U.S. patent application number 15/615276 was filed with the patent office on 2017-12-28 for antibacterial agents.
The applicant listed for this patent is Achaogen, Inc.. Invention is credited to James Bradley Aggen, Frederick Cohen, Paola Dozzo, Micah James Gliedt, Darin James Hildebrandt, Timothy Robert Kane, Ramesh Annasaheb Kasar, Martin Sheringham Linsell, Qing Lu, Glenn A. McEnroe, Brian D. Patterson.
Application Number | 20170369426 15/615276 |
Document ID | / |
Family ID | 48485512 |
Filed Date | 2017-12-28 |
View All Diagrams
United States Patent
Application |
20170369426 |
Kind Code |
A1 |
Patterson; Brian D. ; et
al. |
December 28, 2017 |
ANTIBACTERIAL AGENTS
Abstract
Antibacterial compounds of formula (I) are provided:
##STR00001## as well as stereoisomers and pharmaceutically
acceptable salts thereof; pharmaceutical compositions comprising
such compounds; methods of treating bacterial infections by the
administration of such compounds; and processes for the preparation
of such compounds.
Inventors: |
Patterson; Brian D.; (San
Francisco, CA) ; Lu; Qing; (Foster City, CA) ;
Aggen; James Bradley; (Burlingame, CA) ; Dozzo;
Paola; (San Francisco, CA) ; Kasar; Ramesh
Annasaheb; (Bellevue, WA) ; Linsell; Martin
Sheringham; (San Mateo, CA) ; Kane; Timothy
Robert; (Moss Beach, CA) ; Gliedt; Micah James;
(Sunnyvale, CA) ; Hildebrandt; Darin James;
(Cupertino, CA) ; McEnroe; Glenn A.; (San Mateo,
CA) ; Cohen; Frederick; (San Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Achaogen, Inc. |
South San Francisco |
CA |
US |
|
|
Family ID: |
48485512 |
Appl. No.: |
15/615276 |
Filed: |
June 6, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15179751 |
Jun 10, 2016 |
9701622 |
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15615276 |
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14537048 |
Nov 10, 2014 |
9403758 |
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15179751 |
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PCT/US2013/040571 |
May 10, 2013 |
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14537048 |
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61645439 |
May 10, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 2601/02 20170501;
C07C 2601/04 20170501; A61P 31/04 20180101; C07C 2601/08 20170501;
C07D 213/81 20130101; C07C 317/50 20130101; C07D 333/70 20130101;
C07D 213/64 20130101; C07D 213/79 20130101; C07C 317/46 20130101;
C07C 317/28 20130101; C07C 313/12 20130101; C07C 313/04 20130101;
C07C 323/60 20130101; C07C 259/06 20130101; C07D 471/04 20130101;
C07C 323/42 20130101 |
International
Class: |
C07C 259/06 20060101
C07C259/06; C07D 333/70 20060101 C07D333/70; C07C 313/04 20060101
C07C313/04; C07C 313/12 20060101 C07C313/12; C07D 213/81 20060101
C07D213/81; C07D 213/79 20060101 C07D213/79; C07D 213/64 20060101
C07D213/64; C07C 323/60 20060101 C07C323/60; C07C 323/42 20060101
C07C323/42; C07C 317/50 20060101 C07C317/50; C07C 317/46 20060101
C07C317/46; C07C 317/28 20060101 C07C317/28; C07D 471/04 20060101
C07D471/04 |
Claims
1. A compound of formula I: ##STR00306## or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein: A is selected
from the group consisting of: (a) substituted C.sub.1-C.sub.6
alkyl, wherein at least one substituent is hydroxy; and (b)
substituted C.sub.3-C.sub.6 cycloalkyl, wherein at least one
substituent is selected from hydroxy and hydroxyalkyl; G is
selected from the group consisting of: (a)
--CH.dbd.CH--C.ident.C--; (b) --C.ident.C--CH.dbd.CH--; (c)
--C.ident.C--C.ident.C--; ##STR00307## D is: ##STR00308## wherein W
is N or N.sup.+--O.sup.-; and E is --C(CH.sub.3).sub.2SCH.sub.3,
--C(CH.sub.3).sub.2S(O)CH.sub.3,
--C(CH.sub.3).sub.2S(O).sub.2CH.sub.3, or --C(O)NHCH.sub.3.
2. A compound according to claim 1, wherein A is substituted
C.sub.1-C.sub.6 alkyl, wherein at least one substituent is
hydroxy.
3. A compound according to claim 2, wherein A is substituted
C.sub.1-C.sub.6 alkyl, wherein at least two substituents are
hydroxy.
4. A compound according to claim 2, wherein A is hydroxymethyl,
hydroxyethyl, hydroxypropyl or dihydroxypropyl.
5. A compound according to claim 1, wherein A is substituted
C.sub.3-C.sub.6 cycloalkyl, wherein at least one substituent is
selected from hydroxy and hydroxyalkyl.
6. A compound according to claim 5, wherein A is substituted
C.sub.3-C.sub.6 cycloalkyl, wherein at least one substituent is
hydroxymethyl.
7. A compound according to claim 6, wherein A is
hydroxymethylcyclopropyl.
8. A compound according to claim 5, wherein A is substituted
C.sub.3-C.sub.6 cycloalkyl, wherein at least one substituent is
hydroxy.
9. A compound according to claim 1, wherein G is
--C.ident.C--C.ident.C--.
10-15. (canceled)
16. A compound according to claim 1, wherein E is
--C(CH.sub.3).sub.2SCH.sub.3.
17. A compound according to claim 1, wherein E is
--C(CH.sub.3).sub.2S(O).sub.2CH.sub.3.
18. A compound according to claim 1, wherein E is
--C(CH.sub.3).sub.2S(O)CH.sub.3.
19. A compound according to claim 1, wherein E is
--C(O)NHCH.sub.3.
20. A compound, or a pharmaceutically acceptable salt thereof, of
claim 1, selected from the group consisting of:
N-hydroxy-2-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phe-
nyl)-1,6-naphthyridine-4-carboxamide (Compound 1);
N-hydroxy-2-(4-(6-hydroxyhexa-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carb-
oxamide (Compound 10);
N-hydroxy-2-(4-(5-hydroxypenta-1,3-diynyl)phenyl)-1,6-naphthyridine-4-car-
boxamide (Compound 11);
N-hydroxy-2-(4-(5-hydroxyhexa-1,3-diynyl)phenyl)-1,6-naphthyridine-4-carb-
oxamide (Compound 12);
N-hydroxy-2-(4-(6-hydroxy-5-methylhexa-1,3-diynyl)phenyl)-1,6-naphthyridi-
ne-4-carboxamide (Compound 13);
2-(4-(5,6-dihydroxyhexa-1,3-diynyl)phenyl)-N-hydroxy-1,6-naphthyridine-4--
carboxamide (Compound 14);
2-(4-(6,7-dihydroxyhepta-1,3-diynyl)phenyl)-N-hydroxy-1,6-naphthyridine-4-
-carboxamide (Compound 15);
N-hydroxy-2-(4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)phenyl)-1,6--
naphthyridine-4-carboxamide (Compound 16);
N-hydroxy-2-(4-((3-hydroxycyclobutyl)buta-1,3-diynyl)phenyl)-1,6-naphthyr-
idine-4-carboxamide (Compound 18);
N-hydroxy-2-(4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)phenyl)-1,6-
-naphthyridine-4-carboxamide (Compound 19);
N-hydroxy-2-(4-(((1R,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)phe-
nyl)-1,6-naphthyridine-4-carboxamide (Compound 20);
N-hydroxy-2-(4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)phenyl)-1,6-naphthyrid-
ine-4-carboxamide (Compound 21);
N-hydroxy-2-(4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)phenyl)-1,6-naphthyri-
dine-4-carboxamide (Compound 22);
4-(hydroxycarbamoyl)-2-(4-(6-hydroxyhexa-1,3-diynyl)phenyl)-1,6-naphthyri-
dine 6-oxide (Compound 23);
4-(hydroxycarbamoyl)-2-(4-(5-hydroxypenta-1,3-diynyl)phenyl)-1,6-naphthyr-
idine 6-oxide (Compound 24);
4-(hydroxycarbamoyl)-2-(4-(5-hydroxyhexa-1,3-diynyl)phenyl)-1,6-naphthyri-
dine 6-oxide (Compound 25);
2-(4-(6-hydroxy-5-methylhexa-1,3-diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6--
naphthyridine 6-oxide (Compound 26);
2-(4-(5,6-dihydroxyhexa-1,3-diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6-napht-
hyridine 6-oxide (Compound 27);
2-(4-(6,7-dihydroxyhepta-1,3-diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6-naph-
thyridine 6-oxide (Compound 28);
4-(hydroxycarbamoyl)-2-(4-((3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)p-
henyl)-1,6-naphthyridine 6-oxide (Compound 29);
4-(hydroxycarbamoyl)-2-(4-((3-hydroxycyclobutyl)buta-1,3-diynyl)phenyl)-1-
,6-naphthyridine 6-oxide (Compound 30);
4-(hydroxycarbamoyl)-2-(4-((3-(hydroxymethyl)cyclopentyl)buta-1,3-diynyl)-
phenyl)-1,6-naphthyridine 6-oxide (Compound 31);
4-(hydroxycarbamoyl)-2-(4-(((1R,2S)-2-(hydroxymethyl)cyclopropyl)buta-1,3-
-diynyl)phenyl)-1,6-naphthyridine 6-oxide (Compound 32);
2-(4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6-
-naphthyridine 6-oxide (Compound 33); and
2-(4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)phenyl)-4-(hydroxycarbamoyl)-1,-
6-naphthyridine 6-oxide (Compound 34).
21. (canceled)
22. A compound of formula II: ##STR00309## or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein: A is selected
from the group consisting of: (a) substituted C.sub.1-C.sub.6
alkyl, wherein at least one substituent is hydroxy; and (b)
substituted C.sub.3-C.sub.6 cycloalkyl, wherein at least one
substituent is selected from hydroxy and hydroxyalkyl; G is
selected from the group consisting of: a) --CH.dbd.CH--C.ident.C--;
(b) --C.ident.C--CH.dbd.CH--; ##STR00310## D is selected from the
group consisting of: ##STR00311## wherein: Q is O or NR, wherein R
is hydrogen or an unsubstituted C.sub.1-C.sub.3 alkyl; R.sup.1 and
R.sup.2 independently are selected from the group consisting of
hydrogen, substituted C.sub.1-C.sub.3 alkyl, and unsubstituted
C.sub.1-C.sub.3 alkyl, or R.sup.1 and R.sup.2, together with the
carbon atom to which they are attached, form an unsubstituted
C.sub.3-C.sub.6 cycloalkyl group or an unsubstituted 4-6 membered
heterocyclic group; and R.sup.3 is selected from the group
consisting of hydrogen, substituted C.sub.1-C.sub.6-alkyl,
unsubstituted C.sub.1-C.sub.6-alkyl, substituted cycloalkyl,
unsubstituted cycloalkyl, substituted cycloalkylalkyl,
unsubstituted cycloalkylalkyl, substituted aryl, unsubstituted
aryl, substituted arylalkyl, unsubstituted arylalkyl, substituted
heterocyclyl, or unsubstituted heterocyclyl, substituted
heterocyclylalkyl, unsubstituted heterocyclylalkyl, substituted
heteroaryl, unsubstituted heteroaryl, substituted heteroarylalkyl,
and unsubstituted heteroarylalkyl.
23. The compound of claim 22, wherein A is substituted
C.sub.1-C.sub.6 alkyl, wherein at least one substituent is
hydroxy.
24. The compound of claim 23, wherein A is substituted
C.sub.1-C.sub.6 alkyl, wherein at least two substituents are
hydroxy.
25. The compound of claim 23, wherein A is hydroxymethyl,
hydroxyethyl, hydroxypropyl or dihydroxypropyl.
26. The compound of claim 22, wherein A is substituted
C.sub.3-C.sub.6 cycloalkyl, wherein at least one substituent is
selected from hydroxy and hydroxyalkyl.
27. The compound of claim 26, wherein A is substituted
C.sub.3-C.sub.6 cycloalkyl, wherein at least one substituent is
hydroxymethyl.
28. The compound of claim 26, wherein A is substituted
C.sub.3-C.sub.6 cycloalkyl, wherein at least one substituent is
hydroxy.
29. A compound, or a pharmaceutically acceptable salt thereof,
according to claim 22, wherein the compound is selected from the
group consisting of:
N-hydroxy-4-(4-(4-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)ethynyl)phen-
yl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
(Compound 51);
N-hydroxy-4-(4-(4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)ethynyl)phe-
nyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
(Compound 52);
N-hydroxy-4-(4-(4-(((1R,2S)-2-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)--
2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
(Compound 53);
N-hydroxy-4-(4-(4-(((1S,2R)-2-(hydroxymethyl)cyclopropyl)ethynyl)phe-
nyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
(Compound 54);
N-hydroxy-4-(4-(4-(3-hydroxyprop-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2--
methyl-2-(methylsulfonyl)butanamide (Compound 55);
N-hydroxy-4-(4-(4-(4-hydroxybut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-m-
ethyl-2-(methylsulfonyl)butanamide (Compound 56);
N-hydroxy-4-(4-(4-(3-hydroxybut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-m-
ethyl-2-(methylsulfonyl)butanamide (Compound 57);
N-hydroxy-4-(4-(4-(4-hydroxy-3-methylbut-1-ynyl)phenyl)-2-oxopyridin-1(2H-
)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 58);
4-(4-(4-(3,4-dihydroxybut-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydroxy-
-2-methyl-2-(methylsulfonyl)butanamide (Compound 59);
4-(4-(4-(4,5-dihydroxypent-1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hydrox-
y-2-methyl-2-(methylsulfonyl)butanamide (Compound 60);
N-hydroxy-4-(4-(4-((3-hydroxycyclobutyl)ethynyl)phenyl)-2-oxopyridin-1(2H-
)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 61);
N-hydroxy-4-(4-(4-((3-(hydroxymethyl)cyclobutyl)ethynyl)phenyl)-2-oxopyri-
din-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 62);
N-hydroxy-4-(4-(4-((3-(hydroxymethyl)cyclopentyl)ethynyl)phenyl)-2-oxopyr-
idin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 63);
N-hydroxy-4-(4-(4-(4-hydroxy-3-methoxybut-1-ynyl)phenyl)-2-oxopyridin-1(2-
H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 64);
N-hydroxy-4-(4-(4-(5-hydroxy-4-methoxypent-1-ynyl)phenyl)-2-oxopyridin-1(-
2H)-yl)-2 methyl-2-(methylsulfonyl)butanamide (Compound 65);
N-hydroxy-4-(4-(4-((E)-2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)vinyl)phen-
yl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
(Compound 83);
N-hydroxy-4-(4-(4-((E)-2-((1S,2R)-2-(hydroxymethyl)cyclopropyl)vinyl-
)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
(Compound 84);
N-hydroxy-4-(4-(4-((E)-2-((1S,2S)-2-(hydroxymethyl)cyclopropyl)vinyl)phen-
yl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
(Compound 85);
N-hydroxy-4-(4-(4-((E)-2-((1R,2R)-2-(hydroxymethyl)cyclopropyl)vinyl-
)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
(Compound 86);
(E)-N-hydroxy-4-(4-(4-(3-hydroxyprop-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl-
-2-methyl-2-(methylsulfonyl)butanamide (Compound 87);
(E)-N-hydroxy-4-(4-(4-(4-hydroxybut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-
-2-methyl-2-(methylsulfonyl)butanamide (Compound 88);
(E)-N-hydroxy-4-(4-(4-(3-hydroxybut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-
-2-methyl-2-(methylsulfonyl)butanamide (Compound 89);
(E)-N-hydroxy-4-(4-(4-(4-hydroxy-3-methylbut-1-enyl)phenyl)-2-oxopyridin--
1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 90);
(E)-4-(4-(4-(3,4-dihydroxybut-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hyd-
roxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 91);
(E)-4-(4-(4-(4,5-dihydroxypent-1-enyl)phenyl)-2-oxopyridin-1(2H)-yl)-N-hy-
droxy-2-methyl-2-(methylsulfonyl)butanamide (Compound 92);
(E)-N-hydroxy-4-(4-(4-(2-(3-hydroxycyclobutyl)vinyl)phenyl)-2-oxopyridin--
1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 93);
(E)-N-hydroxy-4-(4-(4-(2-(3-(hydroxymethyl)cyclobutyl)vinyl)phenyl)-2-oxo-
pyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound
94);
(E)-N-hydroxy-4-(4-(4-(2-(3-(hydroxymethyl)cyclopentyl)vinyl)phenyl)-2-ox-
opyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound
95);
(E)-N-hydroxy-4-(4-(4-(4-hydroxy-3-methoxybut-1-enyl)phenyl)-2-oxopyridin-
-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound 96); and
(E)-N-hydroxy-4-(4-(4-(5-hydroxy-4-methoxypent-1-enyl)phenyl)-2-oxopyridi-
n-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (Compound
97).
30. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier or diluent and a compound, or a stereoisomer or
pharmaceutically acceptable salt thereof, according to claim 1
31. A method for treating a bacterial infection in a subject
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound, or a stereoisomer
or pharmaceutically acceptable salt thereof, according to claim
1.
32. A method according to claim 31, wherein said bacterial
infection is a gram-negative bacterial infection.
33. A method according to claim 32, wherein said gram-negative
bacterial infection is Pseudomonas aeruginosa, Stenotrophomonas
maltophilia, Burkholderia cepacia, Alcaligenes xylosoxidans,
Enterobacteriaceae, Haemophilus, Francisellaceae, or a Neisseria
species.
34. A method for treating a bacterial infection in a subject
comprising administering to a subject in need thereof a
therapeutically effective amount of a pharmaceutical composition
according to claim 30.
35. A method according to claim 34, wherein said bacterial
infection is a gram-negative bacterial infection.
36. A method according to claim 35, wherein said gram-negative
bacterial infection is Pseudomonas aeruginosa, Stenotrophomonas
maltophilia, Burkholderia cepacia, Alcaligenes xylosoxidans,
Enterobacteriaceae, Haemophilus, Francisellaceae, or a Neisseria
species.
37. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier or diluent and a compound, or a stereoisomer or
pharmaceutically acceptable salt thereof, according to claim
22.
38. A method for treating a bacterial infection in a subject
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound, or a stereoisomer
or pharmaceutically acceptable salt thereof, according to claim
22.
39. A method for treating a bacterial infection in a subject
comprising administering to a subject in need thereof a
therapeutically effective amount of a pharmaceutical composition,
according to claim 37.
Description
I. CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 15/179,751, filed Jun. 10, 2016 (now allowed), which is a
continuation of U.S. application Ser. No. 14/537,048, filed Nov.
10, 2014, now U.S. Pat. No. 9,403,758, which is a continuation of
International PCT Application No. PCT/US2013/040571, which was
filed on May 10, 2013, which claims the benefit under 35 U.S.C.
.sctn.119(e) of U.S. Provisional Patent Application No. 61/645,439,
filed May 10, 2012. The foregoing applications are incorporated
herein by reference in their entireties.
II. BACKGROUND OF THE INVENTION
[0002] A. Field of the Invention
[0003] 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 subjects with such pharmaceutical formulations,
and methods of preparing such pharmaceutical formulations and
inhibitors. The invention described herein pertains to treating
gram-negative infections by administering compounds capable of
inhibiting activity of
UDP-3-O--(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase
(LpxC), either alone or in combination with administering a second
antibacterial compound.
[0004] B. Introduction
[0005] Over the past several decades, the frequency of
antimicrobial resistance and its association with serious
infectious diseases have increased at alarming rates. The problem
of antibacterial resistance is compounded by the existence of
bacterial strains resistant to multiple antibacterials. Thus there
is a need for new antibacterials, particularly antibacterials with
novel mechanisms of action. A previously unexploited but highly
conserved target, LpxC, provides a new opportunity for developing
broad-spectrum antibacterial small molecules that comprise a new
class of active bactericidal chemical entities that should
encounter little, if any, naturally-occurring, target-related
resistance. LpxC (the enzyme
uridyldiphospho-3-O--(R-hydroxydecanoyl)-N-acetylglucosamine
deacetylase) is present across all Gram-negative bacterial species
of interest and is involved in the first committed step in outer
membrane biosynthesis. Thus LpxC is essential for survival and
presents an ideal target for antibiotic activity in Gram-negative
bacterial species.
[0006] Researchers have identified some compounds with
antibacterial activity that target lipid A biosynthesis. For
example, Jackman et al. (J. Biol. Chem., 2000, 275(15),
11002-11009); Wyckoff et al. (Trends in Microbiology, 1998, 6(4),
154-159); U.S. Patent Application Publication No. 2001/0053555
(published 20 Dec. 2001, corresponding to International PCT
Publication No. WO 98/18754, published 7 May 1998); International
PCT Publication No. WO 00/61134 (published 19 Oct. 2000); U.S.
Patent Application Publication No. 2004/0229955 (published 18 Nov.
2004); International PCT Publication No. WO 2008/027466 (published
6 Mar. 2008); International PCT Publication No. WO 2008/105515
(published 4 Sep. 2008); International PCT Publication No. WO
2008/154642 (published 18 Dec. 2008); International PCT Publication
No. WO 2009/158369 (published 30 Dec. 2009); International PCT
Publication No. WO 2010/017060 (published 11 Feb. 2010);
International PCT Publication No. WO 2010/024356 (published 4 Mar.
2010); International PCT Publication No. WO 2010/031750 (published
25 Mar. 2010); International PCT Publication No. WO 2010/032147
(published 25 Mar. 2010); International PCT Publication No. WO
2010/100475 (published 10 Sep. 2010); International PCT Publication
No. WO 2011/045703 (published 21 Apr. 2011); International PCT
Publication No. WO 2011/073845 (published 23 Jun. 2011); and
International PCT Publication No. WO 2011/132712 (published 27 Oct.
2011) all disclose compounds having antibacterial anti-LpxC
activity. The commercial development of these LpxC inhibitors has
been complicated by toxicity of these compounds in mammalian
animals at concentrations at or near those required for
antibacterial activity.
[0007] Although there have been advances in the field, there
remains a need for LpxC inhibitors that have activity as
bactericidal agents against gram-negative bacteria and have an
acceptable efficacy and toxicity/tolerance profile. It is,
accordingly, an object of this invention to provide compounds and
combinations of such compounds for use in the preparation of
non-toxic antibacterials and other pharmaceuticals capable of
inhibiting gram-negative bacterial infections.
III. BRIEF SUMMARY OF THE INVENTION
[0008] 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.
[0009] In one aspect the invention provides compounds of formula
I:
##STR00002##
and stereoisomers and, pharmaceutically acceptable salts thereof,
wherein
[0010] A is selected from the group consisting of: [0011] (a)
substituted C.sub.1-C.sub.6 alkyl, wherein at least one substituent
is hydroxy; and [0012] (b) substituted C.sub.3-C.sub.6 cycloalkyl,
wherein at least one substituent is selected from hydroxy and
hydroxyalkyl;
[0013] G is selected from the group consisting of: [0014] (a)
--C.ident.C--; [0015] (b) --CH.dbd.CH--C.ident.C--; [0016] (c)
--C.ident.C--CH.dbd.CH--; [0017] (d) --C.ident.C--C.ident.C--;
##STR00003##
[0017] and [0018] (g) phenyl; and
[0019] D is selected from the group consisting of:
##STR00004##
wherein W is N or N.sup.+--O.sup.-;
##STR00005##
wherein [0020] R.sup.1 and R.sup.2 are each independently selected
from hydrogen and methyl; and [0021] E is
--C(CH.sub.3).sub.2SCH.sub.3, --C(CH.sub.3).sub.2S(O)CH.sub.3,
--C(CH.sub.3).sub.2S(O).sub.2CH.sub.3, or --C(O)NHCH.sub.3.
[0022] In one aspect, the invention provides compounds of formula
II:
##STR00006##
and stereoisomers and pharmaceutically acceptable salts thereof,
wherein
[0023] A is selected from the group consisting of: [0024] (a)
substituted C.sub.1-C.sub.6 alkyl, wherein at least one substituent
is hydroxy; and [0025] (b) substituted C.sub.3-C.sub.6 cycloalkyl,
wherein at least one substituent is selected from hydroxy and
hydroxyalkyl;
[0026] G is selected from the group consisting of: [0027] (a)
--C.ident.C--; [0028] (b) --CH.dbd.CH--C.ident.C--; [0029] (c)
--C.ident.C--CH.dbd.CH--; [0030] (d) --C.ident.C--C.ident.C--;
##STR00007##
[0030] and [0031] (g) phenyl; and
[0032] D is selected from the group consisting of:
##STR00008## [0033] wherein [0034] Q is O or NR, wherein R is
hydrogen or an unsubstituted C.sub.1-C.sub.3 alkyl; [0035] R.sup.1
and R.sup.2 independently are selected from the group consisting of
hydrogen, and substituted or unsubstituted C.sub.1-C.sub.3 alkyl,
or R.sup.1 and R.sup.2, together with the carbon atom to which they
are attached, form an unsubstituted C.sub.3-C.sub.6 cycloalkyl
group or an unsubstituted 4-6 membered heterocyclic group; and
[0036] R.sup.3 is selected from the group consisting of hydrogen,
substituted or unsubstituted C.sub.1-C.sub.6-alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkylalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heterocyclylalkyl, substituted or
unsubstituted heteroaryl, and substituted or unsubstituted
heteroarylalkyl.
[0037] In another aspect, the present invention provides a
pharmaceutical composition comprising a compound of Formula I, or a
stereoisomer or pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier or diluent. In another aspect,
the present invention provides a pharmaceutical composition
comprising a compound of Formula II, or a stereoisomer or
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier or diluent.
[0038] In another aspect, the present invention provides a
pharmaceutical composition comprising an effective amount of an
antibacterial compound of Formula I, or a stereoisomer or
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier or diluent. In another aspect, the present
invention provides a pharmaceutical composition comprising an
effective amount of an antibacterial compound of Formula II, or a
stereoisomer or pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier or diluent.
[0039] In another aspect, the present invention provides a method
of inhibiting a deacetylase enzyme in gram-negative bacteria,
thereby affecting bacterial growth, comprising administering to a
subject in need of such inhibition an LpxC-inhibitory compound of
Formula I or a stereoisomer or pharmaceutically acceptable salt
thereof. In another aspect, the present invention provides a method
of inhibiting a deacetylase enzyme in gram-negative bacteria,
thereby affecting bacterial growth, comprising administering to a
subject in need of such inhibition an LpxC-inhibitory compound of
Formula II or a stereoisomer or pharmaceutically acceptable salt
thereof.
[0040] In another aspect, the present invention provides a method
of inhibiting LpxC, thereby modulating the virulence of a bacterial
infection, comprising administering to a subject in need of such
inhibition an LpxC-inhibitory compound of Formula I or a
stereoisomer or pharmaceutically acceptable salt thereof. In
another aspect, the present invention provides a method of
inhibiting LpxC, thereby modulating the virulence of a bacterial
infection, comprising administering to a subject in need of such
inhibition an LpxC-inhibitory compound of Formula II or a
stereoisomer or pharmaceutically acceptable salt thereof.
[0041] In another aspect, the present invention provides a method
for treating a subject having a bacterial infection comprising
administering to the subject in need thereof an antibacterially
effective amount of a compound of Formula I, or a stereoisomer or
pharmaceutically acceptable salt thereof. In another aspect, the
present invention provides a method for treating a subject having a
bacterial infection comprising administering to the subject in need
thereof an antibacterially effective amount of a compound of
Formula II, or a stereoisomer or pharmaceutically acceptable salt
thereof. In a more specific embodiment of the method of treatment,
the bacterial infection is a gram-negative bacterial infection. In
a further specific embodiment the subject is a mammal and in
certain embodiments, a human.
[0042] In another aspect, the present invention provides a method
of administering an antibacterially effective amount of a compound
of Formula I, or a stereoisomer or pharmaceutically acceptable salt
thereof, to a subject infected with a fermentative or
non-fermentative gram-negative bacteria. In another aspect, the
present invention provides a method of administering an
antibacterially effective amount of a compound of Formula II, or a
stereoisomer or pharmaceutically acceptable salt thereof, to a
subject infected with a fermentative or non-fermentative
gram-negative bacteria. Examples of such bacteria include
Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia
cepacia, Alcaligenes xylosoxidans, Enterobacteriaceae, Haemophilus,
Franciscellaceae (e.g., Franciscella tularensis) and Neisseria
species.
[0043] In another aspect, the present invention provides a method
of administering an antibacterially effective amount of a compound
of Formula I, or a stereoisomer or pharmaceutically acceptable salt
thereof, to a subject infected with gram-negative bacteria. In
another aspect, the present invention provides a method of
administering an antibacterially effective amount of a compound of
Formula II, or a stereoisomer or pharmaceutically acceptable salt
thereof, to a subject infected with gram-negative bacteria.
Examples of such bacteria include Enterobacteriaceae, such as
Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter,
Salmonella, Providencia, Yersinia (e.g., Yersinia pestis),
Morganella, Cedecea, Edwardsiella species and Escherichia coli.
[0044] These and other aspects of the invention will be evident
upon reference to the following detailed description.
IV. DETAILED DESCRIPTION OF THE INVENTION
[0045] 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. The invention further provides compositions and
methods for treating gram-negative infections by administering
compounds capable of inhibiting activity of
UDP-3-O--(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase
(LpxC), either alone or in combination with administering a second
antibacterial compound
A. Definitions
[0046] The following abbreviations and definitions are used
throughout this application:
[0047] "LpxC" is an abbreviation that stands for
UDP-3-O--(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase.
[0048] As used herein, the following definitions shall apply unless
otherwise indicated.
[0049] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl
groups having from 1 to 10 carbon atoms and preferably 1 to 6
carbon atoms. This term includes, by way of example, linear and
branched hydrocarbyl groups such as methyl (CH.sub.3--), ethyl
(CH.sub.3CH.sub.2--), n-propyl (CH.sub.3CH.sub.2CH.sub.2--),
isopropyl ((CH.sub.3).sub.2CH--), n-butyl
(CH.sub.3CH.sub.2CH.sub.2CH.sub.2--), isobutyl
((CH.sub.3).sub.2CHCH.sub.2--), sec-butyl
((CH.sub.3)(CH.sub.3CH.sub.2)CH--), t-butyl ((CH.sub.3).sub.3C--),
n-pentyl (CH.sub.3CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and
neopentyl ((CH.sub.3).sub.3CCH.sub.2--).
[0050] "Alkoxy" refers to the group --O-alkyl, wherein alkyl is as
defined herein. Alkoxy includes methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the
like.
[0051] "Amino" refers to the group --NH.sub.2.
[0052] "Primary alcohol" refers to the group -alkyl-OH, wherein the
hydroxyl radical is connected to a primary carbon. Examples include
--CH.sub.2OH (hydroxymethyl), --CH.sub.2CH.sub.2OH (hydroxymethyl)
and --CH(CH.sub.3)CH.sub.2OH (1-hydroxypropan-2-yl).
[0053] "Alkenyl" refers to straight chain or branched hydrocarbyl
groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon
atoms and having at least 1 and preferably from 1 to 2 sites of
vinyl (>C.dbd.C<) unsaturation. Such groups are exemplified
by vinyl, allyl, and but-3-en-1-yl. Included within this term are
the cis and trans isomers or mixtures of these isomers.
[0054] "Alkynyl" refers to straight or branched monovalent
hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2
to 3 carbon atoms and having at least 1 and preferably from 1 to 2
sites of acetylenic --C.ident.C-- unsaturation. Examples of such
alkynyl groups include acetylenyl (--C.ident.CH), and propargyl
(--CH.sub.2C.ident.CH).
[0055] "Carboxyl" or "carboxy" refers to --COOH or salts
thereof.
[0056] "Cyano" or "nitrile" refers to the group --CN.
[0057] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 13
carbon atoms having single. Examples of cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like.
[0058] "Guanidino" refers to the group --NHC(.dbd.NH)NH.sub.2.
[0059] "Halo" or "halogen" refers to fluoro, chloro, bromo, and
iodo and is typically fluoro or chloro.
[0060] "Hydroxy" or "hydroxyl" refers to the group --OH.
[0061] "Heterocycle," "heterocyclic," and "heterocyclyl" refer to a
saturated or unsaturated group having a single ring, and having
from 3 to 15 ring atoms, including 1 to 4 hetero atoms. These ring
atoms are selected from the group consisting of nitrogen, sulfur,
or oxygen. In one implementation, the nitrogen and/or sulfur
atom(s) of the heterocyclic group are optionally oxidized to
provide for the N-oxide, --S(O)--, or --SO.sub.2-- moieties.
[0062] "Nitro" refers to the group --NO.sub.2.
[0063] "Nitroso" refers to the group --NO.
[0064] "Oxo" refers to the atom (.dbd.O).
[0065] "Substituted" refers to a group having one or more hydrogens
replaced with substituents selected from the group consisting of
alkoxy, acyl, acylamino, acyloxy, amino, aminocarbonyl,
aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, amidino, carboxyl, carboxyl ester, (carboxyl
ester)amino, (carboxyl ester)oxy, cyano, guanidino, halo, hydroxy,
nitro, SO.sub.3H, sulfonyl, sulfonyloxy, thioacyl, thiol, and
alkylthio, wherein said substituents are as defined herein. In
certain substituted cyclic groups, "substituted" also refers to a
group having two hydrogens replaced with a single double bonded
oxygen atom (an oxo group) or a single double bonded sulfur atom
(thioxo). In some implementations, the substituted group has 1 to 3
of the aforementioned substituents. In other implementations, the
substituted group has 1 to 2 of the aforementioned substituents
[0066] "Sulfonyl" refers to the group --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-- alkenyl,
--SO.sub.2-substituted alkenyl, wherein alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl are
as defined herein. Sulfonyl includes groups such as
methyl-SO.sub.2--.
[0067] "Sulfonyloxy" refers to the group --OSO.sub.2-alkyl,
--OSO.sub.2-substituted alkyl, --OSO.sub.2-alkenyl,
--OSO.sub.2-substituted alkenyl, --OSO.sub.2-alkynyl,
--OSO.sub.2-substituted alkynyl, wherein alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl are
as defined herein.
[0068] "Thioacyl" refers to the groups H--C(S)--, alkyl-C(S)--,
substituted alkyl-C(S)--, alkenyl-C(S)--, substituted
alkenyl-C(S)--, alkynyl-C(S)--, and substituted alkynyl-C(S)--,
wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, and substituted alkynyl are as defined herein.
[0069] "Thiol" refers to the group --SH.
[0070] "Thioxo" refers to the atom (.dbd.S).
[0071] "Alkylthio" refers to the group --S-alkyl, wherein alkyl is
as defined herein. In other implementations, sulfur may be oxidized
to --S(O)--. The sulfoxide may exist as one or more
stereoisomers.
[0072] Unless indicated otherwise, the nomenclature of substituents
that are not explicitly defined herein are arrived at by naming the
terminal portion of the functionality followed by the adjacent
functionality toward the point of attachment. For example, the
substituent "arylalkyloxycarbonyl" refers to the group
(aryl)-(alkyl)-O--C(O)--.
[0073] Generally, reference to a certain element such as hydrogen
or H is meant to include all isotopes of that element. For example,
if a substituent group is defined to include hydrogen or H, it also
includes deuterium and tritium.
[0074] The subject invention also includes isotopically-labeled
compounds of the present invention, that are structurally identical
to those disclosed herein, 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.
[0075] "Stereoisomer" and "stereoisomers" refer to compounds that
have same atomic connectivity but different atomic arrangement in
space. Stereoisomers include cis-trans isomers, E and Z isomers,
enantiomers, and diastereomers.
[0076] "Tautomer" refers to alternate forms of a molecule that
differ in the position of a proton, such as enol-keto and
imine-enamine tautomers, or the tautomeric forms of heteroaryl
groups containing a --N.dbd.C(H)--NH-- ring atom arrangement, such
as pyrazoles, imidazoles, benzimidazoles, triazoles, and
tetrazoles. A person of ordinary skill in the art would recognize
that other tautomeric ring atom arrangements are possible.
[0077] "Subject" refers to human and non-human animals, especially
mammals.
[0078] "Pharmaceutically acceptable salt" refers to
pharmaceutically acceptable salts of a compound, which salts are
derived from a variety of organic and inorganic counter ions well
known in the art and include, by way of example only, sodium,
potassium, calcium, magnesium, ammonium, tetraalkylammonium, and
the like; and when the molecule contains a basic functionality,
salts of organic or inorganic acids, such as hydrochloride,
hydrobromide, tartrate, mesylate, acetate, maleate, oxalate,
phosphate, sulfate and the like.
[0079] "Pharmaceutically effective amount" and "therapeutically
effective amount" refer to an amount of a compound sufficient to
treat a specified disorder or disease or one or more of its
symptoms and/or to prevent the occurrence of the disease or
disorder.
[0080] "Co-administration" can be in the form of a single
formulation (combining, for example, a compound of the present
invention and a second antibacterial agent with pharmaceutically
acceptable excipients, optionally segregating the two active
ingredients in different excipient mixtures designed to
independently control their respective release rates and durations)
or by independent administration of separate formulations
containing the active agents. "Co-administration" further includes
concurrent administration (administration of a compound of the
present invention and a second antibacterial agent at the same
time) and time varied administration (administration of a compound
of the present invention at a time different from that of the
second antibacterial agent), as long as both the compound of the
present invention and the second antibacterial agent are present in
the body in therapeutically effective concentrations during at
least partially overlapping times.
[0081] The term "antibacterial agent" refers to agents that have
either bactericidal or bacteriostatic activity. 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.
[0082] Unless the context requires otherwise, throughout the
specification and claims which follow, the word "comprise" and
variations thereof, such as, "comprises" and "comprising" are to be
construed in an open, inclusive sense, that is as "including, but
not limited to".
[0083] Reference throughout this specification to "one embodiment"
or "an embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment of the present invention. Thus,
the appearances of the phrases "in one embodiment" or "in an
embodiment" in various places throughout this specification are not
necessarily all referring to the same embodiment. Furthermore, the
particular features, structures, or characteristics may be combined
in any suitable manner in one or more embodiments.
B. Compounds, Compositions and Use Thereof
[0084] In one aspect, the invention provides compounds of formula
I:
##STR00009##
and stereoisomers, pharmaceutically acceptable salts, and esters
thereof, wherein
[0085] A is selected from the group consisting of: [0086] (a)
substituted C.sub.1-C.sub.6 alkyl, wherein at least one substituent
is hydroxy; and [0087] (b) substituted C.sub.3-C.sub.6 cycloalkyl,
wherein at least one substituent is selected from hydroxy and
hydroxyalkyl;
[0088] G is selected from the group consisting of: [0089] (a)
--C.ident.C--; [0090] (b) --CH.dbd.CH--C.ident.C--; [0091] (c)
--C.ident.C--CH.dbd.CH--; [0092] (d) --C.ident.C--C.ident.C--;
##STR00010##
[0092] and [0093] (g) phenyl; and
[0094] D is selected from the group consisting of:
##STR00011##
wherein W is N or N.sup.+--O.sup.-;
##STR00012##
wherein [0095] R.sup.1 and R.sup.2 are each independently selected
from hydrogen and methyl; and [0096] E is
--C(CH.sub.3).sub.2SCH.sub.3, --C(CH.sub.3).sub.2S(O)CH.sub.3,
--C(CH.sub.3).sub.2S(O).sub.2CH.sub.3, or --C(O)NHCH.sub.3.
[0097] In one aspect, the invention provides compounds of formula
II:
##STR00013##
and stereoisomers, pharmaceutically acceptable salts, and esters
thereof, wherein
[0098] A is selected from the group consisting of: [0099] (a)
substituted C.sub.1-C.sub.6 alkyl, wherein at least one substituent
is hydroxy; and [0100] (b) substituted C.sub.3-C.sub.6 cycloalkyl,
wherein at least one substituent is selected from hydroxy and
hydroxyalkyl;
[0101] G is selected from the group consisting of: [0102] (a)
--C.ident.C--; [0103] (b) --CH.dbd.CH--C.ident.C--; [0104] (c)
--C.ident.C--CH.dbd.CH--; [0105] (d) --C.ident.C--C.ident.C--;
##STR00014##
[0105] and [0106] (g) phenyl; and
[0107] D is selected from the group consisting of:
##STR00015## [0108] wherein [0109] Q is O or NR, wherein R is
hydrogen or an unsubstituted C.sub.1-C.sub.3 alkyl; [0110] R.sup.1
and R.sup.2 independently are selected from the group consisting of
hydrogen, and substituted or unsubstituted C.sub.1-C.sub.3 alkyl,
or R.sup.1 and R.sup.2, together with the carbon atom to which they
are attached, form an unsubstituted C.sub.3-C.sub.6 cycloalkyl
group or an unsubstituted 4-6 membered heterocyclic group; and
[0111] R.sup.3 is selected from the group consisting of hydrogen,
substituted or unsubstituted C.sub.1-C.sub.6-alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkylalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heterocyclylalkyl, substituted or
unsubstituted heteroaryl, and substituted or unsubstituted
heteroarylalkyl. In certain embodiments, A is substituted
C.sub.1-C.sub.6 alkyl, wherein at least one substituent is hydroxy.
In certain embodiments, A is substituted C.sub.1-C.sub.6 alkyl,
wherein at least two substituents are hydroxy. For example, in
certain embodiments A is hydroxymethyl, hydroxyethyl, hydroxypropyl
or dihydroxypropyl.
[0112] In other embodiments, A is substituted C.sub.3-C.sub.6
cycloalkyl, wherein at least one substituent is selected from
hydroxy and hydroxyalkyl. In certain embodiments, A is substituted
C.sub.3-C.sub.6 cycloalkyl, wherein at least one substituent is
hydroxymethyl. For example, in certain embodiments A is
hydroxymethylcyclopropyl. In other embodiments, A is substituted
C.sub.3-C.sub.6 cycloalkyl, wherein at least one substituent is
hydroxy.
In certain embodiments, G is --C.ident.C--C.ident.C--. In certain
embodiments of compounds of Formula I, D is
##STR00016##
wherein W is N or N.sup.+--O.sup.-. In other embodiments of
compounds of Formula I, D is
##STR00017##
In still other embodiments of compounds of Formula I, D is
##STR00018##
Finally, in still other embodiments of compounds of Formula I, D
is
##STR00019##
In certain embodiments, R.sup.1 is hydrogen. Similarly, in certain
embodiments, R.sup.2 is hydrogen. In certain embodiments of
compounds of Formula I, E is --C(CH.sub.3).sub.2SCH.sub.3. In other
embodiments, E is --C(CH.sub.3).sub.2S(O).sub.2CH.sub.3. In still
other embodiments, E is --C(CH.sub.3).sub.2S(O)CH.sub.3. In still
other embodiments, E is --C(O)NHCH.sub.3. The compounds of the
invention include the compounds of Table I below.
TABLE-US-00001 TABLE I # structure name 1 ##STR00020##
N-hydroxy-2-(4-(((trans)-2- (hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)phenyl)-1,6-naphthyridine-4- carboxamide 2 ##STR00021##
N-hydroxy-4-(4-(((trans)-2- (hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)phenyl)picolinamide 3 ##STR00022##
N-((R)-1-(hydroxyamino)-3-methyl-3-
(methylthio)-1-oxobutan-2-yl)-4-(((trans)-2-
(hydroxymethyl)cyclopropyl)buta-1,3- diynyl)benzamide 4
##STR00023## N-((2R)-1-(hydroxyamino)-3-methyl-3-
(methylsulfinyl)-1-oxobutan-2-yl)-4- (((trans)-2-
(hydroxymethyl)cyclopropyl)buta-1,3- diynyl)benzamide 5
##STR00024## N-((R)-1-(hydroxyamino)-3-methyl-3-
(methylsulfonyl)-1-oxobutan-2-yl)-4- (((trans)-2-
(hydroxymethyl)cyclopropyl)buta-1,3- diynyl)benzamide 6
##STR00025## N-((S)-3-amino-1-(hydroxyamino)-3-
methyl-1-oxobutan-2-yl)-6-(((trans)-2-
(hydroxymethyl)cyclopropyl)ethynyl)-2- naphthamide 7 ##STR00026##
N-((S)-3-amino-1-(hydroxyamino)-3-
methyl-1-oxobutan-2-yl)-6-(((trans)-2-
(hydroxymethyl)cyclopropyl)ethynyl)benzo [b]thiophene-2-carboxamide
8 ##STR00027## N1-hydroxy-2-(4-(((1R,2R)-2-
(hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)benzamido)-N3-methylmalonamide 9 ##STR00028##
N-hydroxy-4-(4-(((trans)-2- (hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)phenyl)-2-methyl-2- (methylsulfonyl)butanamide 10
##STR00029## N-hydroxy-2-(4-(6-hydroxyhexa-1,3-
diynyl)phenyl)-1,6-naphthyridine-4- carboxamide 11 ##STR00030##
N-hydroxy-2-(4-(5-hydroxypenta-1,3-
diynyl)phenyl)-1,6-naphthyridine-4- carboxamide 12 ##STR00031##
N-hydroxy-2-(4-(5-hydroxyhexa-1,3-
diynyl)phenyl)-1,6-naphthyridine-4- carboxamide 13 ##STR00032##
N-hydroxy-2-(4-(6-hydroxy-5-methylhexa-
1,3-diynyl)phenyl)-1,6-naphthyridine-4- carboxamide 14 ##STR00033##
2-(4-(5,6-dihydroxyhexa-1,3- diynyl)phenyl)-N-hydroxy-1,6-
naphthyridine-4-carboxamide 15 ##STR00034##
2-(4-(6,7-dihydroxyhepta-1,3- diynyl)phenyl)-N-hydroxy-1,6-
naphthyridine-4-carboxamide 16 ##STR00035## N-hydroxy-2-(4-((3-
(hydroxymethyl)cyclobutyl)buta-1,3-
diynyl)phenyl)-1,6-naphthyridine-4- carboxamide 17 ##STR00036##
N-hydroxy-2-(4-((3- (hydroxymethyl)cyclobutyl)buta-1,3-
diynyl)phenyl)-1,6-naphthyridine-4- carboxamide 18 ##STR00037##
N-hydroxy-2-(4-((3- hydroxycyclobutyl)buta-1,3-diynyl)phenyl)-
1,6-naphthyridine-4-carboxamide 19 ##STR00038## N-hydroxy-2-(4-((3-
(hydroxymethyl)cyclopentyl)buta-1,3-
diynyl)phenyl)-1,6-naphthyridine-4- carboxamide 20 ##STR00039##
N-hydroxy-2-(4-(((1R,2S)-2- (hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)phenyl)-1,6-naphthyridine-4- carboxamide 21 ##STR00040##
N-hydroxy-2-(4-(6-hydroxy-5- methoxyhexa-1,3-diynyl)phenyl)-1,6-
naphthyridine-4-carboxamide 22 ##STR00041##
N-hydroxy-2-(4-(7-hydroxy-6- methoxyhepta-1,3-diynyl)phenyl)-1,6-
naphthyridine-4-carboxamide 23 ##STR00042##
4-(hydroxycarbamoyl)-2-(4-(6- hydroxyhexa-1,3-diynyl)phenyl)-1,6-
naphthyridine 6-oxide 24 ##STR00043## 4-(hydroxycarbamoyl)-2-(4-(5-
hydroxypenta-1,3-diynyl)phenyl)-1,6- naphthyridine 6-oxide 25
##STR00044## 4-(hydroxycarbamoyl)-2-(4-(5-
hydroxyhexa-1,3-diynyl)phenyl)-1,6- naphthyridine 6-oxide 26
##STR00045## 2-(4-(6-hydroxy-5-methylhexa-1,3-
diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6- naphthyridine 6-oxide 27
##STR00046## 2-(4-(5,6-dihydroxyhexa-1,3-
diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6- naphthyridine 6-oxide 28
##STR00047## 2-(4-(6,7-dihydroxyhepta-1,3-
diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6- naphthyridine 6-oxide 29
##STR00048## 4-(hydroxycarbamoyl)-2-(4-((3-
(hydroxymethyl)cyclobutyl)buta-1,3-
diynyl)phenyl)-1,6-naphthyridine 6-oxide 30 ##STR00049##
4-(hydroxycarbamoyl)-2-(4-((3-
hydroxycyclobutyl)buta-1,3-diynyl)phenyl)- 1,6-naphthyridine
6-oxide 31 ##STR00050## 4-(hydroxycarbamoyl)-2-(4-((3-
(hydroxymethyl)cyclopentyl)buta-1,3-
diynyl)phenyl)-1,6-naphthyridine 6-oxide 32 ##STR00051##
4-(hydroxycarbamoyl)-2-(4-(((1R,2S)-2-
(hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)phenyl)-1,6-naphthyridine 6-oxide 33 ##STR00052##
2-(4-(6-hydroxy-5-methoxyhexa-1,3-
diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6- naphthyridine 6-oxide 34
##STR00053## 2-(4-(7-hydroxy-6-methoxyhepta-1,3-
diynyl)phenyl)-4-(hydroxycarbamoyl)-1,6- naphthyridine 6-oxide 35
##STR00054## N-hydroxy-4-(4-(((1S,2S)-2-
(hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 36 ##STR00055##
N-hydroxy-4-(4-(((1R,2R)-2- (hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 37 ##STR00056##
N-hydroxy-4-(4-(((1R,2S)-2- (hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 38 ##STR00057##
N-hydroxy-4-(4-(((1S,2R)-2- (hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 39 ##STR00058##
N-hydroxy-4-(4-(5-hydroxypenta-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 40 ##STR00059##
N-hydroxy-4-(4-(6-hydroxyhexa-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 41 ##STR00060##
N-hydroxy-4-(4-(5-hydroxyhexa-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 42 ##STR00061##
N-hydroxy-4-(4-(6-hydroxy-5-methylhexa-
1,3-diynyl)-2-oxopyridin-1(2H)-yl)-2-
methyl-2-(methylsulfonyl)butanamide 43 ##STR00062##
4-(4-(5,6-dihydroxyhexa-1,3-diynyl)-2-
oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-
2-(methylsulfonyl)butanamide 44 ##STR00063##
4-(4-(6,7-dihydroxyhepta-1,3-diynyl)-2-
oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-
2-(methylsulfonyl)butanamide 45 ##STR00064## N-hydroxy-4-(4-((3-
hydroxycyclobutyl)buta-1,3-diynyl)-2-
oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 46
##STR00065## N-hydroxy-4-(4-((3-
(hydroxymethyl)cyclobutyl)buta-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 47 ##STR00066## N-hydroxy-4-(4-((3-
(hydroxymethyl)cyclopentyl)buta-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 48 ##STR00067##
N-hydroxy-4-(4-(6-hydroxy-5- methoxyhexa-1,3-diynyl)-2-oxopyridin-
1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 49 ##STR00068##
N-hydroxy-4-(4-(7-hydroxy-6- methoxyhepta-1,3-diynyl)-2-oxopyridin-
1(2H)-yl)-2-methyl-2- (methylsulfonyl)bulanamide 50 ##STR00069##
N-hydroxy-4-(4-(6-hydroxyhexa-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 51 ##STR00070##
N-hydroxy-4-(4-(4-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)ethynyl)
phenyl)-2-oxopyridin-1(2H)-yl)-2-
methyl-2-(methylsulfonyl)butanamide 52 ##STR00071##
N-hydroxy-4-(4-(4-(((1R,2R)-2- (hydroxymethyl)cyclopropyl)ethynyl)
phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-
2-(methylsulfonyl)butanamide 53 ##STR00072##
N-hydroxy-4-(4-(4-(((1R,2S)-2- (hydroxymethyl)cyclopropyl)ethynyl)
phenyl)-2-oxopyridin-1(2H)-yl)-2-
methyl-2-(methylsulfonyl)butanamide 54 ##STR00073##
N-hydroxy-4-(4-(4-(((1S,2R)-2- (hydroxymethyl)cyclopropyl)ethynyl)
phenyl)-2-oxopyridin-1(2H)-yl)-2-
methyl-2-(methylsulfonyl)butanamide 55 ##STR00074##
N-hydroxy-4-(4-(4-(3-hydroxyprop-1-
ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-
methyl-2-(methylsulfonyl)butanamide 56 ##STR00075##
N-hydroxy-4-(4-(4-(4-hydroxybut-1-
ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-
methyl-2-(methylsulfonyl)butanamide 57 ##STR00076##
N-hydroxy-4-(4-(4-(3-hydroxybut-1-
ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-
methyl-2-(methylsulfonyl)butanamide 58 ##STR00077##
N-hydroxy-4-(4-(4-(4-hydroxy-3-methylbut-
1-ynyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-
methyl-2-(methylsulfonyl)butanamide 59 ##STR00078##
4-(4-(4-(3,4-dihydroxybut-1-ynyl)phenyl)-
2-oxopyridin-1(2H)-yl)-N-hydroxy-2-
methyl-2-(methylsulfonyl)butanamide 60 ##STR00079##
4-(4-(4-(4,5-dihydroxypent-1-ynyl)phenyl)-
2-oxopyridin-1(2H)-yl)-N-hydroxy-2-
methyl-2-(methylsulfonyl)butanamide 61 ##STR00080##
N-hydroxy-4-(4-(4-((3- hydroxycyclobutyl)ethynyl)phenyl)-2-
oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 62
##STR00081## N-hydroxy-4-(4-(4-((3-
(hydroxymethyl)cyclobutyl)ethynyl)
phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 63 ##STR00082## N-hydroxy-4-(4-(4-((3-
(hydroxymethyl)cyclopentyl)ethynyl)
phenyl)-2-oxopyridin-1(2H)-yl)-2-
methyl-2-(methylsulfonyl)butanamide 64 ##STR00083##
N-hydroxy-4-(4-(4-(4-hydroxy-3-
methoxybut-1-ynyl)phenyl)-2-oxopyridin- 1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 65 ##STR00084##
N-hydroxy-4-(4-(4-(5-hydroxy-4-
methoxypent-1-ynyl)phenyl)-2-oxopyridin- 1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 66 ##STR00085##
N-hydroxy-4-(4-(6-hydroxyhexa-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 67 ##STR00086##
N-hydroxy-4-(4-(4-((2S)-2- (hydroxymethyl)cyclopropyl)phenyl)-2-
oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 68
##STR00087## N-hydroxy-4-(4-(4-((2R)-2-
(hydroxymethyl)cyclopropyl)phenyl)-2-
oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 69
##STR00088## N-hydroxy-4-(4-(4-((2S)-2-
(hydroxymethyl)cyclopropyl)phenyl)-2-
oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide
70 ##STR00089## N-hydroxy-4-(4-(4-((2R)-2-
(hydroxymethyl)cyclopropyl)phenyl)-2-
oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 71
##STR00090## N-hydroxy-4-(4-(4-
(hydroxymethyl)phenyl)-2-oxopyridin- 1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 72 ##STR00091## N-hydroxy-4-(4-(4-(2-
hydroxyethyl)phenyl)-2-oxopyridin-1(2H)-
yl)-2-methyl-2-(methylsulfonyl)butanamide 73 ##STR00092##
N-hydroxy-4-(4-(4-(1- hydroxyethyl)phenyl)-2-oxopyridin-1(2H)-
yl)-2-methyl-2-(methylsulfonyl)butanamide 74 ##STR00093##
N-hydroxy-4-(4-(4-(1-hydroxypropan-2-
yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-
2-(methyisulfonyl)butanamide 75 ##STR00094##
4-(4-(4-(1,2-dihydroxyethyl)phenyl)-2-
oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-
2-(methylsulfonyl)butanamide 76 ##STR00095##
4-(4-(4-(2,3-dihydroxypropyl)phenyl)-2-
oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-
2-(methylsulfonyl)butanamide 77 ##STR00096## N-hydroxy-4-(4-(4-(3-
hydroxycyclobutyl)phenyl)-2-oxopyridin- 1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 78 ##STR00097## N-hydroxy-4-(4-(4-(3-
(hydroxymethyl)cyclobutyl)phenyl)-2-
oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 79
##STR00098## N-hydroxy-4-(4-(4-(3-
(hydroxymethyl)cyclopentyl)phenyl)-2-
oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 80
##STR00099## N-hydroxy-4-(4-(4-(2-hydroxy-1-
methoxyethyl)phenyl)-2-oxopyridin-1(2H)-
yl)-2-methyl-2-(methylsulfonyl)butanamide 81 ##STR00100##
N-hydroxy-4-(4-(4-(3-hydroxy-2- methoxypropyl)phenyl)-2-oxopyridin-
1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 82 ##STR00101##
N-hydroxy-4-(4-(6-hydroxyhexa-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 83 ##STR00102##
N-hydroxy-4-(4-(4-((E)-2-((1R,2S)-2-
(hydroxymethyl)cyclopropyl)vinyl)phenyl)-
2-oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 84
##STR00103## N-hydroxy-4-(4-(4-((E)-2-((1S,2R)-2-
(hydroxymethyl)cyclopropyl)vinyl)phenyl)-
2-oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 85
##STR00104## N-hydroxy-4-(4-(4-((E)-2-((1S,2S)-2-
(hydroxymethyl)cyclopropyl)vinyl)phenyl)-
2-oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 86
##STR00105## N-hydroxy-4-(4-(4-((E)-2-((1R,2R)-2-
(hydroxymethyl)cyclopropyl)vinyl)phenyl)-
2-oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 87
##STR00106## (E)-N-hydroxy-4-(4-(4-(3-hydroxyprop-1-
enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-
methyl-2-(methylsulfonyl)butanamide 88 ##STR00107##
(E)-N-hydroxy-4-(4-(4-(4-hydroxybut-1-
enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-
methyl-2-(methylsulfonyl)butanamide 89 ##STR00108##
(E)-N-hydroxy-4-(4-(4-(3-hydroxybut-1-
enyl)phenyl)-2-oxopyridin-1(2H)-yl)-2-
methyl-2-(methylsulfonyl)butanamide 90 ##STR00109##
(E)-N-hydroxy-4-(4-(4-(4-hydroxy-3-
methylbut-1-enyl)phenyl)-2-oxopyridin- 1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 91 ##STR00110##
(E)-4-(4-(4-(3,4-dihydroxybut-1-
enyl)phenyl)-2-oxopyridin-1(2H)-yl)-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide 92 ##STR00111##
(E)-4-(4-(4-(4,5-dihydroxypent-1-
enyl)phenyl)-2-oxopyridin-1(2H)-yl)-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide 93 ##STR00112##
(E)-N-hydroxy-4-(4-(4-(2-(3- hydroxycyclobutyl)vinyl)phenyl)-2-
oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 94
##STR00113## (E)-N-hydroxy-4-(4-(4-(2-(3-
(hydroxymethyl)cyclobutyl)vinyl)phenyl)-2-
oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 95
##STR00114## (E)-N-hydroxy-4-(4-(4-(2-(3-
(hydroxymethyl)cyclopentyl)vinyl)phenyl)-
2-oxopyridin-1(2H)-yl)-2-methyl-2- (methylsulfonyl)butanamide 96
##STR00115## (E)-N-hydroxy-4-(4-(4-(4-hydroxy-3-
methoxybut-1-enyl)phenyl)-2-oxopyridin- 1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 97 ##STR00116##
(E)-N-hydroxy-4-(4-(4-(5-hydroxy-4-
methoxypent-1-enyl)phenyl)-2-oxopyridin- 1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 98 ##STR00117##
N-hydroxy-4-(4-(6-hydroxyhexa-1,3-
diynyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 99 ##STR00118##
N-hydroxy-4-(4-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)phenyl)-2-methyl-2- (methylsulfonyl)butanamide 100
##STR00119## N-hydroxy-4-(4-(((1R,2R)-2-
(hydroxymethyl)cyclopropyl)buta-1,3- diynyl)phenyl)-2-methyl-2-
(methylsulfonyl)butanamide 101 ##STR00120##
N-hydroxy-4-(4-(((1R,2S)-2- (hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)phenyl)-2-methyl-2- (methylsulfonyl)butanamide 102
##STR00121## N-hydroxy-4-(4-(((1S,2R)-2-
(hydroxymethyl)cyclopropyl)buta-1,3- diynyl)phenyl)-2-methyl-2-
(methylsulfonyl)butanamide 103 ##STR00122##
N-hydroxy-4-(4-(5-hydroxypenta-1,3- diynyl)phenyl)-2-methyl-2-
(methylsulfonyl)butanamide 104 ##STR00123##
N-hydroxy-4-(4-(6-hydroxyhexa-1,3- diynyl)phenyl)-2-methyl-2-
(methylsulfonyl)butanamide 105 ##STR00124##
N-hydroxy-4-(4-(5-hydroxyhexa-1,3- diynyl)phenyl)-2-methyl-2-
(methylsulfonyl)butanamide 106 ##STR00125##
N-hydroxy-4-(4-(6-hydroxy-5-methylhexa-
1,3-diynyl)phenyl)-2-methyl-2- (methylsulfonyl)butanamide 107
##STR00126## 4-(4-(5,6-dihydroxyhexa-1,3-
diynyl)phenyl)-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 108
##STR00127## 4-(4-(6,7-dihydroxyhepta-1,3-
diynyl)phenyl)-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 109
##STR00128## N-hydroxy-4-(4-((3-
hydroxycyclobutyl)buta-1,3-diynyl)phenyl)-
2-methyl-2-(methylsulfonyl)butanamide 110 ##STR00129##
N-hydroxy-4-(4-((3- (hydroxymethyl)cyclobutyl)buta-1,3-
diynyl)phenyl)-2-methyl-2- (methylsulfonyl)butanamide 111
##STR00130## N-hydroxy-4-(4-((3-
(hydroxymethyl)cyclopentyl)buta-1,3- diynyl)phenyl)-2-methyl-2-
(methylsulfonyl)butanamide 112 ##STR00131##
N-hydroxy-4-(4-(6-hydroxy-5-
methoxyhexa-1,3-diynyl)phenyl)-2-methyl-
2-(methylsulfonyl)butanamide 113 ##STR00132##
N-hydroxy-4-(4-(7-hydroxy-6- methoxyhepta-1,3-diynyl)phenyl)-2-
methyl-2-(methylsulfonyl)butanamide 114 ##STR00133##
N-hydroxy-4-(4-(6-hydroxyhexa-1,3- diynyl)phenyl)-2-methyl-2-
(methylsulfonyl)butanamide 115 ##STR00134##
N-hydroxy-4-(4'-(((1S,2S)-2- (hydroxymethyl)cyclopropyl)ethynyl)
biphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanamide 116
##STR00135## N-hydroxy-4-(4'-(((1R,2R)-2-
(hydroxymethyl)cyclopropyl)ethynyl) biphenyl-4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 117 ##STR00136##
N-hydroxy-4-(4'-(((1R,2S)-2- (hydroxymethyl)cyclopropyl)ethynyl)
biphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanamide 118
##STR00137## N-hydroxy-4-(4'-(((1S,2R)-2-
(hydroxymethyl)cyclopropyl)ethynyl) biphenyl-4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 119 ##STR00138##
N-hydroxy-4-(4'-(3-hydroxyprop-1- ynyl)biphenyl-4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 120 ##STR00139##
N-hydroxy-4-(4'-(4-hydroxybut-1- ynyl)biphenyl-4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 121 ##STR00140##
N-hydroxy-4-(4'-(3-hydroxybut-1- ynyl)biphenyl-4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 122 ##STR00141##
N-hydroxy-4-(4'-(4-hydroxy-3-methylbut-1-
ynyl)biphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanamide 123
##STR00142## 4-(4'-(3,4-dihydroxybut-1-ynyl)biphenyl-4-
yl)-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 124
##STR00143## 4-(4'-(4,5-dihydroxypent-1-ynyl)biphenyl-4-
yl)-N-hydroxy-2-methyl-2- (methylsulfonyl)butanamide 125
##STR00144## N-hydroxy-4-(4'-((3-
hydroxycyclobutyl)ethynyl)biphenyl-4-yl)-
2-methyl-2-(methylsulfonyl)butanamide 126 ##STR00145##
N-hydroxy-4-(4'-((3- (hydroxymethyl)cyclobutyl)ethynyl)
biphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanamide 127
##STR00146## N-hydroxy-4-(4'-((3-
(hydroxymethyl)cyclopentyl)ethynyl) biphenyl-4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 128 ##STR00147##
N-hydroxy-4-(4'-(4-hydroxy-3-methoxybut-
1-ynyl)biphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanamide 129
##STR00148## N-hydroxy-4-(4'-(5-hydroxy-4-
methoxypent-1-ynyl)biphenyl-4-yl)-2-
methyl-2-(methylsulfonyl)butanamide 130 ##STR00149##
N-hydroxy-4-(4-(6-hydroxyhexa-1,3- diynyl)phenyl)-2-methyl-2-
(methylsulfonyl)butanamide 131 ##STR00150##
N-hydroxy-4-(4'-((2S)-2- (hydroxymethyl)cyclopropyl)biphenyl-4-yl)-
2-methyl-2-(methylsulfonyl)butanamide 132 ##STR00151##
N-hydroxy-4-(4'-((2R)-2- (hydroxymethyl)cyclopropyl)biphenyl-4-yl)-
2-methyl-2-(methylsulfonyl)butanamide 133 ##STR00152##
N-hydroxy-4-(4'-((2S)-2- (hydroxymethyl)cyclopropyl)biphenyl-4-yl)-
2-methyl-2-(methylsulfonyl)butanamide 134 ##STR00153##
N-hydroxy-4-(4'-((2R)-2- (hydroxymethyl)cyclopropyl)biphenyl-4-yl)-
2-methyl-2-(methylsulfonyl)butanamide 135 ##STR00154##
N-hydroxy-4-(4'-(hydroxymethyl)biphenyl- 4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 136 ##STR00155##
N-hydroxy-4-(4'-(2-hydroxyethyl)biphenyl- 4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 137 ##STR00156##
N-hydroxy-4-(4'-(1-hydroxyethyl)biphenyl- 4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 138 ##STR00157##
N-hydroxy-4-(4'-(1-hydroxypropan-2- yl)biphenyl-4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 139 ##STR00158##
4-(4'-(1,2-dihydroxyethyl)biphenyl-4-yl)-N- hydroxy-2-methyl-2-
(methylsulfonyl)butanamide 140 ##STR00159##
4-(4'-(2,3-dihydroxypropyl)biphenyl-4-yl)- N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide
141 ##STR00160## N-hydroxy-4-(4'-(3-
hydroxycyclobutyl)biphenyl-4-yl)-2-methyl-
2-(methylsulfonyl)butanamide 142 ##STR00161## N-hydroxy-4-(4'-(3-
(hydroxymethyl)cyclobutyl)biphenyl-4-yl)-
2-methyl-2-(methylsulfonyl)butanamide 143 ##STR00162##
N-hydroxy-4-(4'-(3- (hydroxymethyl)cyclopentyl)biphenyl-4-yl)-
2-methyl-2-(methylsulfonyl)butanamide 144 ##STR00163##
N-hydroxy-4-(4'-(2-hydroxy-1-
methoxyethyl)biphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanamide
145 ##STR00164## N-hydroxy-4-(4'-(3-hydroxy-2-
methoxypropyl)biphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanamide
146 ##STR00165## N-hydroxy-4-(4'-((E)-2-((1R,2S)-2-
(hydroxymethyl)cyclopropyl)vinyl)biphenyl- 4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 147 ##STR00166##
N-hydroxy-4-(4'-((E)-2-((1S,2R)-2-
(hydroxymethyl)cyclopropyl)vinyl)biphenyl- 4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 148 ##STR00167##
N-hydroxy-4-(4'-((E)-2-((1S,2S)-2-
(hydroxymethyl)cyclopropyl)vinyl)biphenyl- 4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 149 ##STR00168##
N-hydroxy-4-(4'-((E)-2-((1R,2R)-2-
(hydroxymethyl)cyclopropyl)vinyl)biphenyl- 4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 150 ##STR00169##
(E)-N-hydroxy-4-(4'-(3-hydroxyprop-1-
enyl)biphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanamide 151
##STR00170## (E)-N-hydroxy-4-(4'-(4-hydroxybut-1-
enyl)biphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanamide 152
##STR00171## (E)-N-hydroxy-4-(4'-(3-hydroxybut-1-
enyl)biphenyl-4-yl)-2-methyl-2- (methylsulfonyl)butanamide 153
##STR00172## (E)-N-hydroxy-4-(4'-(4-hydroxy-3-
methylbut-1-enyl)biphenyl-4-yl)-2-methyl-
2-(methylsulfonyl)butanamide 154 ##STR00173##
(E)-4-(4'-(3,4-dihydroxybut-1-
enyl)biphenyl-4-yl)-N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide 155 ##STR00174##
(E)-4-(4'-(4,5-dihydroxypent-1-
enyl)biphenyl-4-yl)-N-hydroxy-2-methyl-2-
(methylsulfonyl)butanamide 156 ##STR00175##
(E)-N-hydroxy-4-(4'-(2-(3-
hydroxycyclobutyl)vinyl)biphenyl-4-yl)-2-
methyl-2-(methylsulfonyl)butanamide 157 ##STR00176##
(E)-N-hydroxy-4-(4'-(2-(3-
(hydroxymethyl)cyclobutyl)vinyl)biphenyl- 4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 158 ##STR00177##
(E)-N-hydroxy-4-(4'-(2-(3-
(hydroxymethyl)cyclopentyl)vinyl)biphenyl- 4-yl)-2-methyl-2-
(methylsulfonyl)butanamide 159 ##STR00178##
(E)-N-hydroxy-4-(4-(4-(4-hydroxy-3-
methoxybut-1-enyl)phenyl)-2-oxopyridin- 1(2H)-yl)-2-methyl-2-
(methylsulfonyl)butanamide 160 ##STR00179##
(R)-N-(1-(hydroxyamino)-3-methyl-3-
(methylsulfonyl)-1-oxobutan-2-yl)-4-(5-
hydroxypenta-1,3-diynyl)benzamide 161 ##STR00180##
(R)-N-(1-(hydroxyamino)-3-methyl-3-
(methylsulfonyl)-1-oxobutan-2-yl)-4-(6-
hydroxyhexa-1,3-diynyl)benzamide 162 ##STR00181##
4-(5,6-dihydroxyhexa-1,3-diynyl)-N-((R)-1-
(hydroxyamino)-3-methyl-3- (methylsulfonyl)-1-oxobutan-2-
yl)benzamide 163 ##STR00182##
4-(6,7-dihydroxyhepta-1,3-diynyl)-N-((R)-
1-(hydroxyamino)-3-methyl-3- (methylsulfonyl)-1-oxobutan-2-
yl)benzamide 164 ##STR00183##
4-(6-hydroxy-5-methylhexa-1,3-diynyl)-N-
((R)-1-(hydroxyamino)-3-methyl-3- (methylsulfonyl)-1-oxobutan-2-
yl)benzamide 165 ##STR00184## (R)-N-(1-(hydroxyamino)-3-methyl-3-
(methylsulfonyl)-1-oxobutan-2-yl)-4-((3-
hydroxycyclobutyl)buta-1,3- diynyl)benzamide 166 ##STR00185##
(R)-N-(1-(hydroxyamino)-3-methyl-3-
(methylsulfonyl)-1-oxobutan-2-yl)-4-((3-
(hydroxymethyl)cyclobutyl)buta-1,3- diynyl)benzamide 167
##STR00186## N-((R)-1-(hydroxyamino)-3-methyl-3-
(methylsulfonyl)-1-oxobutan-2-yl)-4-((3-
(hydroxymethyl)cyclopentyl)buta-1,3- diynyl)benzamide 168
##STR00187## N-((R)-1-(hydroxyamino)-3-methyl-3-
(methylsulfonyl)-1-oxobutan-2-yl)-4-(5-
hydroxyhexa-1,3-diynyl)benzamide 169 ##STR00188##
4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)-
N-((R)-1-(hydroxyamino)-3-methyl-3- (methylsulfonyl)-1-oxobutan-2-
yl)benzamide 170 ##STR00189##
4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)-
N-((R)-1-(hydroxyamino)-3-methyl-3- (methylsulfonyl)-1-oxobutan-2-
yl)benzamide 171 ##STR00190## N-((R)-1-(hydroxyamino)-3-methyl-3-
(methylsulfonyl)-1-oxobutan-2-yl)-4-((2-
(hydroxymethyl)cyclopropyl)buta-1,3- diynyl)benzamide 172
##STR00191## N-((2R)-1-(hydroxyamino)-3-methyl-3-
(methylsulfinyl)-1-oxobutan-2-yl)-4-(5-
hydroxypenta-1,3-diynyl)benzamide 173 ##STR00192##
N-((2R)-1-(hydroxyamino)-3-methyl-3-
(methylsulfinyl)-1-oxobutan-2-yl)-4-(6-
hydroxyhexa-1,3-diynyl)benzamide 174 ##STR00193##
4-(5,6-dihydroxyhexa-1,3-diynyl)-N-((2R)-
1-(hydroxyamino)-3-methyl-3- (methylsulfinyl)-1-oxobutan-2-
yl)benzamide 175 ##STR00194##
4-(6,7-dihydroxyhepta-1,3-diynyl)-N-((2R)-
1-(hydroxyamino)-3-methyl-3- (methylsulfinyl)-1-oxobutan-2-
yl)benzamide 176 ##STR00195##
4-(6-hydroxy-5-methylhexa-1,3-diynyl)-N-
((R)-1-(hydroxyamino)-3-methyl-3- (methylsulfonyl)-1-oxobutan-2-
yl)benzamide 177 ##STR00196## N-((2R)-1-(hydroxyamino)-3-methyl-3-
(methylsulfinyl)-1-oxobutan-2-yl)-4-((3-
hydroxycyclobutyl)buta-1,3- diynyl)benzamide 178 ##STR00197##
N-((2R)-1-(hydroxyamino)-3-methyl-3-
(methylsulfinyl)-1-oxobutan-2-yl)-4-((3-
(hydroxymethyl)cyclobutyl)buta-1,3- diynyl)benzamide 179
##STR00198## N-((2R)-1-(hydroxyamino)-3-methyl-3-
(methylsulfinyl)-1-oxobutan-2-yl)-4-((3-
(hydroxymethyl)cyclopentyl)buta-1,3- diynyl)benzamide 180
##STR00199## N-((2R)-1-(hydroxyamino)-3-methyl-3-
(methylsulfinyl)-1-oxobutan-2-yl)-4-(5-
hydroxyhexa-1,3-diynyl)benzamide 181 ##STR00200##
4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)-
N-((2R)-1-(hydroxyamino)-3-methyl-3- (methylsulfinyl)-1-oxobutan-2-
yl)benzamide 182 ##STR00201##
4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)-
N-((2R)-1-(hydroxyamino)-3-methyl-3- (methylsulfinyl)-1-oxobutan-2-
yl)benzamide 183 ##STR00202## N-((2R)-1-(hydroxyamino)-3-methyl-3-
(methylsulfinyl)-1-oxobutan-2-yl)-4-((2-
(hydroxymethyl)cyclopropyl)buta-1,3- diynyl)benzamide 184
##STR00203## N-((R)-1-(hydroxyamino)-3-methyl-3-
(methylthio)-1-oxobutan-2-yl)-4-((2-
(hydroxymethyl)cyclopropyl)buta-1,3- diynyl)benzamide 185
##STR00204## (R)-N-(1-(hydroxyamino)-3-methyl-3-
(methylthio)-1-oxobutan-2-yl)-4-(5-
hydroxypenta-1,3-diynyl)benzamide 186 ##STR00205##
(R)-N-(1-(hydroxyamino)-3-methyl-3-
(methylthio)-1-oxobutan-2-yl)-4-(6-
hydroxyhexa-1,3-diynyl)benzamide 187 ##STR00206##
4-(5,6-dihydroxyhexa-1,3-diynyl)-N-((R)-1-
(hydroxyamino)-3-methyl-3-(methylthio)-1- oxobutan-2-yl)benzamide
188 ##STR00207## 4-(6,7-dihydroxyhepta-1,3-diynyl)-N-((R)-
1-(hydroxyamino)-3-methyl-3-(methylthio)- 1-oxobutan-2-yl)benzamide
189 ##STR00208## 4-(6-hydroxy-5-methylhexa-1,3-diynyl)-N-
((R)-1-(hydroxyamino)-3-methyl-3-
(methylthio)-1-oxobutan-2-yl)benzamide 190 ##STR00209##
(R)-N-(1-(hydroxyamino)-3-methyl-3-
(methylthio)-1-oxobutan-2-yl)-4-((3- hydroxycyclobutyl)buta-1,3-
diynyl)benzamide 191 ##STR00210##
(R)-N-(1-(hydroxyamino)-3-methyl-3-
(methylthio)-1-oxobutan-2-yl)-4-((3-
(hydroxymethyl)cyclobutyl)buta-1,3- diynyl)benzamide 192
##STR00211## N-((R)-1-(hydroxyamino)-3-methyl-3-
(methylthio)-1-oxobutan-2-yl)-4-((3-
(hydroxymethyl)cyclopentyl)buta-1,3- diynyl)benzamide 193
##STR00212## N-((R)-1-(hydroxyamino)-3-methyl-3-
(methylthio)-1-oxobutan-2-yl)-4-(5-
hydroxyhexa-1,3-diynyl)benzamide 194 ##STR00213##
4-(6-hydroxy-5-methoxyhexa-1,3-diynyl)-
N-((R)-1-(hydroxyamino)-3-methyl-3-
(methylthio)-1-oxobutan-2-yl)benzamide 195 ##STR00214##
4-(7-hydroxy-6-methoxyhepta-1,3-diynyl)-
N-((R)-1-(hydroxyamino)-3-methyl-3-
(methylthio)-1-oxobutan-2-yl)benzamide 196 ##STR00215##
N-((R)-1-(hydroxyamino)-3-methyl-3-
(methylthio)-1-oxobutan-2-yl)-4-((2-
(hydroxymethyl)cyclopropyl)buta-1,3- diynyl)benzamide 197
##STR00216## N1-hydroxy-2-(4-((2-
(hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)benzamido)-N3-methylmalonamide 198 ##STR00217##
N1-hydroxy-2-(4-(5-hydroxypenta-1,3-
diynyl)benzamido)-N3-methylmalonamide 199 ##STR00218##
N1-hydroxy-2-(4-(6-hydroxyhexa-1,3-
diynyl)benzamido)-N3-methylmalonamide 200 ##STR00219##
N1-hydroxy-2-(4-(5-hydroxyhexa-1,3-
diynyl)benzamido)-N3-methylmalonamide 201 ##STR00220##
2-(4-(5,6-dihydroxyhexa-1,3- diynyl)benzamido)-N1-hydroxy-N3-
methylmalonamide 202 ##STR00221## 2-(4-(6,7-dihydroxyhepta-1,3-
diynyl)benzamido)-N1-hydroxy-N3- methylmalonamide 203 ##STR00222##
N1-hydroxy-2-(4-(6-hydroxy-5- methylhexa-1,3-diynyl)benzamido)-N3-
methylmalonamide 204 ##STR00223## N1-hydroxy-2-(4-((3-
hydroxycyclobutyl)buta-1,3- diynyl)benzamido)-N3-methylmalonamide
205 ##STR00224## N1-hydroxy-2-(4-((3-
(hydroxymethyl)cyclobutyl)buta-1,3-
diynyl)benzamido)-N3-methylmalonamide 206 ##STR00225##
N1-hydroxy-2-(4-((3- (hydroxymethyl)cyclopentyl)buta-1,3-
diynyl)benzamido)-N3-methylmalonamide 207 ##STR00226##
N1-hydroxy-2-(4-(6-hydroxy-5- methoxyhexa-1,3-diynyl)benzamido)-N3-
methylmalonamide 208 ##STR00227## N1-hydroxy-2-(4-(7-hydroxy-6-
methoxyhepta-1,3-diynyl)benzamido)-N3- methylmalonamide 209
##STR00228## N1-hydroxy-2-(4-((2-
(hydroxymethyl)cyclopropyl)buta-1,3- diynyl)-N-methylbenzamido)-N3-
methylmalonamide 210 ##STR00229##
N1-hydroxy-2-(4-(5-hydroxypenta-1,3- diynyl)-N-methylbenzamido)-N3-
methylmalonamide 211 ##STR00230##
N1-hydroxy-2-(4-(6-hydroxyhexa-1,3- diynyl)-N-methylbenzamido)-N3-
methylmalonamide
217 ##STR00231## N1-hydroxy-2-(4-(5-hydroxyhexa-1,3-
diynyl)-N-methylbenzamido)-N3- methylmalonamide 213 ##STR00232##
2-(4-(5,6-dihydroxyhexa-1,3-diynyl)-N-
methylbenzamido)-N1-hydroxy-N3- methylmalonamide 214 ##STR00233##
2-(4-(6,7-dihydroxyhepta-1,3-diynyl)-N-
methylbenzamido)-N1-hydroxy-N3- methylmalonamide 215 ##STR00234##
N1-hydroxy-2-(4-(6-hydroxy-5- methylhexa-1,3-diynyl)-N-
methylbenzamido)-N3-methylmalonamide 216 ##STR00235##
N1-hydroxy-2-(4-((3- hydroxycyclobutyl)buta-1,3-diynyl)-N-
methylbenzamido)-N3-methylmalonamide 217 ##STR00236##
N1-hydroxy-2-(4-((3- (hydroxymethyl)cyclobutyl)buta-1,3-
diynyl)-N-methylbenzamido)-N3- methylmalonamide 218 ##STR00237##
N1-hydroxy-2-(4-((3- (hydroxymethyl)cyclopentyl)buta-1,3-
diynyl)-N-methylbenzamido)-N3- methylmalonamide 219 ##STR00238##
N1-hydroxy-2-(4-(6-hydroxy-5- methoxyhexa-1,3-diynyl)-N-
methylbenzamido)-N3-methylmalonamide 220 ##STR00239##
N1-hydroxy-2-(4-(7-hydroxy-6- methoxyhepta-1,3-diynyl)-N-
methylbenzamido)-N3-methylmalonamide 221 ##STR00240##
N1-hydroxy-2-(4-((2- (hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)benzamido)-N3,2- dimethylmalonamide 222 ##STR00241##
N1-hydroxy-2-(4-(5-hydroxypenta-1,3- diynyl)benzamido)-N3,2-
dimethylmalonamide 223 ##STR00242##
N1-hydroxy-2-(4-(6-hydroxyhexa-1,3- diynyl)benzamido)-N3,2-
dimethylmalonamide 224 ##STR00243##
N1-hydroxy-2-(4-(5-hydroxyhexa-1,3- diynyl)benzamido)-N3,2-
dimethylmalonamide 225 ##STR00244## 2-(4-(5,6-dihydroxyhexa-1,3-
diynyl)benzamido)-N1-hydroxy-N3,2- dimethylmalonamide 226
##STR00245## 2-(4-(6,7-dihydroxyhepta-1,3-
diynyl)benzamido)-N1-hydroxy-N3,2- dimethylmalonamide 227
##STR00246## N1-hydroxy-2-(4-(6-hydroxy-5-
methylhexa-1,3-diynyl)benzamido)-N3,2- dimethylmalonamide 228
##STR00247## N1-hydroxy-2-(4-((3- hydroxycyclobutyl)buta-1,3-
diynyl)benzamido)-N3,2- dimethylmalonamide 229 ##STR00248##
N1-hydroxy-2-(4-((3- (hydroxymethyl)cyclobutyl)buta-1,3-
diynyl)benzamido)-N3,2- dimethylmalonamide 230 ##STR00249##
N1-hydroxy-2-(4-((3- (hydroxymethyl)cyclopentyl)buta-1,3-
diynyl)benzamido)-N3,2- dimethylmalonamide 231 ##STR00250##
N1-hydroxy-2-(4-(6-hydroxy-5- methoxyhexa-1,3-diynyl)benzamido)-
N3,2-dimethylmalonamide 232 ##STR00251##
N1-hydroxy-2-(4-(7-hydroxy-6- methoxyhepta-1,3-diynyl)benzamido)-
N3,2-dimethylmalonamide 233 ##STR00252## N1-hydroxy-2-(4-((2-
(hydroxymethyl)cyclopropyl)buta-1,3-
diynyl)-N-methylbenzamido)-N3,2- dimethylmalonamide 234
##STR00253## N1-hydroxy-2-(4-(5-hydroxypenta-1,3-
diynyl)-N-methylbenzamido)-N3,2- dimethylmalonamide 235
##STR00254## N1-hydroxy-2-(4-(6-hydroxyhexa-1,3-
diynyl)-N-methylbenzamido)-N3,2- dimethylmalonamide 236
##STR00255## N1-hydroxy-2-(4-(5-hydroxyhexa-1,3-
diynyl)-N-methylbenzamido)-N3,2- dimethylmalonamide 237
##STR00256## 2-(4-(5,6-dihydroxyhexa-1,3-diynyl)-N-
methylbenzamido)-N7-hydroxy-N3,2- dimethylmalonamide 238
##STR00257## 2-(4-(6,7-dihydroxyhepta-1,3-diynyl)-N-
methylbenzamido)-N1-hydroxy-N3,2- dimethylmalonamide 239
##STR00258## N1-hydroxy-2-(4-(6-hydroxy-5-
methylhexa-1,3-diynyl)-N- methylbenzamido)-N3,2- dimethylmalonamide
240 ##STR00259## N1-hydroxy-2-(4-((3-
hydroxycyclobutyl)buta-1,3-diynyl)-N- methylbenzamido)-N3,2-
dimethylmalonamide 241 ##STR00260## N1-hydroxy-2-(4-((3-
(hydroxymethyl)cyclobutyl)buta-1,3-
diynyl)-N-methylbenzamido)-N3,2- dimethylmalonamide 242
##STR00261## N1-hydroxy-2-(4-((3-
(hydroxymethyl)cyclopentyl)buta-1,3-
diynyl)-N-methylbenzamido)-N3,2- dimethylmalonamide 243
##STR00262## N1-hydroxy-2-(4-(6-hydroxy-5-
methoxyhexa-1,3-diynyl)-N- methylbenzamido)-N3,2-
dimethylmalonamide 244 ##STR00263## N1-hydroxy-2-(4-(7-hydroxy-6-
methoxyhepta-1,3-diynyl)-N- methylbenzamido)-N3,2-
dimethylmalonamide
[0113] 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
hydroxamic acids or similar scaffolds having a wide variety of
substituents are comprehensively reviewed in Kline, T., et al.,
"Potent, novel in vitro inhibitors of the Pseudomonas aeruginosa
deacetylase LpxC" J. Med Chem. 2002, 45(14), 3112-29; U.S. Pat. No.
5,925,659; Pirrung, M. C., et al., "A Convenient Procedure for the
Preparation of Amino Acid Hydroxamates from Esters" J. Org. Chem.
1995, 60, 8084-8085; Nhu, K., et al., "A New and Efficient Solid
Phase Synthesis of Hydroxamic Acids" J. Org. Chem. 1997, 62,
7088-7089; International PCT Publication No. WO98/18754; Mellor, S.
L., et al., "N-Fmoc-aminoxy-2-chlorotrityl Polystyrene Resin: A
Facile Solid-phase Methodology for the Synthesis of Hydroxamic
Acids" Tetrahedron Lett. 1997, 38, 3311-3314; Khan, S. I., et al.,
"A Facile and Convenient Solid-phase Procedure for Synthesizing
Nucleoside Hydroxamic Acids" Terahedron. Lett. 1998, 39, 8031-8034;
Zhang, Y., et al., "Design, Combinatorial Chemical Synthesis, and
in vitro Characterization of Novel Urea Based Gelatinase
Inhibitors" Bioorg. Med. Chem. Lett. 1999, 9, 2823-2826; Ito, Y.,
et al., "Synthetic Reactions by Complex Catalysts. XXXI, A Novel
and Versatile Method of Heterocycle Synthesis" J. Am Chem. Soc.
1973, 95, 4447-4448; Ito, Y., et al., "Synthetic Reactions by
Complex Catalysts XXXV" Syn. Commun. 1974, 4, 97-103; Witte, H., et
al., "Cyclische Imidsaurester aus Nitrilen und Aminoalkoholen"
Liebigs Ann. Chem. 1974, 996-1009; Pattenden, G., et al.,
"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 1993, 1, 1629-1636; Boyce, R. J., et al., "Total Synthesis of
Thiangazole, A Novel Naturally Occurring HIV-1 Inhibitor from
Polyangium sp." Tetrahedron 1995, 51, 7321-7330; Galeotti, N., et
al., "Synthesis of Peptidyl Aldehydes from Thiazolines"
Tetrahedron. Lett. 1997, 38, 2459-2462; Charette, A. B., et al.,
"Mild Method for the Synthesis of Thiazolines from Secondary and
Tertiary Amides" J. Org. Chem. 1998, 63, 908-909; Bergeron, R. J.,
et al., "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., et al.,
"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., et al., "Novel Synthesis of
2-Thioazolines" Tetrahedron Lett. 2000, 41, 3381-3384; and Wipf,
P., et al., "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.
[0114] In another aspect, the present invention provides a
pharmaceutical composition comprising a compound of Formula I, or a
stereoisomer or pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier or diluent.
[0115] In another aspect, the invention provides a method of
inhibiting a deacetylase enzyme in a gram-negative bacteria,
thereby affecting bacterial growth, comprising administering to a
subject in need of such inhibition a compound of Formula I or a
stereoisomer or pharmaceutically acceptable salt thereof.
[0116] In another aspect, the invention provides a method of
inhibiting LpxC, thereby modulating the virulence of a bacterial
infection, comprising administering to a subject in need of such
inhibition a compound of Formula I or a stereoisomer or
pharmaceutically acceptable salt thereof. In certain embodiments of
the method of inhibiting LpxC using a compound of the present
invention, the IC.sub.50 value of the compound is less than or
equal to 10 .mu.M with respect to LpxC. In other 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.
[0117] In another aspect, the invention provides a method for
treating a subject having a gram-negative bacterial infection
comprising administering to the subject in need thereof an
antibacterially effective amount of a compound of Formula I or a
stereoisomer or pharmaceutically acceptable salt thereof.
[0118] In another aspect, the invention provides a method of
administering a therapeutically effective amount of a compound of
Formula I or a stereoisomer or pharmaceutically acceptable salt
thereof to a subject infected with a fermentative or
non-fermentative gram-negative bacteria. Examples of fermentative
or non-fermentative gram-negative bacteria include Pseudomonas
aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia,
Alcaligenes xylosoxidans, Enterobacteriaceae, Haemophilus,
Franciscellaceae (e.g., Franciscella tularensis) and Neisseria
species.
[0119] In another aspect, the invention provides a method of
administering an inhibitory amount of a compound described herein
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, Yersinia (e.g., Yersinia pestis), Morganella, Cedecea,
Edwardsiella species and Escherichia coli.
[0120] In certain embodiments, the subject may be a mammal, and in
some embodiments, a human.
[0121] Bacterial infections susceptible to treatment according to
the present invention include primary infections and co-infections
caused by a species of bacteria and one or more additional
infectious agents such as, for example, bacteria, virus, parasite
and fungus.
[0122] 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.
[0123] Compounds of the invention also are useful in treating
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
non-antibacterial agent.
[0124] For sepsis, septic shock, systemic inflammation, localized
inflammation, chronic obstructive pulmonary disease (COPD) and
acute exacerbations of chronic bronchitis (AECB), representative
non-antibacterial agents include antiendotoxins including endotoxin
receptor-binding antibodies, endotoxin-binding antibodies,
anti-CD14-binding protein antibodies,
antilipopolysaccharide-binding protein antibodies and tyrosine
kinase inhibitors.
[0125] In treatment of serious or chronic respiratory tract
infections, compounds of the present invention may also be used
with non-antibacterial agents administered via inhalation.
Representative 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 albuterol, salbuterol, budesonide, beclomethasone,
dexamethasone, nedocromil, beclomethasone, fluticasone,
flunisolide, triamcinolone, ibuprofin, rofecoxib, naproxen,
celecoxib, nedocromil, ipratropium, metaproterenol, pirbuterol,
salmeterol, formoterol, indacaterol, bronchiodilators, mucolytics,
calfactant, beractant, poractant alfa, surfaxin or pulmozyme (also
called domase alfa).
[0126] 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, 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, Klebsiella species, and Proteus
species, infections caused by other bacterial species such as
Neisseria species, Shigella species, Salmonella species,
Helicobacter pylori, Vibrionaceae and Bordetella species, as well
as infections caused by a Brucella species, Francisella tularensis
and/or Yersinia Pestis.
[0127] When used for treating subjects infected with gram-negative
bacterial infections, compounds of the present invention can be
used to sensitize gram-negative bacteria to the effects of a second
agent.
[0128] The present invention provides novel combinations of
compounds including a compound of Formula I, or a stereoisomer or
pharmaceutically acceptable salt thereof, as well as methods for
treating subjects infected with gram-negative bacteria. The novel
combinations 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 novel
combinations in preparing medicaments and pharmaceutical
formulations, for use of the combinations in treating bacterial
infections in a subject.
[0129] In one embodiment, a second antibacterial agent is used in
combination with a compound of Formula I, or stereoisomer or
pharmaceutically acceptable salt thereof. Examples of suitable
second antibactieral agents include, but are not limited to,
vancomycin, linezolid, azithromycin, imipenem, teicoplanin,
daptomycin, clindamycin, rifampin, cefotaxime, gentamicin,
novobiocin or telavancin. In one such embodiment, the antibacterial
agent is vancomycin, teicoplanin, rifampin, azithromycin,
telavancin or novobiocin. In certain embodiments the second
antibacterial agent is vancomycin or rifampin. In some embodiments
of the invention, the second antibacterial agent and/or the
compound of Formula I, or stereoisomer or pharmaceutically
acceptable salt thereof, is administered at a sub-therapeutic dose,
wherein a subtherapeutic dose is a dose that would be insufficient
to treat bacterial infections, if administered alone.
[0130] Pharmaceutical compositions of the present invention
comprise a therapeutically effective amount of a compound of
Formula I, or a stereoisomer or pharmaceutically acceptable salt
thereof, formulated together with one or more pharmaceutically
acceptable carriers or diluents. 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 (as by intravenous, intramuscular or subcutaneous
injection), 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.
[0131] 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.
[0132] 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, 1%
lidocaine, 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.
[0133] 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.
[0134] 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.
[0135] 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.
[0136] 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.
[0137] 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.
[0138] 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.
[0139] 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.
[0140] 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.
[0141] The antibacterial 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.
[0142] 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.
[0143] 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.
[0144] 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 subjects 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.
[0145] 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.
[0146] 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.
[0147] 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.
[0148] 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.
[0149] According to the methods of treatment of the present
invention, bacterial infections are treated or prevented in a
subject such as a human or lower mammal by administering to the
subject a therapeutically effective amount of a compound of Formula
I, or a stereoisomer or pharmaceutically acceptable salt thereof,
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
subject 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 subject; 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.
[0150] 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 200 mg/kg body
weight or more usually from 0.1 to 50 mg/kg body weight. In certain
embodiments, the total daily dose administered to a human or other
mammal is from 1.0 to 100 mg/kg body weight or from 5.0 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 subject in need of such treatment from about 10
mg to about 15 g of the compound(s) of this invention per day in
single or multiple doses, more usually, from 100 mg to 5 g, and
even more usually from 250 mg to 1 g per day in single or multiple
doses.
[0151] 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] The kits of the present invention may also include, in
addition to a compound of the present invention, one or more
additional pharmaceutically active compounds. For example, the
additional compound second antibacterial. The additional compounds
may be administered in the same dosage form as the compound of the
present invention or in a different dosage form. Likewise, the
additional compounds can be administered at the same time as the
compound of the present invention or at different times.
[0157] Compositions of the present compounds may also be used in
combination with other known antibacterial agents of similar
spectrum to (1) 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 a compound of the present invention and a
second antibacterial compound or administration of a compound of
the present inventive compounds followed by or preceded by
administration of a second antibacterial agent.
[0158] 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.
V. EXAMPLES
[0159] HPLC: Angilent 1200; Mobile Phase: A: water (0.01% TFA)
B:ACN (0.01% TFA); Column: ZORBAX SB-C18, 5 um, 4.6*150 mm; Oven
Temperature: 50.degree. C. LCMS: Angilent 1200; Mobile Phase: A:
water(0.01% TFA) B:ACN(0.01% TFA), Column: SunFire C18 3.5 um,
4.6*50 mm; Oven Temperature: 50.degree. C. GCMS: Agilent instrument
(7890A Series gas chromatograph with a Mass Selective Detector
5975C; injector volume: 1 mL; initial column temperature:
40.degree. C.; final column temperature: 250 C; ramp time: 8.4 min;
gas flow rate: 1.2 mL/min; column: 5% phenyl methyl silox,
Model:Agilent 19091s-433:325C, dimensions: 30.0 m'250 u m'0.25 um)
NMR: Bruker AVANCE III 400 MHz, UltraShield-Plus.TM. Digital
NMR
[0160] A. Compound Synthesis
[0161] Referring to the examples that follow, compounds of the
present invention were characterized by high performance liquid
chromatography (HPLC) using a Waters Millennium chromatography
system with a 2690 Separation Module (Milford, Mass.) or an Agilent
1200; Mobile Phase: A: water(0.01% TFA) B:ACN(0.01% TFA); Column:
ZORBAX SB-C18, 5 um, 4.6*150 mm; Oven Temperature: 50.degree. C. or
an Agilent 1100 series chromatography system (Santa Clara, Ca). The
analytical columns were Phenomenex Luna C18(2) reversed phase, 10
.mu.m, 100 .ANG., axia packed, 2.0.times.50 mm and the preparative
columns were Phenomenex Luna C18(2) reversed phase, 10 .mu.m, 100
.ANG., axia packed, 21.2.times.250 or 50.times.250 mm. A gradient
elution was used, typically starting with 100% water and
progressing to 100% acetonitrile over a varying lengths of time All
solvents contained 0.1% acetic acid (AcOH). Compounds were detected
by ultraviolet light (UV) absorption at either 220 or 254 nm. In
some instances, purity was assessed by thin layer chromatography
(TLC) using glass or plastic backed silica gel plates, such as, for
example, Baker-Flex Silica Gel 1 B2-F flexible sheets. TLC results
were readily detected visually under ultraviolet light, or by
employing well known iodine vapor and other various staining
techniques
[0162] Mass spectrometric analysis was performed on one of three
LCMS instruments: a Waters System. (Alliance HT HPLC and a
Micromass ZQ mass spectrometer; Column: Eclipse XDB-C--18,
2.1.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.). or an Agilent System (Series 1100 HPLC;
Column: Waters Sunfire C18 reversed phase, 2.5 .mu.m, 100 .ANG.,
2.1.times.50 mm; solvent system: 1-95% acetonitrile in water with
0.1% TFA; flow rate 0.5 mL/min; molecular weight range 150-1500;
cone Voltage 70 V; column temperature 35.degree. C.), or an Agilent
1200; Mobile Phase: A:water (0.01% TFA) B:ACN(0.01% TFA), Column:
SunFire C18 3.5 um, 4.6*50 mm; Oven Temperature: 50.degree. C. All
masses are reported as those of the protonated parent ions.
[0163] 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 min;
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); or
Agilent instrument (7890A Series gas chromatograph with a Mass
Selective Detector 5975C; injector volume: 1 mL; initial column
temperature: 40.degree. C.; final column temperature: 250 C; ramp
time: 8.4 min; gas flow rate: 1.2 mL/min; column: 5% phenyl methyl
silox, Model:Agilent 19091s-433:325C, dimensions: 30.0 m'250 u
m'0.25 um).
[0164] Nuclear magnetic resonance (NMR) analysis was performed with
a Varian 300 MHz NMR (Palo Alto, Calif.). and a Varian Unity Enova
400 MHz NMR spectrometer (Palo Alto, Calif.), or Bruker AVANCE III
400 MHz, UltraShield-Plus.TM. Digital NMR. The spectral reference
was either TMS or the known chemical shift of the solvent. Some
compound samples were run at elevated temperatures (e.g. 75.degree.
C.) to promote increased sample solubility.
[0165] Procedure 1 (C-C Coupling Reaction Using CuCl-Cadiot):
[0166] Hydroxylamine hydrochloride (0.23 mmol, 0.06 eq) and CuCl
(0.08, 0.02 eq) were dissolved in 23% aqueous n-butylamine (1 mL)
and the resulting solution was cooled to 0.degree. C. A solution of
the alkyne (4.3 mmol, 1.1 eq) in 23% aqueous n-butylamine (2 mL)
was then added. The bromo-alkyne (3.92 mmol) and hydroxylamine
hydrochloride (0.23 mmol, 0.06 eq) were dissolved in 23% aqueous
n-butylamine (2 mL) and THF (3 mL), and they were slowly added to
the reaction mixture. The reaction was stirred for 1 hr, followed
by quenching with EtOAc and water. The organic layer was separated
and washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to yield the desired coupled
product.
[0167] Procedure 2 (Boc Deprotection Using TFA):
[0168] To the Boc-protected compound (3.39 mmol) at 0.degree. C.
was added a TFA:DCM solution (9 mL, 2:1) and the reaction was
stirred for 1 hr. The reaction was concentrated under reduced
pressure to yield a crude residue, which was azeotroped with IPA
twice to yield the desired deprotected product.
[0169] Procedure 3 (Hydroxamate Formation):
[0170] To a stirring solution of the ester (3.38 mmol) in IPA (4
mL) at 0.degree. C. was slowly added 50% aqueous hydroxylamine (40
eq), and the reaction was stirred overnight. The reaction was
quenched with AcOH (0.12 mol, 20 eq) or until the pH was 6. The
volatiles were removed under reduced pressure, and the resulting
solution was purified by RP HPLC.
[0171] Procedure 4A (Formation of Imine in Reductive Amination to
NHMe):
[0172] To a stirring solution of the amine (2.37 g, 7.20 mmol) in
DMF (14.39 mL) was added DIPEA (1.88 mL, 10.79 mmol) followed by
formaldehyde (37% in water) (1.07 mL, 14.39 mmol) and the reaction
was stirred for 2 hr. The excess aldehyde was quenched with
n-butylamine (30% in water) (2.63 g, 10.79 mmol) and stirred for 1
hr. The reaction mixture was diluted with water, and lyophilized to
yield the desired imine.
[0173] Procedure 4B (Reduction to Amine in Reductive Amination to
NHMe):
[0174] To a stirring solution of the imine (3.96 g, 11.60 mmol) in
THF (23.17 mL) and MeOH (2.439 mL) was added acetic acid (1.33 mL,
23.20 mmol) followed by sodium cyanoborohydride (10.94 g, 174 mmol)
and the reaction was stirred for 1 hr. The reaction mixture was
diluted with water (7 mL) and concentrated under reduced pressure
to yield the amine.
4-(bromoethynyl) benzoic acid (INT-1)
##STR00264##
[0176] Ethynyltrimethylsilane (82.4 g, 0.84 mol) was added dropwise
over 10 min under a nitrogen atmosphere to a solution of methyl
4-bromobenzoate (150 g, 0.7 mol), PdCl.sub.2 (PPh.sub.3).sub.2(15
g, 0.021 mol) and CuI (13 g, 0.07 mol) in TEA (1.5 L) and the
reaction was stirred at 90.degree. C. for 30 minutes. Solids were
collected by filtration and washed with EtOAc (5.times.500 mL). The
filtrate was concentrated under reduced pressure to give a residue,
which was distilled under reduced pressure to yield methyl
4-((trimethylsilyl) ethynyl) benzoate (INT-1.2) as an off-white
solid (156 g, 96%).
[0177] To a solution of methyl 4-((trimethylsilyl) ethynyl)benzoate
(156 g, 0.67 mol) in methanol (800 mL) was added dropwise
KOH/methanol (18 g/250 mL) keeping the temperature below 10.degree.
C. The reaction mixture was allowed to warm to room temperature for
5 min and was then neutralized with 2M HCl. Methyl
4-ethynylbenzoate (INT-1.3) was collected by filtration as a white
solid (97 g, 90%). MS: m/z calcd for C.sub.10H.sub.8O.sub.2160.0,
found [M+H].sup.+ 161.
##STR00265##
[0178] To a solution of methyl 4-ethynylbenzoate (50 g, 0.31 mol)
in acetone (750 mL) was added AgNO.sub.3 (5 g, 29.7 mmol) and the
reaction mixture was stirred for 1 hr. NBS (61.2 g, 0.34 mol) was
added and the reaction mixture was stirred at room temperature for
20 hr, filtered and concentrated under reduced pressure. The
residue was diluted in EA, and washed with iced 20%
H.sub.2SO.sub.4. The organic layer was washed with water and brine,
dried (Na.sub.2SO.sub.4), filtered, concentrated under reduced
pressure to give a residue, which was recrystallized from MeOH (1
mL/4 g) to yield methyl 4-(bromoethynyl) benzoate (INT-1.4) as an
off-yellow solid (67 g, 90%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.98 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 3.92 (s,
3H).
[0179] To a solution of methyl 4-(bromoethynyl) benzoate (67 g, 280
mmol) in CH.sub.3OH/THF/H.sub.2O=5/5/1 (1100 mL) was added NaOH
(44.84 g) and the reaction mixture was stirred at 25.degree. C. for
3 hr. The volatiles were removed under reduced pressure and the
resulting solution was neutralized with 1 N HCl to pH 3-5. Solids
were collected by filtration, washed with water and dried at
50.degree. C. for 5 hr to yield 4-(bromoethynyl) benzoic acid
(INT-1) (61 g, 96%).
1.
N-hydroxy-2-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)p-
henyl)-1, 6-naphthyridine-4-carboxamide (1)
##STR00266##
[0181] To a stirring solution of 4-amino-3-bromopyridine (1.1, 173
mg, 1 mmol) and Et.sub.3N (132 mg, 1.3 mmol) in DCM (5 mL) was
added dropwise pivaloyl chloride (133 mg, 1.1 mmol), and the
reaction was stirred at room temperature for 3 hr. The mixture was
washed with water (2.times.), NaHCO.sub.3, brine, dried and
concentrated under reduced pressure to give the product 1.2 as a
solid. MS: m/z calcd for C.sub.10H.sub.13BrN.sub.2O 256.02/258.02,
found [M+H].sup.+ 257/259.
##STR00267##
[0182] A mixture of compound 1.2 (5 g, 19.4 mmol) and 10% Pd/C (500
mg) in MeOH (70 mL) was stirred under H.sub.2 (1 atm) at room
temperature overnight. The Pd/C was removed by filtration and the
solvent was concentrated under reduced pressure to yield a crude,
which was dissolved in EtOAc. The organic layer was washed with
NaHCO.sub.3, brine, dried and concentrated under reduced pressure
to give the product 1.3 as a solid. MS: m/z calcd for
C.sub.10H.sub.14N.sub.2O 178.11, found [M+H].sup.+ 179.
##STR00268##
[0183] To a solution of compound 1.3 (5.34 g, 30 mmol) in THF (200
mL) at -78.degree. C. was added dropwise n-BuLi (47 mL, 75 mmol)
and the reaction was stirred for 3 hr at -10.degree. C. The
reaction was cooled to -78.degree. C. and a solution of diethyl
oxalate (22 g, 150 mmol) in THF (20 mL) was added dropwise and the
mixture was stirred overnight at room temperature. NH.sub.4Cl was
added, and the reaction was extracted with EtOAc, washed with
brine, dried, concentrated under reduced pressure and purified by
flash chromatography (silica gel/EtOAc/PE 1:10-1:8) to give the
product 1.4 as a solid. MS: m/z calcd for
C.sub.14H.sub.18N.sub.2O.sub.4 278.13, found [M+H].sup.+ 279.
##STR00269##
[0184] Compound 1.7 was synthesized according to the procedure
described in International PCT Patent Application Publication No.
WO2012/154204.
##STR00270##
1-(4-((trimethylsilyl)ethynyl)phenyl)ethanone (1.9)
TABLE-US-00002 [0185] Reagent MW Eq. mmol g, mL Compound 1.8 198
1.0 101 20 g ethynyl(trimethyl)silane 98 1.4 141 13.8 g
Pd(PPh.sub.3).sub.2Cl.sub.2 701 0.05 5.1 3.6 g Cul 190 0.1 10 1.9
TEA 300 mL
[0186] To a stirring solution of compound 1.8 (20 g, 101 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 3.6 g, 141 mmol), CuI (1.9 g, 10 mmol)
in TEA (300 mL) under argon was added ethynyl(trimethyl)silane
(13.8 g, 141 mmol) at 90.degree. C. and the reaction mixture was
stirred at 90.degree. C. for 4 hr. The solids were removed by
filtration, and rinsed with ethyl acetate (3.times.80 mL). The
filtrate was concentrated under reduced pressure to give a crude,
which was purified by flash chromatography (silica gel/ethyl
acetate in petroleum ether 5%-10% v/v) to give compound 1.9 as a
yellow oil (19 g, 90%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.92 (d, J=8, 2H), 7.56 (d, J=8, 2H), 2.56 (s, 3H), 0.23 (s,
9H).
1-(4-ethynylphenyl)ethanone (1.10)
TABLE-US-00003 [0187] Reagent MW Eq. mmol g, mL Compound 1.9 216
1.0 88 19 g KOH 56 0.5 44 2.46 g MeOH 200 mL
[0188] To a stirring solution of compound 1.9 (19 g, 88 mmol) in
MeOH (200 mL) was added a solution of KOH (2.46 g, 44 mmol) in MeOH
(20 mL) at 10.degree. C. and the mixture was stirred at room
temperature for 1 hr. AcOH was added until the pH was 7, and the
reaction mixture was concentrated under reduced pressure. The
residue was dissolved in ethyl acetate (200 mL), washed with 5%
aqueous NaHCO.sub.3 (100 mL), brine (100 mL), dried, and
concentrated under reduced pressure to give compound 1.10 as a
white solid (12 g, 95%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.95 (d, J=8, 2H), 7.62 (d, J=8, 2H), 4.49 (s, 1H), 2.59
(s, 3H).
1-(4-(bromoethynyl)phenyl)ethanone 1.11
TABLE-US-00004 [0189] Reagent MW Eq. Mmol g, mL Compound 1.11 144
1.0 83.3 12 g NBS 177 1.2 99.96 17.7 g AgNO.sub.3 169 0.095 7.9
1.34 g Acetone 200 mL
[0190] To a stirring solution of compound 1.10 (12 g, 83.3 mmol) in
acetone (200 mL) was added AgNO.sub.3 (1.34 g, 7.9 mmol) and the
the reaction was stirred for 30 min. NBS (17.7 g, 99.96 mmol) was
then added and the reaction mixture was stirred at 20.degree. C.
for 14 hr. Solids were removed by filtration and the filtrate was
concentrated under reduced pressure to give a crude, which was
purified by flash chromatography (silica gel/ethyl acetate in
petroleum ether 5%-10% v/v) to give compound 1.11 as a white solid
(14 g, 76%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.95 (d,
J=8, 2H), 7.62 (d, J=8, 2H), 2.58 (s, 3H).
1-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)etha-
none (1.12)
TABLE-US-00005 [0191] Reagent MW Eq. mmol g, mL Compound 1.11 198
1.0 4.5 1.0 g Compound 1.7 96 1.5 6.75 648 mg
Pd(PPh.sub.3).sub.2Cl.sub.2 701 0.05 0.225 158 mg Cul 190 0.1 0.45
90 mg TEA 101 2 9 1.16 g THF 30 mL
[0192] To a stirring solution of compound 1.11 (1.0 g, 4.5 mmol),
compound 1.7 (648 mg, 6.75 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (158
mg, 0.22 mmol), and CuI (90 mg, 0.45 mmol) in THF (30 mL) under
argon was added TEA (1.16 g, 9 mmol) and the mixture was stirred at
20.degree. C. for 14 hr. Solids were removed by filtration and
rinsed with ethyl acetate (3.times.80 mL), the filtrate was
concentrated under reduced pressure to yield a crude, which was
purified by flash chromatography (silica gel/ethyl acetate in
petroleum ether 15%-50% v/v) to give compound 1.12 as a yellow
solid (450 mg, 42%). MS: m/z calcd for C.sub.16H.sub.14O.sub.2
238.1, found [M+H].sup.+ 239. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.89 (d, J=8.4, 2H), 7.53 (d, J=8.4, 2H), 3.61 (dd, J=6,
11.6, 1H), 3.51 (dd, J=6.8, 11.6, 1H), 2.59 (s, 3H), 1.57-1.62 (m,
1H), 1.49 (brs, 1H), 1.37-1.41 (m, 1H), 1.06-1.10 (m, 1H),
0.88-0.93 (m, 1H).
##STR00271##
[0193] To a stirring solution of compound 1.4 (139 mg, 0.5 mmol) in
EtOH (10 mL) was added KOH (112 mg, 2.0 mmol, 4 M), and the
reaction was heated at 100.degree. C. for 3 hr. Racemic compound
1.12 (178.5 mg, 0.75 mmol) was added and the mixture was stirred
overnight at 100.degree. C. The solvent was concentrated under
reduced pressure. Water was added, and the reaction was washed with
Et.sub.2O. The reaction mixture was adjusted to pH 1-2 with acetic
acid, and the resulting solids were collected by filtration and
dried to yield the desired product 1.13. MS: m/z calcd for
C.sub.23H.sub.16N.sub.2O.sub.3 368.12, found [M+H].sup.+ 369.
##STR00272##
[0194] To a stirring solution of compound 1.13 (184 mg, 0.5 mmol)
in DMF (10 mL) was added K.sub.2CO.sub.3 (138 mg, 1.0 mmol),
followed by iodomethane (74.55 mg, 0.52 mmol) and the reaction was
stirred overnight at room temperature. The reaction was quenched
with water, extracted with EtOAc, washed with brine, dried,
concentrated under reduced pressure to give a crude, which was
purified by flash chromatography (silica gel/PE:EtOAc 1.5:1-1:1.5)
to yield a solid, which was recrystallized from EA/PE (1:5) to give
the desired product 1.14. MS: m/z calcd for
C.sub.24H.sub.18N.sub.2O.sub.3 382.13, found [M+H].sup.+ 383.
##STR00273##
[0195] Compound 1.14 (500 mg) was converted to
N-hydroxy-2-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-
phenyl)-1,6-naphthyridine-4-carboxamide (1, 339 mg, 68%) using
Procedure 3: MS: m/z calcd for C.sub.23H.sub.17N.sub.3O.sub.3
383.13, found [M+H].sup.+ 384.
2.
N-hydroxy-4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)p-
henyl)picolinamide (2)
##STR00274##
[0197] To a stirring solution of compound 2.1 (27.8 g, 0.15 mol),
compound 2.2 (45.7 g, 0.18 mol) and
PdCl.sub.2(PPh.sub.3).sub.2(5.26 g, 7.5 mmol) in 1,4-dioxane (500
mL), was added KOAc (22.0 g, 0.225 mol) under an argon atmosphere
and the mixture was stirred at 80.degree. C. for 15 hr. The solvent
was removed under reduced pressure, and the residue was diluted
with PE (500 mL). Solids were removed by filtration, and the
filtrate was concentrated under reduced pressure to give a crude,
which was purified by flash chromatography (silica gel/PE:EA 10:1)
to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
(2.3, 32.5 g, 95%) as a white solid.
##STR00275##
[0198] To a stirring solution of compound 2.3 (32.4 g, 0.14 mol),
compound 2.4 (32.2 g, 0.17 mol) and Pd(PPh.sub.3).sub.4(8.08 g, 7
mmol) in 1,4-dioxane/methanol (800 mL, 1:1) was added
Na.sub.2CO.sub.3 (22.3 g, 0.21 mol) under an argon atmosphere and
the mixture was stirred at 80.degree. C. for 15 hr. The solvent was
removed under reduced pressure and the resulting residue was
diluted with water (500 mL) and extracted with EtOAc (3.times.500
mL). The combined organic layers were dried and concentrated under
reduced pressure to give a crude, which was purified by flash
chromatography (silica gel/PE:EA 2:1) to give ethyl
4-(4-formylphenyl)picolinate (2.5, 14.2 g, 40%) as a yellow
solid.
##STR00276##
[0199] To a stirring solution of compound 2.5 (12.7 g, 50 mmol) in
CH.sub.3OH (300 mL) was added the Bestmann reagent (14.4 g, 75
mmol) followed by K.sub.2CO.sub.3 (20.8 g, 150 mmol) and the
reaction was stirred for 5 hr. The reaction mixture was diluted
with water (500 mL) and extracted with Et.sub.2O (3.times.300 mL).
The combined organic layers were dried and concentrated under
reduced pressure to give a crude, which was purified by flash
chromatography (silica gel/PE:Et.sub.2O 10:1-5:1) to give methyl
4-(4-ethynylphenyl)picolinate (2.6, 4.0 g, 33.9%) as a white
solid.
##STR00277##
[0200] To a stirring solution of racemic compound 2.7 (4.8 g, 50
mmol) and AgNO.sub.3 (0.85 g, 5 mmol) in acetone (200 mL) was added
NBS (10.7 g, 60 mmol) under an argon atmosphere and the mixture was
stirred at room temperature for 15 hr. The mixture was filtered and
the residue was taken up with acetone, the combined organic layers
were concentrated under reduced pressure to give a crude, which was
purified by flash chromatography (silica gel/PE:EA 5:1) to give
(2-trans-(bromoethynyl)cyclopropyl)methanol (2.8, 5.2 g, 60%) as a
colorless oil.
##STR00278##
[0201] To a stirring solution of compound 2.6 (1.77 g, 7.5 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (262 mg, 0.37 mmol), CuI (143 mg, 0.75
mmol), and DIPEA (2.9 g, 22.5 mmol) in THF (50 mL) was added
compound 2.8 (1.84 g, 10.5 mmol) under an argon atmosphere, and the
mixture was stirred at room temperature for 5 hr. The solvent was
removed under reduced pressure, and the resulting residue was
diluted with water (100 mL) and extracted with EtOAc (3.times.150
mL). The combined organic layers were dried and concentrated under
reduced pressure to give a red oil, which was purified by flash
chromatography (silica gel/PE:EA 5:1.about.3:1) to yield methyl
4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)pic-
olinate (2.9, 570 mg, 23%): MS: m/z calcd for
C.sub.21H.sub.17NO.sub.3 331.12, found [M+H].sup.+ 332; .sup.1H-NMR
(DMSO-d.sub.6, 400 MHz) .delta. 8.77 (d, J=5.6 Hz, 1H), 8.30 (s,
1H), 7.99 (d, J=5.6 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4
Hz, 2H), 4.72 (t, J=5.6 Hz, 1H), 3.91 (s, 3H), 3.44 (m, 1H), 3.24
(m, 1H), 1.45 (m, 2H), 0.88 (m, 2H).
##STR00279##
[0202] Methyl
4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)pic-
olinate (2.9, 500 mg) was treated according to Procedure 3 to give
N-hydroxy-4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)-
phenyl)picolinamide (2, 157 mg, 31%). MS: m/z calcd for
C.sub.20H.sub.16N.sub.2O.sub.3 332.12, found [M+H].sup.+ 333.1.
3.
N--((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(((-
trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide
(3)
##STR00280##
[0204] To a stirring suspension of
(R)-2-amino-3-mercapto-3-methylbutanoic acid (3.1, 9 g, 60.3 mmol)
in DMF (20 mL) was added BOC-anhydride (14.0 mL, 60.3 mmol)
followed by TEA (8.41 mL, 63.3 mmol) and the reaction mixture was
stirred for 18 hr. Excess solvent was removed under reduced
pressure. The crude product was treated with methyl iodide (18.83
g, 133 mmol) in DMF (20 mL) and Cs.sub.2CO.sub.3 (43.2 g, 133 mmol)
at room temperature for 18 hr. Water (100 mL) was added and the
product was extracted with ethyl acetate (2.times.200 mL), dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to give
compound 3.2 (12.62 g) as a white solid. Subsequent BOC
deprotection was achieved by treatment with TFA (20 mL) in
CH.sub.2Cl.sub.2 (20 mL) for 5 hr. The solvent was removed under
reduced pressure to give the desired product 3.3 (8.2 g).
##STR00281##
[0205] A stirring solution of racemic
((trans)-2-ethynylcyclopropyl)methanol (1.7, 11 g, 106 mmol),
copper(I) chloride (0.20 g, 2.03 mmol), and hydroxylamine
hydrochloride (0.42 g, 6.08 mmol) in 30% aqueous butylamine (156
mL) was poured into a 1 L jacketed reactor and cooled to 0.degree.
C. A solution of 4-(bromoethynyl)benzoic acid (INT-1, 22.81 g, 101
mmol) and hydroxylamine hydrochloride (0.42 g, 6.08 mmol) in 30%
aqueous butylamine (111 mL) was then added dropwise and the
reaction was stirred for 2 hr. The reaction mixture was washed with
MTBE (2.times.230 mL) and the aqueous layer was diluted with methyl
THF (460 mL). The solution was cooled to 00.degree. C. and
acidified by dropwise addition of 6M HCl (100 ml) to pH 1. The
reaction mixture was filtered through Celite, and washed with
methyl-THF (230 ml). The two layers were partitioned and the
aqueous layer was back-extracted with methyl-THF (230 mL). The
organic layers were washed with 2M HCl (2.times.230 mL), water (230
ml), and brine (230 ml), dried over Na.sub.2SO.sub.4 and filtered.
The organic layer was concentrated under reduced pressure until the
solution turned cloudy, then heptane (230 mL) was added. The
resulting solution was concentrated under reduced pressure to 5
volumes and then additional heptane (230 mL) was added. The
resulting solution was concentrated to 5 volumes to give a slurry.
The solids were collected by filtration, washed with heptane (50
mL), and dried under reduced pressure to yield
4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzoic
acid (3.4, 3.96 g). MS: m/z calcd for C.sub.15H.sub.12O.sub.3
240.08, found [M-H].sup.+239.1. .sup.1H NMR (DMSO-d.sub.6, 400 MHz)
.delta. 13.18 (s, 1H), 7.85 (d, 2H), 7.61 (d, 2H), 4.72 (t, 1H),
3.39-3.52 (m, 1H), 3.21-3.32 (m, 1H), 1.41-1.51 (m, 2H), 0.81-0.99
(m, 2H).
##STR00282##
[0206] To a stirring solution of triethylamine (1.06 g, 10.52
mmol), and (R)-methyl 2-amino-3-methyl-3-(methylthio)butanoate
(3.3, 1.86 g, 10.52 mmol) was added a solution of racemic
4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzoic
acid (3.4, 2.5 g, 10.52 mmol) in DMF (40 mL), followed by
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (4 g, 10.52 mmol) and the reaction was
stirred for 2 hr. Water (100 mL) was added and the mixture was
extracted with ethyl acetate (2.times.100 mL), dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to yield
a crude, which was purified by flash chromatography (silica
gel/ethyl acetate 10-40% in hexanes) to yield the corresponding
ester 3.5 (2.6 g), which was converted to
N--((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(((tr-
ans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide (3)
using Procedure 3. MS: m/z calcd for
C.sub.21H.sub.24N.sub.2O.sub.4S 400.15, found [M+H].sup.+ 401.
4.
N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2-yl)-4-
-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide
(4)
##STR00283##
[0208] To a stirring solution of
N--((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-(((tr-
ans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide (3,
0.2 g, 0.50 mmol) in acetonitrile/water (20 mL) was added 30%
aqueous hydrogen peroxide (0.015 mL, 0.50 mmol) and the reaction
mixture was stirred at room temperature for 18 hr. The reaction
mixture was lyophylized to afford
N-((2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfinyl)-1-oxobutan-2--
yl)-4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide
(4, 200 mg, 449 mmol, 90%). MS: m/z calcd for
C.sub.21H.sub.24N.sub.2O.sub.5S 416.14, found [M+H].sup.+ 417.
5.
N--((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)-4-
-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide
(5)
##STR00284##
[0210]
N--((R)-1-(hydroxyamino)-3-methyl-3-(methylthio)-1-oxobutan-2-yl)-4-
-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide
(3, 120 mg, 0.3 mmol) in 22% acetonitrile-water (100 mL) was
treated with 30% peracetic acid (1 mL) overnight at room
temperature. The reaction was lyophilized to afford
N--((R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl)-4-(-
((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide
(5, 130 mg). MS: m/z calcd for C21H.sub.24N.sub.2O.sub.6S 432.14,
found [M+H].sup.+ 433.
6.
N--((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-6-(((trans)--
2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamide (6)
##STR00285##
[0212] To a stirring solution of 6-bromo-2-naphthoic acid (6.1, 1.0
g, 4.0 mmol), racemic ((trans)-2-ethynylcyclopropyl)methanol (1.7,
0.5 g, 5.2 mmol), copper(I) iodide (30 mg, 0.16 mmol) and
palladium(II) bis(triphenylphosphine) dichloride (56 mg, 0.08 mmol)
in tetrahydrofuran (7.5 mL) under a nitrogen atmosphere was added
triethylamine (2.5 mL) and the reaction was stirred for 1 week. The
reaction was partitioned between 2N aqueous sodium hydroxide and
ethyl acetate. The aqueous layer was acidified with conc HCl and
extracted with ethyl acetate. The organic layer was washed with
water, saturated sodium chloride and dried over magnesium sulfate,
filtered and concentrated under reduced pressure to give
6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthoic acid
(6.2, 1.0 g, 94%).
##STR00286##
[0213] To a stirring suspension of
(S)-methyl-2-amino-3-((tert-butoxycarbonyl)amino)-3-methylbutanoate
oxalate (6.3, 1.6 g, 4.9 mmol) and
6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthoic acid
(6.2, 1.0 g, 3.8 mmol) in ACN (10 mL) at 00.degree. C. was added
triethylamine (2.1 mL, 15 mmol), followed by the portionwise
addition of a solution of HATU (3.0 g, 7.9 mmol) in ACN (10 mL) and
the reaction mixture was stirred at 00.degree. C. for 75 min. The
reaction was concentrated under reduced pressure to yield a
residue, which was partitioned between MTBE and water. The organic
layer was washed with 1M citric acid, water, saturated sodium
bicarbonate (2.times.), saturated sodium chloride, dried over
magnesium sulfate, filtered and concentrated under reduced pressure
to give (S)-methyl
3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropy-
l)ethynyl)-2-naphthamido)-3-methylbutanoate (6.4), which was
carried through to the next step without further purification.
##STR00287##
[0214] To a stirring solution of (S)-methyl
3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropy-
l)ethynyl)-2-naphthamido)-3-methylbutanoate (6.4) in methanol (10
mL) was added 4N HCl in dioxane (10 mL) and the reaction mixture
was stirred at rt for 2 hr, then at 4.degree. C. overnight. The
mixture was concentrated under reduced pressure to give a residue,
which was partitioned between water and MTBE. The aqueous layer was
basified with saturated sodium bicarbonate and extracted with ethyl
acetate. The organic layer was washed with saturated sodium
chloride, dried over magnesium sulfate, filtered and concentrated
under reduced pressure to give (S)-methyl
3-amino-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamid-
o)-3-methylbutanoate (6.5, 1.2 g, 3.0 mmol, 79%).
##STR00288##
[0215] Compound 6.5 (1.2 g) was treated according to Procedure 3 to
yield the desired compound
N--((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-6-(((trans)-2--
(hydroxymethyl)cyclopropyl)ethynyl)-2-naphthamide (6, 400 mg, 1.01
mmol, 33.3% yield). MS: m/z calcd for
C.sub.22H.sub.25N.sub.3O.sub.4 395.18, found [M+H].sup.+ 396.2.
7.
N--((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-6-(((trans)--
2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamide
(7)
##STR00289##
[0217] To a stirring solution of
6-bromobenzo[b]thiophene-2-carboxylic acid (7.1, 1.0 g, 3.9 mmol)
in DMF (7.5 mL) under a nitrogen atmosphere were added racemic
((trans)-2-ethynylcyclopropyl)methanol (1.7, 935 mg, 9.7 mmol),
copper(I) iodide (30 mg, 0.16 mmol) and palladium(II)
bis(triphenylphosphine) dichloride (56 mg, 0.08 mmol), followed by
triethylamine (2.5 mL) and the reaction was stirred at room
temperature for 1 hr, and then at 40.degree. C. for 20 hr. The
reaction mixture was partitioned between 2N aqueous sodium
hydroxide and ethyl acetate. The aqueous layer was acidified with
conc HCl and extracted with ethyl acetate. The resulting organic
layer was washed with water, saturated sodium chloride, dried over
magnesium sulfate, filtered and concentrated under reduced pressure
to give
6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carb-
oxylic acid (7.2, 900 mg, 3.3 mmol, 85%).
##STR00290##
[0218] To a stirring solution of (S)-methyl
2-amino-3-((tert-butoxycarbonyl)amino)-3-methylbutanoate oxalate
6.3 (1.4 g, 4.3 mmol),
6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carb-
oxylic acid (7.2, 900 mg, 3.3 mmol) in ACN (10 mL) at 0.degree. C.
was added triethylamine (1.8 mL, 13 mmol), followed by the
portionwise addition of a suspension of HATU (2.6 g, 6.9 mmol) in
ACN (10 mL), and the reaction mixture was stirred at 00.degree. C.
for 105 min. The reaction mixture was concentrated under reduced
pressure, and the residue was partitioned between MTBE and water.
The organic layer was washed with 1M citric acid, water, saturated
sodium bicarbonate (2.times.), saturated sodium chloride, dried
over magnesium sulfate, filtered and concentrated under reduced
pressure to give (S)-methyl
3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropy-
l)ethynyl)benzo [b]thiophene-2-carboxamido)-3-methylbutanoate
(7.3), which was carried through to the next step without further
purification.
##STR00291##
[0219] To a stirring solution of (S)-methyl
3-((tert-butoxycarbonyl)amino)-2-(6-(((trans)-2-(hydroxymethyl)cyclopropy-
l)ethynyl)benzo[b]thiophene-2-carboxamido)-3-methylbutanoate (7.3)
in methanol (10 mL) was added 4N HCl in dioxane (10 mL) and the
reaction was stirred at room temperature for 2 hr, then at
4.degree. C. overnight. The reaction mixture was concentrated under
reduced pressure to yield a residue, which was partitioned between
water and MTBE. The aqueous layer was basified with saturated
sodium bicarbonate and extracted with ethyl acetate. The organic
layer was washed with saturated sodium chloride, dried over
magnesium sulfate, filtered and concentrated under reduced pressure
to give (S)-methyl
3-amino-2-(6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiop-
hene-2-carboxamido)-3-methylbutanoate (7.4, 880 mg, 2.2 mmol,
67%).
##STR00292##
[0220] Compound 7.4 (0.88 g) was treated according to Procedure 3
to yield the desired compound
N--((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-6-(((trans)-2--
(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxamide
(7, 16.3 mg, 0.041 mmol, 1.85% yield). MS: m/z calcd for
C.sub.20H.sub.23N.sub.3O.sub.4S 401.14, found [M+H].sup.+
402.2.
8.
N1-hydroxy-2-(4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)-
benzamido)-N3-methylmalonamide (8)
##STR00293##
[0222] To a stirring solution of diethyl
2-((tert-butoxycarbonyl)amino)malonate (8.1, 0.93 mL, 3.63 mmol) in
methanol (10 mL) was added 40% methanamine in water (0.32 mL, 3.63
mmol) and the reaction was stirred at room temperature for 27 days.
The reaction was concentrated under reduced pressure to give an
oil, which was purified by flash chromatography (silica gel/10%
MeOH/DCM) to provide compound 8.2 (592 mg, 66.2% yield). MS: m/z
calcd for C.sub.10H.sub.18N.sub.2O.sub.5 246.12, found [M+Na].sup.+
269.1.
##STR00294##
[0223] Compound 8.2 (0.59 g, 2.40 mmol) was dissolved in DCM (3 mL)
and TFA (3 mL) and the reaction was stirred for 30 min. The
reaction mixture was concentrated under reduced pressure to give
compound 8.3 (0.88 g), which was carried through to the next step
without further purification. MS: m/z calcd for
C.sub.5H.sub.10N.sub.2O.sub.3 146.07, found [M+H].sup.+ 147.1.
##STR00295## ##STR00296##
[0224] The synthesis of compound 8.14 was carried out as described
in International PCT Patent Application Publication No.
WO2012/154204.
##STR00297##
[0225] To a stirring solution of compound 8.3 (375 mg, 1.44 mmol)
in ACN (3 mL) was added compound 8.14 (315 mg, 1.31 mmol), followed
by DIPEA (1.01 mL, 5.77 mmol) and the reaction mixture was cooled
to 00.degree. C. HATU (548 mg, 1.44 mmol) was added and the
reaction was allowed to warm to room temperature. After 1 hr solids
were collected by filtration, and washed with ACN to yield compound
8.15 (200 mg, 41.4% yield). MS: m/z calcd for
C.sub.20H.sub.20N.sub.2O.sub.5 368.14, found [M+H].sup.+ 369.1.
##STR00298##
[0226] To a stirring solution of compound 8.15 (200 mg, 0.54 mmol)
in THF (1.0 mL) and methanol (1 mL) was added dropwise over 1 min a
solution of 50% hydroxamic acid in water (1 mL) and the reaction
was stirred at room temperature for 3 hr. The reaction mixture was
concentrated under reduced pressure to give a crude, which was
purified by RP HPLC (0.1% AcOH in water and ACN) to give
N1-hydroxy-2-(4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)be-
nzamido)-N3-methylmalonamide (8, 47.7 mg, 23.8% yield). MS: m/z
calcd for C.sub.19H.sub.19N.sub.3O.sub.5 369.13, found [M+H].sup.+
370.1. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 10.84 (br, 1H),
9.06 (s, 1H), 8.57 (d, 1H), 8.02 (d, 1H), 7.89 (d, 2H), 7.60 (d,
2H), 4.99 (d, 1H), 4.70 (t, 1H), 3.43-3.37 (m, 1H), 3.29-3.22 (m,
1H), 2.60 (d, 3H), 1.46-1.41 (m, 2H), 0.94-0.86 (m, 2H).
9.
N-hydroxy-4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)p-
henyl)-2-methyl-2-(methylsulfonyl)butanamide (9)
##STR00299##
[0228] A solution of 2-(4-bromophenyl)ethanol (20.0 g, 100 mol) in
CH.sub.2Cl.sub.2 (10 mL) was added dropwise to a solution of
imidazole (22.4 mg, 0.33 mmol), PPh.sub.3 (33.3 g, 127 mmol), and
I.sub.2 (32.5 g, 130 mmol) in CH.sub.2Cl.sub.2 (50 mL) at
00.degree. C., and the reaction was warmed to room temperature and
stirred overnight. The reaction mixture was washed with saturated
aqueous sodium thiosulfate (2.times.50 mL), brine, dried over
Na.sub.2SO4, filtered and concentrated under reduced pressure to
give a crude, which was purified by flash chromatography (silica
gel/PE) to yield 1-bromo-4-(2-iodoethyl)benzene (9.2, 22.7 g, 73%)
as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 53.13 (t, J=7.6
Hz, 2H), 3.32 (t, J=7.6 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 7.44 (d,
J=8.2 Hz, 2H).
Methyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate
##STR00300##
[0230] Compound 9.3 was synthesized according to the procedure
described in WO 2011045703.
##STR00301##
[0231] To a stirring suspension of methyl
4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.3, 6.36
g, 18.23 mmol), bis(triphenylphosphine)palladium(II) chloride (1.28
mg, 1.82 mmol) and copper(I) iodide (347 mg, 1.82 mmol) in
triethylamine (30 mL) was added ethynyltrimethylsilane (0.92 mL,
6.49 mmol) and the reaction mixture was heated to 80.degree. C.
briefly, and then allowed to stir at room temperature for 18 hr.
Volatiles were removed under reduced pressure and the resulting
residue was purified by flash chromatography (silica gel/15-50%
EtOAc/hexanes) to yield methyl
2-methyl-2-(methylsulfonyl)-4-(4-((trimethylsilyl)ethynyl)phenyl)butanoat-
e (9.4, 4.0 g, 59.9% yield). MS: m/z calcd for
C.sub.18H.sub.26O.sub.4SSi 366.13, found [M+H].sup.+ 367.2.
##STR00302##
[0232] To a stirring solution of methyl
2-methyl-2-(methylsulfonyl)-4-(4-((trimethylsilyl)ethynyl)phenyl)butanoat-
e (9.4, 4.4 g, 12.0 mmol) in methanol (80 mL) was added
K.sub.2CO.sub.3 (100 mg, 0.720 mmol) and the reaction was stirred
at room temperature for 3 hr. The reaction mixture was filtered
through celite, concentrated under reduced pressure to give a
residue, which was dissolved in DCM, filtered and concentrated
under reduced pressure to yield methyl
4-(4-ethynylphenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.5, 2.49
g, 70.5%). MS: m/z calcd for C.sub.15H.sub.18O.sub.4S 294.09, found
[M+H].sup.+ 295.2.
##STR00303##
[0233] To a stirring solution of methyl
4-(4-ethynylphenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.5, 2.49
g, 8.46 mmol) and silver nitrate (144 mg, 0.85 mmol) in acetone (24
mL) was added NBS (2.5 g, 14.33 mmol) and the reaction was stirred
at room temperature for 1.5 hr. Solvent was removed under reduced
pressure to give a residue, which was purified by flash
chromatography (silica gel/30-50% EtOAc/hexanes) to yield methyl
4-(4-(bromoethynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanoate
(9.6, 150 mg, 0.40 mmol, 4.75%). MS: m/z calcd for
C.sub.15H.sub.17BrO.sub.4S 372.0/374.0, found [M+H].sup.+
373.0/375.0.
##STR00304##
[0234] To a stirring solution of racemic
((trans)-2-ethynylcyclopropyl)methanol (1.7) in n-butylamine (750
.mu.L, 30% in 1:1 water/THF) at -10.degree. C. was added a solution
of copper chloride (4 mg) in n-butylamine (300 .mu.L, 30% in 1:1
water/THF) and NH.sub.2OH (12 .mu.L of 50% in water) and the
reaction was stirred for 10 min. A solution of methyl
4-(4-(bromoethynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanoate
(9.6) in n-butylamine (750 .mu.L, 30% in 1:1 water/THF) and
NH.sub.2OH (12 .mu.L of 50% in water, 0.201 mmol) at -10.degree. C.
was then added dropwise over 10 min and the reaction was stirred at
-10.degree. C. for 10 min. The reaction mixture was diluted with
EtOAc (10 mL) and washed with 1 M citric acid (5 mL). The organic
layer was washed with water (2.times.5 mL), sodium bicarbonate (5
mL), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to give a thick oil (9.7), which was carried
through to the next step without further purification. MS: m/z
calcd for C.sub.21H.sub.24O.sub.5S 388.13, found [M+H].sup.+
389.2.
##STR00305##
[0235] To a stirring solution of methyl
4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)-2--
methyl-2-(methylsulfonyl) butanoate (9.7) in isopropanol (1.3 mL)
at 00.degree. C. was added hydroxylamine (946 .mu.L, 15.44 mmol,
50% in water) and the reaction was stirred at room temperature
overnight. The reaction mixture was neutralized with AcOH (884
.mu.L, 15.44 mmol) and concentrated under reduced pressure to give
a crude, which was purified by RP-HPLC (0-30% ACN in water) to
yield N-hydroxy-4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)
buta-1,3-diynyl)phenyl)-2-methyl-2-(methylsulfonyl)butanamide (9,
22.6 mg, 22.6% yield). MS: m/z calcd for C.sub.20H.sub.23NO.sub.5S
389.13, found [M+H].sup.+ 390.2.
[0236] B. Antimicrobial Activity
1. Bacterial Screens and Cultures
[0237] Bacterial isolates were cultivated from -70.degree. C.
frozen stocks by overnight passages at 35.degree. C. in ambient air
on Mueller-Hinton agar (Beckton Dickinson, Franklin Lakes, N.J.).
Clinical isolates tested were obtained from various geographically
diverse hospitals in the US and abroad (Focus Diagnostics, Herndon,
Va. and JMI, North Liberty, Iowa). Quality control strains were
from the American Type Culture Collection (ATCC; Rockville,
Md.).
2. Susceptibility Testing
[0238] Minimum Inhibitory Concentrations (MICs) were determined by
the broth microdilution method in accordance with the Clinical and
Laboratory Standards Institute (CLSI) guidelines. In brief,
organism suspensions were adjusted to a 0.5 McFarland standard to
yield a final inoculum between 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
(Beckton Dickinson). 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 hr. Following incubation, the lowest
concentration of the drug that prevented visible growth (OD600
nm<0.05) was recorded as the MIC. Performance of the assay was
monitored by the use of laboratory quality-control strains and
levofloxacin, a compound with a defined MIC spectrum, in accordance
with CLSI guidelines. Typically, compounds of the present invention
have MIC values of 0.03-32 .mu.g/mL. To this end, data for certain
representative compounds is shown in Table II below.
TABLE-US-00006 TABLE II Minimum Inhibitory Concentrations (MICs)
cmpd. AECO AKPN APAE 1 A A C 2 A C C 3 A A A 4 A C A 5 A A A 6 B C
A 7 B C B 8 A A A 9 A B A
MIC Key:
[0239] A=MIC's of 1.0 .mu.g/mL or less
[0240] B=MIC's of greater than 1.0 .mu.g/mL to 8.0 .mu.g/mL
[0241] C=MIC's of greater than 8.0 .mu.g/mL to 16.0 .mu.g/mL
[0242] D=MIC's of greater than 16.0 .mu.g/mL
* AECO is Escherichia coli ATCC25922. AKPN is Klebsiella pneumonia
ATCC43816. APAE is Pseudomonas aeruginosa ATCC27853.
[0243] 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.
[0244] Furthermore, while particular embodiments of the present
invention have been shown and described herein for purposes of
illustration, it will be understood, of course, that the invention
is not limited thereto since modifications may be made by persons
skilled in the art, particularly in light of the foregoing
teachings, without deviating from the spirit and scope of the
invention. Accordingly, the invention is not limited except as by
the appended claims.
[0245] All of the U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non-patent publications referred to in this
specification are incorporated herein by reference, in their
entirety to the extent not inconsistent with the present
description.
* * * * *