethyl-N-((1R,2R)-2-hydroxy-1-
{[hydroxy({[3-(2-oxopyrrolidin-1-
yl)propyl]amino}amino}carbonyl)amino]methyl}propyl)-
1,1'-biphenyl-4-carboxamide 497.6 431 ##STR607## (1R,2R)-3-[({[2-
(dimethylamino)amino}carbonyl)(hydroxy)amino]-
2-{[(4'-ethyl-1,1'-biphenyl-4- yl)carbonyl]amino}-1-methylpropyl 2-
(dimethylamino)ethylcarbamate 557.7 432 ##STR608## (1R,2R)-3-[{[(2-
cyanoethyl)amino]carbonyl}(hydroxy)amino]-
2-{[(4'-ethyl-1,1'-biphenyl-4- yl)carbonyl]amino}-1-methylpropyl 2-
cyanoethylcarbamate 521.6 433 ##STR609##
N-{(1E)-1-[(E)-(hydroxyimino)methyl]prop-1-
enyl}-4'-propyl-1,1'-biphenyl-4-carboxamide 323.4 434 ##STR610##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-(pyridin-
3-ylethynyl)benzamide 340.3 435 ##STR611## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[3-
(methylamino)prop-1-ynyl]benzamide 306.3 436 ##STR612##
N-[(1S)-1-[(dimethylamino)methyl]-2-
(hydroxyamino)-2-oxoethyl]-4'-ethyl-1,1'- biphenyl-4-carboxamide
356.4 437 ##STR613## N-[1-(N-hydroxycarbamoylmethyl)(1R,2R)-2-
hydroxypropyl][4-(4- ethylphenyl)phenyl]carboxamide 357.4 438
##STR614## N-[(1S)-1-[(diethylamino)methyl]-2-
(hydroxyamino)-2-oxoethyl]-4'-ethyl-1,1'- biphenyl-4-carboxamide
384.5 439 ##STR615## N-[(3-aminophenyl)ethynyl]-N-{(1S,2R)-2-
hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide 354.4 440
##STR616## 4-[3-(dimethylamino)prop-1-ynyl]-N-{(1S,2R)-
2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide 320.4 441
##STR617## 4-[3-(dimethylamino)prop-1-ynyl]-N-{(1S,2R)-
2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide 320.4 442
##STR618## 4-({4-[(aminoacetyl)amino]phenyl}ethynyl)-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]carbonyl}benzamide
411.4 443 ##STR619## 3'-fluoro-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4'-methyl-
1,1'-biphenyl-4-carboxamide 347.4 444 ##STR620##
N-[(1S)-1-formyl-2-methylpropyl]-1,1'- biphenyl-4-carboxamide 282.4
445 ##STR621## N-{(1S)-1-[(E)-(hydroxyimino)methyl]-2-
methylpropyl}-1,1'-biphenyl-4-carboxamide 297.4 446 ##STR622##
N-((1E)-1-{(E)- [(aminocarbonyl)hydrazono]methyl}prop-1-
enyl)-4'-propyl-1,1'-biphenyl-4-carboxamide 365.4 447 ##STR623##
4-[(4-aminophenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 354.4 448 ##STR624##
4-{[3-(aminomethyl)phenyl]ethynyl}-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 368.4 449 ##STR625##
N-(2-aminoethyl)-3-({4-[({(1S,2R)-2-hydroxy- 1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)benz-
amide 425.5 450 ##STR626## N-((1S)-1-{(E)-
[(aminocarbonyl)hydrozono]methyl}-2-
methylpropyl)-1,1'-biphenyl-4-carboxamide 339.4 451 ##STR627##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[3-
(propanoylamino)phenyl]ethynyl}benzamide 410.4 452 ##STR628##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[3-
(morpholin-4- ylmethyl)phenyl]ethynyl}benzamide 438.5 453
##STR629## 4-[(3-{[(2- aminoethyl)amino]methyl}phenyl)ethynyl]-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
411.5 454 ##STR630## N-[(1R)-2-(hydroxyamino)-1-(hydroxymethyl)-
2-oxoethyl]-4'-propyl-1,1'-biphenyl-4- carboxamide 343.4 455
##STR631## N-[1-(N-hydroxycarbomoylmethyl)(1R,2R)-2-
hydroxypropyl][4-(2- phenylethynyl)phenyl]carboxamide 353.4 456
##STR632## 4'-ethyl-N-[(1R,2R)-1- [(hydroxyamino)carbonyl]-2-
(methyloxy)propyl]-1,1'-biphenyl-4- carboxamide 357.4 457
##STR633## 4'-ethyl-N-[(1S)-1-[(ethylamino)methyl]-2-
(hydroxyamino)-2-oxoethyl]-1,1'-biphenyl-4- carboxamide 356.4 458
##STR634## 4'-ethyl-N-[(1S)-2-(hydroxyamino)-2-oxo-1-
({[(2S)-pyrrolidin-2- ylmethyl]amino}methyl)ethyl]-1,1'-biphenyl-4-
carboxamide 411.5 459 ##STR635## N-[(1S)-1-[(ethylamino)methyl]-2-
(hydroxyamino)-2-oxoethyl]-4- (phenylethynyl)benzamide 352.4 460
##STR636## N-[(1S)-2-(hydroxyamino)-2-oxo-1-({[(2S)-
pyrrolidin-2-ylmethyl]amino}methyl)ethyl]-4-
(phenylethynyl)benzamide 407.5 461 ##STR637##
4'-ethyl-N-((1S)-2-(hydroxyamino)-1-{[(1-
methylethyl)amino]methyl}-2-oxoethyl)-1,1'- biphenyl-4-carboxamide
370.5 462 ##STR638## 4'-ethyl-N-[(1S)-2-(hydroxyamino)-1-({[2-
(methylamino)ethyl]amino}methyl)-2-
oxoethyl]-1,1'-biphenyl-4-carboxamide 385.5 463 ##STR639##
4'-ethyl-N-((1S)-2-(hydroxyamino)-1-{[(1-
methylpiperidin-4-yl)amino]methyl}-2-
oxoethyl)-1,1'-biphenyl-4-carboxamide 425.5 464 ##STR640##
N-((1S)-2-(hydroxyamino)-1-{[(1-
methylethyl)amino]methyl}-2-oxoethyl)-4- (phenylethynyl)benzamide
366.4 465 ##STR641## N-[(1S)-2-(hydroxyamino)-1-({[2-
(methylamino)ethyl]amino}methyl)-2-
oxoethyl]-4-(phenylethynyl)benzamide
381.4 466 ##STR642## N-((1S)-2-(hydroxyamino)-1-{[(1-
methylpiperidin-4-yl)amino]methyl}-2-
oxoethyl)-4-(phenylethynyl)benzamide 421.5 467 ##STR643##
N-[(1S)-1-{[(2-aminoethyl)amino]methyl}-2-
(hydroxyamino)-2-oxoethyl]-4- (phenylethynyl)benzamide 367.4 468
##STR644## N-[(1S)-1-{[bis(2-aminoethyl)amino]methyl}-
2-(hydroxyamino)-2-oxoethyl]-4- (phenylethynyl)benzamide 410.5 469
##STR645## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4- [(morpholin-4-
ylacetyl)amino]phenyl}ethynyl)benzamide 481.5 470 ##STR646##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[4-
(propanoylamino)phenyl]ethynyl}benzamide 410.4 471 ##STR647##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-({4-
[(trifluoromethyl)oxy]phenyl}ethynyl)benzamide 423.4 472 ##STR648##
1,1-dimethylethyl (2S)-3-(hydroxyamino)-3- oxo-2-{[(4-{[3-
(propanoylamino)phenyl]ethynyl}phenyl)carbonyl]amino}propyl-
carbamate 495.5 473 ##STR649## 1,1-dimethylethyl
(2S)-3-(hydroxyamino)-3- oxo-2-{[(4-pent-1-
ynylphenyl)carbonyl]amino}propylcarbamate 390.4 474 ##STR650##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{[3-
(propanoylamino)phenyl]ethynyl}benzamide 395.4 475 ##STR651##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-pent-1-ynylbenzamide 290.3 476 ##STR652##
4-(phenyloxy)benzaldehyde thiosemicarbazone 272.3 477 ##STR653##
4-(phenyloxy)benzaldehyde semicarbazone 256.3 478 ##STR654## 4-{[3-
(trifluoromethyl)phenyl]oxy}benzaldehyde thiosemicarbazone 340.3
479 ##STR655## 4-[(3,4-difluorophenyl)ethynyl]-N-{(1S,2R)-2-
hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide 375.3 480
##STR656## 4[[(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-
yl)ethynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 373.3 481 ##STR657##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-phenylbuta-1,3-diynyl)benzamide 348.4 482 ##STR658##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4'-propyl-1,1'-biphenyl-4- carboxamide 342.4 483
##STR659## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-1,1':4',1''-terphenyl-4-carboxamide 376.4 484 ##STR660##
N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-1,1':4',1''-
terphenyl-4-carboxamide 391.4 485 ##STR661## 1,1-dimethylethyl
(2S)-2-[({4[(4-{[({[1,1-
dimethylethyl)oxy]carbonyl}amino)acetyl]amino}phenyl)ethynyl]phen-
yl}carbonyl)amino]- 3-(hydroxyamino)-3-oxopropylcarbamate 596.6 486
##STR662## N-[(1S,2R)-1-(hydrazinocarbonyl)-2-
hydroxypropyl]-4-(phenylethynyl)benzamide 338.4 487 ##STR663##
2-[(2S,3R)-3-hydroxy-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)butanoyl]hydrazinecarboxamide
381.4 488 ##STR664## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(2-
methylphenyl)ethynyl]benzamide 353.4 489 ##STR665##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(3-
hydroxyphenyl)ethynyl]benzamide 355.4 490 ##STR666##
4-({3-[(aminoacetyl)amino]phenyl}ethynyl)-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 411.4 491 ##STR667##
4-{[4- ({[(cyanomethyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
450.5 492 ##STR668## 4'-ethyl-N-{(1S)-2-(hydroxyamino)-2-oxo-1-
[(tetrahydro-2H-pyran-4- ylamino)methyl]ethyl}-1,1'-biphenyl-4-
carboxamide 412.5 493 ##STR669## N-{(1S)-2-(hydroxyamino)-2-oxo-1-
[(tetrahydro-2H-pyran-4- ylamino)methyl]ethyl}-4-
(phenylethynyl)benzamide 408.5 494 ##STR670##
4-[(4-chlorophenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 373.8 495 ##STR671##
N-{(1S,2R)-2-hydroxy-1- [(hydrxoyamino)carbonyl]propyl}-4-[(4-
methylphenyl)ethynyl]benzamide 353.4 496 ##STR672##
4-[(2-fluorophenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 357.4 497 ##STR673##
4-[(3-fluorophenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 357.4 498 ##STR674##
4-[(4-fluorophenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 357.4 499 ##STR675##
4-[(4- {[(cyclopropylamino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
451.5 500 ##STR676## 4-({4-[({[2-
(dimethylamino)ethyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
482.6 501 ##STR677## 4-({4-[({[2-
(acetylamino)ethyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
496.5 502 ##STR678## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[({[3- (2-oxopyrrolidin-1-
yl)propyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 536.6 503
##STR679## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[(pyridin-3-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 502.5 504
##STR680## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[(2- pyridin-2-
ylethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 516.6 505
##STR681## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-{[(4- methylpiperazin-1-
yl)acetyl]amino}phenyl)ethynyl]benzamide 494.6 506 ##STR682##
4-({4-[(1,4'-bipiperidin-1'-
ylacetyl)amino]phenyl}ethynyl)-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 562.7 507 ##STR683##
1-(2-{[4-({4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)phen-
yl]amino}-2-oxoethyl)piperidine-4-carboxamide 522.6 508 ##STR684##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(4-
{[(piperidin-3- ylamino)acetyl]amino}phenyl)ethynyl]benzamide 494.6
509 ##STR685## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4- {[(piperidin-4-
ylamino)acetyl]amino}phenyl)ethynyl]benzamide 494.6 510 ##STR686##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[4-
({[(piperidin-2-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 508.6 511
##STR687## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[(piperidin-3-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 508.6 512
##STR688## 4-[(4-{[(3-aminopyrrolidin-1-
yl)acetyl]amino}phenyl)ethynyl]-N-{(1S,2R)- 2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 480.5 513 ##STR689##
4-({4-[(azepan-1- ylacetyl)amino]phenyl}ethynyl)-N-{(1S,2R)-2-
hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide 493.6 514
##STR690## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[(4- morpholin-4-
ylphenyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 572.6 515
##STR691## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2-
hydroxyethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 440.5 516
##STR692## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(cyclopropylamino)acetyl]amino}phenyl)ethynyl]benzamide 436.5 517
##STR693## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[3-(2-oxopyrrolidin-1-
yl)propyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 521.6 518
##STR694## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(4-methylpiperazin-1-
yl)acetyl]amino}phenyl)ethynyl]benzamide 479.6 519 ##STR695##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(pyridin-3-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 487.5 520
##STR696## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(piperidin-1-
ylacetyl)amino]phenyl}ethynyl)benzamide 464.5 521 ##STR697##
4-{[4-({[(2- hydroxyethyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
455.5 522 ##STR698## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[({[2-
(methyloxy)ethyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 469.5
523 ##STR699## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4- [({methyl[2-
(methyloxy)ethyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 483.5
524 ##STR700## 4-{[4-({[[2-
(dimethylamino)ethyl](methyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy- 1-[(hydroxyamino)carbonyl]propyl}benzamide
496.6 525 ##STR701## 4-{[4-({[(3R)-3-(dimethylamino)pyrrolidin-1-
yl]acetyl}amino)phenyl]ethynyl}-N-{(1S,2R)- 2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 508.6 526 ##STR702##
4-{[4-({[(3S)-3-(dimethylamino)pyrrolidin-1-
yl]acetyl}amino)phenyl]ethynyl}-N-{(1S,2R)- 2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 508.6 527 ##STR703##
4-{[4-({[(3R)-3-(acetylamino)pyrrolidin-1-
yl]acetyl}amino)phenyl]ethynyl}-N-{(1S,2R)- 2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 522.6 528 ##STR704##
4-{[4-({[(3S)-3-(acetylamino)pyrrolidin-1-
yl]acetyl}amino)phenyl]ethynyl}-N-{(1S,2R)- 2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 522.6 529 ##STR705##
4-{[4-({[(3R)-1-azabicyclo[2.2.2]oct-3-
ylamino]acetyl}amino)phenyl]ethynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 520.6 530 ##STR706##
4-{[4-({[(3S)-1-azabicyclo[2.2.2]oct-3-
ylamino]acetyl}amino)phenyl]ethynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 520.6 531 ##STR707##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-({4-
[({[(2R)-pyrrolidin-2-
ylmethyl]amino)acetyl)amino]phenyl}ethynyl)benzamide 494.6 532
##STR708## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4- [({[(2S)-pyrrolidin-2-
ylmethyl]amino)acetyl)amino]phenyl}ethynyl)benzamide 494.6 533
##STR709## 4-{[4-({[(3-
aminocyclohexyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
508.6 534 ##STR710## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl)propyl}-4-[(4-{[(3- hydroxypiperidin-1-
yl)acetyl]amino}phenyl)ethynyl]benzamide 495.5 535 ##STR711##
N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl)propyl}-4-{[4-({[(3- morpholin-4-
ylpropyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 538.6 536
##STR712## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl)propyl}-4-{[4-({[(2-
methylpropyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 467.5 537
##STR713## 4-[(4- {[(ethylamino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
439.5 538 ##STR714## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4- [(piperidin-1-
ylacetyl)amino]phenyl}ethynyl)benzamide 479.5 539 ##STR715##
N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[(3-
hydroxypropyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 469.5 540
##STR716## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[({[3-
(methyloxy)propyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 483.5
541 ##STR717## 4-{[4-({[(2-
cyanoethyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
464.5 542 ##STR718## N-{(1S,2R)-2-hydroxy-1-
[(hrdroxyamino)carbonyl]propyl}-4-{[4-({[(2- pyrrolidin-1-
ylethyl)amino]acetyl}amino)phenyl]ethynyl)benzamide 508.6 543
##STR719## N-{(1S,2R)-2-hydroxy-1-
[(hrdroxyamino)carbonyl]propyl}-4-[(4-{[(2- methyl-1H-imidazol-1-
yl)acetyl]amino}phenyl)ethynyl]benzamide 476.5 544 ##STR720##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-[(4-
{[(methylamino)acetyl]amino}phenyl)ethynyl]benzamide 410.4 545
##STR721## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2-
methylpropyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 452.5 546
##STR722## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[2-
(methyloxy)ethyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 454.5
547 ##STR723## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({methyl[2-
(methyloxy)ethyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 468.5
548 ##STR724## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(3-
hydroxypropyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 454.5 549
##STR725## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[3-
(methyloxy)propyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 468.5
550 ##STR726## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[2-
(dimethylamino)ethyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
467.5 551 ##STR727## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[[2-
(dimethylamino)ethyl](methyl)amino]acetyl}amino)phen-
yl]ethynyl}benzamide 481.6 552 ##STR728## 4-({4-[({[2-
(acetylamino)ethyl]amino}acetyl)amino]phenyl}ethynyl)-
N-[(1S)-1-(aminomethyl)-2- (hydroxyamino)-2-oxoethyl]benzamide
481.5 553 ##STR729## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2-
cyanoethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 449.5 554
##STR730## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2-pyrrolidin-1-
ylethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 493.6 555
##STR731## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[4-
(dimethylamino)butyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
495.6 556 ##STR732## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(morpholin-4-
ylacetyl)amino]phenyl}ethynyl)benzamide 466.5 557 ##STR733##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(azepan-1- ylacetyl)amino]phenyl}ethynyl)benzamide
478.6 558 ##STR734## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(pyrrolidin-1-
ylacetyl)amino]phenyl}ethynyl)benzamide 450.5 559 ##STR735##
1-{2-[(4-{[4-({[(1S)-1-(aminomethyl)-2- (hydroxyamino)-2-
oxoethyl]amino}carbonyl)phenyl]ethynyl}phenyl)amino]-
2-oxoethyl}piperidine-4-carboxamide 507.6 560 ##STR736##
4-{[4-({[(3R)-3-(acetylamino)pyrrolidin-1-
yl]acetyl}amino)phenyl]ethynyl}-N-[(1S)-1-
(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 507.6 561
##STR737## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(3R)-3- (dimethylamino)pyrrolidin-1-
yl]acetyl}amino)phenyl]ethynyl}benzamide 493.6 562 ##STR738##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(3-aminopyrrolidin-1-
yl)acetyl]amino}phenyl)ethynyl]benzamide 465.5 563 ##STR739##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(piperidin-3-
ylamino)acetyl]amino}phenyl)ethynyl]benzamide 479.6 564 ##STR740##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(piperidin-4-
ylamino)acetyl]amino}phenyl)ethynyl]benzamide 479.6 565 ##STR741##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(piperidin-2-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 493.6 566
##STR742## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(piperidin-3-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 493.6 567
##STR743## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(pyridin-2-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 487.5 568
##STR744## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(pyridin-4-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 487.5 569
##STR745## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2-pyridin-2-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 501.6 570
##STR746## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2-pyridin-3-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 501.6 571
##STR747## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2-pyridin-4-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 501.6 572
##STR748## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(phenylamino)acetyl]amino}phenyl)ethynyl]benzamide 472.5 573
##STR749## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-
({[(phenylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 486.5
574 ##STR750## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2-
phenylethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 500.6 575
##STR751## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(1H-imidazol-1-
ylacetyl)amino]phenyl}ethynyl)benzamide 447.5 576 ##STR752##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-({4-[(1H-
imidazol-1- ylacetyl)amino]phenyl}ethynyl)benzamide 462.5 577
##STR753## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-
{[(phenylamino)acetyl]amino}phenyl)ethynyl]benzamide 487.5 578
##STR754## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[(2-
phenylethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 515.6 579
##STR755## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[(3-
phenylpropyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 529.6 580
##STR756## 4-[(3- {[(aminoacetyl)amino]methyl}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
425.5 581 ##STR757## 4-[(2-aminopyrimidin-5-yl)ethynyl]-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
356.4 582 ##STR758## 4-[(4-acetylphenyl)ethynyl]-N-{(1S,2R)-2-
hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide 381.4 583
##STR759## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-{[({2-
[4-(phenylmethyl)piperazin-1-
yl]ethyl}amino)acetyl]amino}phenyl)ethynyl]benzamide 613.7 584
##STR760## 4-{[4-
({[(aminoacetyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
468.5 585 ##STR761## 4-{[4-({[4-(2-hydroxyethyl)piperazin-1-
yl]acetyl}amino)phenyl]ethynyl}-N-{(1S,2R)- 2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 524.6 586 ##STR762##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-({4-
[({(3R)-3-[(trifluoroacetyl)amino]pyrrolidin-1-
yl}acetyl)amino]phenyl}ethynyl)benzamide 576.5 587 ##STR763##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(4-
{[(methylamino)acetyl]amino}phenyl)ethynyl]benzamide 425.5 588
##STR764## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[(piperazin-1-
ylacetyl)amino]phenyl}ethynyl)benzamide 480.5 589 ##STR765##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[4-
({[(pyridin-2- ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide
502.5 590 ##STR766## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[(pyridin-4-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 502.5 591
##STR767## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[(2- pyridin-3-
ylethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 516.6 592
##STR768## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[(2- pyridin-4-
ylethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 516.6 593
##STR769## 4-({4-[({[(2-
fluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
519.5 594 ##STR770## 4-({4-[({[(2-
chlorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
536.0 595 ##STR771## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-{[({[2-
(methyloxy)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benz-
amide 531.6 596 ##STR772## 4-({4-[({[(3-
fluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
519.5 597 ##STR773## 4-({4-[({[(3-
chlorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
536.0 598 ##STR774## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-{[({[3-
(methyloxy)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benz-
amide 531.6 599 ##STR775## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[({[(3-
methylphenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
515.6 600 ##STR776## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-
{[({[(3-(trifluoromethyl)phenyl]methyl}amino)acetyl]amino}phen-
yl)ethynyl]benzamide 569.5 601 ##STR777## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[({3-
[(trifluoromethyl)oxy]phenyl}methyl)amino]acetyl}amino)phen-
yl]ethynyl}benzamide 585.5 602 ##STR778## 5-({4-[({[(4-
fluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
519.5 603 ##STR779## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[({[(4-
methylphenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
515.6 604 ##STR780## 4-[(4-{[({[4-
(dimethylamino)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}benzamide
544.6 605 ##STR781## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-{[({[4-
(trifluoromethyl)phenyl]methyl}amino)acetyl]amino}phen-
yl)ethynyl]benzamide 569.5 606 ##STR782## 4-[(4-{[({[4-fluoro-2-
(trifluoromethyl)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy- 1-[(hydroxyamino)carbonyl]propyl}benzamide
587.5 607 ##STR783## 4-({4-[({[(2,4-
difluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
537.5 608 ##STR784## 4-({4-[({[(2,4-
dichlorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
570.4 609 ##STR785## 4-{[4-({[(2-
fluorophenyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
505.5 610 ##STR786## 4-{[4-({[(4-
fluorophenyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
505.5 611 ##STR787## 4-({4-[({[(3,5-
difluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
537.5 612 ##STR788## 4-{[4-({[(4-
bromophenyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
566.4 613 ##STR789## 4-({4-[({[4-
(dimethylamino)phenyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
530.6 614 ##STR790## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(2S)-2-
aminopropanoyl]amino}phenyl)ethynyl]benzamide 410.4 615 ##STR791##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(2R)-2-
aminopropanoyl]amino}phenyl)ethynyl]benzamide 410.4 616 ##STR792##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(2S)-2-amino-4-
methylpentanoyl]amino}phenyl)ethynyl]benzamide 452.5 617 ##STR793##
4-[(4-{[(2S,3R)-2-amino-3- hydroxybutanoyl]amino}phenyl)ethynyl]-N-
[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 440.5
618 ##STR794## 4-[(4-{[(2S)-2-amino-4-
cyanobutanoyl]amino}phenyl)ethynyl]-N-
[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 449.5
619 ##STR795## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(2S)-2,3-
diaminopropanoyl]amino}phenyl)ethynyl]benzamide 425.5 620
##STR796## (2S)-N-(4-{[4-({[(1S)-1-(aminomethyl)-2-
(hydroxyamino)-2-
oxoethyl]amino}carbonyl)phenyl]ethynyl}phenyl)pyrrolidine-
2-carboxamide 436.5 621 ##STR797##
(2S)-N-(4-{[4-({[(1S)-1-(aminomethyl)-2- (hydroxyamino)-2-
oxoethyl]amino}carbonyl)phenyl]ethynyl}phenyl)piperidine-
2-carboxamide 450.5 622 ##STR798##
N-(4-{[4-({[(1S)-1-(aminomethyl)-2- (hydroxyamino)-2-
oxoethyl]amino}carbonyl)phenyl]ethynyl}phenyl)piperidine-
3-carboxamide 450.5 623 ##STR799##
4-[(4-{[(2S)-2-amino-3-(1H-imidazol-4-
yl)propanoyl]amino}phenyl)ethynyl]-N-[(1S)-
1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 476.5 624
##STR800## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4- methylphenyl)ethynyl]benzamide 338.4 625
##STR801## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(2- fluorophenyl)ethynyl]benzamide 342.3 626
##STR802## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(3- fluorophenyl)ethynyl]benzamide 342.3 627
##STR803## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4- fluorophenyl)ethynyl]benzamide 342.3 628
##STR804## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4- chlorophenyl)ethynyl]benzamide 358.8 629
##STR805## 4-[(4-{[(2S)-2-amino-4-
methylpentanoyl]amino}phenyl)ethynyl]-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 467.5 630 ##STR806##
4-[(4-{[(2S)-2-amino-4- cyanobutanoyl]amino}phenyl)ethynyl]-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
464.5 631 ##STR807## 4-[(4-{[(2S)-2,3-
diaminopropanoyl]amino}phenyl)ethynyl]-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 440.5 632 ##STR808##
N-[4-({4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)phen-
yl]piperidine-3-carboxamide 465.5 633 ##STR809##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-({3-
[(morpholin-4- ylacetyl)amino]phenyl}ethynyl)benzamide 481.5 634
##STR810## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(pyrazin- 2-ylethynyl)benzamide
341.3 635 ##STR811## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[({[3- (1H-imidazol-1-
yl)propyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 519.6 636
##STR812## N-((1S)-2-(hydroxyamino)-1-{[({[3-(1H- imidazol-1-
yl)propyl]amino}acetyl)amino]methyl}-2-
oxoethyl)-4-(phenylethynyl)benzamide 489.5 637 ##STR813##
4-({4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phen-
yl}ethynyl)benzoic acid 383.4 638 ##STR814##
N-(2-{[4-({4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)phen-
yl]amino}-2-oxoethyl)-1,3-benzodioxole-4-carboxamide 559.5 639
##STR815## 4-({4-[((2R)-2-{[(2R)-2,5- diaminopentanoyl]amino}-4-
phenylbutanoyl)amino]phenyl}ethynyl)-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 629.7 640 ##STR816##
4-[(4-{[(2R)-2-amino-4- phenylbutanoyl]amino}phenyl)ethynyl]-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
515.6 641 ##STR817## 4-[(4-{[(2S)-2-amino-3-
phenylpropanoyl]amino}phenyl)ethynyl]-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 501.6 642 ##STR818##
4-{[4-({[(2- aminoethyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
454.5 643 ##STR819## N-{(1S)-2-(hydroxyamino)-1-[({[methyl(1-
methylpiperidin-4- yl)amino]acetyl}amino)methyl]-2-oxoethyl}-4-
(phenylethynyl)benzamide 492.6 644 ##STR820## 4-[(4-
{[(cyclobutylamino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
465.5 645 ##STR821## 4-[(4-
{[(cyclopentylamino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
479.5 646 ##STR822## 4-[(4-
{[(cyclohexylamino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
493.6 647 ##STR823## 4-[(4-
{[(cycloheptylamino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
507.6 648 ##STR824## 4-[(4-
{[(cyclooctylamino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
521.6 649 ##STR825## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-
{[(propylamino)acetyl]amino}phenyl)ethynyl]benzamide 453.5 650
##STR826## 4-[(4- {[(hexylamino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
495.6 651 ##STR827## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[(1-
methylethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 453.5 652
##STR828## 4-{[4-({[(1,1-
dimethylethyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
467.5 653 ##STR829## 4-{[4-
({[ethyl(methyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
453.5 654 ##STR830## 4-[(4-
{[(diethylamino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
467.5 655 ##STR831## 4-{[4-({[(1,1-
dimethylethyl)(methyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
481.6 656 ##STR832## 4-{[4-
({[cyclohexyl(methyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
507.6 657 ##STR833## 4-{[4-({[bis(1-
methylethyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
495.6 658 ##STR834## 4-{[4-
({[(cyclohexylmethyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
507.6 659 ##STR835## 4-{[4-({[(2,3-
dimethylcyclohexyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
521.6 660 ##STR836## 4-{[4-({[(1R,2R,4S)-bicyclo[2.2.1]hept-2-
ylamino]acetyl}amino)phenyl]ethynyl}-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 505.6
661 ##STR837## 4-[(4-{[({[(1S,2R,5S)-6,6-
dimethylbicyclo[3.1.1]hept-2-
yl]methyl}amino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
547.7 662 ##STR838## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[4-
(trifluoromethyl)piperidin-1-
yl]acetyl}amino)phenyl]ethynyl}benzamide 547.5 663 ##STR839##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-({4-[({[(2-
fluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
504.5 664 ##STR840## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(2-
chlorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
521.0 665 ##STR841## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(2-
methylphenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
500.6 666 ##STR842## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(2-
(methyloxy)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benz-
amide 516.6 667 ##STR843##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-({4-[({[(2-
(trifluoromethyl)phenyl]methyl}amino)acetyl]amino}phen-
yl)ethynyl]benzamide 554.5 668 ##STR844##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{[4-({[({2-
[(trifluoromethyl)oxy]phenyl}methyl)amino]acetyl}amino)phen-
yl]ethynyl}benzamide 570.5 669 ##STR845##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-({4-[({[(3-
fluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
504.5 670 ##STR846## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(3-
chlorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
521.0 671 ##STR847## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(3-
methylphenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
500.6 672 ##STR848## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(3-
(methyloxy)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benz-
amide 516.6 673 ##STR849##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-({4-[({[(3-
(trifluoromethyl)phenyl]methyl}amino)acetyl]amino}phen-
yl)ethynyl]benzamide 554.5 674 ##STR850##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{[4-({[({3-
[(trifluoromethyl)oxy]phenyl}methyl)amino]acetyl}amino)phen-
yl]ethynyl}benzamide 570.5 675 ##STR851##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{[4-[({[(4-
fluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
504.5 676 ##STR852## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-[({[(4-
chlorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
521.0
[0956] TABLE-US-00065 Example Structure Name MH+ 677 ##STR853##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-({4-[({[(4-
methylphenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
500.6 678 ##STR854## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[({[4-
(methyloxy)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benzamide
516.6 679 ##STR855## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[({[4-
(trifluoromethyl)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benzamid-
e 554.5 680 ##STR856## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[({[4-(1,1-
dimethylethyl)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benzamide
542.6 681 ##STR857## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(1R)-1-
phenylethyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 500.6 682
##STR858## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(1S)-1-
phenylethyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 500.6 683
##STR859## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-
({[(cyclohexylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide
492.6 684 ##STR860## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(cyclobutylamino)acetyl]amino}phenyl)ethynyl]benzamide 450.5 685
##STR861## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(cyclopentylamino)acetyl]amino}phenyl)ethynyl]benzamide 464.5 686
##STR862## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(cyclohexylamino)acetyl]amino}phenyl)ethynyl]benzamide 478.6 687
##STR863## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(cycloheptylamino)acetyl]amino}phenyl)ethynyl]benzamide 492.6 688
##STR864## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(cyclooctylamino)acetyl]amino}phenyl)ethynyl]benzamide 506.6 689
##STR865## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(ethylamino)acetyl]amino}phenyl)ethynyl]benzamide 424.5 690
##STR866## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(propylamino)acetyl]amino}phenyl)ethynyl]benzamide 438.5 691
##STR867## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(butylamino)acetyl]amino}phenyl)ethynyl]benzamide 452.5 692
##STR868## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(hexylamino)acetyl]amino}phenyl)ethynyl]benzamide 480.6 693
##STR869## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(1-
methylethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 438.5 694
##STR870## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(1,1-
dimethylethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 452.5 695
##STR871## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-
({[ethyl(methyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 438.5
696 ##STR872## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(diethylamino)acetyl]amino}phenyl)ethynyl]benzamide 452.5 697
##STR873## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(1,1-
dimethylethyl)(methyl)amino]acetyl}amino)phenyl]ethynyl}benzamide
466.6 698 ##STR874## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-
({[cyclohexyl(methyl)amino]acetyl}amino)phenyl]ethynyl}benzamide
492.6 699 ##STR875## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[2-(2-
fluorophenyl)ethyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
518.6 700 ##STR876## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[2-(3-
fluorophenyl)ethyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
518.6 701 ##STR877## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[2-(4-
fluorophenyl)ethyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
518.6 702 ##STR878## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(1S,2R)-2-
phenylcyclopropyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 512.6
703 ##STR879## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(2,4-
difluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
522.5 704 ##STR880## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(2,4-
dichlorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
555.4 705 ##STR881## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[({[4-fluoro-2-
(trifluoromethyl)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benzamid-
e 572.5 706 ##STR882## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(2,5-
difluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
522.5 707 ##STR883## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(3,4-
difluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
522.5 708 ##STR884## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(3,4-
dichlorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
555.4 709 ##STR885## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(3,4-
dimethylphenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
514.6 710 ##STR886## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(3,5-
difluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
522.5 711 ##STR887## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(3,5-
dichlorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
555.4 712 ##STR888## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[({[3,5-
bis(trifluoromethyl)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benz-
amide 622.5 713 ##STR889##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-({4-[({[(4-
nitrophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
531.5 714 ##STR890## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-[{(pyridin-2-
ylamino)acetyl]amino}phenyl)ethynyl]benzamide 473.5 715 ##STR891##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-[{(pyridin-3-
ylamino)acetyl]amino}phenyl)ethynyl]benzamide 473.5 716 ##STR892##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{[4-({[(2-
fluorophenyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 490.5 717
##STR893## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(3-
fluorophenyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 490.5 718
##STR894## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(4-
fluorophenyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 490.5 719
##STR895## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(pyridin-4-
ylamino)acetyl]amino}phenyl)ethynyl]benzamide 473.5 720 ##STR896##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2,2,2-
trifluoroethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 478.4
721 ##STR897## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4- {[(pyridin-2-
ylamino)acetyl]amino}phenyl)ethynyl]benzamide 488.5 722 ##STR898##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(4-
{[(pyridin-3- ylamino)acetyl]amino}phenyl)ethynyl]benzamide 488.5
723 ##STR899## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4- {[(pyridin-4-
ylamino)acetyl]amino}phenyl)ethynyl]benzamide 488.5 724 ##STR900##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(4-{[(4-
phenylpiperazin-1- yl)acetyl]amino}phenyl)ethynyl]benzamide 556.6
725 ##STR901## 4-{[4-({[4-(4-fluorophenyl)piperazin-1-
yl]acetyl}amino)phenyl]ethynyl}-N-{(1S,2R)- 2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 574.6 726 ##STR902##
4-{{4-({[(1-acetylpiperidin-4-
yl)cyclopropyl)amino]acetyl}amino)phenyl]ethynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 576.7 727 ##STR903##
4-[(4- {[(butylamino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
467.5 728 ##STR904## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4- [({[(1R)-1-
phenylethyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 515.6 729
##STR905## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4- [({[(1S)-1-
phenylethyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 515.6 730
##STR906## 4-{[4-
({[cyclopropyl(methyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
465.5 731 ##STR907## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-
({[methyl(phenylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide
515.6 732 ##STR908## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-
({[cyclopropyl(methyl)amino]acetyl}amino)phenyl]ethynyl}benzamide
450.5 733 ##STR909## 4-[(4-{[(2S)-2-
aminopropanoyl]amino}phenyl)ethynyl]-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 425.5 734 ##STR910##
4-[(4-{[(2R)-2- aminopropanoyl]amino}phenyl)ethynyl]-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
425.5 735 ##STR911## 4-[(4-{[(2S)-2-amino-3-
methylbutanoyl]amino}phenyl)ethynyl]-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 453.5 736 ##STR912##
4-[(4-{[(2S,3R)-2-amino-3- hydroxybutanoyl]amino}phenyl)ethynyl]-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
455.5 737 ##STR913## (2S)-N-[4-({4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)phenyl]pyr-
rolidine-2-carboxamide 451.5 738 ##STR914##
4-[(4-{[(2S)-2-amino-3-(1H-imidazol-4-
yl)propanoyl]amino}phenyl)ethynyl]-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 491.5 739 ##STR915##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(4-
{[(methyloxy)acetyl]amino}phenyl)ethynyl]benzamide 426.4 740
##STR916## 4-[(4-{[(2S)-2-amino-3-
methylbutanoyl]amino}phenyl)ethynyl]-N-
[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 438.5
741 ##STR917## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(3-
phenylpropyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 514.6 742
##STR918## N-{(1S,2R)--2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(thien-2- ylethynyl)benzamide
345.4 743 ##STR919## 4-({4-[((2S)-2-{[(2S)-2,5-
diaminopentanoyl]amino}-3- phenylpropanoyl)amino]phenyl}ethynyl)-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
615.7 744 ##STR920## 3,4-dihydroxy-N-[(2S)-3-(hydroxyamino)-3-
oxo-2-({[4- (phenylethynyl)phenyl]carbonyl}amino)propyl]benzamide
460.5 745 ##STR921## 1,1-dimethylethyl 3-[(2-{[(2S)-3-
(hydroxyamino)-3-oxo-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)propyl]amino}-
2-oxoethyl)amino]propylcarbamate 538.6 746 ##STR922##
N-[(1S)-2-(hydroxyamino)-1-({[(4-
methylpiperazin-1-yl)acetyl]amino}methyl)-2-
oxoethyl]-4-(phenylethynyl)benzamide 464.5 747 ##STR923##
4-{[4-({2-[(2-aminoethyl)amino]-2-
oxoethyl}oxy)phenyl]ethynyl}-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 455.5 748 ##STR924##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{[3-
(aminomethyl)phenyl]ethynyl}benzamide 353.4 749 ##STR925##
1,1-dimethylethyl (2S)-3-(hydroxyamino)-2-
[({4-[(4-{[2-(hydroxyamino)-2-
oxoethyl]oxy}phenyl)ethynyl]phenyl}carbonyl)amino]-3-oxopropylcarbamate
513.5 750 ##STR926## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[2-(hydroxyamino)-2-
oxoethyl]oxy}phenyl)ethynyl]benzamide 413.4 751 ##STR927##
3,4-dihydroxy-N-(2-{[4-({4-[({(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)phen-
yl]amino}-2-oxoethyl)benzamide 547.5 752 ##STR928##
4-({4-[({[(2S)-2,5-
diaminopentanoyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}benzamide
525.6 753 ##STR929## 4-[(4-{[(2-
aminoethyl)amino]carbonyl}phenyl)ethynyl]- N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 425.5 754 ##STR930##
N-[(1S)-1-[({[(3- aminopropyl)amino]acetyl}amino)methyl]-2-
(hydroxyamino)-2-oxoethyl]-4- (phenylethynyl)benzamide 438.5 755
##STR931## 3-({4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)benzoic
acid 383.4 756 ##STR932## 4-{[4-({[(3-
aminopropyl)amino]acetyl}amino)phenyl]ethynyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 468.5 757 ##STR933##
N-{(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(pyrazin-2-ylethynyl)benzamide 326.3 758 ##STR934##
4-({3-[(4- aminobutanoyl)amino]phenyl}ethynyl)-N-
[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 424.5
759 ##STR935## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(2S)-2,5-
diaminopentanoyl]amino}phenyl)ethynyl]benzamide 453.5 760
##STR936## 4-({2-[(aminoacetyl)amino]phenyl}ethynyl)-N-
[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 396.4
761 ##STR937## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[2-(ethylamino)-2-
oxoethyl]phenyl}ethynyl)benzamide 409.5 762 ##STR938##
4-({4-[(aminoacetyl)amino]-3- methylphenyl}ethynyl)-N-[(1S)-1-
(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 410.4 763
##STR939## 4-({4-[(aminoacetyl)amino]phenyl}ethynyl)-N-
[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-3-fluorobenzamide 414.4 764 ##STR940##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{[4-
({[(cyanomethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 435.5
765 ##STR941## [4-({4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)phenyl]aceti-
c acid 397.4 766 ##STR942##
4-amino-2-({[4-({4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)phen-
yl]carbonyl}amino)-4-oxobutanoic acid 497.5 767 ##STR943##
4-amino-2-[({[4-({4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phen-
yl}ethynyl]oxy}acetyl)amino]-4-oxobutanoic acid 527.5 768
##STR944## N-((1S)-2-(hydroxyamino)-1-{[(morpholin-4-
ylacetyl)amino]methyl}-2-oxoethyl)-4- (phenylethynyl)benzamide
451.5 769 ##STR945## N-[(1S)-1-[({[(2,3-
dihydroxypropyl)thio]acetyl}amino)methyl]-2-
(hydroxyamino)-2-oxoethyl]-4- (phenylethynyl)benzamide 472.5 770
##STR946## methyl (2S)-3-amino-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)propanoate 323.4 771
##STR947## N-{(1S)-2-(hydroxyamino)-2-oxo-1-[({[(2-
phenylethyl)amino]acetyl}amino)methyl]ethyl}-4-(phenylethynyl)benzamide
485.6 772 ##STR948## 4-[(4-{2-[(2-aminoethyl)amino]-2-
oxoethyl)phenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 439.5 773 ##STR949##
4-[(4-{[(6- aminohexyl)amino]carbonyl}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
481.6 774 ##STR950## 4-[4-(4-
{[(ethylamino)acetyl]amino)phenyl)buta-1,3-
diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 463.5 775 ##STR951##
4-[4-(4-
{[(cyclopropylamino}phenyl)buta-1,3-diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 475.5 776 ##STR952##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-(4-{4-
[(piperidin-1-ylacetyl)amino]phenyl}buta-1,3- diynyl)benzamide
503.6 777 ##STR953## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[4-(4-
{[(phenylamino)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 511.5
778 ##STR954## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{4-[4-
({[(phenylmethyl)amino]acetyl}amino)phenyl]buta-1,3-diynyl}benzamide
525.6 779 ##STR955## N-{(1S,2R)-2-amino-1-
[(hydroxyamino)carbonyl]propyl}-4'-ethyl-1,1'-
biphenyl-4-carboxamide 342.4 780 ##STR956## 4-[(4-
{[(dimethylamino)acetyl]amino}phenyl)ethynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 439.5 781 ##STR957##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-({4-
[(pyrrolidin-1- ylacetyl)amino]phenyl}ethynyl)benzamide 465.5 782
##STR958## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-
{[(pentylamino)acetyl]amino}phenyl)ethynyl]benzamide 481.6 783
##STR959## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[(thien-2-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 507.6 784
##STR960## 4-{[4-({[(1H-benzimidazol-2-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
541.6 785 ##STR961## 4-{[4-({[(1-benzothien-3-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
557.6 786 ##STR962## 4-(4-{4-[({[(2-
fluorophenyl)methyl]amino}acetyl)amino]phenyl}buta-
1,3-diynyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 543.6 787 ##STR963##
4-(4-{4-[({[(3- fluorophenyl)methyl]amino}acetyl)amino]phenyl}buta-
1,3-diynyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 543.6 788 ##STR964##
4-(4-{4-[({[(4- fluorophenyl)methyl]amino}acetyl)amino]phenyl}buta-
1,3-diynyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 543.6 789 ##STR965##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-(4-{4-
[({[(2-
methylphenyl)methyl]amino}acetyl)amino]phenyl}buta-1,3-diynyl)benzamide
539.6 790 ##STR966## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(4-{4- [({[(3-
methylphenyl)methyl]amino}acetyl)amino]phenyl}buta-1,3-diynyl)benzamide
539.6 791 ##STR967## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(4-{4- [({[(4-
methylphenyl)methyl]amino}acetyl)amino]phenyl}buta-1,3-diynyl)benzamide
539.6 792 ##STR968## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{4-[4- ({[(pyridin-2-
ylmethyl)amino]acetyl}amino)phenyl]buta-1,3- diynyl}benzamide 526.6
793 ##STR969## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{4-[4- ({[(pyridin-3-
ylmethyl)amino]acetyl}amino)phenyl]buta-1,3- diynyl}benzamide 526.6
794 ##STR970## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{4-[4- ({[(pyridin-4-
ylmethyl)amino]acetyl}amino)phenyl]buta-1,3- diynyl}benzamide 526.6
795 ##STR971## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{4-[4- {[({[2-
(methyloxy)phenyl]methyl}amino)acetyl]amino}phenyl)buta-
1,3-diynyl]benzamide 555.6 796 ##STR972## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{4-[4- {[({[3-
(methyloxy)phenyl]methyl}amino)acetyl]amino}phenyl)buta-
1,3-diynyl]benzamide 555.6 797 ##STR973## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{4-[4- {[({[4-
(methyloxy)phenyl]methyl}amino)acetyl]amino}phenyl)buta-
1,3-diynyl]benzamide 555.6 798 ##STR974## 4-{4-[4-({[(2-
fluorophenyl)amino]acetyl)amino)phenyl]buta-
1,3-diynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 529.5 799 ##STR975##
4-{4-[4-({[(3- fluorophenyl)amino]acetyl)amino)phenyl]buta-
1,3-diynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 529.5 800 ##STR976##
4-{4-[4-({[(4- fluorophenyl)amino]acetyl)amino)phenyl]buta-
1,3-diynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 529.5 801 ##STR977##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[4-(4-
{[(pyridin-2- ylamino)acetyl]amino}phenyl)buta-1,3-diynyl]benzamide
512.5 802 ##STR978## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[4-(4- {[(pyridin-3-
ylamino)acetyl]amino}phenyl)buta-1,3-diynyl]benzamide 512.5 803
##STR979## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[4-(4- {[(pyridin-4-
ylamino)acetyl]amino}phenyl)buta-1,3-diynyl]benzamide 512.5 804
##STR980## 4-[4-(4- {[(cyclobutylamino)acetyl]amino}phenyl)buta-
1,3-diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 489.5 805 ##STR981##
4-[4-(4- {[(cyclopentylamino)acetyl]amino}phenyl)buta-
1,3-diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 503.6 806 ##STR982##
4-[4-(4- {[(cyclohexylamino)acetyl]amino}phenyl)buta-
1,3-diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 517.6 807 ##STR983##
4-[4-(4- {[(cycloheptylamino)acetyl]amino}phenyl)buta-
1,3-diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 531.6 808 ##STR984##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[4-(4-
{[(methylamino)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 449.5
809 ##STR985## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[4-(4-
{[(propylamino)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 477.5
810 ##STR986## 4-[4-(4- {[(butylamino)acetyl]amino}phenyl)buta-1,3-
diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 491.6 811 ##STR987##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[4-(4-
{[(pentylamino)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 505.6
812 ##STR988## 4-[4-(4- {[(hexylamino)acetyl]amino}phenyl)buta-1,3-
diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 519.6 813 ##STR989##
4-{4-[4- ({[ethyl(methyl)amino]acetyl}amino)phenyl]buta-
1,3-diynyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 477.5 814 ##STR990##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{4-[4-
({[(1- methylethyl)amino]acetyl}amino)phenyl]buta-
1,3-diynyl}benzamide 477.5 815 ##STR991## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{4-[4- ({[(2-
methylpropyl)amino]acetyl}amino)phenyl]buta- 1,3-diynyl}benzamide
491.6 816 ##STR992## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{4-[4- ({[(2,2,2-
trifluoroethyl)amino]acetyl}amino)phenyl]buta-1,3-diynyl}benzamide
517.5 817 ##STR993## 4-{4-[4-({[(2-
hydroxyethyl)amino]acetyl}amino)phenyl]buta-
1,3-diynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 479.5 818 ##STR994##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-(4-{4-
[({[2-
(methyloxy)ethyl]amino}acetyl)amino]phenyl}buta-1,3-diynyl)benzamide
493.5 819 ##STR995## 4-(4-{4-[({[2-
(dimethylamino)ethyl]amino}acetyl)amino]phenyl}buta-
1,3-diynyl)-N-{(1S,2R)-2-hydroxy-
1-[(hydroxyamino)carbonyl]propyl}benzamide 506.6 820 ##STR996##
4-{4-[4-({[(2- cyanoethyl)amino]acetyl}amino)phenyl]buta-
1,3-diynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 488.5 821 ##STR997##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-(4-{4-
[(pyrrolidin-1-ylacetyl)amino]phenyl}buta-1,3- diynyl)benzamide
489.5 822 ##STR998## 4-(4-{4-[(azepan-1-
ylacetyl)amino]phenyl}buta-1,3-diynyl)-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 517.6 823 ##STR999##
N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[4-(4-{[(4- methylpiperazin-1-
yl)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 518.6 824
##STR1000## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(4-{4-
[(morpholin-4-ylacetyl)amino]phenyl}buta-1,3- diynyl)benzamide
505.5 825 ##STR1001## 4-{4-[4-
({[cyclohexyl(methyl)amino]acetyl}amino)phenyl]buta-
1,3-diynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 531.6 826 ##STR1002##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-(4-{4-
[({[(1R)-1- phenylethyl]amino}acetyl)amino]phenyl}buta-
1,3-diynyl)benzamide 539.6 827 ##STR1003## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(4-{4- [({[(1S)-1-
phenylethyl]amino}acetyl)amino]phenyl}buta- 1,3-diynyl)benzamide
539.6 828 ##STR1004## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{4-[4- ({[(2-
phenylethyl)amino]acetyl}amino)phenyl]buta- 1,3-diynyl}benzamide
539.6 829 ##STR1005## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(4-{4-
[(1H-imidazol-1-ylacetyl)amino]phenyl}buta- 1,3-diynyl)benzamide
486.5 830 ##STR1006## 4-{4-[4-({[(1R,2R,4S)-bicyclo[2.2.1]hept-2-
ylamino]acetyl}amino)phenyl]buta-1,3-
diynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 529.6 831 ##STR1007##
4-{4-[4- ({[(cyclohexylmethyl)amino]acetyl}amino)phenyl]buta-
1,3-diynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 531.6 832 ##STR1008##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4'-ethyl-2-fluoro-1,1'-biphenyl-4- carboxamide 346.4 833
##STR1009## 4-({4-[(aminoacetyl)amino]phenyl}ethynyl)-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-3-
(methyloxy)benzamide 441.5 834 ##STR1010##
4'-ethyl-N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-2-
(methyloxy)-1,1'-biphenyl-4-carboxamide 373.4 835 ##STR1011##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-3-
(methyloxy)-4-(phenylethynyl)benzamide 369.4 836 ##STR1012##
4-[(4-ethylphenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 367.4 837 ##STR1013##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(4-
hydroxyphenyl)ethynyl]benzamide 355.4 838 ##STR1014##
2-[(2-{[(2S)-3-(hydroxyamino)-3-oxo-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)propyl]amino}-
2-oxoethyl)thio]propanoic acid 470.5 839 ##STR1015##
4-amino-2-[(2-{[(2S)-3-(hydroxyamino)-3-oxo- 2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)propyl]amino}-
2-oxoethyl)amino]-4-oxobutanoic acid 496.5 840 ##STR1016##
1,1-dimethylethyl 4-amino-2-[(2-{[(2S)-3-
(hydroxyamino)-3-oxo-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)propyl]amino}-
2-oxoethyl)amino]-4-oxobutanoate 552.6 841 ##STR1017##
2,6-dihydroxy-N-[(2S)-3-(hydroxyamino)-3- oxo-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)propyl]pyridine-4-carboxamide
461.4 842 ##STR1018## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4- aminophenyl)ethynyl]benzamide 339.4 843
##STR1019## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4- ethylphenyl)ethynyl]benzamide 352.4 844
##STR1020## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-ethylphenyl)ethynyl]-3- fluorobenzamide 370.4 845
##STR1021## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(3- aminopropanoyl)amino]phenyl}ethynyl)benzamide
410.4 846 ##STR1022## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(dimethylamino)acetyl]amino)phenyl)ethynyl]benzamide 424.5 847
##STR1023## 4-({4-[(4- aminobutanoyl)amino]phenyl}ethynyl)-N-
[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 424.5
848 ##STR1024## N-{(1S)-2-(hydroxyamino)-1-[({[2-
(methyloxy)phenyl]methyl}amino)methyl]-2-
oxoethyl}-4-(phenylethynyl)benzamide 444.5 849 ##STR1025##
N-[(1S)-1-[(diprop-2-enylamino)methyl]-2-
(hydroxyamino)-2-oxoethyl]-4- (phenylethynyl)benzamide 404.5 850
##STR1026## N-[(1S)-2-(hydroxyamino)-1-({[({[2-
(methyloxy)phenyl]methyl}amino)acetyl]amino}methyl)-2-oxoethyl]-4-
(phenylethynyl)benzamide 501.6 851 ##STR1027##
N-[(1S)-2-(hydroxyamino)-1-{[({[2-
(methyloxy)phenyl]thio}acetyl)amino]methyl}-
2-oxoethyl)-4-(phenylethynyl)benzamide 504.6 852 ##STR1028##
(2S,3R)-3-amino-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)butanoic acid 323.4 853
##STR1029## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4- {[(dimethylamino)acetyl]amino}phenyl)buta-
1,3-diynyl]benzamide 448.5 854 ##STR1030##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-[4-(4-
{[(ethylamino)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 448.5
855 ##STR1031## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4-
{[(cyclopropylamino)acetyl]amino}phenyl)buta-1,3-diynyl]benzamide
460.5 856 ##STR1032## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[(piperidin-1- ylacetyl)amino]phenyl}buta-1,3-
diynyl)benzamide 488.6 857 ##STR1033##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-[4-(4-
{[(phenylamino)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 496.5
858 ##STR1034## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-
({[(phenylmethyl)amino]acetyl}amino)phenyl]buta-1,3-diynyl}benzamide
510.6 859 ##STR1035## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4-aminophenyl)buta-1,3- diynyl]benzamide 363.4 860
##STR1036## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4- {[(pyrazin-2-
ylamino)acetyl]amino}phenyl)ethynyl]benzamide 489.5 861 ##STR1037##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(4-{[(4-
phenylpiperidin-1- yl)acetyl]amino}phenyl)ethynyl]benzamide 555.6
862 ##STR1038## 4-{[4-({[4-(2-fluorophenyl)piperazin-1-
yl]acetyl}amino)phenyl]ethynyl}-N-{(1S,2R)- 2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 574.6
863 ##STR1039## 4-{[4-({[(1S,4R)-bicyclo[2,2,1]hept-2-
ylamino]acetyl}amino)phenyl]ethynyl}-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 505.6 864 ##STR1040##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-({4-
[({[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-
yl]amino}acetyl)amino]phenyl}ethynyl)benzamide 547.7 865
##STR1041## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-
({[(tricyclo[3.3.1.1.about.3,7.about.]dec-1-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 559.7 866
##STR1042## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[(4-
methylcyclohexyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 507.6
867 ##STR1043## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[(2,2,2-
trifluoroethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 493.5
868 ##STR1044## 4-({4-[({[2-(2-
fluorophenyl)ethyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
533.6 869 ##STR1045## 4-({4-[({[2-(3-
fluorophenyl)ethyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
533.6 870 ##STR1046## 4-({4-[({[2-(4-
fluorophenyl)ethyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
533.6 871 ##STR1047## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4- [({[(1S,2R)-2-
phenylcyclopropyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 527.6
872 ##STR1048## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[({[(2-
methylphenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
515.6 873 ##STR1049## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-{[({[2-
(trifluoromethyl)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benzamid-
e 569.5 874 ##STR1050## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[({2-
[(trifluoromethyl)oxy]phenyl}methyl)amino]acetyl}amino)phen-
yl]ethynyl}benzamide 585.5 875 ##STR1051## 4-({4-[({[(4-
chlorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
536.0 876 ##STR1052## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-{[({[4-
(methyloxy)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benzamide
531.6 877 ##STR1053## 4-[(4-{[({[4-(1,1-
dimethylethyl)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
557.7 878 ##STR1054## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[({[(4-
nitrophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
546.5 879 ##STR1055## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[({4-
[(trifluoromethyl)oxy]phenyl}methyl)amino]acetyl}amino)phen-
yl]ethynyl}benzamide 585.5 880 ##STR1056## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-[(4-{[({[4-
(methylthio)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benzamide
547.6 881 ##STR1057## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[({4-
[(trifluoromethyl)thio]phenyl}methyl)amino]acetyl}amino)phen-
yl]ethynyl}benzamide 601.6 882 ##STR1058## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-{[({[4-
(methylsulfonyl)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benzamide
579.6 883 ##STR1059## 4-({4-[({[(2,5-
difluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
537.5 884 ##STR1060## 4-({4-[({[(2,6-
difluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
537.5 885 ##STR1061## 4-({4-[({[(3,4-
difluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
537.5 886 ##STR1062## 4-({4-[({[(3,4-
dichlorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
570.4 887 ##STR1063## 4-({4-[({[(3,4-
dimethylphenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
529.6 888 ##STR1064## 4-({4-[({[(3,5-
dichlorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
570.4 889 ##STR1065## 4-({4-[({[(3,5-
bis(trifluoromethyl)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]-
N-{(1S,2R)-2- hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
637.5 890 ##STR1066## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4- [({[(2,3,4-
trifluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
555.5 891 ##STR1067## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4- [({[(2,4,5-
trifluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
555.5 892 ##STR1068## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4- [({[(3,4,5-
trifluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
555.5 893 ##STR1069## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(pentylamino)acetyl]amino}phenyl)ethynyl]benzamide 466.6 894
##STR1070## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(thien-2-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 492.6 895
##STR1071## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(4-phenylpiperidin-1-
yl)acetyl]amino}phenyl)ethynyl]benzamide 540.6 896 ##STR1072##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(4-phenylpiperazin-1-
yl)acetyl]amino}phenyl)ethynyl]benzamide 541.6 897 ##STR1073##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[4-(2- fluorophenyl)piperazin-1-
yl]acetyl}amino)phenyl]ethynyl}benzamide 559.6 898 ##STR1074##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[4-(4- fluorophenyl)piperazin-1-
yl]acetyl}amino)phenyl]ethynyl}benzamide 559.6 899 ##STR1075##
4-{[4-({[(1-acetylpiperidin-4-
yl)(cyclopropyl)amino]acetyl}amino)phenyl]ethynyl}-
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-oxoethyl]benzamide 561.7
900 ##STR1076## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2,3-
dimethylcyclohexyl)amino]acetyl}amino)phenyl]ethynyl}benzamide
506.6 901 ##STR1077## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(1R,2R,4S)- bicyclo[2.2.1]hept-2-
ylamino]acetyl}amino)phenyl]ethynyl}benzamide 490.6 902 ##STR1078##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[({[(1S,2R,5S)-6,6- dimethylbicyclo[3.1.1]hept-2-
yl]methyl}amino)acetyl]amino}phenyl)ethynyl]benzamide 532.7 903
##STR1079## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(1S,4R)-bicyclo[2.2.1]hept- 2-
ylamino]acetyl}amino)phenyl]ethynyl}benzamide 490.6 904 ##STR1080##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(1S,2S,3S,5R)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-
yl]amino}acetyl)amino]phenyl}ethynyl)benzamide 532.7 905
##STR1081## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(tricyclo[3.3.1.1.about.3,7.about.]dec- 1-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 544.7 906
##STR1082## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(2,6-
difluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
522.5 907 ##STR1083## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[({[4-
(methylthio)phenyl]methyl}amino)acetyl]amino}phenyl)ethynyl]benzamide
532.6 908 ##STR1084## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[({[4-
(methylsulfonyl)yl]methyl}amino)acetyl]amino}phenyl)ethynyl]benzamide
564.6 909 ##STR1085## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[({4-
[(trifluoromethyl)thio]phenyl}methyl)amino]acetyl}amino)phen-
yl]ethynyl}benzamide 586.6 910 ##STR1086##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{[4-({[({4-
[(trifluoromethyl)oxy]phenyl}methyl)amino]acetyl}amino)phen-
yl]ethynyl}benzamide 570.5 911 ##STR1087##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(2,4,5-
trifluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
540.5 912 ##STR1088## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(2,3,4-
trifluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
540.5 913 ##STR1089## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(3,4,5-
trifluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
540.5 914 ##STR1090## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[(pyrrolidin-1- ylacetyl)amino]phenyl}buta-1,3-
diynyl)benzamide 474.5 915 ##STR1091##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[(azepan-1- ylacetyl)amino]phenyl}buta-1,3-
diynyl)benzamide 502.6 916 ##STR1092##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[(piperazin-1- ylacetyl)amino]phenyl}buta-1,3-
diynyl)benzamide 489.5 917 ##STR1093##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4-{[(4-methylpiperazin-1-
yl)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 503.6 918
##STR1094## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[(morpholin-4- ylacetyl)amino]phenyl}buta-1,3-
diynyl)benzamide 490.5 919 ##STR1095##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{4-[4-
({[cyclohexyl(methyl)amino]acetyl}amino)phenyl]buta-1,3-diynyl}benzamide
516.6 920 ##STR1096## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[({[(2-
fluorophenyl)methyl]amino}acetyl)amino]phenyl}buta-1,3-diynyl)benzamide
528.6 921 ##STR1097## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[({[(3-
fluorophenyl)methyl]amino}acetyl)amino]phenyl}buta-1,3-diynyl)benzamide
528.6 922 ##STR1098## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[({[(4-
fluorophenyl)methyl]amino}acetyl)amino]phenyl}buta-1,3-diynyl)benzamide
528.6 923 ##STR1099## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[({[(2-
methylphenyl)methyl]amino}acetyl)amino]phenyl}buta-1,3-diynyl)benzamide
524.6 924 ##STR1100## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[({[(3-
methylphenyl)methyl]amino}acetyl)amino]phenyl}buta-1,3-diynyl)benzamide
524.6 925 ##STR1101## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[({[(4-
methylphenyl)methyl]amino}acetyl)amino]phenyl}buta-1,3-diynyl)benzamide
524.6 926 ##STR1102## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(pyridin-2-
ylmethyl)amino]acetyl}amino)phenyl]buta-1,3- diynyl}benzamide 511.6
927 ##STR1103## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(pyridin-3-
ylmethyl)amino]acetyl}amino)phenyl]buta-1,3- diynyl}benzamide 511.6
928 ##STR1104## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(pyridin-4-
ylmethyl)amino]acetyl}amino)phenyl]buta-1,3- diynyl}benzamide 511.6
929 ##STR1105## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4-{[({[2-
(methyloxy)phenyl]methyl}amino)acetyl]amino}phenyl)buta-
1,3-diynyl]benzamide 540.6 930 ##STR1106##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4-{[({[3-
(methyloxy)phenyl]methyl}amino)acetyl]amino}phenyl)buta-
1,3-diynyl]benzamide 540.6 931 ##STR1107##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4-{[({[4-
(methyloxy)phenyl]methyl}amino)acetyl]amino}phenyl)buta-
1,3-diynyl]benzamide 540.6 932 ##STR1108##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(2-
fluorophenyl)amino]acetyl}amino)phenyl]buta- 1,3-diynyl}benzamide
514.5 933 ##STR1109## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(3-
fluorophenyl)amino]acetyl}amino)phenyl]buta- 1,3-diynyl}benzamide
514.5 934 ##STR1110## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(4-
fluorophenyl)amino]acetyl}amino)phenyl]buta- 1,3-diynyl}benzamide
514.5 935 ##STR1111## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4-{[(pyridin-2-
ylamino)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 497.5 936
##STR1112## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4-{[(pyridin-3-
ylamino)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 497.5 937
##STR1113## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4-{[(pyridin-4-
ylamino)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 497.5 938
##STR1114## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4- {[(cyclobutylamino)acetyl]amino}phenyl)buta-
1,3-diynyl]benzamide 474.5 939 ##STR1115##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-[4-(4-
{[(cyclopentylamino)acetyl]amino}phenyl)buta- 1,3-diynyl]benzamide
488.6 940 ##STR1116## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4- {[(cyclohexylamino)acetyl]amino}phenyl)buta-
1,3-diynyl]benzamide 502.6 941 ##STR1117##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-[4-(4-
{[(cycloheptylamino)acetyl]amino}phenyl)buta- 1,3-diynyl]benzamide
516.6 942 ##STR1118## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4- {[(methylamino)acetyl]amino}phenyl)buta-1,3-
diynyl]benzamide 434.5 943 ##STR1119##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-[4-(4-
{[(propylamino)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 462.5
944 ##STR1120## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4- {[(butylamino)acetyl]amino}phenyl)buta-1,3-
diynyl]benzamide 476.5 945 ##STR1121##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-[4-(4-
{[(pentylamino)acetyl]amino}phenyl)buta-1,3- diynyl]benzamide 490.6
946 ##STR1122## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4- {[(hexylamino)acetyl]amino}phenyl)buta-1,3-
diynyl]benzamide 504.6 947 ##STR1123##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{4-[4-
({[ethyl(methyl)amino]acetyl}amino)phenyl]buta-1,3-diynyl}benzamide
462.5 948 ##STR1124## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(1-
methylethyl)amino]acetyl}amino)phenyl]buta- 1,3-diynyl}benzamide
462.5 949 ##STR1125## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(2-
methylpropyl)amino]acetyl}amino)phenyl]buta- 1,3-diynyl}benzamide
476.5 950 ##STR1126## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(2-
hydroxyethyl)amino]acetyl}amino)phenyl]buta- 1,3-diynyl}benzamide
464.5 951 ##STR1127## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[({[2-
(methyloxy)ethyl]amino}acetyl)amino]phenyl}buta-1,3-diynyl)benzamide
478.5 952 ##STR1128## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[({[2-
(dimethylamino)ethyl]amino}acetyl)amino]phenyl}buta-1,3-diynyl)benzamide
491.6 953 ##STR1129## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(2- cyanoethyl)amino]acetyl}amino)phenyl]buta-
1,3-diynyl}benzamide 473.5 954 ##STR1130##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(thien-2-
ylmethyl)amino]acetyl}amino)phenyl]buta-1,3- diynyl}benzamide 516.6
955 ##STR1131## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[({[(1R)-1-
phenylethyl]amino}acetyl)amino]phenyl}buta- 1,3-diynyl)benzamide
524.6 956 ##STR1132## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[({[(1S)-1-
phenylethyl]amino}acetyl)amino]phenyl}buta- 1,3-diynyl)benzamide
524.6 957 ##STR1133## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(2-
phenylethyl)amino]acetyl}amino)phenyl]buta- 1,3-diynyl}benzamide
524.6 958 ##STR1134## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4-[(1H-imidazol-1- ylacetyl)amino]phenyl}buta-1,3-
diynyl)benzamide 471.5 959 ##STR1135##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(1R,2R,4S)- bicyclo[2.2.1]hept-2-
ylamino]acetyl}amino)phenyl]buta-1,3- diynyl}benzamide 514.6 960
##STR1136## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-
({[(cyclohexylmethyl)amino]acetyl}amino)phenyl]buta-1,3-diynyl}benzamide
516.6 961 ##STR1137## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(6-
piperidin-1-ylpyridin-3-yl)ethynyl]benzamide 423.5 962 ##STR1138##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[6-(4-
methylpiperazin-1-yl)pyridin-3- yl]ethynyl}benzamide 438.5 963
##STR1139## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(6-
piperazin-1-ylpyridin-3-yl)ethynyl]benzamide 424.5 964 ##STR1140##
4-[(6-azepan-1-ylpyridin-3-yl)ethynyl]-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 437.5 965 ##STR1141##
4-{[6-(cyclobutylamino)pyridin-3-yl]ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
409.5 966 ##STR1142## 4-{[6-(cyclohexylamino)pyridin-3-yl]ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
437.5 967 ##STR1143## 4-{[6-(butylamino)pyridin-3-yl]ethynyl)-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
411.5 968 ##STR1144## 4-({6-[(2-hydroxyethyl)amino]pyridin-3-
yl}ethynyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 399.4 969 ##STR1145##
4-[(6-{[2-(dimethylamino)ethyl]amino}pyridin-
3-yl)ethynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 426.5 970 ##STR1146##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-({6-
[(phenylmethyl)amino]pyridin-3- yl}ethynyl)benzamide 445.5 971
##STR1147## 4-[(6-{[(4-fluorophenyl)methyl]amino}pyridin-
3-yl)ethynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 463.5 972 ##STR1148##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[6-
(pyridin-4-ylamino)pyridin-3- yl]ethynyl}benzamide 432.4 973
##STR1149## 4-[(6-chloropyridin-3-yl)ethynyl]-N-{(1S,2R)-
2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide 374.8 974
##STR1150## 1,1-dimethylethyl (2S)-2-[({4-[(4-
ethylphenyl)ethynyl]phenyl}carbonyl)amino]-
3-(hydroxyamino)-3-oxopropylcarbamate 452.5 975 ##STR1151##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[(1S)-1-(aminomethyl)-2- (hydroxyamino)-2-
oxoethyl]amino}carbonyl)phenyl]buta-1,3- diynyl}benzamide 493.5 976
##STR1152## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- (morpholin-4-
ylmethyl)phenyl]ethynyl}benzamide 438.5 977 ##STR1153## 4-[(4-{[(2-
aminoethyl)amino]methyl}phenyl)ethynyl]-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 411.5 978 ##STR1154##
4-({4-[((2S)-2-amino-5-
{[amino(imino)methyl]amino}pentanoyl)amino]phenyl}ethynyl)-
N-[(1S)-1-(aminomethyl)-2- (hydroxyamino)-2-oxoethyl]benzamide
495.6 979 ##STR1155## (2S)-6-amino-2-({[4-({4-[({(1S,2R)-2-
hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)phen-
yl]carbonyl}amino)hexanoic acid 511.5 980 ##STR1156##
(2S)-6-amino-2-({[4-({4-[({(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)phen-
yl]acetyl}amino)hexanoic acid 525.6 981 ##STR1157##
5-{[(2S)-3-(hydroxyamino)-3-oxo-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)propyl]amino}-5-oxopentanoic
acid 438.4 982 ##STR1158##
N-(2-aminoethyl)-N'-[(2S)-3-(hydroxyamino)- 3-oxo-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)propyl]pentanediamide
480.5
983 ##STR1159## N-[(1S)-1-[(2,6-dioxopiperidin-1-yl)methyl]-2-
(hydroxyamino)-2-oxoethyl]-4- (phenylethynyl)benzamide 420.4 984
##STR1160## N,N'-bis[(2S)-3-(hydroxyamino)-3-oxo-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)propyl]pentanediamide 743.8
985 ##STR1161## N-((1S)-2-(hydroxyamino)-2-oxo-1-{[({[(1S)- 1-
phenylethyl]amino}acetyl)amino]methyl}ethyl)-4-(phenylethynyl)benzamide
485.6 986 ##STR1162## N-{(1S)-2-hydroxy-1-
[(hydroxyamino)carbonyl]-2-methylpropyl)-4-
(phenylethynyl)benzamide 353.4 987 ##STR1163##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(6-piperidin-1-ylpyridin-3- yl)ethynyl]benzamide 408.5
988 ##STR1164## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(6-morpholin-4-ylpyridin-3- yl)ethynyl]benzamide 410.4
989 ##STR1165## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[6-(4-methylpiperazin-1-
yl)pyridin-3-yl]ethynyl}benzamide 423.5 990 ##STR1166##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(6-piperazin-1-ylpyridin-3- yl)ethynyl]benzamide 409.5
991 ##STR1167## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(6-azepan-1-ylpyridin-3- yl)ethynyl]benzamide 422.5
992 ##STR1168## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[6-(cyclobutylamino)pyridin-3- yl]ethynyl}benzamide
394.4 993 ##STR1169## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[6-(cyclohexylamino)pyridin-3- yl]ethynyl}benzamide
422.5 994 ##STR1170## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[6-(butylamino)pyridin-3- yl]ethynyl}benzamide 396.5
995 ##STR1171## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(6-{[2- (methyloxy)ethyl]amino}pyridin-3-
yl)ethynyl]benzamide 398.4 996 ##STR1172## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl)-4-{[4- (piperidin-1-
ylmethyl)phenyl]ethynyl}benzamide 436.5 997 ##STR1173##
4-[(4-{[(2S)-2-amino-3-(4-
aminophenyl)propanoyl]amino}phenyl)ethynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 516.6 998 ##STR1174##
4-((2S)-2-amino-3-{[4-({4-[({(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}ethynyl)phen-
yl]amino}-3-oxopropyl)benzoic acid 545.6 999 ##STR1175## 573.6 1000
##STR1176## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[({[1- (hydroxymethyl)-2-
methylpropyl]amino}acetyl)amino]phenyl}ethynyl)benzamide 497.6 1001
##STR1177## 4-[4-(3-aminophenyl)buta-1,3-diynyl]-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
378.4 1002 ##STR1178## 4-[4-(3-{[(2-
aminoethyl)amino]methyl}phenyl)buta-1,3-
diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 435.5 1003 ##STR1179##
5-[(4-{[4-({[(1S)-1-(aminomethyl)-2- (hydroxyamino)-2-
oxoethyl]amino}carbonyl)phenyl]ethynyl}phenyl)amino]-5-oxopentanoic
acid 453.5 1004 ##STR1180## N-(2-aminoethyl)-3-{4-[4-({[(1S)-1-
(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]amino}carbonyl)phenyl]buta-1,3- diynyl}benzamide 434.5
1005 ##STR1181## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[3-(aminomethyl)phenyl]buta- 1,3-diynyl}benzamide
377.4 1006 ##STR1182## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[3- (trifluoromethyl)phenyl]buta-1,3-
diynyl}benzamide 416.4 1007 ##STR1183##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-buta-1,3-diynylbenzamide 272.3 1008 ##STR1184##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(2-methylphenyl)buta-1,3- diynyl]benzamide 362.4
1009 ##STR1185## 4-(4-{4-[(3- aminopropanoyl)amino]phenyl}buta-1,3-
diynyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 449.5 1010 ##STR1186##
{[(aminoacetyl)amino]methyl}phenyl)buta-1,3-
diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 449.5 1011 ##STR1187##
4-(4-{3-[(aminoacetyl)amino]phenyl}buta-1,3-
diynyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 435.4 1012 ##STR1188##
4-[4-(4-{[(2S)-2- aminopropanoyl]amino}phenyl)buta-1,3-
diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 449.5 1013 ##STR1189##
4-(4-{4-[(aminoacetyl)amino]phenyl}buta-1,3-
diynyl)-N-[(1S)-1-(aminomethyl)-2-
(hydroxyamino)-2-oxoethyl]benzamide 420.4 1014 ##STR1190## 4-[4-(3-
{[(aminoacetyl)amino]methyl}phenyl)buta-1,3-
diynyl]-N-[(1S)-1-(aminomethyl)-2-
(hydroxyamino)-2-oxoethyl]benzamide 434.5 1015 ##STR1191##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-(4-{4-[(3-
aminopropanoyl)amino]phenyl}buta-1,3- diynyl)benzamide 434.5 1016
##STR1192## 4-(4-{3-[(aminoacetyl)amino]phenyl}buta-1,3-
diynyl)-N-[(1S)-1-(aminomethyl)-2-
(hydroxyamino)-2-oxoethyl]benzamide 420.4 1017 ##STR1193##
4-[(4-{[(2S)-2-amino-3-(4-
hydroxyphenyl)propanoyl]amino}phenyl)ethynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 517.6 1018 ##STR1194##
4-(4-{4-[(aminoacetyl)amino]phenyl}buta-1,3-
diynyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 435.4 1019 ##STR1195##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-({4-
[(butylamino)methyl]phenyl}ethynyl)benzamide 409.5 1020 ##STR1196##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-(piperidin-1- ylmethyl)phenyl]ethynyl}benzamide
421.5 1021 ##STR1197## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4- formylphenyl)ethynyl]benzamide 352.4 1022
##STR1198## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-
[(methylsulfonyl)amino]phenyl}ethynyl)benzamide 432.5 1023
##STR1199## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(methylsulfonyl)amino]phenyl}ethynyl)benzamide
417.5 1024 ##STR1200## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(phenylsulfonyl)amino]phenyl}ethynyl)benzamide
479.5 1025 ##STR1201## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-{4- [(phenylsulfonyl)amino]phenyl}buta-1,3-
diynyl)benzamide 503.5 1026 ##STR1202##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-(morpholin-4- ylmethyl)phenyl]ethynyl}benzamide
423.5 1027 ##STR1203## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(4-methylpiperazin-1-
yl)methyl]phenyl}ethynyl)benzamide 436.5 1028 ##STR1204##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-[(4-{[(2-
hydroxyethyl)amino]methyl}phenyl)ethynyl]benzamide 397.4 1029
##STR1205## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[2-
(methyloxy)ethyl]amino}methyl)phenyl]ethynyl}benzamide 411.5 1030
##STR1206## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(cyclohexylamino)methyl]phenyl}ethynyl)benzamide
435.5 1031 ##STR1207## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[(phenylmethyl)amino]methyl}phenyl)ethynyl]benzamide 443.5 1032
##STR1208## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(6-chloropyridin-3- yl)ethynyl]benzamide 359.8 1033
##STR1209## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(4-{4-
[({[6-(methyloxy)pyridin-3- yl]amino}acetyl)amino]phenyl}buta-1,3-
diynyl)benzamide 542.6 1034 ##STR1210##
4-{4-[4-({[(6-chloropyridin-3-
yl)amino]acetyl}amino)phenyl]buta-1,3-
diynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 547.0 1035 ##STR1211##
N-{(1S,2R)-2--hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[4-
(pyrrolidin-1- ylmethyl)phenyl]ethynyl}benzamide 422.5 1036
##STR1212## 4-({4-[(ethylamino)methyl]phenyl}ethynyl)-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
396.5 1037 ##STR1213## 4-({4-
[(dimethylamino)methyl]phenyl}ethynyl)-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 396.5 1038 ##STR1214##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-({4-[(4-
methylpiperazin-1- yl)methyl]phenyl}ethynyl)benzamide 451.5 1039
##STR1215## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[3- (1H-imidazol-1-
yl)propyl]amino}methyl)phenyl]ethynyl}benzamide 476.5 1040
##STR1216## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-thien-2-ylbuta-1,3- diynyl)benzamide 354.4 1041
##STR1217## N,N,N-triethyl-2{[4-(4-{4-[({(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}buta-
1,3-diynyl)phenyl]amino}-2- oxoethanaminium 520.6 1042 ##STR1218##
4-[4-(2-aminophenyl)buta-1,3-diynyl]-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 378.4 1043 ##STR1219##
4-[4-(3-{[(2- aminoethyl)amino]methyl}phenyl)buta-1,3-
diynyl]-N-[(1S)-1-(aminomethyl)-2-
(hydroxyamino)-2-oxoethyl]benzamide 420.5 1044 ##STR1220##
4-buta-1,3-diynyl-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 287.3 1045 ##STR1221##
4-[4-(4-{[(2S)-2-amino-4- methylpentanoyl]amino}phenyl)buta-1,3-
diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 491.6 1046 ##STR1222##
(2S)-N-[4-(4-{4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}buta-
1,3-diynyl)phenyl]pyrrolidine- 2-carboxamide 475.5 1047 ##STR1223##
(2S)-N-[4-(4-{4-[({(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}buta-
1,3-diynyl)phenyl]piperidine- 2-carboxamide 489.5 1048 ##STR1224##
4-[4-(4-{[(2S)-2,3- diaminopropanoyl]amino}phenyl)buta-1,3-
diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 464.5 1049 ##STR1225##
4-[4-(4-{[(2S)-2-amino-3-(1H-imidazol-4-
yl)propanoyl]amino}phenyl)buta-1,3-diynyl]- N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 515.5 1050 ##STR1226##
N-[1-[(hydroxyamino)carbonyl]-2- (propylamino)propyl]-4-[(4-
{[(propylamino)acetyl]amino}phenyl)ethynyl]benzamide 494.6 1051
##STR1227## 4-[(4-
{[(cyclobutylamino)acetyl]amino}phenyl)ethynyl]-N-{2-(cyclobutylamino)-1-
[(hydroxyamino)carbonyl]propyl}benzamide 518.6 1052 ##STR1228##
N-{(1S,2R)-2-amino-1- [(hydroxyamino)carbonyl]propyl}-4-[(4-
{[(cyclopropylamino)acetyl]amino}phenyl)ethynyl]benzamide 450.5
1053 ##STR1229## 1-[(1R,2S)-2-[({4-[(4-
{[(cyclopropylamino)acetyl]amino}phenyl)ethynyl]phenyl}carbonyl)amino]-3-
(hydroxyamino)-1-methyl-3-oxopropyl]triaza-1,2-dien-2-ium 477.5
1054 ##STR1230## N-{(1S,2R)-2-amino-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[({[(4-
fluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
518.6 1055 ##STR1231## N-{(1S,2R)-2-amino-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[({[(3-
fluorophenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
518.6 1056 ##STR1232## N-{(1S,2R)-2-amino-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-
{[(propylamino)acetyl]amino}phenyl)ethynyl]benzamide 452.5 1057
##STR1233## N-{(1S,2R)-2-amino-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-
({[(phenylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 500.6
1058 ##STR1234## 1-((1R,2S)-3-hydroxyamino)-1-methyl-3-oxo-
2-{[(4-{[4-
({[(phenylmethyl)amino]acetyl}amino)phenyl]ethynyl}phenyl)carbon-
yl]amino}propyl)triaza-1,2-dien-2-ium 527.6 1059 ##STR1235##
N-{(1S,2R)-2-amino-1- [(hydroxyamino)carbonyl]propyl}-4-[(4-
{[(cyclobutylamino)acetyl]amino}phenyl)ethynyl]benzamide 464.5 1060
##STR1236## 1-[(1R,2S)-2-[({4-[(4-
{[(cyclobutylamino)acetyl]amino}phenyl)ethynyl]phenyl}carbonyl)amino]-3-
(hydroxyamino)-1-methyl-3-oxopropyl]triaza-1,2-dien-2-ium 491.5
1061 ##STR1237## 4-[(4-ethylphenyl)ethynyl]-N-{(1S)-1-
[(hydroxyamino)carbonyl]-2- methylpropyl}benzamide 365.4 1062
##STR1238## 4-(4-{4-[(ethylamino)methyl]phenyl}buta-1,3-
diynyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 420.5 1063 ##STR1239##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(3-aminophenyl)buta-1,3- diynyl]benzamide 363.4 1064
##STR1240## 4-(4-{3-[(4-aminobutanoyl)amino]phenyl}buta-
1,3-diynyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 463.5 1065 ##STR1241##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[4-(3-
hydroxyphenyl)buta-1,3-diynyl]benzamide 379.4 1066 ##STR1242##
4-(4-{2-[(aminoacetyl)amino]phenyl}buta-1,3-
diynyl)-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 435.4 1067 ##STR1243##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[2,4-bis(methyloxy)pyrimidin-
5-yl]buta-1,3-diynyl}benzamide 410.4 1068 ##STR1244##
(2S)-6-amino-2-{[(4-{4-[4-({[(1S)-1-
(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]amino}carbonyl)phenyl]buta-1,3-
diynyl}phenyl)carbonyl]amino}hexanoic acid 520.6 1069 ##STR1245##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(2-aminophenyl)buta-1,3- diynyl]benzamide 363.4 1070
##STR1246## 4-[4-(4-{2-[(2-aminoethyl)amino]-2-
oxoethyl}phenyl)buta-1,3-diynyl]-N-[(1S)-1-
(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 448.5 1071
##STR1247## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(2-aminopyrimidin-5-yl)buta- 1,3-diynyl]benzamide
365.4 1072 ##STR1248## 4-(4-{3-[(4-aminobutanoyl)amino]phenyl}buta-
1,3-diynyl)-N-[(1S)-1-(aminomethyl)-2-
(hydroxyamino)-2-oxoethyl]benzamide 448.5 1073 ##STR1249##
4-(4-{2-[(aminoacetyl)amino]phenyl}buta-1,3-
diynyl)-N-[(1S)-1-(aminomethyl)-2-
(hydroxyamino)-2-oxoethyl]benzamide 420.4 1074 ##STR1250##
4-[4-(4-{2-[(2-aminoethyl)amino]-2-
oxoethyl}phenyl)buta-1,3-diynyl]-N-{(1S,2R)- 2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 463.5 1075 ##STR1251##
4-[4-(4-{[(2,3- dihydroxypropyl)amino]methyl}phenyl)buta-
1,3-diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 466.5 1076 ##STR1252##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-(4-{4-
[({[2-
(methyloxy)phenyl]methyl}amino)methyl]phenyl}buta-1,3-diynyl)benzamide
512.6 1077 ##STR1253## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(4-{4-
[(pyridin-2-ylamino)methyl]phenyl}buta-1,3- diynyl)benzamide 469.5
1078 ##STR1254## 4-[4-(4-{[(2-
aminoethyl)amino]methyl}phenyl)buta-1,3-
diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 435.5 1079 ##STR1255##
4-[(4-ethylphenyl)ethynyl]-N-[(1R)-1-
[(ethylthio)methyl]-2-(hydroxyamino)-2- oxoethyl]benzamide 397.5
1080 ##STR1256## 4-[(4-{[(2S)-2-
aminopropanoyl]amino}phenyl)ethynyl]-N-
[(1R)-1-[(ethylthio)methyl]-2-(hydroxyamino)- 2-oxoethyl]benzamide
455.5 1081 ##STR1257## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(3-chlorophenyl)buta-1,3- diynyl]benzamide 382.8
1082 ##STR1258## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[3-(methyloxy)phenyl]buta-1,3- diynyl}benzamide
378.4 1083 ##STR1259## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(4-{4-
[(methylsulfonyl)amino]phenyl}buta-1,3- diynyl)benzamide 456.5 1084
##STR1260## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(4-{3-
[(methylsulfonyl)amino]phenyl}buta-1,3- diynyl)benzamide 456.5 1085
##STR1261## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-(4-pyrazin-2-ylbuta-1,3- diynyl)benzamide 350.3 1086
##STR1262## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[4-(3-
nitrophenyl)buta-1,3-diynyl]benzamide 408.4 1087 ##STR1263##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(3-
{[(methylsulfonyl)amino]methyl}phenyl)ethynyl]benzamide 446.5 1088
##STR1264## 4-[(2-formylphenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 367.4 1089 ##STR1265##
N-{(1R,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(3-
{[(methylsulfonyl)amino]methyl}phenyl)ethynyl]benzamide 446.5 1090
##STR1266## 4-({2-[(aminoacetyl)amino]phenyl}ethynyl)-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
411.4 1091 ##STR1267## N-{(1S)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{4-[3-
(morpholin-4-ylmethyl)phenyl]buta-1,3- diynyl}benzamide 462.5 1092
##STR1268## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(methylamino)methyl]phenyl}ethynyl)benzamide
367.4 1093 ##STR1269## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(ethylamino)methyl]phenyl}ethynyl)benzamide 381.4
1094 ##STR1270## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(propylamino)methyl]phenyl}ethynyl)benzamide
395.5 1095 ##STR1271## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(pentylamino)methyl]phenyl}ethynyl)benzamide
423.5 1096 ##STR1272## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(hexylamino)methyl]phenyl}ethynyl)benzamide 437.6
1097 ##STR1273## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(1-
methylethyl)amino]methyl}phenyl)ethynyl]benzamide 395.5 1098
##STR1274## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(2-
methylpropyl)amino]methyl}phenyl)ethynyl]benzamide 409.5 1099
##STR1275## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(1,1-
dimethylethyl)amino]methyl}phenyl)ethynyl]benzamide 409.5 1100
##STR1276## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(dimethylamino)methyl]phenyl}ethynyl)benzamide
381.4 1101 ##STR1277## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[ethyl(methyl)amino]methyl}phenyl)ethynyl]benzamide 395.5 1102
##STR1278## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[2-
(dimethylamino)ethyl]amino}methyl)phenyl]ethynyl}benzamide 424.5
1103 ##STR1279## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[4-
(dimethylamino)butyl]amino}methyl)phenyl]ethynyl}benzamide 452.6
1104 ##STR1280## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(2-
cyanoethyl)amino]methyl}phenyl)ethynyl]benzamide 406.5 1105
##STR1281## 4-{[4-({[2-
(acetylamino)ethyl]amino}methyl)phenyl]ethynyl}-N-[(1S)-1-(aminomethyl)-2-
- (hydroxyamino)-2-oxoethyl]benzamide 438.5 1106 ##STR1282##
4-[(4-{[(2- aminoethyl)amino]methyl}phenyl)ethynyl]-N-
[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 396.5
1107 ##STR1283## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(3-
hydroxypropyl)amino]methyl}phenyl)ethynyl]benzamide 411.5 1108
##STR1284## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[3-
(methyloxy)propyl]amino}methyl)phenyl]ethynyl}benzamide 425.5 1109
##STR1285## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({methyl[2-
(methyloxy)ethyl]amino}methyl)phenyl]ethynyl}benzamide 425.5 1110
##STR1286## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[3-(2-oxopyrrolidin-1-
yl)propyl]amino}methyl)phenyl]ethynyl}benzamide 478.6 1111
##STR1287## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(3-morpholin-4-
ylpropyl)amino]methyl}phenyl)ethynyl]benzamide 480.6 1112
##STR1288## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(cyclopropylamino)methyl]phenyl}ethynyl)benzamide
393.5 1113 ##STR1289## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(cyclobutylamino)methyl]phenyl}ethynyl)benzamide
407.5 1114 ##STR1290## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(cyclopentylamino)methyl]phenyl}ethynyl)benzamide
421.5 1115 ##STR1291## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(cycloheptylamino)methyl]phenyl}ethynyl)benzamide
449.6 1116 ##STR1292## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(cyclooctylamino)methyl]phenyl}ethynyl)benzamide
463.6 1117 ##STR1293## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-(pyrrolidin-1- ylmethyl)phenyl]ethynyl}benzamide
407.5 1118 ##STR1294## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-(azepan-1- ylmethyl)phenyl]ethynyl}benzamide 435.5
1119 ##STR1295## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(3R)-3- (dimethylamino)pyrrolidin-1-
yl]methyl}phenyl)ethynyl]benzamide 450.6 1120 ##STR1296##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(3S)-3- (dimethylamino)pyrrolidin-1-
yl]methyl}phenyl)ethynyl]benzamide 450.6 1121 ##STR1297##
4-[(4-{[(3R)-3-(acetylamino)pyrrolidin-1-
yl]methyl}phenyl)ethynyl]-N-[(1S)-1-
(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 464.5 1122
##STR1298## 4-[(4-{[(3S)-3-(acetylamino)pyrrolidin-1-
yl]methyl}phenyl)ethynyl]-N-[(1S)-1-
(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 464.5 1123
##STR1299## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-(1,4'-bipiperidin-1'-
ylmethyl)phenyl]ethynyl}benzamide 504.6 1124 ##STR1300##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-[(4-
{[(cyclohexylmethyl)amino]methyl}phenyl)ethynyl]benzamide 449.6
1125 ##STR1301## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-
{[cyclohexyl(methyl)amino]methyl}phenyl)ethynyl]benzamide 449.6
1126 ##STR1302## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(1R)-1-
phenylethyl]amino}methyl)phenyl]ethynyl}benzamide 457.5 1127
##STR1303## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(1S)-1-
phenylethyl]amino}methyl)phenyl]ethynyl}benzamide 457.5 1128
##STR1304## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(thien-2-
ylmethyl)amino]methyl}phenyl)ethynyl]benzamide 449.5 1129
##STR1305## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(2-
phenylethyl)amino]methyl}phenyl)ethynyl]benzamide 457.5 1130
##STR1306## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(piperidin-3-
ylamino)methyl]phenyl}ethynyl)benzamide 436.5 1131 ##STR1307##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(piperidin-4-
ylamino)methyl]phenyl}ethynyl)benzamide 436.5 1132 ##STR1308##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(piperidin-2-
ylmethyl)amino]methyl}phenyl)ethynyl]benzamide 450.6 1133
##STR1309## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(piperidin-3-
ylmethyl)amino]methyl}phenyl)ethynyl]benzamide 450.6 1134
##STR1310## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2R)-pyrrolidin-2-
ylmethyl]amino}methyl)phenyl]ethynyl}benzamide 436.5 1135
##STR1311## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2S)-pyrrolidin-2-
ylmethyl]amino}methyl)phenyl]ethynyl}benzamide 436.5 1136
##STR1312## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(pyrrolidin-3-
ylamino)methyl]phenyl}ethynyl)benzamide 422.5 1137 ##STR1313##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{[4-({[(2-
fluorophenyl)methyl]amino}methyl)phenyl]ethynyl}benzamide 461.5
1138 ##STR1314## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(3-
fluorophenyl)methyl]amino}methyl)phenyl]ethynyl}benzamide 461.5
1139 ##STR1315## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(4-
fluorophenyl)methyl]amino}methyl)phenyl]ethynyl}benzamide 461.5
1140 ##STR1316## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(2-
methylphenyl)methyl]amino}methyl)phenyl]ethynyl}benzamide 457.5
1141 ##STR1317## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(3-
methylphenyl)methyl]amino}methyl)phenyl]ethynyl}benzamide 457.5
1142 ##STR1318## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(4-
methylphenyl)methyl]amino}methyl)phenyl]ethynyl}benzamide 457.5
1143 ##STR1319## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[2-
(methyloxy)phenyl]methyl}amino)methyl]phenyl}ethynyl)benzamide
473.5 1144 ##STR1320## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[3-
(methyloxy)phenyl]methyl}amino)methyl]phenyl}ethynyl)benzamide
473.5 1145 ##STR1321## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[4-
(methyloxy)phenyl]methyl}amino)methyl]phenyl}ethynyl)benzamide
473.5 1146 ##STR1322## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4- [(phenylamino)methyl]phenyl}ethynyl)benzamide
429.5 1147 ##STR1323## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(pyridin-3-
ylmethyl)amino]methyl}phenyl)ethynyl]benzamide 444.5 1148
##STR1324## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(4-phenylpiperidin-1-
yl)methyl]phenyl}ethynyl)benzamide 497.6 1149 ##STR1325##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(4-phenylpiperazin-1-
yl)methyl]phenyl}ethynyl)benzamide 498.6 1150 ##STR1326##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(1R,2R,4S)- bicyclo[2.2.1]hept-2-
ylamino]methyl}phenyl)ethynyl]benzamide 447.5 1151 ##STR1327##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({[(1S,2R,5S)-6,6- dimethylbicyclo[3.1.1]hept-2-
yl]methyl}amino)methyl]phenyl}ethynyl)benzamide 489.6 1152
##STR1328## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(1S,4R)-bicyclo[2.2.1]hept-
2-ylamino]methyl}phenyl)ethynyl]benzamide 447.5 1153 ##STR1329##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[(1S,2S,3S,5R)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-
yl]amino}methyl)phenyl]ethynyl}benzamide 489.6 1154 ##STR1330##
1-((1R,2S)-3-(hydroxyamino)-1-methyl-3-oxo-
2-{[(4-{[4-({[(pyridin-4-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}phenyl)carbonyl]amino}prop-
yl)triaza-1,2-dien-2-ium 528.6 1155 ##STR1331##
1-((1R,2S)-3-(hydroxyamino)-1-methyl-3-oxo-
2-{[(4-{[4-({[(pyridin-3-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}phenyl)carbonyl]amino}prop-
yl)triaza-1,2-dien- 2-ium 528.6 1156 ##STR1332##
N-{(1S,2R)-2-amino-1- [(hydroxyamino)carbonyl]propyl}-4-{[4-
({[(pyridin-4- ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide
501.6 1157 ##STR1333## N-{(1S,2R)-2-amino-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[(pyridin-3-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 501.6 1158
##STR1334## N-[1-[(hydroxyamino)carbonyl]-2-
(methylamino)propyl]-4-{[4-
({[(phenylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 514.6
1159 ##STR1335## 4-[(4-
{[(cyclobutylamino)acetyl]amino}phenyl)ethynyl]-
N-[1-[(hydroxyamino)carbonyl]-2- (methylamino)propyl]benzamide
478.6 1160 ##STR1336## 4-[(4-{[(2S)-2-
aminopropanoyl]amino}phenyl)ethynyl]-N-
[(1R)-1-{[ethyl(hydroxy)-lambda.about.4.about..about.sulfanyl]methyl}-2-(-
hydroxyamino)-2- oxoethyl]benzamide 473.6 1161 ##STR1337##
4-[(4-ethylphenyl)ethynyl]-N- hydroxybenzamide 266.3 1162
##STR1338## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(2,4-difluorophenyl)buta-1,3- diynyl]benzamide 384.4
1163 ##STR1339## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(2- aminophenyl)ethynyl]benzamide 339.4 1164
##STR1340## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(3- {[(methylsulfonyl)amino]methyl}phenyl)buta-
1,3-diynyl]benzamide 455.5 1165 ##STR1341##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-[4-(3-
{[(methylsulfonyl)amino]methyl}phenyl)buta- 1,3-diynyl]benzamide
455.5 1166 ##STR1342## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({3- [(methylsulfonyl)amino]phenyl}ethynyl)benzamide
417.5 1167 ##STR1343## 4-[(4-{[(2S)-2-
aminopropanoyl]amino}phenyl)ethynyl]-N- hydroxybenzamide 324.4 1168
##STR1344## 4-[(2-{[(2- aminoethyl)amino]methyl}phenyl)ethynyl]-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
411.5 1169 ##STR1345## N-{(1R,2R)-2-amino-1-
[(hydroxyamino)carbonyl]propyl}-4- (phenylethynyl)benzamide 338.4
1170 ##STR1346## N-{(1R,2R)-2-amino-1-
[(hydroxyamino)carbonyl]propyl}-4-[4-(4-
aminophenyl)buta-1,3-diynyl]benzamide 377.4 1171 ##STR1347##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(3-hydroxyphenyl)buta-1,3- diynyl]benzamide 364.4
1172 ##STR1348## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[3-(morpholin-4-
ylmethyl)phenyl]buta-1,3-diynyl}benzamide 447.5 1173 ##STR1349##
N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-[({[2-
(methyloxy)phenyl]methyl}amino)methyl]phenyl}ethynyl)benzamide
488.6 1174 ##STR1350## 4-[(4-{[(2,3-
dihydroxypropyl)amino]methyl}phenyl)ethynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 442.5 1175 ##STR1351##
4-({2- [(dimethylamino)methyl]phenyl}ethynyl)-N-
{(1S,2R)-2--hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
396.5 1176 ##STR1352## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-
[(methylamino)methyl]phenyl}ethynyl)benzamide 382.4 1177
##STR1353## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-
[(propylamino)methyl]phenyl}ethynyl)benzamide 410.5 1178
##STR1354## 4-({4-[(butylamino)methyl]phenyl}ethynyl)-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
424.5 1179 ##STR1355## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-
[(pentylamino)methyl]phenyl}ethynyl)benzamide 438.5 1180
##STR1356## 4-({4-[(hexylamino)methyl]phenyl}ethynyl)-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
452.6 1181 ##STR1357## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-{[(1-
methylethyl)amino]methyl}phenyl)ethynyl]benzamide 410.5 1182
##STR1358## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-{[(2-
methylpropyl)amino]methyl}phenyl)ethynyl]benzamide 424.5 1183
##STR1359## 4-[(4-{[(1,1-
dimethylethyl)amino]methyl}phenyl)ethynyl]- N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 424.5 1184 ##STR1360##
4-[(4- {[ethyl(methyl)amino]methyl}phenyl)ethynyl]-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
410.5 1185 ##STR1361## 4-{[4-({[2-
(dimethylamino)ethyl]amino}methyl)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
439.5 1186 ##STR1362## 4-{[4-({[4-
(dimethylamino)butyl]amino}methyl)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
467.6 1187 ##STR1363## 4-[(4-{[(2-
hydroxyethyl)amino]methyl}phenyl)ethynyl]- N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 412.5 1188 ##STR1364##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-[(4-{[(3-
hydroxypropyl)amino]methyl}phenyl)ethynyl]benzamide 426.5 1189
##STR1365## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({methyl[2-
(methyloxy)ethyl]amino}methyl)phenyl]ethynyl}benzamide 440.5 1190
##STR1366## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[2-
(methyloxy)ethyl]amino}methyl)phenyl]ethynyl}benzamide 426.5 1191
##STR1367## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[3-
(methyloxy)propylamino}methyl)phenyl]ethynyl}benzamide 440.5 1192
##STR1368## 4-[(4-{[(2- cyanoethyl)amino]methyl}phenyl)ethynyl]-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
421.5 1193 ##STR1369## 4-{[4-({[2-
(acetylamino)ethyl]amino}methyl)phenyl]ethynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 453.5 1194 ##STR1370##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[4-({[3-
(2-oxopyrrolidin-1- yl)propyl]amino}methyl)phenyl]ethynyl}benzamide
493.6 1195 ##STR1371## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-{[(3- morpholin-4-
ylpropyl)amino]methyl}phenyl)ethynyl]benzamide 495.6 1196
##STR1372## 4-({4- [(cyclopropylamino)methyl]phenyl}ethynyl}-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
408.5 1197 ##STR1373## 4-({4-
[(cyclobutylamino)methyl]phenyl}ethynyl}-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 422.5 1198 ##STR1374##
4-({4- [(cyclopentylamino)methyl]phenyl}ethynyl}-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
436.5 1199 ##STR1375## 4-({4-
[(cyclohexylamino)methyl]phenyl}ethynyl}-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 450.5 1200 ##STR1376##
4-({4- [(cycloheptylamino)methyl]phenyl}ethynyl}-N-
{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
464.6 1201 ##STR1377## 4-({4-
[(cyclooctylamino)methyl]phenyl}ethynyl}-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 478.6 1202 ##STR1378##
4-{[4-(azepan-1-ylmethyl)phenyl]ethynyl}-N- {(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 450.5 1203 ##STR1379##
4-[(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-
yl]methyl}phenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 465.6 1204 ##STR1380##
4-[(4-{[(3S)-3-(dimethylamino)pyrrolidin-1-
yl]methyl}phenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 465.6 1205 ##STR1381##
4-[(4-{[(3R)-3-(acetylamino)pyrrolidin-1-
yl]methyl}phenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 479.5 1206 ##STR1382##
4-[(4-{[(3S)-3-(acetylamino)pyrrolidin-1-
yl]methyl}phenyl)ethynyl]-N-{(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 479.5 1207 ##STR1383##
4-{[4-(1,4'-bipiperidin-1'- ylmethyl)phenyl]ethynyl}-N-{(1S,2R)-2-
hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide 519.7 1208
##STR1384## 4-[(4-
{[(cyclohexylmethyl)amino]methyl}phenyl)ethynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 464.6 1209 ##STR1385##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-({4-[(4-
phenylpiperazin-1- yl)methyl]phenyl}ethynyl)benzamide 513.6 1210
##STR1386## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-{[(2-
phenylethyl)amino]methyl}phenyl)ethynyl]benzamide 472.6 1211
##STR1387## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[(1R)-1-
phenylethyl]amino}methyl)phenyl]ethynyl}benzamide 472.6 1212
##STR1388## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[(1S)-1-
phenylethyl]amino}methyl)phenyl]ethynyl}benzamide 472.6 1213
##STR1389## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4- {[(thien-2-
ylmethyl)amino]methyl}phenyl)ethynyl]benzamide 464.6 1214
##STR1390## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4- [(piperidin-3-
ylamino)methyl]phenyl}ethynyl)benzamide 451.5 1215 ##STR1391##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-({4-
[(piperidin-4- ylamino)methyl]phenyl}ethynyl)benzamide 451.5 1216
##STR1392## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4- {[(piperidin-2-
ylmethyl)amino]methyl}phenyl)ethynyl]benzamide 465.6 1217
##STR1393## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4- {[(piperidin-3-
ylmethyl)amino]methyl}phenyl)ethynyl]benzamide 465.6 1218
##STR1394## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4- ({[(2R)-pyrrolidin-2-
ylmethyl]amino}methyl)phenyl]ethynyl}benzamide 451.5 1219
##STR1395## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4- ({[(2S)-pyrrolidin-2-
ylmethyl]amino}methyl)phenyl]ethynyl}benzamide 451.5 1220
##STR1396## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4- [(pyrrolidin-3-
ylamino)methyl]phenyl}ethynyl)benzamide 437.5 1221 ##STR1397##
4-{[4-({[(2-
fluorophenyl)methyl]amino}methyl)phenyl]ethynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 476.5 1222 ##STR1398##
4-{[4-({[(3-
fluorophenyl)methyl]amino}methyl)phenyl]ethynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 476.5 1223 ##STR1399##
4-{[4-({[(4-
fluorophenyl)methyl]amino}methyl)phenyl]ethynyl}-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 476.5 1224 ##STR1400##
N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[(2-
methylphenyl)methyl]amino}methyl)phenyl]ethynyl}benzamide 472.6
1225 ##STR1401## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[(3-
methylphenyl)methyl]amino}methyl)phenyl]ethynyl}benzamide 472.6
1226 ##STR1402## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-({[(4-
methylphenyl)methyl]amino}methyl)phenyl]ethynyl}benzamide 472.6
1227 ##STR1403## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4-
{[(phenylmethyl)amino]methyl}phenyl)ethynyl]benzamide 458.5 1228
##STR1404## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-({4-
[(phenylamino)methyl]phenyl}ethynyl)benzamide 444.5 1229
##STR1405## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-[(4- {[(pyridin-3-
ylmethyl)amino]methyl}phenyl)ethynyl]benzamide 459.5 1230
##STR1406## 4-[(4-{[(1R,2R,4S)-bicyclo[2.2.1]hept-2-
ylamino]methyl}phenyl)ethynyl]-N-{(1S,2R)- 2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 462.6 1231 ##STR1407##
(3R)-N-hydroxy-3-({[4-
(phenylethynyl)phenyl]carbonyl}amino)piperidine-3-carboxamide 364.4
1232 ##STR1408## 4-({[4-
(phenylethynyl)phenyl]carbonyl}amino)piperidine-4-carboxylic acid
349.4 1233 ##STR1409## N-{(1S)-2-(hydroxyamino)-2-oxo-1-[(2S)-
pyrrolidin-2-ylmethyl]ethyl}-4- (phenylethynyl)benzamide 378.4 1234
##STR1410## (3R)-3-{[(4'-ethyl-1,1'-biphenyl-4-
yl)carbonyl]amino}-N-hydroxypiperidine-3- carboxamide 368.4 1235
##STR1411## 1,1-dimethylethyl 3-(4-{4-[({(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]phenyl}buta-
1,3-diynyl)phenylcarbamate 478.5 1236 ##STR1412##
4-[4-(3-amino-4-methylphenyl)buta-1,3-
diynyl]-N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 392.4 1237 ##STR1413##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(3-amino-4-methylphenyl)buta- 1,3-diynyl]benzamide
377.4 1238 ##STR1414## 4-(4-{4-[(aminoacetyl)amino]-3-
methylphenyl}buta-1,3-diynyl)-N-[(1S)-1-
(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]benzamide 434.5 1239
##STR1415## N-{(1S,2R)-2-amino-1-
[(hydroxyamino)carbonyl]propyl}-4-(2- phenylethenyl)benzamide 340.4
1240 ##STR1416## N-[(2R)-2-amino-3-(hydroxyamino)-3-
oxopropyl]-4'-ethyl-1,1'-biphenyl-4- carboxamide 328.4 1241
##STR1417## N-[(2R)-2-amino-3-(hydroxyamino)-3-
oxopropyl]-4-(phenylethynyl)benzamide 324.4 1242 ##STR1418##
N-[(2R)-2-amino-3-(hydroxyamino)-3- oxopropyl]-4-(4-
chlorophenyl)cyclohexanecarboxamide 340.8 1243 ##STR1419##
N-[(2S)-2-amino-3-(hydroxyamino)-3- oxopropyl]-4-(4-
chlorophenyl)cyclohexanecarboxamide 340.8 1244 ##STR1420##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-[2-(4-
methylphenyl)ethyl]benzamide 342.4 1245 ##STR1421##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-[4-(4-
aminophenyl)butyl]benzamide 371.4 1246 ##STR1422##
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-{[4-
({[methyl(pyridin-2-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 516.6 1247
##STR1423## 4-{[4-({[[(2-
fluorophenyl)methyl](methyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
533.6 1248 ##STR1424## 4-{[4-({[[(3-
fluorophenyl)methyl](methyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
533.6 1249 ##STR1425## 4-{[4-({[[(4-
fluorophenyl)methyl](methyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
533.6 1250 ##STR1426## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[[(2-
fluorophenyl)methyl](methyl)amino]acetyl}amino)phenyl]ethynyl}benzamide
518.6 1251 ##STR1427## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[[(3-
fluorophenyl)methyl](methyl)amino]acetyl}amino)phenyl]ethynyl}benzamide
518.6 1252 ##STR1428## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[[(4-
fluorophenyl)methyl](methyl)amino]acetyl}amino)phenyl]ethynyl}benzamide
518.6 1253 ##STR1429## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({methyl[(2-
methylphenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
514.6 1254 ##STR1430## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[({methyl[(4-
methylphenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
514.6 1255 ##STR1431## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-
({[methyl(phenylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide
500.6 1256 ##STR1432## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-
({[methyl(propyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 467.5
1257 ##STR1433## 4-{[4-
({[butyl(methyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
481.6 1258 ##STR1434## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4-
({[methyl(pentyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 495.6
1259 ##STR1435## 4-{[4-
({[hexyl(methyl)amino]acetyl}amino)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
509.6 1260 ##STR1436## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[methyl(1-
methylethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 467.5 1261
##STR1437## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- ({[methyl(2-
methylpropyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 481.6 1262
##STR1438## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- [({methyl[(2-
methylphenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
529.6 1263 ##STR1439## N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- [({methyl[(4-
methylphenyl)methyl]amino}acetyl)amino]phenyl}ethynyl)benzamide
529.6 1264 ##STR1440## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-
({[methyl(propyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 452.5
1265 ##STR1441## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-
({[butyl(methyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 466.6
1266 ##STR1442## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-
({[methyl(pentyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 480.6
1267 ##STR1443## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-
({[hexyl(methyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 494.6
1268 ##STR1444## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[methyl(1-
methylethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 452.5 1269
##STR1445## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[methyl(1-
methylpropyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 466.6 1270
##STR1446## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[methyl(pyridin-2-
ylmethyl)amino]acetyl}amino)phenyl]ethynyl}benzamide 501.6 1271
##STR1447## 4-{[4-({[(3,4-
dihydroxyphenyl)methyl]amino}methyl)phenyl]ethynyl}-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
490.5 1272 ##STR1448## 4-({2-[(aminoacetyl)amino]phenyl}ethynyl)-N-
{(1S,2S)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
411.4 1273 ##STR1449## 4-[(4-{[(2S)-2-
aminopropanoyl]amino}phenyl)ethynyl]-N- {(1S,2S)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 425.5 1274 ##STR1450##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{[4-
(diethylamino)phenyl]ethynyl}benzamide 395.5 1275 ##STR1451##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-(ethylamino)phenyl]buta- 1,3-diynyl}benzamide
391.4 1276 ##STR1452## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[(4-{[(2-amino-2-
oxoethyl)amino]methyl}phenyl)ethynyl]benzamide 410.4 1277
##STR1453## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4-({[1-(hydroxymethyl)-2-
methylpropyl]amino}methyl)phenyl]ethynyl}benzamide 439.5 1278
##STR1454## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-({4-[(pyridin-2-
ylamino)methyl]phenyl}ethynyl)benzamide 430.5 1279 ##STR1455##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[3-(ethylamino)phenyl]buta- 1,3-diynyl}benzamide
391.4 1280 ##STR1456## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[3- (ethylamino)phenyl]ethynyl}benzamide 367.4 1281
##STR1457## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4- (hydroxymethyl)phenyl]ethynyl}benzamide 354.4 1282
##STR1458## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[3- (diethylamino)phenyl]ethynyl}benzamide 395.5 1283
##STR1459## N-{(1S,2S)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-{[4- (morpholin-4-
ylmethyl)phenyl]ethynyl}benzamide 438.5 1284 ##STR1460## 4-({4-
[(dimethylamino)methyl]phenyl}ethynyl)-N- {(1S,2S)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 396.5 1285 ##STR1461##
4-[(4-aminophenyl)ethynyl]-N-{(1S,2S)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 354.4 1286 ##STR1462##
4-[4-(4-aminophenyl)buta-1,3-diynyl]-N- {(1S,2S)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}benzamide 378.4 1287 ##STR1463##
1,1-dimethylethyl 4-(4-{4-[({(1S,2R)-2- hydroxy-1-
[(hydroxyamino)carbonyl]propyl}amino)carbonyl]buta-
1,3-diynyl)phenylcarbamate 478.5 1288 ##STR1464##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-({[1-(hydroxymethyl)-2-
methylpropyl]amino}methyl)phenyl]buta-1,3- diynyl}benzamide 463.5
1289 ##STR1465## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-[4-(4-hydroxyphenyl)buta-1,3- diynyl]benzamide 364.4
1290 ##STR1466## 4-[(2,4-difluorophenyl)ethynyl]-N-{(1S,2S)-2-
hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide 375.3 1291
##STR1467## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{4-[4-(morpholin-4-
ylmethyl)phenyl]buta-1,3-diynyl}benzamide 447.5 1292 ##STR1468##
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2- oxoethyl]-4-{4-[4-
(hydroxymethyl)phenyl]buta-1,3- diynyl}benzamide 378.4 1293
##STR1469## 4-({3-[(2-aminoethyl)amino]phenyl}ethynyl)-
N-{(1S,2R)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}benzamide
397.4 1294 ##STR1470## N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-
oxoethyl]-4-{[4- (trifluoromethyl)phenyl]ethynyl}benzamide 392.3
1295 ##STR1471## (2S,3R)-3-hydroxy-2-({[4-
(phenylethynyl)phenyl]carbonyl}amino)butanoic acid 324.3 1296
##STR1472## N-((1S,2R)-1-{[(2- aminoethyl)amino]carbonyl}-2-
hydroxypropyl)-4-(phenylethynyl)benzamide 366.4 1297 ##STR1473##
1,1-dimethylethyl (2S)-3-(hydroxyamino)-3-
oxo-2-({[4-(4-phenylbuta-1,3-
diynyl)phenyl]carbonyl}amino)propylcarbamate 448.5 1298 ##STR1474##
N-{(1S,2R)-2-hydroxy-1-
[(hydroxyamino)carbonyl]propyl}-4-(4-{4-[(3-
morpholin-4-ylpropyl)amino]phenyl}buta-1,3- diynyl)benzamide 505.6
1299 ##STR1475## N-{(1S,2R)-2-hydroxy-1-({[2-
(methylthio)phenyl]amino}carbonyl)propyl]-4-
(phenylethynyl)benzamide 445.6 1300 ##STR1476##
N-{(1S,2R)-2-hydroxy-1-[(pyridin-2- ylamino)carbonyl]propyl}-4-
(phenylethynyl)benzamide 400.4 1301 ##STR1477##
N-((1S)-1-(aminomethyl)-2-{[(1,1-
dimethylethyl)oxy]amino}-2-oxoethyl)-4-(4-
phenylbuta-1,3-diynyl)benzamide 404.5 1302 ##STR1478##
N-{(1S,2S)-2-hydroxy-1- [(hydroxyamino)carbonyl]propyl}-4-(4-
phenylbuta-1,3-diynyl)benzamide 363.4 1303 ##STR1479##
(2S,3R)-N,3-dihydroxy-2-({[4-(4-phenylbuta-
1,3-diynyl)phenyl]methyl}amino)butanamide 349.4 1304 ##STR1480##
1,1-dimethylethyl (2S)-3-(hydroxyamino)-3-
oxo-2-({[4-(4-phenylbuta-1,3-
diynyl)phenyl]methyl}amino)propylcarbamate 434.5 1305 ##STR1481##
(2S)-3-amino-N-hydroxy-2-({[4-(4-phenylbuta-
1,3-diynyl)phenyl]methyl}amino)propanamide 334.4 1306 ##STR1482##
N-[(1S)-2-(hydroxyamino)-1-(hydroxymethyl)- 2-oxoethyl]-4-
[(trifluoromethyl)oxy]benzamide 309.2 1307 ##STR1483##
N-{2-hydroxy-1-[(hydroxyamino)carbonyl]-2- phenylethyl}-4-
[(trifluoromethyl)oxy]benzamide 385.3
* * * * *