U.S. patent application number 12/944699 was filed with the patent office on 2011-09-01 for boron-containing small molecules.
This patent application is currently assigned to Anacor Pharmaceuticals, Inc.. Invention is credited to Tsutomu Akama, Vincent S. Hernandez, Michael Richard Kevin Alley, Xianfeng Li, Yang Liu, James A. Nieman, Jacob J. Plattner, Suoming Zhang, Yanchen Zhang, Yasheen Zhou.
Application Number | 20110212918 12/944699 |
Document ID | / |
Family ID | 43384475 |
Filed Date | 2011-09-01 |
United States Patent
Application |
20110212918 |
Kind Code |
A1 |
Hernandez; Vincent S. ; et
al. |
September 1, 2011 |
BORON-CONTAINING SMALL MOLECULES
Abstract
This invention relates to, among other items, 6-substituted
benzoxaborole compounds and their use for treating bacterial
infections.
Inventors: |
Hernandez; Vincent S.;
(Watsonville, CA) ; Li; Xianfeng; (Cupertino,
CA) ; Zhang; Suoming; (Palo Alto, CA) ; Akama;
Tsutomu; (Sunnyvale, CA) ; Zhang; Yanchen;
(Union City, CA) ; Liu; Yang; (Foster City,
CA) ; Plattner; Jacob J.; (Orinda, CA) ; Kevin
Alley; Michael Richard; (Santa Clara, CA) ; Zhou;
Yasheen; (Moraga, CA) ; Nieman; James A.;
(Sherwood Park, CA) |
Assignee: |
Anacor Pharmaceuticals,
Inc.
Palo Alto
CA
|
Family ID: |
43384475 |
Appl. No.: |
12/944699 |
Filed: |
November 11, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61260384 |
Nov 11, 2009 |
|
|
|
61260373 |
Nov 11, 2009 |
|
|
|
Current U.S.
Class: |
514/64 ; 435/184;
544/229; 546/13; 548/110; 560/12; 560/13; 564/8 |
Current CPC
Class: |
A61P 31/04 20180101;
C07F 5/025 20130101 |
Class at
Publication: |
514/64 ; 546/13;
564/8; 435/184; 548/110; 560/13; 560/12; 544/229 |
International
Class: |
A61K 31/69 20060101
A61K031/69; C07F 5/02 20060101 C07F005/02; C12N 9/99 20060101
C12N009/99; A01N 55/08 20060101 A01N055/08; A61P 31/04 20060101
A61P031/04; A01P 1/00 20060101 A01P001/00 |
Claims
1. A compound, or a salt thereof, having a structure which is
##STR00246## wherein R.sup.5 is H or halogen; one of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 is halogen or --NHC(O)OR.sup.30 or
alkyl substituted with --C(O)OR.sup.30 or alkyl substituted with
--S(O).sub.2R.sup.30 or alkyl substituted with halogen or alkyl
substituted with hydroxy or alkyl substituted with cyano or alkyl
substituted with --NHC(O)OR.sup.30 or alkyl substituted with
unsubstituted oxazolyl or alkyl substituted with alkyl substituted
oxazolyl or alkyl substituted with unsubstituted oxadiazolyl or
alkyl substituted with alkyl substituted oxadiazolyl or alkyl
substituted with --C(O)NHR.sup.35, wherein R.sup.30 is
unsubstituted alkyl and R.sup.35 is unsubstituted alkyl or
unsubstituted cycloalkyl, and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10 and R.sup.11 are
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
2. The compound of claim 1, having a structure which is
##STR00247##
3. The compound of claim 1, having a structure which is
##STR00248## wherein R.sup.a6 is F or Cl or Br.
4. The compound of claim 1, having a structure which is
##STR00249## wherein R.sup.a6 is F or Cl or Br.
5. A combination comprising: a) a compound of claim 1, or a
pharmaceutically acceptable salt thereof; and b) a therapeutically
active agent.
6. A pharmaceutical formulation comprising: a) a compound of claim
1 or a combination of claim 5, or a pharmaceutically acceptable
salt thereof; and b) a pharmaceutically acceptable excipient.
7. The pharmaceutical formulation of claim 6, wherein said
formulation is a unit dosage form.
8. The pharmaceutical formulation of claim 6, wherein said
formulation is a member selected from an oral unit dosage form and
a topical unit dosage form.
9. A method of killing or inhibiting the growth of a bacteria, said
method comprising: contacting said bacteria with an effective
amount of a compound of claim 1 or a combination of claim 5, or a
pharmaceutically acceptable salt thereof, thereby killing or
inhibiting the growth of the bacteria.
10. A method of treating a bacterial infection comprising:
administering to an animal suffering from said infection an
effective amount of a compound of claim 1, or a
pharmaceutically-acceptable salt thereof, thereby treating the
bacterial infection.
11. The method of claim 10, wherein said animal is a human.
12. A method of inhibiting the editing domain of a t-RNA
synthetase, comprising: contacting the synthetase with an effective
amount of a compound of claim 1, or a pharmaceutically-acceptable
salt thereof, thereby inhibiting the synthetase.
13. The method of claim 12, wherein the synthetase is a leucyl
t-RNA synthetase.
14. The use of a compound of claim 1 or a combination of claim 6 or
a pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for the treatment and/or prophylaxis of bacterial
infection.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Pat.
App. No. 61/260,384, filed Nov. 11, 2009, and U.S. Provisional Pat.
App. No. 61/260,373, filed Nov. 11, 2009, each of which is
incorporated by reference in its entirety for all purposes.
BACKGROUND OF THE INVENTION
[0002] The global rise of bacteria and other microorganisms
resistant to antibiotics and antimicrobials in general, poses a
major threat. Deployment of massive quantities of antimicrobial
agents into the ecosphere during the past 60 years has introduced a
powerful selective pressure for the emergence and spread of
antimicrobial-resistant pathogens. Thus, there is a need to
discover new broad spectrum antimicrobials, such as antibiotics,
useful in combating microorganisms, especially those with
multidrug-resistance.
[0003] Boron-containing molecules, such as
1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborole (also sometimes known
as 1-hydroxy-benzo[c][1,2]oxaborole or oxaboroles or cyclic boronic
esters), useful as antimicrobials have been described previously,
such as in U.S. patent application Ser. Nos. 12/142,692; 11/505,591
and 11/357,687. Generally speaking, a
1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborole has the following
structure and substituent numbering system:
##STR00001##
Surprisingly, it has now been discovered that certain classes of
1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaboroles which are substituted
with at least two moieties on an aryl or heteroaryl sulfonamide
moiety at the 6-position are surprisingly effective antibacterials.
This, and other uses of these
1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaboroles are described
herein.
SUMMARY OF THE INVENTION
[0004] In a first aspect, the invention provides a compound having
a structure which is
##STR00002##
wherein R.sup.5 is H or halogen; one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is halogen or --NHC(O)OR.sup.30 or alkyl
substituted with --C(O)OR.sup.30 or alkyl substituted with
--S(O).sub.2R.sup.30 or alkyl substituted with halogen or alkyl
substituted with hydroxy or alkyl substituted with cyano or alkyl
substituted with --NHC(O)OR.sup.30 or alkyl substituted with
unsubstituted oxazolyl or alkyl substituted with alkyl substituted
oxazolyl or alkyl substituted with unsubstituted oxadiazolyl or
alkyl substituted with alkyl substituted oxadiazolyl or alkyl
substituted with --C(O)NHR.sup.35, wherein R.sup.30 is
unsubstituted alkyl and R.sup.35 is unsubstituted alkyl or
unsubstituted cycloalkyl, and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10 and R.sup.11 are
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0005] In a second aspect, the invention provides a combination
comprising: a) a compound of the invention, or a pharmaceutically
acceptable salt thereof; and b) a therapeutically active agent.
[0006] In a third aspect, the invention provides a pharmaceutical
formulation comprising: a) a compound of the invention, or a
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient.
[0007] In a fourth aspect, the invention provides a method of
killing or inhibiting the growth of a bacteria, said method
comprising: contacting said bacteria with an effective amount of a
compound of the invention or a combination of the invention, or a
pharmaceutically acceptable salt thereof, thereby killing or
inhibiting the growth of the bacteria.
[0008] In a fifth aspect, the invention provides a method of
treating a bacterial infection comprising: administering to an
animal suffering from said infection an effective amount of a
compound of the invention, or a pharmaceutically-acceptable salt
thereof, thereby treating the bacterial infection.
[0009] In a sixth aspect, the invention provides a method of
inhibiting the editing domain of a t-RNA synthetase, comprising:
contacting the synthetase with an effective amount of a compound of
the invention, or a pharmaceutically-acceptable salt thereof,
thereby inhibiting the synthetase.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 displays biological data for exemplary compounds of
the invention.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions and Abbreviations
[0011] As used herein, the singular forms "a," "an", and "the"
include plural references unless the context clearly dictates
otherwise. For example, reference to "an active agent" includes a
single active agent as well as two or more different active agents
in combination. It is to be understood that present teaching is not
limited to the specific dosage forms, carriers, or the like,
disclosed herein and as such may vary.
[0012] The abbreviations used herein generally have their
conventional meaning within the chemical and biological arts.
[0013] The following abbreviations have been used: Ac is acetyl;
AcOH is acetic acid; ACTBr is cetyltrimethylammonium bromide; AIBN
is azobisisobutyronitrile or 2,2 azobisisobutyronitrile; aq. is
aqueous; Ar is aryl; B.sub.2pin.sub.2 is bis(pinacolato)diboron; Bn
is, in general, benzyl [see Cbz for one example of an exception];
(BnS).sub.2 is benzyl disulfide; BnSH is benzyl thiol or benzyl
mercaptan; BnBr is benzyl bromide; Boc is tert-butoxy carbonyl;
Boc.sub.2O is di-tert-butyl dicarbonate; Bz is, in general,
benzoyl; BzOOH is benzoyl peroxide; Cbz or Z is benzyloxycarbonyl
or carboxybenzyl; Cs.sub.2CO.sub.3 is cesium carbonate; CSA is
camphor sulfonic acid; CTAB is cetyltrimethylammonium bromide; Cy
is cyclohexyl; DABCO is 1,4-diazabicyclo[2.2.2]octane; DCM is
dichloromethane or methylene chloride; DHP is dihydropyran; DIAD is
diisopropyl azodicarboxylate; DIEA or DIPEA is
N,N-diisopropylethylamine; DMAP is 4-(dimethylamino)pyridine; DME
is 1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMSO is
dimethylsulfoxide; equiv or eq. is equivalent; EtOAc is ethyl
acetate; EtOH is ethanol; Et.sub.2O is diethyl ether; EDCI is
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; ELS
is evaporative light scattering; equiv or eq is equivalent; h is
hours; HATU is
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate; HOBt is N-hydroxybenzotriazole; HCl is
hydrochloric acid; HPLC is high pressure liquid chromatography;
ISCO Companion is automated flash chromatography equipment with
fraction analysis by UV absorption available from Presearch; KOAc
or AcOK is potassium acetate; K.sub.2CO.sub.3 is potassium
carbonate; LiAlH.sub.4 or LAH is lithium aluminum hydride; LDA is
lithium diisopropylamide; LHMDS is lithium bis(trimethylsilyl)
amide; KHMDS is potassium bis(trimethylsilyl) amide; LiOH is
lithium hydroxide; m-CPBA is 3-chloroperoxybenzoic acid; MeCN or
ACN is methyl cyanide or cyanomethane or ethanenitrile or
acetonitrile which are all names for the same compound; MeOH is
methanol; MgSO.sub.4 is magnesium sulfate; mins or min is minutes;
Mp or MP is melting point; NaCNBH.sub.3 is sodium cyanoborohydride;
NaOH is sodium hydroxide; Na.sub.2SO.sub.4 is sodium sulfate; NBS
is N-bromosuccinimide; NH.sub.4Cl is ammonium chloride; NIS is
N-iodosuccinimide; N.sub.2 is nitrogen; NMM is N-methylmorpholine;
n-BuLi is n-butyllithium; overnight is O/N; PdCl.sub.2(pddf) is
1,1'-Bis(diphenylphosphino) ferrocene]dichloropalladium(II); Pd/C
is the catalyst known as palladium on carbon; Pd.sub.2(dba).sub.3
is an organometallic catalyst known as tris(dibenzylideneacetone)
dipalladium(0); Ra Ni or Raney Ni is Raney nickel; Ph is phenyl;
PMB is p-methoxybenzyl; PrOH is 1-propanol; iPrOH is 2-propanol;
POCl.sub.3 is phosphorus chloride oxide; PTSA is para-toluene
sulfonic acid; Pyr. or Pyr or Py as used herein means Pyridine; RT
or rt or r.t. is room temperature; sat. is saturated; Si-amine or
S.sub.1--NH.sub.2 is amino-functionalized silica, available from
SiliCycle; Si-pyr is pyridyl-functionalized silica, available from
SiliCycle; TEA or Et.sub.3N is triethylamine; TFA is
trifluoroacetic acid; Tf.sub.2O is trifluoromethanesulfonic
anhydride; THF is tetrahydrofuran; TFAA is trifluoroacetic
anhydride; THP is tetrahydropyranyl; TMSI is trimethylsilyl iodide;
H.sub.2O is water; diNO.sub.2PhSO.sub.2Cl is dinitrophenyl sulfonyl
chloride; 3-F-4-NO.sub.2-PhSO.sub.2Cl is
3-fluoro-4-nitrophenylsulfonyl chloride;
2-MeO-4-NO.sub.2-PhSO.sub.2Cl is 2-methoxy-4-nitrophenylsulfonyl
chloride; and (EtO).sub.2POCH.sub.2COOEt is a triethylester of
phosphonoacetic acid known as triethyl phosphonoacetate.
[0014] "Compound of the invention," as used herein refers to the
compounds discussed herein, salts (e.g. pharmaceutically acceptable
salts), prodrugs, solvates and hydrates of these compounds.
[0015] MIC, or minimum inhibitory concentration, is the point where
the compound stops more than 50% of cell growth, preferably 60% of
cell growth, preferably 70% of cell growth, preferably 80% of cell
growth, preferably 90% of cell growth, relative to an untreated
control.
[0016] The term "poly" as used herein means at least 2. For
example, a polyvalent metal ion is a metal ion having a valency of
at least 2.
[0017] "Moiety" refers to a radical of a molecule that is attached
to the remainder of the molecule.
[0018] The symbol , whether utilized as a bond or displayed
perpendicular to a bond, indicates the point at which the displayed
moiety is attached to the remainder of the molecule.
[0019] The term "alkyl," by itself or as part of another
substituent, means, unless otherwise stated, a straight or branched
chain, or cyclic hydrocarbon radical, or combination thereof, which
may be fully saturated, mono- or polyunsaturated and can include
di- and multivalent radicals, having the number of carbon atoms
designated (i.e. C.sub.1-C.sub.10 means one to ten carbons). In
some embodiments, the term "alkyl" means a straight or branched
chain, or combinations thereof, which may be fully saturated, mono-
or polyunsaturated and can include di- and multivalent radicals.
Examples of saturated hydrocarbon radicals include, but are not
limited to, groups such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,
(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for
example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An
unsaturated alkyl group is one having one or more double bonds or
triple bonds. Examples of unsaturated alkyl groups include, but are
not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,
2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-
and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
[0020] The term "alkylene" by itself or as part of another
substituent means a divalent radical derived from an alkane, as
exemplified, but not limited, by
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. Typically, an alkyl (or
alkylene) group will have from 1 to 24 carbon atoms, with those
groups having 10 or fewer carbon atoms being preferred in the
invention. A "lower alkyl" or "lower alkylene" is a shorter chain
alkyl or alkylene group, generally having eight or fewer carbon
atoms.
[0021] The term "alkenylene" by itself or as part of another
substituent means a divalent radical derived from an alkene.
[0022] The term "cycloalkylene" by itself or as part of another
substituent means a divalent radical derived from a cycloalkyl.
[0023] The term "heteroalkylene" by itself or as part of another
substituent means a divalent radical derived from an
heteroalkane.
[0024] The term "heterocycloalkylene" by itself or as part of
another substituent means a divalent radical derived from an
heteroalkane.
[0025] The term "arylene" by itself or as part of another
substituent means a divalent radical derived from an aryl.
[0026] The term "heteroarylene" by itself or as part of another
substituent means a divalent radical derived from heteroaryl.
[0027] The terms "alkoxy," "alkylamino" and "alkylthio" (or
thioalkoxy) are used in their conventional sense, and refer to
those alkyl groups attached to the remainder of the molecule via an
oxygen atom, an amino group, or a sulfur atom, respectively.
[0028] The term "heteroalkyl," by itself or in combination with
another term, means, unless otherwise stated, a stable straight or
branched chain, or cyclic hydrocarbon radical, or combinations
thereof, consisting of the stated number of carbon atoms and at
least one heteroatom. In some embodiments, the term "heteroalkyl,"
by itself or in combination with another term, means a stable
straight or branched chain, or combinations thereof, consisting of
the stated number of carbon atoms and at least one heteroatom. In
an exemplary embodiment, the heteroatoms can be selected from the
group consisting of B, O, N and S, and wherein the nitrogen and
sulfur atoms may optionally be oxidized and the nitrogen heteroatom
may optionally be quaternized. The heteroatom(s) B, O, N and S may
be placed at any interior position of the heteroalkyl group or at
the position at which the alkyl group is attached to the remainder
of the molecule. Examples include, but are not limited to,
--CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --CH.sub.2--CH.dbd.N--OCH.sub.3, and
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3. Up to two heteroatoms may be
consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3.
Similarly, the term "heteroalkylene" by itself or as part of
another substituent means a divalent radical derived from
heteroalkyl, as exemplified, but not limited by,
--CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--. For
heteroalkylene groups, heteroatoms can also occupy either or both
of the chain termini (e.g., alkyleneoxy, alkylenedioxy,
alkyleneamino, alkylenediamino, and the like). Still further, for
alkylene and heteroalkylene linking groups, no orientation of the
linking group is implied by the direction in which the formula of
the linking group is written. For example, the formula
--C(O).sub.2R'-- represents both --C(O).sub.2R'-- and
--R'C(O).sub.2--.
[0029] The terms "cycloalkyl" and "heterocycloalkyl", by themselves
or in combination with other terms, represent, unless otherwise
stated, cyclic versions of "alkyl" and "heteroalkyl", respectively.
Additionally, for heterocycloalkyl, a heteroatom can occupy the
position at which the heterocycle is attached to the remainder of
the molecule. Examples of cycloalkyl include, but are not limited
to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl,
cycloheptyl, and the like. Examples of heterocycloalkyl include,
but are not limited to, 1-(1,2,5,6-tetrahydropyridyl),
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,
3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,
tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,
2-piperazinyl, and the like.
[0030] The terms "halo" or "halogen," by themselves or as part of
another substituent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. Additionally, terms such as
"haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl.
For example, the term "halo(C.sub.1-C.sub.4)alkyl" is mean to
include, but not be limited to, trifluoromethyl,
2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the
like.
[0031] The term "aryl" means, unless otherwise stated, a
polyunsaturated, aromatic, substituent that can be a single ring or
multiple rings (preferably from 1 to 3 rings), which are fused
together or linked covalently. The term "heteroaryl" refers to aryl
groups (or rings) that contain from one to four heteroatoms. In an
exemplary embodiment, the heteroatom is selected from B, N, O, and
S, wherein the nitrogen and sulfur atoms are optionally oxidized,
and the nitrogen atom(s) are optionally quaternized. A heteroaryl
group can be attached to the remainder of the molecule through a
heteroatom. Non-limiting examples of aryl and heteroaryl groups
include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,
pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,
5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,
purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,
2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, 6-quinolyl,
dioxaborolane, dioxaborinane and dioxaborepane. Substituents for
each of the above noted aryl and heteroaryl ring systems are
selected from the group of acceptable substituents described
below.
[0032] For brevity, the term "aryl" when used in combination with
other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes those
radicals in which an aryl group is attached through the next moiety
to the rest of the molecule. Thus, the term "arylalkyl" is meant to
include those radicals in which an aryl group is attached to an
alkyl group (e.g., benzyl, 1-(3-nitrophenyl)ethyl and the like). A
substituent such as benzyl or 1-(3-nitrophenyl)ethyl can also be
represented by `substituted alkyl` wherein the ethyl radical is
substituted with a 3-nitrophenyl moiety. The term "aryloxy" is
meant to include those radicals in which an aryl group is attached
to an oxygen atom. The term "aryloxyalkyl" is meant to include
those radicals in which an aryl group is attached to an oxygen atom
which is then attached to an alkyl group (e.g., phenoxymethyl,
3-(1-naphthyloxy)propyl, and the like).
[0033] For brevity, the term "heteroaryl" when used in combination
with other terms (e.g., heteroaryloxy, heteroarylthioxy,
heteroarylalkyl) includes those radicals in which a heteroaryl
group is attached through the next moiety to the rest of the
molecule. Thus, the term "heteroarylalkyl" is meant to include
those radicals in which a heteroaryl group is attached to an alkyl
group (e.g., pyridylmethyl and the like). The term "heteroaryloxy"
is meant to include those radicals in which a heteroaryl group is
attached to an oxygen atom. The term "heteroaryloxyalkyl" is meant
to include those radicals in which an aryl group is attached to an
oxygen atom which is then attached to an alkyl group. (e.g.,
2-pyridyloxymethyl and the like).
[0034] Each of the above terms (e.g., "alkyl," "heteroalkyl,"
"aryl" and "heteroaryl") are meant to include both substituted and
unsubstituted forms of the indicated radical. Preferred
substituents for each type of radical are provided below.
[0035] Substituents for the alkyl and heteroalkyl radicals
(including those groups often referred to as alkylene, alkenyl,
heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are
generically referred to as "alkyl group substituents," and they can
be one or more of a variety of groups selected from, but not
limited to: --R', --OR', .dbd.O, =NR', .dbd.N--OR', --NR'R'',
--SR', -halogen, --SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R',
--CONR'R'', --OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''',
--NR''C(O).sub.2R', --NR'--C(NR'R''R''').dbd.NR'''',
--NR''--C(NR'R'').dbd.NR''', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NR''SO.sub.2R', --CN, --NO.sub.2, --N.sub.3,
--CH(Ph).sub.2, fluoro(C.sub.1-C.sub.4)alkoxy, and
fluoro(C.sub.1-C.sub.4)alkyl, in a number ranging from zero to (2
m'+1), where m' is the total number of carbon atoms in such
radical. R', R'', R''', R'''' and R''''' each preferably
independently refer to hydrogen, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted aryl, e.g., aryl
substituted with 1-3 halogens, substituted or unsubstituted alkyl,
alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound
of the invention includes more than one R group, for example, each
of the R groups is independently selected as are each R', R'',
R''', R'''' and R''''' groups when more than one of these groups is
present. When R' and R'' are attached to the same nitrogen atom,
they can be combined with the nitrogen atom to form a 5-, 6-, or
7-membered ring. For example, --NR'R.sup.11 is meant to include,
but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the
above discussion of substituents, one of skill in the art will
understand that the term "alkyl" is meant to include groups
including carbon atoms bound to groups other than hydrogen groups,
such as haloalkyl (e.g., --CF.sub.3 and --CH.sub.2CF.sub.3) and
acyl (e.g., --C(O)CH.sub.3, --C(O)CF.sub.3,
--C(O)CH.sub.2OCH.sub.3, and the like).
[0036] Similar to the substituents described for the alkyl radical,
substituents for the aryl and heteroaryl groups are generically
referred to as "aryl group substituents." The substituents are
selected from, for example: --R', --OR', .dbd.O, .dbd.NR',
.dbd.N--OR', --NR'R'', --SR', -halogen, --SiR'R''R''', --OC(O)R',
--C(O)R', --CO.sub.2R', --CONR'R'', --OC(O)NR'R'', --NR''C(O)R',
--NR'--C(O)NR''R''', --NR''C(O).sub.2R',
--NR'''''--C(NR'R''R''').dbd.NR'''', --NR''--C(NR'R'').dbd.NR''',
--S(O)R', --S(O).sub.2R', --S(O).sub.2NR'R'', --NR''SO.sub.2R',
--CN, --NO.sub.2, --N.sub.3, --CH(Ph).sub.2,
fluoro(C.sub.1-C.sub.4)alkoxy, and fluoro(C.sub.1-C.sub.4)alkyl, in
a number ranging from zero to the total number of open valences on
the aromatic ring system; and where R', R'', R''', R'''' and R'''''
are preferably independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl and substituted or unsubstituted
heteroaryl. When a compound of the invention includes more than one
R group, for example, each of the R groups is independently
selected as are each R', R'', R''', R'''' and R''''' groups when
more than one of these groups is present.
[0037] Two of the substituents on adjacent atoms of the aryl or
heteroaryl ring may optionally be replaced with a substituent of
the formula -T--C(O)--(CRR').sub.q--U--, wherein T and U are
independently --NR--, --O--, --CRR'-- or a single bond, and q is an
integer from 0 to 3. Alternatively, two of the substituents on
adjacent atoms of the aryl or heteroaryl ring may optionally be
replaced with a substituent of the formula
-A-(CH.sub.2).sub.r--B--, wherein A and B are independently
--CRR'--, --O--, --NR--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2NR'-- or a single bond, and r is an integer from 1 to
4. One of the single bonds of the new ring so formed may optionally
be replaced with a double bond. Alternatively, two of the
substituents on adjacent atoms of the aryl or heteroaryl ring may
optionally be replaced with a substituent of the formula
--(CRR').sub.s--X--(CR''R''').sub.d--, where s and d are
independently integers from 0 to 3, and X is --O--, --NR'--, --S--,
--S(O)--, --S(O).sub.2--, or --S(O).sub.2NR'--. The substituents R,
R', R'' and R''' are preferably independently selected from
hydrogen or substituted or unsubstituted
(C.sub.1-C.sub.6)alkyl.
[0038] "Ring" as used herein, means a substituted or unsubstituted
cycloalkyl, substituted or unsubstituted heterocycloalkyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl. A ring includes fused ring moieties. The number of
atoms in a ring is typically defined by the number of members in
the ring. For example, a "5- to 7-membered ring" means there are 5
to 7 atoms in the encircling arrangement. Unless otherwise
specified, the ring optionally includes a heteroatom. Thus, the
term "5- to 7-membered ring" includes, for example phenyl,
pyridinyl and piperidinyl. The term "5- to 7-membered
heterocycloalkyl ring", on the other hand, would include pyridinyl
and piperidinyl, but not phenyl. The term "ring" further includes a
ring system comprising more than one "ring", wherein each "ring" is
independently defined as above.
[0039] As used herein, the term "heteroatom" includes atoms other
than carbon (C) and hydrogen (H). Examples include oxygen (O),
nitrogen (N) sulfur (S), silicon (Si), germanium (Ge), aluminum
(Al) and boron (B).
[0040] The symbol "R" is a general abbreviation that represents a
substituent group that is selected from substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyl and substituted
or unsubstituted heterocycloalkyl groups.
[0041] By "effective" amount of a drug, formulation, or permeant is
meant a sufficient amount of a active agent to provide the desired
local or systemic effect. A "Topically effective," "Cosmetically
effective," "pharmaceutically effective," or "therapeutically
effective" amount refers to the amount of drug needed to effect the
desired therapeutic result.
[0042] The term "pharmaceutically acceptable salt" is meant to
include a salt of a compound of the invention which is prepared
with relatively nontoxic acids or bases, depending on the
particular substituents found on the compounds described herein.
When compounds of the invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable base addition salts include sodium,
potassium, calcium, ammonium, organic amino, or magnesium salt, or
a similar salt. When compounds of the invention contain relatively
basic functionalities, acid addition salts can be obtained by
contacting the neutral form of such compounds with a sufficient
amount of the desired acid, either neat or in a suitable inert
solvent. Examples of pharmaceutically acceptable acid addition
salts include those derived from inorganic acids like hydrochloric,
hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, maleic, malonic, benzoic,
succinic, suberic, fumaric, lactic, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric,
methanesulfonic, and the like. Also included are salts of amino
acids such as arginate and the like, and salts of organic acids
like glucuronic or galactunoric acids and the like (see, for
example, Berge et al., "Pharmaceutical Salts", Journal of
Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds
of the invention contain both basic and acidic functionalities that
allow the compounds to be converted into either base or acid
addition salts.
[0043] The neutral forms of the compounds are preferably
regenerated by contacting the salt with a base or acid and
isolating the parent compounds in the conventional manner. The
parent form of the compound differs from the various salt forms in
certain physical properties, such as solubility in polar
solvents.
[0044] In addition to salt forms, the invention provides compounds
which are in a prodrug form. Prodrugs of the compounds described
herein readily undergo chemical changes under physiological
conditions to provide the compounds of the invention. Additionally,
prodrugs can be converted to the compounds of the invention by
chemical or biochemical methods in an ex vivo environment.
[0045] Certain compounds of the invention can exist in unsolvated
forms as well as solvated forms, including hydrated forms. In
general, the solvated forms are equivalent to unsolvated forms and
are encompassed within the scope of the invention. Certain
compounds of the invention may exist in multiple crystalline or
amorphous forms.
[0046] Certain compounds of the invention possess asymmetric carbon
atoms (optical centers) or double bonds; the racemates,
diastereomers, geometric isomers and individual isomers are
encompassed within the scope of the invention. The graphic
representations of racemic, ambiscalemic and scalemic or
enantiomerically pure compounds used herein are taken from Maehr,
J. Chem. Ed. 1985, 62: 114-120. Solid and broken wedges are used to
denote the absolute configuration of a stereocenter unless
otherwise noted. When the compounds described herein contain
olefinic double bonds or other centers of geometric asymmetry, and
unless specified otherwise, it is intended that the compounds
include both E and Z geometric isomers. Likewise, all tautomeric
forms are included.
[0047] Compounds of the invention can exist in particular geometric
or stereoisomeric forms. The invention contemplates all such
compounds, including cis- and trans-isomers, (-)- and
(+)-enantiomers, (R)- and (S)-enantiomers, diastereomers,
(D)-isomers, (L)-isomers, the racemic mixtures thereof, and other
mixtures thereof, such as enantiomerically or diastereomerically
enriched mixtures, as falling within the scope of the invention.
Additional asymmetric carbon atoms can be present in a substituent
such as an alkyl group. All such isomers, as well as mixtures
thereof, are intended to be included in this invention.
[0048] Optically active (R)- and (S)-isomers and d and/isomers can
be prepared using chiral synthons or chiral reagents, or resolved
using conventional techniques. If, for instance, a particular
enantiomer of a compound of the invention is desired, it can be
prepared by asymmetric synthesis, or by derivatization with a
chiral auxiliary, where the resulting diastereomeric mixture is
separated and the auxiliary group cleaved to provide the pure
desired enantiomers. Alternatively, where the molecule contains a
basic functional group, such as an amino group, or an acidic
functional group, such as a carboxyl group, diastereomeric salts
can be formed with an appropriate optically active acid or base,
followed by resolution of the diastereomers thus formed by
fractional crystallization or chromatographic means known in the
art, and subsequent recovery of the pure enantiomers. In addition,
separation of enantiomers and diastereomers is frequently
accomplished using chromatography employing chiral, stationary
phases, optionally in combination with chemical derivatization
(e.g., formation of carbamates from amines).
[0049] The compounds of the invention may also contain unnatural
proportions of atomic isotopes at one or more of the atoms that
constitute such compounds. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H or T), iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All
isotopic variations of the compounds of the invention, whether
radioactive or not, are intended to be encompassed within the scope
of the invention.
[0050] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable vehicle" refers to any formulation or
carrier medium that provides the appropriate delivery of an
effective amount of an active agent as defined herein, does not
interfere with the effectiveness of the biological activity of the
active agent, and that is sufficiently non-toxic to the host or
patient. Representative carriers include water, oils, both
vegetable and mineral, cream bases, lotion bases, ointment bases
and the like. These bases include suspending agents, thickeners,
penetration enhancers, and the like. Their formulation is well
known to those in the art of cosmetics and topical pharmaceuticals.
Additional information concerning carriers can be found in
Remington: The Science and Practice of Pharmacy, 21st Ed.,
Lippincott, Williams & Wilkins (2005) which is incorporated
herein by reference.
[0051] The term "excipients" is conventionally known to mean
carriers, diluents and/or vehicles used in formulating drug
compositions effective for the desired use.
[0052] The term "microbial infection" or "infection by a
microorganism" refers to any infection of a host tissue by an
infectious agent including, but not limited to, bacteria or
protozoa (see, e.g., Harrison's Principles of Internal Medicine,
pp. 93-98 (Wilson et al., eds., 12th ed. 1991); Williams et al., J.
of Medicinal Chem. 42:1481-1485 (1999), herein each incorporated by
reference in their entirety).
[0053] "Biological medium," as used herein refers to both in vitro
and in vivo biological milieus. Exemplary in vitro "biological
media" include, but are not limited to, cell culture, tissue
culture, homogenates, plasma and blood. In vivo applications are
generally performed in mammals, preferably humans.
[0054] "Inhibiting" and "blocking," are used interchangeably herein
to refer to the partial or full blockade of enzyme. In an exemplary
embodiment, the enzyme is an editing domain of a tRNA
synthetase.
[0055] Boron is able to form dative bonds with oxygen, sulfur or
nitrogen under some circumstances in this invention. Dative bonds
are usually weaker than covalent bonds. In situations where a boron
is covalently bonded to at least one oxygen, sulfur or nitrogen,
and is at the same time datively bonded to an oxygen, sulfur or
nitrogen, respectively, the dative bond and covalent bond between
the boron and the two identical heteroatoms can interconvert or be
in the form of a resonance hybrid. There is potential uncertainty
surrounding the exact nature and extent of electron sharing in
these situations. Generally, in boron compounds comprising both
covalent and coordinate covalent (dative) bonds, the electrons in
such bonds may be partially or fully delocalized.
[0056] Embodiments of the invention also encompass compounds that
are poly- or multi-valent species, including, for example, species
such as dimers, trimers, tetramers and higher homologs of the
compounds of use in the invention or reactive analogues
thereof.
[0057] "Salt counterion", as used herein, refers to positively
charged ions that associate with a compound of the invention when
the boron is fully negatively or partially negatively charged.
Examples of salt counterions include H.sup.+, H.sub.3O.sup.+,
ammonium, potassium, calcium, magnesium and sodium.
[0058] The compounds comprising a boron bonded to a carbon and
three heteroatoms (such as three oxygens described in this section)
can optionally contain a fully negatively charged boron or
partially negatively charged boron, due to the nature of the dative
bond between the boron and one of the oxygens. Due to the negative
charge, a positively charged counterion may associate with this
compound, thus forming a salt. Examples of positively charged
counterions include H.sup.+, H.sub.3O.sup.+, calcium, sodium,
ammonium and potassium. The salts of these compounds are implicitly
contained in descriptions of these compounds.
II. Introduction
[0059] The invention provides novel boron compounds and methods for
the preparation of these molecules. The invention further provides
methods of treating bacterial infections, killing or inhibiting the
growth of bacteria in part or wholly through the use of the
compounds described herein. In another aspect, the invention is a
combination of a compound of the invention and an antibiotic. In
another aspect, the invention is a pharmaceutical formulation
comprising a pharmaceutically acceptable excipient and a compound
of the invention. In another aspect, the invention is a
pharmaceutical formulation comprising a compound of the invention,
an antibiotic, and a pharmaceutically acceptable excipient.
III. a.) Compounds
[0060] In one aspect the invention provides a compound of the
invention. In an exemplary embodiment, the invention provides a
compound described herein, or a salt thereof. In an exemplary
embodiment, the salt of a compound described herein is a
pharmaceutically acceptable salt. In an exemplary embodiment, the
invention provides a compound described herein, or a
pharmaceutically acceptable salt thereof. In an exemplary
embodiment, the invention provides a compound described in a
formula provided herein. In an exemplary embodiment, the invention
provides a compound described herein.
[0061] In an exemplary embodiment, the compound has a structure
which is
##STR00003##
wherein R.sup.5 is H or halogen. In an exemplary embodiment,
R.sup.5 is H. In an exemplary embodiment, R.sup.5 is halogen.
[0062] In an exemplary embodiment, the compound has a structure
which is
##STR00004##
[0063] In an exemplary embodiment, the compound has a structure
which is
##STR00005##
[0064] In an exemplary embodiment, the compound has a structure
which is
##STR00006##
wherein R.sup.5 is H or halogen, and R.sup.40 is nitro or amino or
cyano or halogen. In an exemplary embodiment, R.sup.5 is H and
R.sup.40 is nitro or amino or F or Cl or Br. In an exemplary
embodiment, R.sup.5 is F and R.sup.40 is nitro or amino or F or Cl
or Br. In an exemplary embodiment, R.sup.5 is Cl and R.sup.40 is
nitro or amino or F or Cl or Br.
[0065] In an exemplary embodiment, the compound has a structure
which is
##STR00007##
wherein R.sup.5 is H or halogen, and R.sup.40 is OR.sup.41, wherein
OR.sup.41 is H or methyl or trifluoromethyl or ethyl or propyl or
isopropyl or butyl or t-butyl or isobutyl. In an exemplary
embodiment, R.sup.5 is H and R.sup.40 is OR.sup.41, wherein
OR.sup.41 is methyl or trifluoromethyl or ethyl or propyl or
isopropyl. In an exemplary embodiment, R.sup.5 is F and R.sup.40 is
OR.sup.41, wherein OR.sup.41 is methyl or trifluoromethyl or ethyl
or propyl or isopropyl. In an exemplary embodiment, R.sup.5 is H
and R.sup.40 is OH. In an exemplary embodiment, R.sup.5 is F and
R.sup.40 is OH.
[0066] In an exemplary embodiment, the compound has a structure
which is
##STR00008##
wherein R.sup.5 is H or halogen, and R.sup.40 is CH.sub.2NH.sub.2
or (CH.sub.2).sub.2NH.sub.2, or (CH.sub.2).sub.3NH.sub.2.
[0067] In an exemplary embodiment, the compound has a structure
which is
##STR00009##
wherein R.sup.5 is H or halogen, and R.sup.40 is C(O)NH.sub.2 or
NHC(O)R.sup.42, wherein R.sup.42 is methyl or ethyl or propyl or
isopropyl. In an exemplary embodiment, R.sup.5 is H and R.sup.40 is
C(O)NH.sub.2 or NHC(O)R.sup.42, wherein R.sup.42 is methyl or ethyl
or propyl or isopropyl. In an exemplary embodiment, R.sup.5 is F
and R.sup.40 is C(O)NH.sub.2 or NHC(O)R.sup.42, wherein R.sup.42 is
methyl or ethyl or propyl or isopropyl.
[0068] In an exemplary embodiment, the compound has a structure
which is
##STR00010##
wherein R.sup.5 is H or halogen, and R.sup.40 and R.sup.41 are each
independently selected from the group consisting of F, Cl, and Br.
In an exemplary embodiment, R.sup.5 is H and R.sup.40 is F and
R.sup.41 is F or Cl or Br. In an exemplary embodiment, R.sup.5 is F
and R.sup.40 is F and R.sup.41 is F or Cl or Br. In an exemplary
embodiment, the compound has a structure which is
##STR00011##
wherein R.sup.5, R.sup.40 and R.sup.41 are as described herein.
[0069] In an exemplary embodiment, the compound has a structure
which is
##STR00012##
wherein R.sup.5 is H or halogen, and R.sup.40 is amino or nitro or
C(O)NH.sub.2 or NHC(O)R.sup.42, wherein R.sup.42 is methyl or ethyl
or propyl or isopropyl. In an exemplary embodiment, R.sup.5 is H
and R.sup.40 is C(O)NH.sub.2 or NHC(O)R.sup.42, wherein R.sup.42 is
methyl or ethyl or propyl or isopropyl. In an exemplary embodiment,
R.sup.5 is F and R.sup.40 is C(O)NH.sub.2 or NHC(O)R.sup.42,
wherein R.sup.42 is methyl or ethyl or propyl or isopropyl. In an
exemplary embodiment, R.sup.5 is H and R.sup.40 is amino. In an
exemplary embodiment, R.sup.5 is F and R.sup.40 is amino. In an
exemplary embodiment, R.sup.5 is H and R.sup.40 is nitro. In an
exemplary embodiment, R.sup.5 is F and R.sup.40 is nitro.
[0070] In an exemplary embodiment, the compound has a structure
which is
##STR00013##
wherein R.sup.5 is H or halogen, and R.sup.40 is OR.sup.41, wherein
OR.sup.41 is H or methyl or trifluoromethyl or ethyl or propyl or
isopropyl or butyl or t-butyl or isobutyl. In an exemplary
embodiment, R.sup.5 is H and R.sup.40 is OR.sup.41, wherein
OR.sup.41 is methyl or trifluoromethyl or ethyl or propyl or
isopropyl. In an exemplary embodiment, R.sup.5 is F and R.sup.40 is
OR.sup.41, wherein OR.sup.41 is methyl or trifluoromethyl or ethyl
or propyl or isopropyl. In an exemplary embodiment, R.sup.5 is H
and R.sup.40 is OH. In an exemplary embodiment, R.sup.5 is F and
R.sup.40 is OH.
[0071] In an exemplary embodiment, the compound has a structure
which is
##STR00014##
wherein R.sup.5 is H or halogen, and R.sup.40 is amino. In an
exemplary embodiment, R.sup.5 is H and R.sup.40 is amino. In an
exemplary embodiment, R.sup.5 is F and R.sup.40 is amino. In an
exemplary embodiment, the compound, or a salt thereof, has a
structure which is
##STR00015##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a4, R.sup.a5 and R.sup.a6 is halogen and the remaining
members of R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5 and R.sup.a6 are
H, R.sup.10, R.sup.11 and K are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5, R.sup.a6,
R.sup.5, R.sup.10, R.sup.11 and R.sup.15 are as described herein,
and each hydrogen in said compound or a salt thereof can be
replaced by deuterium. In an exemplary embodiment, R.sup.5 is
halogen, one of R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5 and R.sup.a6
is F or Cl or Br and the remaining members of R.sup.a2, R.sup.a3,
R.sup.a4, R.sup.a5 and R.sup.a6 are H, R are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a4,
R.sup.a5 and R.sup.a6 is F or Cl or Br and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5 and R.sup.a6 are H,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0072] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00016##
wherein R.sup.5 is H or halogen, R.sup.a6 is halogen, R.sup.10,
R.sup.11, and R.sup.15 are each a member independently selected
from the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is F or Cl or Br, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is F or Cl or Br,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0073] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00017##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is OR.sup.20 and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.20 is H or
unsubstituted alkyl, and R.sup.10, R.sup.11 and R.sup.15 are each a
member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is OR.sup.20 and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H, R.sup.20 is H or unsubstituted alkyl, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is OR.sup.20 and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.20 is H or
unsubstituted alkyl, R.sup.10, R.sup.11 and R.sup.15 are each a
member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl.
[0074] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00018##
wherein R.sup.5 is H or halogen, R.sup.a6 is OR.sup.20, R.sup.20 is
H or unsubstituted alkyl, R.sup.10, R.sup.11 and R.sup.15 are each
a member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is OR.sup.20, R.sup.20 is H or unsubstituted
alkyl, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is OR.sup.20, R.sup.20 is H or
unsubstituted alkyl, R.sup.10, R.sup.11 and R.sup.15 are each a
member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl.
[0075] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00019##
wherein R.sup.5 is H or halogen, R.sup.a6 is OR.sup.20, R.sup.20 is
H or unsubstituted alkyl. In an exemplary embodiment, R.sup.5 is F,
R.sup.a6 is OH. In an exemplary embodiment, R.sup.5 is H, R.sup.a6
is OH. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
OCH.sub.3. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
OCH.sub.3. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
OCH.sub.2CH.sub.3. In an exemplary embodiment, R.sup.5 is H,
R.sup.a6 is OCH.sub.2CH.sub.3. In an exemplary embodiment, R.sup.5
is F, R.sup.a6 is OR.sup.20, R.sup.20 is unsubstituted C.sub.3
alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
OR.sup.20, R.sup.20 is unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is OR.sup.20, R.sup.20 is
unsubstituted C.sub.4 alkyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is OR.sup.20, R.sup.20 is unsubstituted C.sub.4 alkyl.
In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is OR.sup.20,
R.sup.20 is unsubstituted C.sub.5 alkyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is OR.sup.20, R.sup.20 is
unsubstituted C.sub.5 alkyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is OR.sup.20, R.sup.20 is unsubstituted C.sub.6 alkyl.
In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is OR.sup.20,
R.sup.20 is unsubstituted C.sub.6 alkyl.
[0076] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00020##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is cyano and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11
and R.sup.15 are each a member independently selected from the
group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10 and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is cyano and the
remaining members of R.sup.a2R.sup.a3, R.sup.a5 and R.sup.a6 are H,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 is cyano and the remaining members of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11 and R.sup.15 are
each a member independently selected from the group consisting of
H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl.
[0077] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00021##
wherein R.sup.5 is H or halogen, R.sup.a6 is cyano, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is cyano, R.sup.10, R.sup.11 and R.sup.15
are each a member independently selected from the group consisting
of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is cyano, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
[0078] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00022##
wherein R.sup.5 is H or halogen, R.sup.a6 is cyano. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is cyano. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is cyano.
[0079] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00023##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is unsubstituted alkyl and the remaining
members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H, R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 is methyl or ethyl or unsubstituted C.sub.3 alkyl or
unsubstituted C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or
unsubstituted C.sub.6 alkyl and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0080] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00024##
wherein R.sup.5 is H or halogen, R.sup.a6 is unsubstituted alkyl,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is halogen, R.sup.a6 is methyl or ethyl or unsubstituted
C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or unsubstituted
C.sub.5 alkyl or unsubstituted C.sub.6 alkyl, R.sup.10, R.sup.11
and R.sup.15 are each a member independently selected from the
group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0081] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00025##
wherein R.sup.5 is H or halogen, R.sup.a6 is unsubstituted alkyl.
In an exemplary embodiment, R.sup.5 is halogen, R.sup.a6 is methyl
or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4
alkyl or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6
alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is methyl
or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4
alkyl or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6
alkyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.3. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.3. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.3. In an exemplary embodiment, R.sup.5 is H,
R.sup.a6 is CH.sub.2CH.sub.3. In an exemplary embodiment, R.sup.5
is F, R.sup.a6 is unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is unsubstituted C.sub.3 alkyl.
In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is unsubstituted
C.sub.4 alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6
is unsubstituted C.sub.4 alkyl. In an exemplary embodiment, R.sup.5
is F, R.sup.a6 is unsubstituted C.sub.5 alkyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is unsubstituted C.sub.5 alkyl.
In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is unsubstituted
C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6
is unsubstituted C.sub.6 alkyl.
[0082] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00026##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is unsubstituted alkenyl or unsubstituted
alkynyl and the remaining members of R.sup.a2, R.sup.a3, R.sup.a5
and R.sup.a6 are H, R.sup.10, R.sup.11 and R.sup.15 are each a
member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, and R.sup.a6 are H,
R.sup.10. R.sup.11 and R.sup.15 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is prop-1-ynyl or
prop-1-enyl or prop-2-ynyl or prop-2-enyl or but-1-ynyl or
but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl,
and the remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 are H, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or
prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl
or but-3-ynyl or but-3-enyl and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0083] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00027##
wherein R.sup.5 is H or halogen, R.sup.a6 is unsubstituted alkenyl
or unsubstituted alkynyl, R.sup.10, R.sup.11 and R.sup.15 are each
a member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10 and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is halogen, R.sup.a6 is prop-1-ynyl or prop-1-enyl or
prop-2-ynyl or prop-2-enyl or but-1-ynyl or but-1-enyl or
but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is prop-1-ynyl or prop-1-enyl or
prop-2-ynyl or prop-2-enyl or but-1-ynyl or but-1-enyl or
but-2-ynyl or but-2-enyl or but-3-ynyl or but-3-enyl, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
[0084] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00028##
wherein R.sup.5 is H or halogen, R.sup.a6 is unsubstituted alkenyl
or unsubstituted alkynyl. In an exemplary embodiment, R.sup.5 is
halogen, R.sup.a6 is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or
prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl
or but-3-ynyl or but-3-enyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or
prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl
or but-3-ynyl or but-3-enyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or
prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl
or but-3-ynyl or but-3-enyl.
[0085] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00029##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is alkyl substituted with cyano and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H, R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl substituted
with cyano or ethyl substituted with cyano or C.sub.3 alkyl
substituted with cyano or C.sub.4 alkyl substituted with cyano or
C.sub.5 alkyl substituted with cyano or C.sub.6 alkyl substituted
with cyano and the remaining members of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11 and R.sup.15 are
each a member independently selected from the group consisting of
H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 is methyl substituted with cyano or ethyl substituted with
cyano or C.sub.3 alkyl substituted with cyano or C.sub.4 alkyl
substituted with cyano or C.sub.5 alkyl substituted with cyano or
C.sub.6 alkyl substituted with cyano and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11
and R.sup.15 are each a member independently selected from the
group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
[0086] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00030##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
cyano, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is halogen, R.sup.a6 is methyl substituted with cyano or
ethyl substituted with cyano or C.sub.3 alkyl substituted with
cyano or C.sub.4 alkyl substituted with cyano or C.sub.5 alkyl
substituted with cyano or C.sub.6 alkyl substituted with cyano,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted with cyano
or ethyl substituted with cyano or C.sub.3 alkyl substituted with
cyano or C.sub.4 alkyl substituted with cyano or C.sub.5 alkyl
substituted with cyano or C.sub.6 alkyl substituted with cyano,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0087] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00031##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
cyano. In an exemplary embodiment, R.sup.5 is halogen, R.sup.a6 is
methyl substituted with cyano or ethyl substituted with cyano or
C.sub.3 alkyl substituted with cyano or C.sub.4 alkyl substituted
with cyano or C.sub.5 alkyl substituted with cyano or C.sub.6 alkyl
substituted with cyano. In an exemplary embodiment, R.sup.5 is H,
R.sup.a6 is methyl substituted with cyano or ethyl substituted with
cyano or C.sub.3 alkyl substituted with cyano or C.sub.4 alkyl
substituted with cyano or C.sub.5 alkyl substituted with cyano or
C.sub.6 alkyl substituted with cyano. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2CN. In an exemplary embodiment,
R.sup.5 is H, R.sup.a6 is CH.sub.2CN. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2CH.sub.2CN. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is CH.sub.2CH.sub.2CN. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CN. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2CN. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CN. In an exemplary embodiment,
R.sup.5 is H, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2CH.sub.2CN. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CN. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CN. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CN. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CN.
[0088] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00032##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is alkyl substituted with hydroxy and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H, R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl substituted
with hydroxy or ethyl substituted with hydroxy or C.sub.3 alkyl
substituted with hydroxy or C.sub.4 alkyl substituted with hydroxy
or C.sub.5 alkyl substituted with hydroxy or C.sub.6 alkyl
substituted with hydroxy and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is methyl substituted with hydroxy or ethyl
substituted with hydroxy or C.sub.3 alkyl substituted with hydroxy
or C.sub.4 alkyl substituted with hydroxy or C.sub.5 alkyl
substituted with hydroxy or C.sub.6 alkyl substituted with hydroxy
and the remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 are H, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0089] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00033##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
hydroxy, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is halogen, R.sup.a6 is methyl substituted with hydroxy or
ethyl substituted with hydroxy or C.sub.3 alkyl substituted with
hydroxy or C.sub.4 alkyl substituted with hydroxy or C.sub.5 alkyl
substituted with hydroxy or C.sub.6 alkyl substituted with hydroxy,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted with
hydroxy or ethyl substituted with hydroxy or C.sub.3 alkyl
substituted with hydroxy or C.sub.4 alkyl substituted with hydroxy
or C.sub.5 alkyl substituted with hydroxy or C.sub.6 alkyl
substituted with hydroxy, R.sup.10, R.sup.11 and R.sup.15 are each
a member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl.
[0090] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00034##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
hydroxy. In an exemplary embodiment, R.sup.5 is halogen, R.sup.a6
is methyl substituted with hydroxy or ethyl substituted with
hydroxy or C.sub.3 alkyl substituted with hydroxy or C.sub.4 alkyl
substituted with hydroxy or C.sub.5 alkyl substituted with hydroxy
or C.sub.6 alkyl substituted with hydroxy. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted with
hydroxy or ethyl substituted with hydroxy or C.sub.3 alkyl
substituted with hydroxy or C.sub.4 alkyl substituted with hydroxy
or C.sub.5 alkyl substituted with hydroxy or C.sub.6 alkyl
substituted with hydroxy. In an exemplary embodiment, R.sup.5 is F,
R.sup.a6 is CH.sub.2OH. In an exemplary embodiment, R.sup.5 is H,
R.sup.a6 is CH.sub.2OH. In an exemplary embodiment, R.sup.5 is F,
R.sup.a6 is CH.sub.2CH.sub.2OH. In an exemplary embodiment, R.sup.5
is H, R.sup.a6 is CH.sub.2CH.sub.2OH. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2OH. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2OH. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH.
[0091] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00035##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is alkyl substituted with OR.sup.30, wherein
R.sup.30 is unsubstituted alkyl, and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11
and R.sup.15 are each a member independently selected from the
group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10 and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl substituted
with OR.sup.30 or ethyl substituted with OR.sup.30 or C.sub.3 alkyl
substituted with OR.sup.30 or C.sub.4 alkyl substituted with
OR.sup.30 or C.sub.5 alkyl substituted with OR.sup.30 or C.sub.6
alkyl substituted with OR.sup.30, wherein R.sup.30 is unsubstituted
alkyl, and the remaining members of R.sup.a2, R.sup.a1, R.sup.a5
and R.sup.a6 are and R.sup.a6 are H, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is methyl substituted with OR.sup.30 or ethyl
substituted with OR.sup.30 or C.sub.3 alkyl substituted with
OR.sup.30 or C.sub.4 alkyl substituted with OR.sup.30 or C.sub.5
alkyl substituted with OR.sup.30 or C.sub.6 alkyl substituted with
OR.sup.30, wherein R.sup.30 is methyl or ethyl or unsubstituted
C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or unsubstituted
C.sub.5 alkyl or unsubstituted C.sub.6 alkyl, and the remaining
members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0092] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00036##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
OR.sup.30, wherein R.sup.30 is unsubstituted alkyl, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is halogen, R.sup.a6 is methyl substituted with OR.sup.30
or ethyl substituted with OR.sup.30 or C.sub.3 alkyl substituted
with OR.sup.30 or C.sub.4 alkyl substituted with OR.sup.30 or
C.sub.5 alkyl substituted with OR.sup.30 or C.sub.6 alkyl
substituted with OR.sup.30, wherein R.sup.30 is unsubstituted
alkyl, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted with
OR.sup.30 or ethyl substituted with OR.sup.30 or C.sub.3 alkyl
substituted with OR.sup.30 or C.sub.4 alkyl substituted with
OR.sup.30 or C.sub.5 alkyl substituted with OR.sup.30 or C.sub.6
alkyl substituted with OR.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl
or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0093] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00037##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
OR.sup.30, wherein R.sup.30 is unsubstituted alkyl. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a2 is alkyl substituted
with OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is CH.sub.2OR.sup.30,
wherein R.sup.30 is methyl or ethyl or unsubstituted C.sub.3 alkyl
or unsubstituted C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or
unsubstituted C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is CH.sub.2OR.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2OR.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted
C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or unsubstituted
C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6
is CH.sub.2OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is CH.sub.2CH.sub.2OR.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted
C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or unsubstituted
C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6
is CH.sub.2CH.sub.2OR.sup.30, wherein R.sup.30 is methyl or ethyl
or unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5
is F, R.sup.a6 is CH.sub.2CH.sub.2OR.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted
C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or unsubstituted
C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6
is CH.sub.2CH.sub.2OR.sup.30, wherein R.sup.30 is methyl or ethyl
or unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5
is H, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2OR.sup.30, wherein
R.sup.30 is methyl or ethyl or unsubstituted C.sub.3 alkyl or
unsubstituted C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or
unsubstituted C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2OR.sup.30, wherein R.sup.30
is methyl or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2OR.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl
or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In
an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2OR.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl.
[0094] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00038##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is alkyl substituted with NH.sub.2 and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H, R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl substituted
with NH.sub.2 or ethyl substituted with NH.sub.2 or C.sub.3 alkyl
substituted with NH.sub.2 or C.sub.4 alkyl substituted with
NH.sub.2 or C.sub.5 alkyl substituted with NH.sub.2 or C.sub.6
alkyl substituted with NH.sub.2 and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11
and R.sup.15 are each a member independently selected from the
group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 is methyl substituted with NH.sub.2 or ethyl substituted
with NH.sub.2 or C.sub.3 alkyl substituted with NH.sub.2 or C.sub.4
alkyl substituted with NH.sub.2 or C.sub.5 alkyl substituted with
NH.sub.2 or C.sub.6 alkyl substituted with NH.sub.2 and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H, R each a member independently selected from the group consisting
of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0095] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00039##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
NH.sub.2, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is halogen, R.sup.a6 is methyl substituted with NH.sub.2 or
ethyl substituted with NH.sub.2 or C.sub.3 alkyl substituted with
NH.sub.2 or C.sub.4 alkyl substituted with NH.sub.2 or C.sub.5
alkyl substituted with NH.sub.2 or C.sub.6 alkyl substituted with
NH.sub.2, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted with
NH.sub.2 or ethyl substituted with NH.sub.2 or C.sub.3 alkyl
substituted with NH.sub.2 or C.sub.4 alkyl substituted with
NH.sub.2 or C.sub.5 alkyl substituted with NH.sub.2 or C.sub.6
alkyl substituted with NH.sub.2, R.sup.10, R.sup.11 and R.sup.15
are each a member independently selected from the group consisting
of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0096] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00040##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
NH.sub.2. In an exemplary embodiment, R.sup.5 is halogen, R.sup.a6
is methyl substituted with NH.sub.2 or ethyl substituted with
NH.sub.2 or C.sub.3 alkyl substituted with NH.sub.2 or C.sub.4
alkyl substituted with NH.sub.2 or C.sub.5 alkyl substituted with
NH.sub.2 or C.sub.6 alkyl substituted with NH.sub.2. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted
with NH.sub.2 or ethyl substituted with NH.sub.2 or C.sub.3 alkyl
substituted with NH.sub.2 or C.sub.4 alkyl substituted with
NH.sub.2 or C.sub.5 alkyl substituted with NH.sub.2 or C.sub.6
alkyl substituted with NH.sub.2. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2NH.sub.2. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is CH.sub.2NH.sub.2. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2NH.sub.2. In an exemplary embodiment, R.sup.5 is H,
R.sup.a6 is CH.sub.2CH.sub.2NH.sub.2. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2NH.sub.2. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2NH.sub.2. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2.
In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2.
[0097] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00041##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is alkyl substituted with R.sup.31, wherein
R.sup.31 is halogen, and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11, and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6,
R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are as described herein,
and each hydrogen in said compound or a salt thereof can be
replaced by deuterium. In an exemplary embodiment, R.sup.5 is
halogen, one of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl
substituted with R.sup.31 or ethyl substituted with R.sup.31 or
C.sub.3 alkyl substituted with R.sup.31 or C.sub.4 alkyl
substituted with R.sup.31 or C.sub.5 alkyl substituted with
R.sup.31 or C.sub.6 alkyl substituted with R.sup.31, wherein
R.sup.31 is halogen, and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is methyl substituted with R.sup.31 or ethyl
substituted with R.sup.31 or C.sub.3 alkyl substituted with
R.sup.31 or C.sub.4 alkyl substituted with R.sup.31 or C.sub.5
alkyl substituted with R.sup.31 or C.sub.6 alkyl substituted with
R.sup.31, wherein R.sup.31 is F or Cl or Br, and the remaining
members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0098] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00042##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
R.sup.31, wherein R.sup.31 is halogen, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and
R.sup.11 are as described herein, and each hydrogen in said
compound or a salt thereof can be replaced by deuterium. In an
exemplary embodiment, R.sup.5 is halogen, R.sup.a6 is methyl
substituted with R.sup.31 or ethyl substituted with R.sup.31 or
C.sub.3 alkyl substituted with R.sup.31 or C.sub.4 alkyl
substituted with R.sup.31 or C.sub.5 alkyl substituted with
R.sup.31 or C.sub.6 alkyl substituted with R.sup.31, wherein
R.sup.31 is halogen, R.sup.10, R.sup.11 and R.sup.15 are each a
member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted with
R.sup.31 or ethyl substituted with R.sup.31 or C.sub.3 alkyl
substituted with R.sup.31 or C.sub.4 alkyl substituted with
R.sup.31 or C.sub.5 alkyl substituted with R.sup.31 or C.sub.6
alkyl substituted with R.sup.31, wherein R.sup.31 is F or Cl or Br,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted
with two R.sup.31, wherein each R.sup.31 is independently selected
from F or Cl or Br or I, R.sup.10, R.sup.11 and R.sup.15 are each a
member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted
with three R.sup.31, wherein each R.sup.31 is independently
selected from F or Cl or Br or I, R.sup.10, R.sup.11 and R.sup.15
are each a member independently selected from the group consisting
of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0099] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00043##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
one R.sup.31, wherein R.sup.31 is F or Cl or Br or I. In an
exemplary embodiment, R.sup.5 is H or halogen, R.sup.a6 is alkyl
substituted with two R.sup.31, wherein each R.sup.31 is
independently selected from F or Cl or Br or I. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted
with three R.sup.31, wherein each R.sup.31 is independently
selected from F or Cl or Br or I. In an exemplary embodiment,
R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
R.sup.31, wherein R.sup.31 is F or Cl or Br. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is CH.sub.2F. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is CH.sub.2F. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is CHF.sub.2. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is CHF.sub.2. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is CF.sub.3. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is CF.sub.3. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a6 is ethyl substituted
with R.sup.31, wherein R.sup.31 is F or Cl or Br. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a6 is ethyl substituted
with two R.sup.31, wherein each R.sup.31 is independently selected
from F or Cl or Br. In an exemplary embodiment, R.sup.5 is H or
halogen, R.sup.a6 is ethyl substituted with three R.sup.31, wherein
each R.sup.31 is independently selected from F or Cl or Br. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is CH.sub.2CH.sub.2F.
In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2F. In an exemplary embodiment, R.sup.5 is H,
R.sup.a6 is CH.sub.2CHF.sub.2. In an exemplary embodiment, R.sup.5
is F, R.sup.a6 is CH.sub.2CHF.sub.2. In an exemplary embodiment,
R.sup.5 is H, R.sup.a6 is CH.sub.2CF.sub.3. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is CH.sub.2CF.sub.3. In an
exemplary embodiment, R.sup.5 is H or halogen, R.sup.a6 is C.sub.3
alkyl substituted with R.sup.31, wherein R.sup.31 is F or Cl or Br.
In an exemplary embodiment, R.sup.5 is H or halogen, R.sup.a6 is
C.sub.3 alkyl substituted with two R.sup.31, wherein each R.sup.31
is independently selected from F or Cl or Br. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a6 is C.sub.3 alkyl
substituted with three R.sup.31, wherein each R.sup.31 is
independently selected from F or Cl or Br. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2F. In
an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2F. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is CH.sub.2CH.sub.2CHF.sub.2. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is CH.sub.2CH.sub.2CHF.sub.2. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CF.sub.3. In an exemplary embodiment, R.sup.5 is F,
R.sup.a6 is CH.sub.2CH.sub.2CF.sub.3.
[0100] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00044##
wherein R.sup.5 is H or halogen, R.sup.a5 is alkyl substituted with
one R.sup.31, wherein R.sup.31 is F or Cl or Br or I. In an
exemplary embodiment, R.sup.5 is H or halogen, R.sup.a5 is alkyl
substituted with two R.sup.31, wherein each R.sup.31 is
independently selected from F or Cl or Br or I. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a5 is alkyl substituted
with three R.sup.31, wherein each R.sup.31 is independently
selected from F or Cl or Br or I. In an exemplary embodiment,
R.sup.5 is H or halogen, R.sup.a5 is alkyl substituted with
R.sup.31, wherein R.sup.31 is F or Cl or Br. In an exemplary
embodiment, R.sup.5 is H, R.sup.a5 is CH.sub.2F. In an exemplary
embodiment, R.sup.5 is F, R.sup.a5 is CH.sub.2F. In an exemplary
embodiment, R.sup.5 is H, R.sup.a5 is CHF.sub.2. In an exemplary
embodiment, R.sup.5 is F, R.sup.a5 is CHF.sub.2. In an exemplary
embodiment, R.sup.5 is H, R.sup.a5 is CF.sub.3. In an exemplary
embodiment, R.sup.5 is F, R.sup.a5 is CF.sub.3. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a5 is ethyl substituted
with R.sup.31, wherein R.sup.31 is F or Cl or Br. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a5 is ethyl substituted
with two R.sup.31, wherein each R.sup.31 is independently selected
from F or Cl or Br. In an exemplary embodiment, R.sup.5 is H or
halogen, R.sup.a5 is ethyl substituted with three R.sup.31, wherein
each R.sup.31 is independently selected from F or Cl or Br. In an
exemplary embodiment, R.sup.5 is H, R.sup.a5 is CH.sub.2CH.sub.2F.
In an exemplary embodiment, R.sup.5 is F, R.sup.a5 is
CH.sub.2CH.sub.2F. In an exemplary embodiment, R.sup.5 is H,
R.sup.a5 is CH.sub.2CHF.sub.2. In an exemplary embodiment, R.sup.5
is F, R.sup.a5 is CH.sub.2CHF.sub.2. In an exemplary embodiment,
R.sup.5 is H, R.sup.a5 is CH.sub.2CF.sub.3. In an exemplary
embodiment, R.sup.5 is F, R.sup.a5 is CH.sub.2CF.sub.3. In an
exemplary embodiment, R.sup.5 is H or halogen, R.sup.a5 is C.sub.3
alkyl substituted with R.sup.31, wherein R.sup.31 is F or Cl or Br.
In an exemplary embodiment, R.sup.5 is H or halogen, R.sup.a5 is
C.sub.3 alkyl substituted with two R.sup.31, wherein each R.sup.31
is independently selected from F or Cl or Br. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a5 is C.sub.3 alkyl
substituted with three R.sup.31, wherein each R.sup.31 is
independently selected from F or Cl or Br. In an exemplary
embodiment, R.sup.5 is H, R.sup.a5 is CH.sub.2CH.sub.2CH.sub.2F. In
an exemplary embodiment, R.sup.5 is F, R.sup.a5 is
CH.sub.2CH.sub.2CH.sub.2F. In an exemplary embodiment, R.sup.5 is
H, R.sup.a5 is CH.sub.2CH.sub.2CHF.sub.2. In an exemplary
embodiment, R.sup.5 is F, R.sup.a5 is CH.sub.2CH.sub.2CHF.sub.2. In
an exemplary embodiment, R.sup.5 is H, R.sup.a5 is
CH.sub.2CH.sub.2CF.sub.3. In an exemplary embodiment, R.sup.5 is F,
R.sup.a5 is CH.sub.2CH.sub.2CF.sub.3.
[0101] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00045##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is alkyl substituted with --C(O)OR.sup.30,
wherein R.sup.30 is unsubstituted alkyl, and the remaining members
of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl substituted
with --C(O)OR.sup.30 or ethyl substituted with --C(O)OR.sup.30 or
C.sub.3 alkyl substituted with --C(O)OR.sup.30 or C.sub.4 alkyl
substituted with --C(O)OR.sup.30 or C.sub.5 alkyl substituted with
--C(O)OR.sup.30 or C.sub.6 alkyl substituted with --C(O)OR.sup.30,
wherein R.sup.30 is unsubstituted alkyl, and the remaining members
of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 is methyl substituted with --C(O)OR.sup.30 or ethyl
substituted with --C(O)OR.sup.30 or C.sub.3 alkyl substituted with
--C(O)OR.sup.30 or C.sub.4 alkyl substituted with --C(O)OR.sup.30
or C.sub.5 alkyl substituted with --C(O)OR.sup.30 or C.sub.6 alkyl
substituted with --C(O)OR.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl
or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl, and
the remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6
are H, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0102] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00046##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--C(O)OR.sup.30, wherein R.sup.30 is unsubstituted alkyl, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is halogen, R.sup.a6 is methyl substituted with
--C(O)OR.sup.30 or ethyl substituted with --C(O)OR.sup.30 or
C.sub.3 alkyl substituted with --C(O)OR.sup.30 or C.sub.4 alkyl
substituted with --C(O)OR.sup.30 or C.sub.5 alkyl substituted with
--C(O)OR.sup.30 or C.sub.6 alkyl substituted with --C(O)OR.sup.30,
wherein R.sup.30 is unsubstituted alkyl, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is methyl
substituted with --C(O)OR.sup.30 or ethyl substituted with
--C(O)OR.sup.30 or C.sub.3 alkyl substituted with --C(O)OR.sup.30
or C.sub.4 alkyl substituted with --C(O)OR.sup.30 or C.sub.5 alkyl
substituted with --C(O)OR.sup.30 or C.sub.6 alkyl substituted with
--C(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0103] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00047##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--C(O)OR.sup.30, wherein R.sup.30 is unsubstituted alkyl. In an
exemplary embodiment, R.sup.5 is H or halogen, R.sup.a6 is alkyl
substituted with --C(O)OR.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl
or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2C(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2C(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2C(O)OR.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl
or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In
an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2C(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is CH.sub.2CH.sub.2C(O)OR.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted
C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or unsubstituted
C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6
is CH.sub.2CH.sub.2C(O)OR.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2CH.sub.2C(O)OR.sup.30, wherein
R.sup.30 is methyl or ethyl or unsubstituted C.sub.3 alkyl or
unsubstituted C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or
unsubstituted C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2CH.sub.2C(O)OR.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)OR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4
alkyl or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6
alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)OR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)OR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4
alkyl or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6
alkyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)OR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2C(O)OCH(CH.sub.3).sub.2. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2C(O)OCH(CH.sub.3).sub.2. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2C(O)OCH(CH.sub.3).sub.2. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2C(O)OCH(CH.sub.3).sub.2. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)OCH(CH.sub.3).sub.2. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)OCH(CH.sub.3).sub.2. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2C(O)OC(CH.sub.3).sub.3. In an exemplary embodiment, R.sup.5
is F, R.sup.a6 is CH.sub.2C(O)OC(CH.sub.3).sub.3. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2C(O)OC(CH.sub.3).sub.3. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2CH.sub.2C(O)OC(CH.sub.3).sub.3.
In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)OC(CH.sub.3).sub.3. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)OC(CH.sub.3).sub.3.
[0104] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00048##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--C(O)OH. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2C(O)OH. In an exemplary embodiment, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2C(O)OH. In an exemplary embodiment, R.sup.5 is H, R.sup.a6
is CH.sub.2CH.sub.2C(O)OH. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2CH.sub.2C(O)OH. In an exemplary embodiment,
R.sup.5 is H, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2C(O)OH. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)OH.
[0105] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00049##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is alkyl substituted with --C(O)NHR.sup.35,
wherein R.sup.35 is unsubstituted alkyl or unsubstituted cyclobutyl
or unsubstituted cyclopentyl or unsubstituted cyclohexyl or
unsubstituted cycloheptyl or unsubstituted cyclooctyl, and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H, R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl substituted
with --C(O)NHR.sup.35 or ethyl substituted with --C(O)NHR.sup.35 or
C.sub.3 alkyl substituted with --C(O)NHR.sup.35 or C.sub.4 alkyl
substituted with --C(O)NHR.sup.35 or C.sub.5 alkyl substituted with
--C(O)NHR.sup.35 or C.sub.6 alkyl substituted with
--C(O)NHR.sup.35, wherein R.sup.35 is unsubstituted alkyl or
unsubstituted cyclobutyl or unsubstituted cyclopentyl or
unsubstituted cyclohexyl or unsubstituted cycloheptyl or
unsubstituted cyclooctyl, and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is methyl substituted with --C(O)NHR.sup.35
or ethyl substituted with --C(O)NHR.sup.35 or C.sub.3 alkyl
substituted with --C(O)NHR.sup.35 or C.sub.4 alkyl substituted with
--C(O)NHR.sup.35, wherein R.sup.35 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted cyclobutyl or unsubstituted cyclopentyl or
unsubstituted cyclohexyl, and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0106] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00050##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--C(O)NHR.sup.35, wherein R.sup.35 is unsubstituted alkyl or
unsubstituted cyclobutyl or unsubstituted cyclopentyl or
unsubstituted cyclohexyl or unsubstituted cycloheptyl or
unsubstituted cyclooctyl, R.sup.10, R.sup.11 and R.sup.15 are each
a member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15R.sup.10, and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is halogen, R.sup.a6 is methyl substituted with
--C(O)NHR.sup.35 or ethyl substituted with --C(O)NHR.sup.35 or
C.sub.3 alkyl substituted with --C(O)NHR.sup.35 or C.sub.4 alkyl
substituted with --C(O)NHR.sup.35 or C.sub.5 alkyl substituted with
--C(O)NHR.sup.35 or C.sub.6 alkyl substituted with
--C(O)NHR.sup.35, wherein R.sup.35 is unsubstituted alkyl or
unsubstituted cyclobutyl or unsubstituted cyclopentyl or
unsubstituted cyclohexyl or unsubstituted cycloheptyl or
unsubstituted cyclooctyl, R.sup.10, R.sup.11 and R.sup.15 are each
a member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted with
--C(O)NHR.sup.35 or ethyl substituted with --C(O)NHR.sup.35 or
C.sub.3 alkyl substituted with --C(O)NHR.sup.35 or C.sub.4 alkyl
substituted with --C(O)NHR.sup.35 or C.sub.5 alkyl substituted with
--C(O)NHR.sup.35 or C.sub.6 alkyl substituted with
--C(O)NHR.sup.35, wherein R.sup.35 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl or
unsubstituted cyclobutyl or unsubstituted cyclopentyl or
unsubstituted cyclohexyl, R.sup.10, R.sup.11 and R.sup.15 are each
a member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl.
[0107] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00051##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--C(O)NHR.sup.35, wherein R.sup.35 is unsubstituted alkyl. In an
exemplary embodiment, R.sup.5 is H or halogen, R.sup.a6 is alkyl
substituted with --C(O)NHR.sup.35, wherein R.sup.35 is methyl or
ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl
or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2C(O)NHR.sup.35, wherein R.sup.35 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2C(O)NHR.sup.35, wherein R.sup.35 is methyl or ethyl or
unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2C(O)NHR.sup.35, wherein R.sup.35 is methyl
or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4
alkyl or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6
alkyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2C(O)NHR.sup.35, wherein R.sup.35 is methyl or ethyl or
unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is CH.sub.2CH.sub.2C(O)NHR.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted
C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or unsubstituted
C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6
is CH.sub.2CH.sub.2C(O)NHR.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2CH.sub.2C(O)NHR.sup.30, wherein
R.sup.30 is methyl or ethyl or unsubstituted C.sub.3 alkyl or
unsubstituted C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or
unsubstituted C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2CH.sub.2C(O)NHR.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)NHR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4
alkyl or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6
alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)NHR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)NHR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4
alkyl or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6
alkyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)NHR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl.
[0108] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00052##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--C(O)NHR.sup.35, wherein R.sup.35 is unsubstituted cyclobutyl or
unsubstituted cyclopentyl or unsubstituted cyclohexyl or
unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an
exemplary embodiment, R.sup.5 is H or halogen, R.sup.a6 is alkyl
substituted with --C(O)NHR.sup.35, wherein R.sup.35 is
unsubstituted cyclobutyl or unsubstituted cyclopentyl or
unsubstituted cyclohexyl or unsubstituted cycloheptyl or
unsubstituted cyclooctyl. In an exemplary embodiment, R.sup.5 is H
or halogen, R.sup.a6 is alkyl substituted with --C(O)NHR.sup.35,
wherein R.sup.35 is unsubstituted cyclobutyl or unsubstituted
cyclopentyl or unsubstituted cyclohexyl or unsubstituted
cycloheptyl or unsubstituted cyclooctyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is CH.sub.2C(O)NHR.sup.35,
wherein R.sup.35 is unsubstituted cyclobutyl or unsubstituted
cyclopentyl or unsubstituted cyclohexyl or unsubstituted
cycloheptyl or unsubstituted cyclooctyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is CH.sub.2C(O)NHR.sup.35,
wherein R.sup.35 is unsubstituted cyclopropyl or unsubstituted
cyclobutyl or unsubstituted cyclopentyl or unsubstituted
cyclohexyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2C(O)NHR.sup.35, wherein R.sup.35 is unsubstituted
cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl
or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2C(O)NHR.sup.35, wherein R.sup.35 is unsubstituted
cyclobutyl or unsubstituted cyclopentyl or unsubstituted
cyclohexyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2C(O)NHR.sup.35, wherein R.sup.35 is unsubstituted
cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl
or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2C(O)NHR.sup.35, wherein R.sup.35 is unsubstituted
cyclobutyl or unsubstituted cyclopentyl or unsubstituted
cyclohexyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2C(O)NHR.sup.35, wherein R.sup.35 is unsubstituted
cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl
or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2C(O)NHR.sup.35, wherein R.sup.35 is unsubstituted
cyclobutyl or unsubstituted cyclopentyl or unsubstituted
cyclohexyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)NHR.sup.35, wherein R.sup.35 is
unsubstituted cyclobutyl or unsubstituted cyclopentyl or
unsubstituted cyclohexyl or unsubstituted cycloheptyl or
unsubstituted cyclooctyl. In an exemplary embodiment, R.sup.5 is H,
R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2C(O)NHR.sup.35, wherein
R.sup.35 is unsubstituted cyclobutyl or unsubstituted cyclopentyl
or unsubstituted cyclohexyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2C(O)NHR.sup.35, wherein
R.sup.35 is unsubstituted cyclobutyl or unsubstituted cyclopentyl
or unsubstituted cyclohexyl or unsubstituted cycloheptyl or
unsubstituted cyclooctyl. In an exemplary embodiment, R.sup.5 is F,
R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2C(O)NHR.sup.35, wherein
R.sup.35 is unsubstituted cyclobutyl or unsubstituted cyclopentyl
or unsubstituted cyclohexyl.
[0109] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00053##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--C(O)NHR.sup.30, wherein R.sup.30 is alkyl substituted with
alkenyl or alkynyl. In an exemplary embodiment, R.sup.5 is H or
halogen, R.sup.a6 is alkyl substituted with --C(O)NHR.sup.30,
wherein R.sup.30 is prop-1-ynyl or prop-1-enyl or prop-2-ynyl or
prop-2-enyl or but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl
or but-3-ynyl or but-3-enyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is CH.sub.2C(O)NHR.sup.30, wherein R.sup.30 is
prop-1-ynyl or prop-1-enyl or prop-2-ynyl or prop-2-enyl or
but-1-ynyl or but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl
or but-3-enyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6
is CH.sub.2C(O)NHR.sup.30, wherein R.sup.30 is prop-1-ynyl or
prop-1-enyl or prop-2-ynyl or prop-2-enyl or but-1-ynyl or
but-1-enyl or but-2-ynyl or but-2-enyl or but-3-ynyl or
but-3-enyl.
[0110] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00054##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--C(O)NHR.sup.30, wherein R.sup.30 is benzyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is CH.sub.2C(O)NHR.sup.30,
wherein R.sup.30 is benzyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2C(O)NHR.sup.30, wherein R.sup.30 is
benzyl.
[0111] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00055##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--C(O)NH.sub.2. In an exemplary embodiment, R.sup.5 is H, R.sup.a6
is CH.sub.2C(O)NH.sub.2. In an exemplary embodiment, R.sup.5 is F,
R.sup.a6 is CH.sub.2C(O)NH.sub.2. In an exemplary embodiment,
R.sup.5 is H, R.sup.a6 is CH.sub.2CH.sub.2C(O)NH.sub.2. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2C(O)NH.sub.2. In an exemplary embodiment, R.sup.5
is H, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2C(O)NH.sub.2. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)NH.sub.2.
[0112] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00056##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--C(O)NHNH.sub.2. In an exemplary embodiment, R.sup.5 is H,
R.sup.a6 is CH.sub.2C(O)NHNH.sub.2. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2C(O)NHNH.sub.2. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2C(O)NHNH.sub.2. In an exemplary embodiment, R.sup.5
is F, R.sup.a6 is CH.sub.2CH.sub.2C(O)NHNH.sub.2. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)NHNH.sub.2. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)NHNH.sub.2.
[0113] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00057##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--C(O)NHOR.sup.30 wherein R.sup.30 is unsubstituted alkyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2C(O)NHOR.sup.30 wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2C(O)NHOR.sup.30 wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2C(O)NHOR.sup.30 wherein R.sup.30 is methyl or ethyl
or unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5
is F, R.sup.a6 is CH.sub.2CH.sub.2C(O)NHOR.sup.30 wherein R.sup.30
is methyl or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)NHOR.sup.30 wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2C(O)NHOR.sup.30 wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl.
[0114] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00058##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--C(O)NR.sup.33R.sup.34, wherein R.sup.33 and R.sup.34, along with
the nitrogen to which they are attached, form a 4 or 5 or 6 or 7 or
8 membered ring. In an exemplary embodiment, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10 and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2C(O)NR.sup.33R.sup.34, wherein R.sup.33 and R.sup.34, along
with the nitrogen to which they are attached, form a 4 or 5 or 6 or
7 or 8 membered ring. In an exemplary embodiment, R.sup.5 is F,
R.sup.a6 is CH.sub.2C(O)NR.sup.33R.sup.34, wherein R.sup.33 and
R.sup.34, along with the nitrogen to which they are attached, form
a 4 or 5 or 6 or 7 or 8 membered ring. In an exemplary embodiment,
R.sup.5 is H, R.sup.a6 is CH.sub.2CH.sub.2C(O)NR.sup.33R.sup.34,
wherein R.sup.33 and R.sup.34, along with the nitrogen to which
they are attached, form a 4 or 5 or 6 or 7 or 8 membered ring. In
an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2C(O)NR.sup.33R.sup.34, wherein R.sup.33 and
R.sup.34, along with the nitrogen to which they are attached, form
a 4 or 5 or 6 or 7 or 8 membered ring.
[0115] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00059##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is alkyl substituted with
--S(O).sub.2R.sup.30, wherein R.sup.30 is unsubstituted alkyl, and
the remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6
are H, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl substituted
with --S(O).sub.2R.sup.30 or ethyl substituted with
--S(O).sub.2R.sup.30 or C.sub.3 alkyl substituted with
--S(O).sub.2R.sup.30 or C.sub.4 alkyl substituted with
--S(O).sub.2R.sup.30 or C.sub.5alkyl substituted with
--S(O).sub.2R.sup.30 or C.sub.6 alkyl substituted with
--S(O).sub.2R.sup.30, wherein R.sup.30 is unsubstituted alkyl, and
the remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6
are H, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 is methyl substituted with --S(O).sub.2R.sup.30 or ethyl
substituted with --S(O).sub.2R.sup.30 or C.sub.3 alkyl substituted
with --S(O).sub.2R.sup.30 or C.sub.4 alkyl substituted with
--S(O).sub.2R.sup.30 or C.sub.5 alkyl substituted with
--S(O).sub.2R.sup.30 or C.sub.6 alkyl substituted with
--S(O).sub.2R.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl, and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0116] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00060##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--S(O).sub.2R.sup.30, wherein R.sup.30 is unsubstituted alkyl,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is halogen, R.sup.a6 is methyl substituted with
--S(O).sub.2R.sup.30 or ethyl substituted with --S(O).sub.2R.sup.30
or C.sub.3 alkyl substituted with --S(O).sub.2R.sup.30 or C.sub.4
alkyl substituted with --S(O).sub.2R.sup.30 or C.sub.5 alkyl
substituted with --S(O).sub.2R.sup.30 or C.sub.6 alkyl substituted
with --S(O).sub.2R.sup.30, wherein R.sup.30 is unsubstituted alkyl,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted with
--S(O).sub.2R.sup.30 or ethyl substituted with --S(O).sub.2R.sup.30
or C.sub.3 alkyl substituted with --S(O).sub.2R.sup.30 or C.sub.4
alkyl substituted with --S(O).sub.2R.sup.30 or C.sub.5 alkyl
substituted with --S(O).sub.2R.sup.30 or C.sub.6 alkyl substituted
with --S(O).sub.2R.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0117] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00061##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--S(O).sub.2R.sup.30, wherein R.sup.30 is unsubstituted alkyl. In
an exemplary embodiment, R.sup.5 is H or halogen, R.sup.a6 is alkyl
substituted with --S(O).sub.2R.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4
alkyl or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6
alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2S(O).sub.2R.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2S(O).sub.2R.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2S(O).sub.2R.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted
C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or unsubstituted
C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6
is CH.sub.2S(O).sub.2R.sup.30, wherein R.sup.30 is methyl or ethyl
or unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5
is H, R.sup.a6 is CH.sub.2CH.sub.2S(O).sub.2R.sup.30, wherein
R.sup.30 is methyl or ethyl or unsubstituted C.sub.3 alkyl or
unsubstituted C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or
unsubstituted C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is CH.sub.2CH.sub.2S(O).sub.2R.sup.30, wherein R.sup.30
is methyl or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2S(O).sub.2R.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl
or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In
an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2S(O).sub.2R.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl. In an exemplary embodiment,
R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2S(O).sub.2R.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted
C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or unsubstituted
C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6
is CH.sub.2CH.sub.2CH.sub.2S(O).sub.2R.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2S(O).sub.2R.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted
C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or unsubstituted
C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6
is CH.sub.2CH.sub.2CH.sub.2S(O).sub.2R.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl.
[0118] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00062##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is alkyl substituted with --S(O)R.sup.30,
wherein R.sup.30 is unsubstituted alkyl, and the remaining members
of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl substituted
with --S(O)R.sup.30 or ethyl substituted with --S(O)R.sup.30 or
C.sub.3 alkyl substituted with --S(O)R.sup.30 or C.sub.4 alkyl
substituted with --S(O)R.sup.30 or C.sub.5 alkyl substituted with
--S(O)R.sup.30 or C.sub.6 alkyl substituted with --S(O)R.sup.30,
wherein R.sup.30 is unsubstituted alkyl, and the remaining members
of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 is methyl substituted with --S(O)R.sup.30 or ethyl
substituted with --S(O)R.sup.30 or C.sub.3 alkyl substituted with
--S(O)R.sup.30 or C.sub.4 alkyl substituted with --S(O)R.sup.30 or
C.sub.5 alkyl substituted with --S(O)R.sup.30 or C.sub.6 alkyl
substituted with --S(O)R.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl
or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl, and
the remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6
are H, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0119] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00063##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--S(O)R.sup.30, wherein R.sup.30 is unsubstituted alkyl, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10 and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is halogen, R.sup.a6 is methyl substituted with
--S(O)R.sup.30 or ethyl substituted with --S(O)R.sup.30 or C.sub.3
alkyl substituted with --S(O)R.sup.30 or C.sub.4 alkyl substituted
with --S(O)R.sup.30 or C.sub.5 alkyl substituted with
--S(O)R.sup.30 or C.sub.6 alkyl substituted with --S(O)R.sup.30,
wherein R.sup.30 is unsubstituted alkyl, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is methyl
substituted with --S(O)R.sup.30 or ethyl substituted with
--S(O)R.sup.30 or C.sub.3 alkyl substituted with --S(O)R.sup.30 or
C.sub.4 alkyl substituted with --S(O)R.sup.30 or C.sub.5 alkyl
substituted with --S(O)R.sup.30 or C.sub.6 alkyl substituted with
--S(O)R.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0120] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00064##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--S(O)R.sup.30, wherein R.sup.30 is unsubstituted alkyl. In an
exemplary embodiment, R.sup.5 is H or halogen, R.sup.a6 is alkyl
substituted with --S(O)R.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl
or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2S(O)R.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2S(O)R.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2S(O)R.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl
or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In
an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2S(O)R.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is CH.sub.2CH.sub.2S(O)R.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted
C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or unsubstituted
C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6
is CH.sub.2CH.sub.2S(O)R.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2CH.sub.2S(O)R.sup.30, wherein
R.sup.30 is methyl or ethyl or unsubstituted C.sub.3 alkyl or
unsubstituted C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or
unsubstituted C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2CH.sub.2S(O)R.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2S(O)R.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl
or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2S(O)R.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2S(O)R.sup.30,
wherein R.sup.30 is methyl or ethyl or unsubstituted C.sub.3 alkyl
or unsubstituted C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or
unsubstituted C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2CH.sub.2CH.sub.2S(O)R.sup.30, wherein
R.sup.30 is methyl or ethyl or unsubstituted C.sub.3 alkyl.
[0121] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00065##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is alkyl substituted with
--NHS(O).sub.2R.sup.30, wherein R.sup.30 is unsubstituted alkyl or
unsubstituted C.sub.3-C.sub.8 cycloalkyl, and the remaining members
of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H are each a
member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl substituted
with --NHS(O).sub.2R.sup.30 or ethyl substituted with
--NHS(O).sub.2R.sup.30 or C.sub.3 alkyl substituted with
--NHS(O).sub.2R.sup.30 or C.sub.4 alkyl substituted with
--NHS(O).sub.2R.sup.30 or C.sub.5 alkyl substituted with
--NHS(O).sub.2R.sup.30 or C.sub.6 alkyl substituted with
--NHS(O).sub.2R.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl or
unsubstituted cyclopropyl or unsubstituted cyclobutyl or
unsubstituted cyclopentyl or unsubstituted cyclohexyl or
unsubstituted cycloheptyl or unsubstituted cyclooctyl, and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H, R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 is methyl substituted with --NHS(O).sub.2R.sup.30 or ethyl
substituted with --NHS(O).sub.2R.sup.30 or C.sub.3 alkyl
substituted with --NHS(O).sub.2R.sup.30 or C.sub.4 alkyl
substituted with --NHS(O).sub.2R.sup.30 or C.sub.5 alkyl
substituted with --NHS(O).sub.2R.sup.30 or C.sub.6 alkyl
substituted with --NHS(O).sub.2R.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4
alkyl or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl
or unsubstituted cyclopropyl or unsubstituted cyclobutyl or
unsubstituted cyclopentyl or unsubstituted cyclohexyl or
unsubstituted cycloheptyl or unsubstituted cyclooctyl, and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5, and R.sup.a6 are
H, R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0122] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00066##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--NHS(O).sub.2R.sup.30, wherein R.sup.30 is unsubstituted alkyl or
unsubstituted C.sub.3-C.sub.8 cycloalkyl, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and
R.sup.11 are as described herein, and each hydrogen in said
compound or a salt thereof can be replaced by deuterium. In an
exemplary embodiment, R.sup.5 is halogen, R.sup.a6 is methyl
substituted with --NHS(O).sub.2R.sup.30 or ethyl substituted with
--NHS(O).sub.2R.sup.30 or C.sub.3 alkyl substituted with
--NHS(O).sub.2R.sup.30 or C.sub.4 alkyl substituted with
--NHS(O).sub.2R.sup.30 or C.sub.5 alkyl substituted with
--NHS(O).sub.2R.sup.30 or C.sub.6 alkyl substituted with
--NHS(O).sub.2R.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl or
unsubstituted cyclopropyl or unsubstituted cyclobutyl or
unsubstituted cyclopentyl or unsubstituted cyclohexyl or
unsubstituted cycloheptyl or unsubstituted cyclooctyl, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted with
--NHS(O).sub.2R.sup.30 or ethyl substituted with
--NHS(O).sub.2R.sup.30 or C.sub.3 alkyl substituted with
--NHS(O).sub.2R.sup.30 or C.sub.4 alkyl substituted with
--NHS(O).sub.2R.sup.30 or C.sub.5 alkyl substituted with
--NHS(O).sub.2R.sup.30 or C.sub.6 alkyl substituted with
--NHS(O).sub.2R.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl or
unsubstituted cyclopropyl or unsubstituted cyclobutyl or
unsubstituted cyclopentyl or unsubstituted cyclohexyl or
unsubstituted cycloheptyl or unsubstituted cyclooctyl, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
[0123] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00067##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--NHS(O).sub.2R.sup.30, wherein R.sup.30 is unsubstituted alkyl or
unsubstituted C.sub.3-C.sub.8 cycloalkyl. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted
with --NHS(O).sub.2R.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl or
unsubstituted cyclopropyl or unsubstituted cyclobutyl or
unsubstituted cyclopentyl or unsubstituted cyclohexyl or
unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2NHS(O).sub.2R.sup.30, wherein R.sup.30 is unsubstituted
cyclopropyl or unsubstituted cyclobutyl or unsubstituted
cyclopentyl or unsubstituted cyclohexyl or unsubstituted
cycloheptyl or unsubstituted cyclooctyl. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is CH.sub.2NHS(O).sub.2R.sup.30,
wherein R.sup.30 is unsubstituted cyclopropyl or unsubstituted
cyclobutyl or unsubstituted cyclopentyl or unsubstituted cyclohexyl
or unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2NHS(O).sub.2R.sup.30, wherein R.sup.30 is
unsubstituted cyclopropyl or unsubstituted cyclobutyl or
unsubstituted cyclopentyl or unsubstituted cyclohexyl or
unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2NHS(O).sub.2R.sup.30, wherein R.sup.30 is
unsubstituted cyclopropyl or unsubstituted cyclobutyl or
unsubstituted cyclopentyl or unsubstituted cyclohexyl or
unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2NHS(O).sub.2R.sup.30, wherein R.sup.30 is
unsubstituted cyclopropyl or unsubstituted cyclobutyl or
unsubstituted cyclopentyl or unsubstituted cyclohexyl or
unsubstituted cycloheptyl or unsubstituted cyclooctyl. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2NHS(O).sub.2R.sup.30, wherein R.sup.30 is
unsubstituted cyclopropyl or unsubstituted cyclobutyl or
unsubstituted cyclopentyl or unsubstituted cyclohexyl or
unsubstituted cycloheptyl or unsubstituted cyclooctyl.
[0124] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00068##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is alkyl substituted with --NHC(O)OR.sup.30,
wherein R.sup.30 is unsubstituted alkyl, and the remaining members
of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is halogen, one of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl substituted
with --NHC(O)OR.sup.30 or ethyl substituted with --NHC(O)OR.sup.30
or C.sub.3 alkyl substituted with --NHC(O)OR.sup.30 or C.sub.4
alkyl substituted with --NHC(O)OR.sup.30 or C.sub.5 alkyl
substituted with --NHC(O)OR.sup.30 or C.sub.6 alkyl substituted
with --NHC(O)OR.sup.30, wherein R.sup.30 is unsubstituted alkyl,
and the remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 are H, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 is methyl substituted with --NHC(O)OR.sup.30 or ethyl
substituted with --NHC(O)OR.sup.30 or C.sub.3 alkyl substituted
with --NHC(O)OR.sup.30 or C.sub.4 alkyl substituted with
--NHC(O)OR.sup.30 or C.sub.5 alkyl substituted with
--NHC(O)OR.sup.30 or C.sub.6 alkyl substituted with
--NHC(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl, and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H, R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0125] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00069##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--NHC(O)OR.sup.30, wherein R.sup.30 is unsubstituted alkyl,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10 and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is halogen, R.sup.a6 is methyl substituted with
--NHC(O)OR.sup.30 or ethyl substituted with --NHC(O)OR.sup.30 or
C.sub.3 alkyl substituted with --NHC(O)OR.sup.30 or C.sub.4 alkyl
substituted with --NHC(O)OR.sup.30 or C.sub.5 alkyl substituted
with --NHC(O)OR.sup.30 or C.sub.6 alkyl substituted with
--NHC(O)OR.sup.30, wherein R.sup.30 is unsubstituted alkyl,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted with
--NHC(O)OR.sup.30 or ethyl substituted with --NHC(O)OR.sup.30 or
C.sub.3 alkyl substituted with --NHC(O)OR.sup.30 or C.sub.4 alkyl
substituted with --NHC(O)OR.sup.30 or C.sub.5 alkyl substituted
with --NHC(O)OR.sup.30 or C.sub.6 alkyl substituted with
--NHC(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0126] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00070##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--NHC(O)OR.sup.30, wherein R.sup.30 is unsubstituted alkyl. In an
exemplary embodiment, R.sup.5 is H or halogen, R.sup.a6 is alkyl
substituted with --NHC(O)OR.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl
or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4
alkyl or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6
alkyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is CH.sub.2CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted
C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or unsubstituted
C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6
is CH.sub.2CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2CH.sub.2NHC(O)OR.sup.30, wherein
R.sup.30 is methyl or ethyl or unsubstituted C.sub.3 alkyl or
unsubstituted C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or
unsubstituted C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4
alkyl or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6
alkyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4
alkyl or unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6
alkyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is methyl
or ethyl or unsubstituted C.sub.3 alkyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2NHC(O)OCH(CH.sub.3).sub.2. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is CH.sub.2NHC(O)OCH(CH.sub.3).sub.2. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2NHC(O)OCH.sub.2CH(CH.sub.3).sub.2. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2NHC(O)OCH.sub.2CH(CH.sub.3).sub.2. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2NHC(O)OCH(CH.sub.2CH.sub.3).sub.2. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2NHC(O)OCH(CH.sub.2CH.sub.3).sub.2.
[0127] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00071##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
--NHC(O)OR.sup.30, wherein R.sup.30 is benzyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is CH.sub.2NHC(O)OR.sup.30,
wherein R.sup.30 is benzyl. In an exemplary embodiment, R.sup.5 is
F, R.sup.a6 is CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is benzyl.
In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is benzyl. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is benzyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is
benzyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
CH.sub.2CH.sub.2CH.sub.2NHC(O)OR.sup.30, wherein R.sup.30 is
benzyl.
[0128] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00072##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is alkyl substituted with R.sup.32, wherein
R.sup.32 is unsubstituted oxazolyl or oxazolyl substituted with
unsubstituted alkyl or unsubstituted oxadiazolyl or oxadiazolyl
substituted with unsubstituted alkyl, and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11
and R.sup.15 are each member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6,
R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are as described herein,
and each hydrogen in said compound or a salt thereof can be
replaced by deuterium. In an exemplary embodiment, R.sup.5 is
halogen, one of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is methyl
substituted with R.sup.32 or ethyl substituted with R.sup.32 or
C.sub.3 alkyl substituted with R.sup.32 or C.sub.4 alkyl
substituted with R.sup.32 or C.sub.5 alkyl substituted with
R.sup.32 or C.sub.6 alkyl substituted with R.sup.32, wherein
R.sup.32 is unsubstituted oxazolyl or oxazolyl substituted with
unsubstituted alkyl or unsubstituted oxadiazolyl or oxadiazolyl or
substituted with unsubstituted alkyl, and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11
and R.sup.15 are each a member independently selected from the
group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 is methyl substituted with R.sup.32 or ethyl substituted
with R.sup.32 or C.sub.3 alkyl substituted with R.sup.32 or C.sub.4
alkyl substituted with R.sup.32 or C.sub.5 alkyl substituted with
R.sup.32 or C.sub.6 alkyl substituted with R.sup.32, wherein
R.sup.32 is unsubstituted oxazolyl or oxazolyl substituted with
unsubstituted alkyl or unsubstituted oxadiazolyl or oxadiazolyl or
substituted with unsubstituted alkyl, and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11
and R.sup.15 are each a member independently selected from the
group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
[0129] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00073##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
R.sup.32, wherein R.sup.32 is unsubstituted oxazolyl or oxazolyl
substituted with unsubstituted alkyl or unsubstituted oxadiazolyl
or oxadiazolyl or substituted with unsubstituted alkyl, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium. In an exemplary embodiment,
R.sup.5 is halogen, R.sup.a6 is methyl substituted with R.sup.32 or
ethyl substituted with R.sup.32 or C.sub.3 alkyl substituted with
R.sup.32 or C.sub.4 alkyl substituted with R.sup.32 or C.sub.5
alkyl substituted with R.sup.32 or C.sub.6 alkyl substituted with
R.sup.32, wherein R.sup.32 is unsubstituted oxazolyl or oxazolyl
substituted with unsubstituted alkyl or unsubstituted oxadiazolyl
or oxadiazolyl or substituted with unsubstituted alkyl, R.sup.10,
R.sup.11 and R.sup.15 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted with
R.sup.32 or ethyl substituted with R.sup.32 or C.sub.3 alkyl
substituted with R.sup.32 or C.sub.4 alkyl substituted with
R.sup.32 or C.sub.5 alkyl substituted with R.sup.32 or C.sub.6
alkyl substituted with R.sup.32, wherein R.sup.32 is unsubstituted
oxazolyl or oxazolyl substituted with unsubstituted alkyl or
unsubstituted oxadiazolyl or oxadiazolyl or substituted with
unsubstituted alkyl, R.sup.10, R.sup.11 and R.sup.15 are each a
member independently selected from the group consisting of H,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl.
[0130] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00074##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
R.sup.32, wherein R.sup.32 is unsubstituted oxazolyl or oxazolyl
substituted with unsubstituted alkyl or unsubstituted oxadiazolyl
or oxadiazolyl or substituted with unsubstituted alkyl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with unsubstituted oxazolyl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is methyl substituted with
unsubstituted oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H
or F, R.sup.a6 is methyl substituted with 4-methyl oxazol-2-yl. In
an exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 5-methyl oxazol-2-yl. In an exemplary embodiment,
R.sup.5 is H or F, R.sup.a6 is methyl substituted with 4-ethyl
oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is methyl substituted with 5-ethyl oxazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 4-unsubstituted C.sub.3 alkyl oxazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 5-unsubstituted C.sub.3 alkyl oxazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 4-unsubstituted C.sub.4 alkyl oxazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 5-unsubstituted C.sub.4 alkyl oxazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 4-unsubstituted C.sub.5 alkyl oxazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 5-unsubstituted C.sub.5 alkyl oxazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 4-unsubstituted C.sub.6 alkyl oxazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 5-unsubstituted C.sub.6 alkyl oxazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl
substituted with unsubstituted oxazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-methyl oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or
F, R.sup.a6 is ethyl substituted with 5-methyl oxazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl
substituted with 4-ethyl oxazol-2-yl. In an exemplary embodiment,
R.sup.5 is H or F, R.sup.a6 is ethyl substituted with 5-ethyl
oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with 4-unsubstituted C.sub.3 alkyl
oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with 5-unsubstituted C.sub.3 alkyl
oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with 4-unsubstituted C.sub.4 alkyl
oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with 5-unsubstituted C.sub.4 alkyl
oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with 4-unsubstituted C.sub.5 alkyl
oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with 5-unsubstituted C.sub.5 alkyl
oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with 4-unsubstituted C.sub.6 alkyl
oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with 5-unsubstituted C.sub.6 alkyl
oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with unsubstituted
oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 4-methyl oxazol-2-yl. In
an exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3
alkyl substituted with 5-methyl oxazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 4-ethyl oxazol-2-yl. In an exemplary embodiment,
R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl substituted with
5-ethyl oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 4-unsubstituted C.sub.3
alkyl oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 5-unsubstituted C.sub.3
alkyl oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 4-unsubstituted C.sub.4
alkyl oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 5-unsubstituted C.sub.4
alkyl oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 4-unsubstituted C.sub.5
alkyl oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 5-unsubstituted C.sub.5
alkyl oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 4-unsubstituted C.sub.6
alkyl oxazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 5-unsubstituted C.sub.6
alkyl oxazol-2-yl.
[0131] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00075##
wherein R.sup.5 is H or halogen, R.sup.a6 is alkyl substituted with
R.sup.32, wherein R.sup.32 is unsubstituted oxadiazolyl or
oxadiazolyl or substituted with unsubstituted alkyl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with unsubstituted oxadiazolyl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is methyl substituted with
unsubstituted oxadiazol-2-yl. In an exemplary embodiment, R.sup.5
is H or F, R.sup.a6 is methyl substituted with unsubstituted 1,2,4
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is methyl substituted with unsubstituted 1,3,4
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is methyl substituted with 4-methyl oxadiazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 5-methyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is methyl substituted with
4-methyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5
is H or F, R.sup.a6 is methyl substituted with 5-methyl 1,2,4
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is methyl substituted with 4-methyl 1,3,4 oxadiazol-2-yl.
In an exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 5-methyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is methyl substituted with
4-ethyl oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or
F, R.sup.a6 is methyl substituted with 5-ethyl oxadiazol-2-yl. In
an exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 4-ethyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is methyl substituted with
5-ethyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5
is H or F, R.sup.a6 is methyl substituted with 4-ethyl 1,3,4
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is methyl substituted with 5-ethyl 1,3,4 oxadiazol-2-yl.
In an exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 4-unsubstituted C.sub.3 alkyl oxadiazol-2-yl. In
an exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 5-unsubstituted C.sub.3 alkyl oxadiazol-2-yl. In
an exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is methyl
substituted with 4-unsubstituted C.sub.3 alkyl 1,2,4
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is methyl substituted with 5-unsubstituted C.sub.3 alkyl
1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or
F, R.sup.a6 is methyl substituted with 4-unsubstituted C.sub.3
alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 5-unsubstituted C.sub.3
alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 4-unsubstituted C.sub.4
alkyl oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or
F, R.sup.a6 is methyl substituted with 5-unsubstituted C.sub.4
alkyl oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or
F, R.sup.a6 is methyl substituted with 4-unsubstituted C.sub.4
alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 5-unsubstituted C.sub.4
alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 4-unsubstituted C.sub.4
alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 5-unsubstituted C.sub.4
alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 4-unsubstituted C.sub.5
alkyl oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or
F, R.sup.a6 is methyl substituted with 5-unsubstituted C.sub.5
alkyl oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or
F, R.sup.a6 is methyl substituted with 4-unsubstituted C.sub.5
alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 5-unsubstituted C.sub.5
alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 4-unsubstituted C.sub.5
alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 5-unsubstituted C.sub.5
alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 4-unsubstituted C.sub.6
alkyl oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or
F, R.sup.a6 is methyl substituted with 5-unsubstituted C.sub.6
alkyl oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or
F, R.sup.a6 is methyl substituted with 4-unsubstituted C.sub.6
alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 5-unsubstituted C.sub.6
alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 4-unsubstituted C.sub.6
alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is methyl substituted with 5-unsubstituted C.sub.6
alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is ethyl substituted with unsubstituted
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with unsubstituted 1,2,4
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with unsubstituted 1,3,4
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with 4-methyl oxadiazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl
substituted with 5-methyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-methyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5
is H or F, R.sup.a6 is ethyl substituted with 5-methyl 1,2,4
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with 4-methyl 1,3,4 oxadiazol-2-yl.
In an exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl
substituted with 5-methyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-ethyl oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or
F, R.sup.a6 is ethyl substituted with 5-ethyl oxadiazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl
substituted with 5-ethyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-ethyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5
is H or F, R.sup.a6 is ethyl substituted with 5-ethyl 1,2,4
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is ethyl substituted with 4-ethyl 1,3,4 oxadiazol-2-yl. In
an exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl
substituted with 5-ethyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-unsubstituted C.sub.3 alkyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
5-unsubstituted C.sub.3 alkyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-unsubstituted C.sub.3 alkyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
5-unsubstituted C.sub.3 alkyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-unsubstituted C.sub.3 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
5-unsubstituted C.sub.3 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-unsubstituted C.sub.4 alkyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
5-unsubstituted C.sub.4 alkyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-unsubstituted C.sub.4 alkyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
5-unsubstituted C.sub.4 alkyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-unsubstituted C.sub.4 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
5-unsubstituted C.sub.4 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-unsubstituted C.sub.5 alkyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
5-unsubstituted C.sub.5 alkyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-unsubstituted C.sub.5 alkyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
5-unsubstituted C.sub.5 alkyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-unsubstituted C.sub.5 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
5-unsubstituted C.sub.5 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-unsubstituted C.sub.6 alkyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
5-unsubstituted C.sub.6 alkyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-unsubstituted C.sub.6 alkyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
5-unsubstituted C.sub.6 alkyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
4-unsubstituted C.sub.6 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is ethyl substituted with
5-unsubstituted C.sub.6 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with unsubstituted oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with unsubstituted 1,2,4 oxadiazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with unsubstituted 1,3,4 oxadiazol-2-yl. In an
exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 4-methyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 5-methyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 4-methyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 5-methyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 4-methyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 5-methyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 4-ethyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 5-ethyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 4-ethyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 5-ethyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 4-ethyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 5-ethyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 4-unsubstituted C.sub.3 alkyl oxadiazol-2-yl. In
an exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3
alkyl substituted with 5-unsubstituted C.sub.3 alkyl
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 4-unsubstituted C.sub.3
alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is C.sub.3 alkyl substituted with 5-unsubstituted
C.sub.3 alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment,
R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl substituted with
4-unsubstituted C.sub.3 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 5-unsubstituted C.sub.3 alkyl 1,3,4
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 4-unsubstituted C.sub.4
alkyl oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or
F, R.sup.a6 is C.sub.3 alkyl substituted with 5-unsubstituted
C.sub.4 alkyl oxadiazol-2-yl. In an exemplary embodiment, R.sup.5
is H or F, R.sup.a6 is C.sub.3 alkyl substituted with
4-unsubstituted C.sub.4 alkyl 1,2,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 5-unsubstituted C.sub.4 alkyl 1,2,4
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 4-unsubstituted C.sub.4
alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is C.sub.3 alkyl substituted with 5-unsubstituted
C.sub.4 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment,
R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl substituted with
4-unsubstituted C.sub.5 alkyl oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 5-unsubstituted C.sub.5 alkyl oxadiazol-2-yl. In
an exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3
alkyl substituted with 4-unsubstituted C.sub.5 alkyl 1,2,4
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 5-unsubstituted C.sub.5
alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is C.sub.3 alkyl substituted with 4-unsubstituted
C.sub.5 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary embodiment,
R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl substituted with
5-unsubstituted C.sub.5 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 4-unsubstituted C.sub.6 alkyl oxadiazol-2-yl. In
an exemplary embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3
alkyl substituted with 5-unsubstituted C.sub.6 alkyl
oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is H or F,
R.sup.a6 is C.sub.3 alkyl substituted with 4-unsubstituted C.sub.6
alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment, R.sup.5 is
H or F, R.sup.a6 is C.sub.3 alkyl substituted with 5-unsubstituted
C.sub.6 alkyl 1,2,4 oxadiazol-2-yl. In an exemplary embodiment,
R
.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl substituted with
4-unsubstituted C.sub.6 alkyl 1,3,4 oxadiazol-2-yl. In an exemplary
embodiment, R.sup.5 is H or F, R.sup.a6 is C.sub.3 alkyl
substituted with 5-unsubstituted C.sub.6 alkyl 1,3,4
oxadiazol-2-yl.
[0132] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00076##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is unsubstituted furan or unsubstituted
oxadiazolyl or unsubstituted triazolyl or alkyl substituted
oxadiazolyl or alkyl substituted triazolyl or pyridine or
pyrimidine, and the remaining members of R.sup.a2, R.sup.a3,
R.sup.a5, and R.sup.a6 are H, R.sup.10, R.sup.11 and R.sup.15 are
each a member independently selected from the group consisting of
H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15, R.sup.10, and R.sup.11 are as described herein, and each
hydrogen in said compound or a salt thereof can be replaced by
deuterium. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
unsubstituted furan. In an exemplary embodiment, R.sup.5 is F,
R.sup.a6 is unsubstituted furan.
[0133] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00077##
wherein R.sup.5 is H or halogen, R.sup.a6 is unsubstituted furan or
unsubstituted oxadiazolyl or unsubstituted triazolyl or alkyl
substituted oxadiazolyl or alkyl substituted triazolyl or pyridine
or pyrimidine, R.sup.10, R.sup.11 and R.sup.15 are each a member
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10 and R.sup.11 are
as described herein, and each hydrogen in said compound or a salt
thereof can be replaced by deuterium.
[0134] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00078##
wherein R.sup.5 is H or halogen, R.sup.a6 is unsubstituted furan or
unsubstituted oxadiazolyl or unsubstituted triazolyl or alkyl
substituted oxadiazolyl or alkyl substituted triazolyl or pyridine
or pyrimidine. In an exemplary embodiment, R.sup.5 is H, R.sup.a6
is unsubstituted furan. In an exemplary embodiment, R.sup.5 is H,
R.sup.a6 is unsubstituted furan-2-yl. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is unsubstituted furan. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is unsubstituted furan-2-yl. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is unsubstituted
1,2,4 oxadiazolyl. In an exemplary embodiment, R.sup.5 is H,
R.sup.a6 is unsubstituted 1,3,4 oxadiazolyl. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is unsubstituted 1,2,4
oxadiazolyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
unsubstituted 1,3,4 oxadiazolyl. In an exemplary embodiment,
R.sup.5 is H, R.sup.a6 is methyl substituted 1,2,4 oxadiazolyl. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is methyl
substituted 1,3,4 oxadiazolyl. In an exemplary embodiment, R.sup.5
is F, R.sup.a6 is methyl substituted 1,2,4 oxadiazolyl. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is methyl substituted
1,3,4 oxadiazolyl. In an exemplary embodiment, R.sup.5 is H,
R.sup.a6 is unsubstituted triazolyl. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is unsubstituted triazolyl. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is methyl triazolyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is methyl substituted
triazolyl. In an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
methyl substituted triazolyl. In an exemplary embodiment, R.sup.5
is F, R.sup.a6 is methyl substituted triazolyl.
[0135] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00079##
wherein R.sup.5 is H or halogen, one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is --NHC(O)OR.sup.30, wherein R.sup.30 is
unsubstituted alkyl, and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6,
R.sup.5, R.sup.15, R.sup.10, and R.sup.11 are as described herein,
and each hydrogen in said compound or a salt thereof can be
replaced by deuterium. In an exemplary embodiment, R.sup.5 is
halogen, one of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 is
--NHC(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl, and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H, R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, one of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 is --NHC(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl
or unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl, and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H, R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0136] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00080##
wherein R.sup.5 is H or halogen, R.sup.a6 is --NHC(O)OR.sup.30,
wherein R.sup.30 is unsubstituted alkyl, R.sup.10, R.sup.11 and
R.sup.15 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.a6, R.sup.5, R.sup.15, R.sup.10, and
R.sup.11 are as described herein, and each hydrogen in said
compound or a salt thereof can be replaced by deuterium. In an
exemplary embodiment, R.sup.5 is halogen, R.sup.a6 is
--NHC(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl,
R.sup.10, R.sup.11 and R.sup.15 are each a member independently
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a6 is --NHC(O)OR.sup.30, wherein
R.sup.30 is methyl or ethyl or unsubstituted C.sub.3 alkyl or
unsubstituted C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or
unsubstituted C.sub.6 alkyl, R.sup.10, R.sup.11 and R.sup.15 are
each a member independently selected from the group consisting of
H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl.
[0137] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00081##
wherein R.sup.5 is H or halogen, R.sup.a6 is --NHC(O)OR.sup.30,
wherein R.sup.30 is unsubstituted alkyl. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a6 is --NHC(O)OR.sup.30,
wherein R.sup.30 is methyl or ethyl or unsubstituted C.sub.3 alkyl
or unsubstituted C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or
unsubstituted C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is --NHC(O)OR.sup.30, wherein R.sup.30 is methyl or
ethyl or unsubstituted C.sub.3 alkyl. In an exemplary embodiment,
R.sup.5 is F, R.sup.a6 is --NHC(O)OR.sup.30, wherein R.sup.30 is
methyl or ethyl or unsubstituted C.sub.3 alkyl or unsubstituted
C.sub.4 alkyl or unsubstituted C.sub.5 alkyl or unsubstituted
C.sub.6 alkyl. In an exemplary embodiment, R.sup.5 is F, R.sup.a6
is --NHC(O)OR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl. In an exemplary embodiment, R.sup.5 is
H, R.sup.a6 is --NHC(O)OCH(CH.sub.3).sub.2. In an exemplary
embodiment, R.sup.5 is F, R.sup.a6 is
--NHC(O)OCH(CH.sub.3).sub.2.
[0138] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00082##
wherein R.sup.5 is H or halogen, R.sup.a6 is --NHC(O)NHR.sup.30,
wherein R.sup.30 is unsubstituted alkyl. In an exemplary
embodiment, R.sup.5 is H or halogen, R.sup.a6 is
--NHC(O)NHR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In an
exemplary embodiment, R.sup.5 is H, R.sup.a6 is --NHC(O)NHR.sup.30,
wherein R.sup.30 is methyl or ethyl or unsubstituted C.sub.3 alkyl.
In an exemplary embodiment, R.sup.5 is F, R.sup.a6 is
--NHC(O)NHR.sup.30, wherein R.sup.30 is methyl or ethyl or
unsubstituted C.sub.3 alkyl or unsubstituted C.sub.4 alkyl or
unsubstituted C.sub.5 alkyl or unsubstituted C.sub.6 alkyl. In an
exemplary embodiment, R.sup.5 is F, R.sup.a6 is --NHC(O)NHR.sup.30,
wherein R.sup.30 is methyl or ethyl or unsubstituted C.sub.3
alkyl.
[0139] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00083##
wherein R.sup.5 is H or halogen, R.sup.a6 is --NHC(O)NH.sub.2. In
an exemplary embodiment, R.sup.5 is H, R.sup.a6 is
--NHC(O)NH.sub.2. In an exemplary embodiment, R.sup.5 is F,
R.sup.a6 is --NHC(O)NH.sub.2.
[0140] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00084##
wherein R.sup.5 is H or halogen, two of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 are each independently selected from the
group consisting of methyl, ethyl, propyl and isopropyl, and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5, and R.sup.a6 are
H, R.sup.10, R.sup.11 are each a member independently selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.10, and R.sup.11 are as described herein, and each hydrogen
in said compound or a salt thereof can be replaced by deuterium. In
an exemplary embodiment, R.sup.5 is F, two of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 are methyl, and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10 and
R.sup.11 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. In
an exemplary embodiment, R.sup.5 is H, two of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 are methyl, and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10 and
R.sup.11 are each a member independently selected from the group
consisting of H, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0141] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00085##
wherein R.sup.5 is H or halogen, two of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 are each independently selected from the
group consisting of methyl, ethyl, propyl and isopropyl, and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H. In an exemplary embodiment, R.sup.5 is F, two of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are methyl, and the remaining
members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H. In an
exemplary embodiment, R.sup.5 is H, two of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 are methyl, and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H.
[0142] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00086##
wherein R.sup.5 is H or halogen, R.sup.a2 and R.sup.a6 are each
independently selected from the group consisting of methyl, ethyl,
propyl and isopropyl. In an exemplary embodiment, R.sup.5 is F,
R.sup.a2 and R.sup.a6 are methyl. In an exemplary embodiment,
R.sup.5 is H, R.sup.a2 and R.sup.a6 are methyl.
[0143] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00087##
wherein R.sup.5 is H or halogen, R.sup.a3 and R.sup.a6 are each
independently selected from the group consisting of methyl, ethyl,
propyl and isopropyl. In an exemplary embodiment, R.sup.5 is F,
R.sup.a1 and R.sup.a6 are methyl. In an exemplary embodiment,
R.sup.5 is H, R.sup.a3 and R.sup.a6 are methyl.
[0144] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00088##
wherein R.sup.5 is H or halogen, two of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 are each independently selected from the
group consisting of F, Cl, Br, methyl, ethyl, propyl and isopropyl,
and the remaining members of R.sup.a2, R.sup.a3.sub.5R.sup.a5 and
R.sup.a6 are H, R.sup.15 is selected from the group consisting of
H, substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted heterocycloalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.a2, R.sup.a3, R.sup.a5, R.sup.a6, R.sup.5,
R.sup.15 are as described herein, and each hydrogen in said
compound or a salt thereof can be replaced by deuterium. In an
exemplary embodiment, R.sup.5 is F, two of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 are methyl, and the remaining members of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.15 is
selected from the group consisting of H, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, two of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 are methyl, and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.15 is selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is F, two of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 are chloro, and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.15 is selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.5 is H, two of R.sup.a2, R.sup.a3, R.sup.a5 and
R.sup.a6 are chloro, and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.15 is selected from
the group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
[0145] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00089##
wherein R.sup.5 is H or halogen, two of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 are each independently selected from the
group consisting of F, Cl, Br, methyl, ethyl, propyl and isopropyl,
and the remaining members of R.sup.a2, R.sup.a3.sub.5R.sup.a5 and
R.sup.a6 are H. In an exemplary embodiment, R.sup.5 is F, two of
R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are methyl, and the
remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are
H. In an exemplary embodiment, R.sup.5 is H, two of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are methyl, and the remaining
members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6 are H.
[0146] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00090##
wherein R.sup.5 is H or halogen, R.sup.a2 and R.sup.a6 are each
independently selected from the group consisting of F, Cl, Br,
methyl, ethyl, propyl and isopropyl. In an exemplary embodiment,
R.sup.5 is F, R.sup.a2 and R.sup.a6 are methyl. In an exemplary
embodiment, R.sup.5 is H, R.sup.a2 and R.sup.a6 are F.
[0147] In an exemplary embodiment, the compound, or a salt thereof,
has a structure which is
##STR00091##
wherein R.sup.5 is H or halogen, R.sup.a3 and R.sup.a5 are each
independently selected from the group consisting of F or Cl. In an
exemplary embodiment, R.sup.5 is F, R.sup.a3 and R.sup.a6 are F or
Cl. In an exemplary embodiment, R.sup.5 is H, R.sup.a3 and R.sup.a6
are F or Cl.
[0148] In various embodiments of the invention, R.sup.10 and/or
R.sup.11 can be a prodrug moiety. Prodrugs of amines are known in
the art. See Krise et al., "Prodrugs of Amines" in Prodrugs;
Springer: 2007; Vol. V, Part III, 801-831. Examples of prodrugs for
amines include, but are not limited to, N-acyl derivatives,
carbamates, N-acyloxyalkyl derivatives, quaternary ammonium
derivatives, N-oxides, N-Mannich bases, Schiff bases, enaminones,
azo derivatives, oxazolidines, and 4-imidazolidinones. One of skill
in the art will be able to select a suitable prodrug moiety.
[0149] In an exemplary embodiment, the prodrug moiety is an acyl
derivative. In an exemplary embodiment, at least one of R.sup.10
and R.sup.11 is
##STR00092##
wherein R.sup.p1 is a member selected from substituted or
unsubstituted alkyl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.p1 is unsubstituted alkyl. In an exemplary
embodiment, R.sup.p1 is unsubstituted alkyl. In an exemplary
embodiment, R.sup.p1 is unsubstituted arylalkyl. In an exemplary
embodiment, R.sup.p1 is methyl. In another exemplary embodiment
R.sup.p1 is CF.sub.3.
[0150] In an exemplary embodiment, the prodrug moiety is an ester.
In an exemplary embodiment, at least one of R.sup.10 and R.sup.11
is
##STR00093##
wherein R.sup.p2 is a member selected from substituted or
unsubstituted alkyl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl
and substituted or unsubstituted heteroaryl. In an exemplary
embodiment, R.sup.p2 is unsubstituted alkyl. In an exemplary
embodiment, R.sup.p2 is methyl. In another exemplary embodiment
R.sup.p2 is ethyl. In another exemplary embodiment R.sup.p2 is
n-propyl. In another exemplary embodiment R.sup.p2 is isopropyl. In
another exemplary embodiment R.sup.p2 is iso-butyl. In another
exemplary embodiment R.sup.p2 is benzyl.
[0151] In an exemplary embodiment, the prodrug moiety is an ester.
In an exemplary embodiment, at least one of R.sup.10 and R.sup.11
is
##STR00094##
wherein R.sup.p3 and R.sup.p4 are members independently selected
from substituted or unsubstituted alkyl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl and substituted or unsubstituted heteroaryl.
[0152] In an exemplary embodiment, the invention provides poly- or
multi-valent species of the compounds of the invention, including a
dimer or a trimer. Another exemplary embodiment of the invention
provides an anhydride of the compounds of the invention. In another
exemplary embodiment, the invention provides poly- or multi-valent
species of the compounds of the invention. In an exemplary
embodiment, the invention provides a dimer of the compounds
described herein. In an exemplary embodiment, the invention
provides a dimer of the compounds described herein.
[0153] In an exemplary embodiment, the invention provides a trimer
of the compounds described herein. In an exemplary embodiment, the
invention provides a trimer of the compounds described herein.
[0154] The compounds of the invention can form a hydrate with
water, solvates with alcohols such as methanol, ethanol, propanol,
and the like; adducts with amino compounds, such as ammonia,
methylamine, ethylamine, and the like; adducts with acids, such as
formic acid, acetic acid and the like; complexes with ethanolamine,
quinoline, amino acids, and the like.
[0155] In an exemplary embodiment, the invention provides a
compound described herein, or a salt, hydrate or solvate thereof,
or a combination thereof. In an exemplary embodiment, the invention
provides a compound described herein, or a salt, hydrate or solvate
thereof. In an exemplary embodiment, the invention provides a
compound described herein, or a salt thereof. In an exemplary
embodiment, the salt is a pharmaceutically acceptable salt. In an
exemplary embodiment, the invention provides a compound described
herein, or a hydrate thereof. In an exemplary embodiment, the
invention provides a compound described herein, or a solvate
thereof. In an exemplary embodiment, the invention provides a
compound described herein, or a prodrug thereof. In an exemplary
embodiment, the invention provides a salt of a compound described
herein. In an exemplary embodiment, the invention provides a
pharmaceutically acceptable salt of a compound described herein. In
an exemplary embodiment, the invention provides a hydrate of a
compound described herein. In an exemplary embodiment, the
invention provides a solvate of a compound described herein. In an
exemplary embodiment, the invention provides a prodrug of a
compound described herein. In an exemplary embodiment, the
invention provides a compound as described in FIG. 1, or a salt
thereof. In an exemplary embodiment, the invention provides a
compound as described in FIG. 1, or a pharmaceutically acceptable
salt thereof.
[0156] In an exemplary embodiment, alkyl is linear alkyl. In
another exemplary embodiment, alkyl is branched alkyl.
[0157] In an exemplary embodiment, heteroalkyl is linear
heteroalkyl. In another exemplary embodiment, heteroalkyl is
branched heteroalkyl.
III. b) Combinations Comprising Additional Therapeutic Agents
[0158] The compounds of the invention may also be used in
combination with additional therapeutic agents. The invention thus
provides, in a further aspect, a combination comprising a compound
of the invention together with at least one additional therapeutic
agent, or a salt, prodrug, hydrate or solvate thereof. In an
exemplary embodiment, the compound of the invention is a compound
described herein, or a salt thereof. In an exemplary embodiment,
the additional therapeutic agent is a compound of the invention. In
an exemplary embodiment, the additional therapeutic agent includes
a boron atom. In an exemplary embodiment, the additional
therapeutic agent does not contain a boron atom. In an exemplary
embodiment, the additional therapeutic agent is a compound
described in section III a).
[0159] When a compound of the invention is used in combination with
a second therapeutic agent active against the same disease state,
the dose of each compound may differ from that when the compound is
used alone. Appropriate doses will be readily appreciated by those
skilled in the art. It will be appreciated that the amount of a
compound of the invention required for use in treatment will vary
with the nature of the condition being treated and the age and the
condition of the patient and will be ultimately at the discretion
of the attendant physician or veterinarian.
[0160] The individual components of such combinations may be
administered either simultaneously or sequentially in a unit dosage
form. The unit dosage form may be a single or multiple unit dosage
forms. In an exemplary embodiment, the invention provides a
combination in a single unit dosage form. An example of a single
unit dosage form is a capsule wherein both the compound of the
invention and the additional therapeutic agent are contained within
the same capsule. In an exemplary embodiment, the invention
provides a combination in a two unit dosage form. An example of a
two unit dosage form is a first capsule which contains the compound
of the invention and a second capsule which contains the additional
therapeutic agent. Thus the term `single unit` or `two unit` or
`multiple unit` refers to the object which the animal (for example,
a human) ingests, not to the interior components of the object.
Appropriate doses of known therapeutic agents will be readily
appreciated by those skilled in the art.
[0161] The combinations referred to herein may conveniently be
presented for use in the form of a pharmaceutical formulation.
Thus, an exemplary embodiment of the invention is a pharmaceutical
formulation comprising a) a compound of the invention; b) an
additional therapeutic agent and c) a pharmaceutically acceptable
excipient. In an exemplary embodiment, the pharmaceutical
formulation is a unit dosage form. In an exemplary embodiment, the
pharmaceutical formulation is a single unit dosage form. In an
exemplary embodiment, the pharmaceutical formulation is a single
unit dosage form which includes a compound of the invention; an
antibiotic and a pharmaceutically acceptable excipient. In an
exemplary embodiment, the pharmaceutical formulation is a single
unit dosage form which includes a compound of the invention; an
antibiotic and at least one pharmaceutically acceptable excipient.
In an exemplary embodiment, the pharmaceutical formulation is a two
unit dosage form. In an exemplary embodiment, the pharmaceutical
formulation is a two unit dosage form comprising a first unit
dosage form and a second unit dosage form, wherein the first unit
dosage form includes a) a compound of the invention and b) a first
pharmaceutically acceptable excipient; and the second unit dosage
form includes c) an additional therapeutic agent and d) a second
pharmaceutically acceptable excipient. In an exemplary embodiment,
the pharmaceutical formulation is a two unit dosage form comprising
a first unit dosage form and a second unit dosage form, wherein the
first unit dosage form includes a) a compound of the invention and
b) a first pharmaceutically acceptable excipient; and the second
unit dosage form includes c) an antibiotic and d) a second
pharmaceutically acceptable excipient.
III. c) Preparation of Boron-Containing Compounds
[0162] Compounds of use in the invention can be prepared using
commercially available starting materials, known intermediates, or
by using the synthetic methods published in references described
and incorporated by reference herein, such as U.S. patent
application Ser. Nos. 12/142,692 and U.S. Pat. Pubs. US20060234981,
US20070155699 and US20070293457.
[0163] The following general procedures were used as indicated in
generating the examples and can be applied, using the knowledge of
one of skill in the art, to other appropriate compounds to obtain
additional analogues.
General Procedure 1: Sulfonylation of Amino
3H-benzo[c][1,2]oxaborol-1-ols
##STR00095##
[0165] The sulfonyl chloride (1-1.2 equiv) and a base (either NMM,
K.sub.2CO.sub.3, or pyridine 3-4 equiv) were added sequentially to
a solution of the amine in MeCN (20 mL/g) at rt or cooled in an ice
bath. After completion (typical duration O/N) the volatiles were
removed in vacuo. H.sub.2O was added to the residue and the mixture
adjusted to .about.pH 6 with dilute HCl. The aqueous layer was then
extracted with organic solvent (typically EtOAc), and the combined
organic fractions dried (either Na.sub.2SO.sub.4 or MgSO.sub.4),
filtered, and concentrated in vacuo. The product was typically
purified by either recrystallization from H.sub.2O, trituration
with CH.sub.2Cl.sub.2 or EtOAc, or flash chromatography.
General Procedure 2: Demethylation of substituted
N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzenesulfo-
namide
##STR00096##
[0167] Boron tribromide (3-5 equiv. 1M solution) was added slowly
to an ice-cold solution of the methoxybenzenesulfonamide in DCM at
0.degree. C. The reaction was allowed to stir at rt and monitored
by TLC. The mixture was purified as: ice was added slowly and
worked up with DCM, the organic layer was washed with brine, dried
over Na.sub.2SO.sub.4 and dried in vacuo. Further purification was
carried out by flash chromatography or preparative HPLC when
required.
General Procedure 3: Deprotection of Substituted
N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl-
)acetamide
##STR00097##
[0169] The acetamide and 1:1 6N HCl: AcOH (5 equiv) were heated to
40.degree. C. for 2 days. Purification involved removal of solvent,
work up with EtOAc and 1N HCl, washed with brine, dry on
Na.sub.2SO.sub.4 and removal of solvent. The product was
recrystallized in EtOAc or purified by flash chromatography or
preparative TLC when required.
General Procedure 4: Deprotection of Cbz Protected Amines/Reduction
of Aromatic Nitro
##STR00098##
[0171] A mixture of starting material, Pd/C (10% wet, 0.2 equiv) in
methanol was placed under a hydrogen atmosphere at 50 psi. The
reaction was monitored by LC/MS. The catalyst was filtered off
through a pad of Celite.RTM. and the solvent was evaporated to give
the amine. The product was purified by flash chromatography or
preparative HPLC when required.
General Procedure 5: Formation of Substituted
Sulfamoylcarbamate
##STR00099##
[0173] A mixture of starting material, the chloroformate (5 equiv.)
in THF was stirred at r.t. or heated to 60.degree. C. if required.
The reaction was monitored by LC/MS. The mixture was dried in
vacuo. The crude product was carried on to next step or purified by
flash chromatography or preparative HPLC when required.
General Procedure 6: Deprotection of 2,2,2-Trifluoroacetyl
Protected Amines
##STR00100##
[0175] The acetamide and NH.sub.3 (7M in MeOH, 5 equiv) was heated
to 80.degree. C. for 2 hrs. The reaction was monitored by LC/MS.
Purification: remove solvent. The product was recrystallized in
EtOAc/MeOH or purified by flash chromatography or preparative HPLC
when required.
General Procedure 15: Methylation of Substituted
N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide
##STR00101##
[0177] MeI (1.5 equiv) was added dropwise to solution of the
benzenesulfonamide and K.sub.2CO.sub.3 (3 equiv) in DMF. The
reaction was allowed to stir at r.t. and monitored by TLC. The
mixture was then worked up with EtOAc, H.sub.2O, brine, dried over
Na.sub.2SO.sub.4 and dried in vacuo. Further purification was
carried out by flash chromatography when required.
General Procedure 16: Demethylation of Substituted
N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenzenesulfo-
namide
##STR00102##
[0179] Boron tribromide (3-5 equiv. 1M solution) was added slowly
to an ice-cold solution of the methoxybenzenesulfonamide in DCM at
0.degree. C. The reaction was allowed to stir at rt and monitored
by TLC. Purification: ice was added slowly and worked up with DCM,
the organic layer was washed brine, dried over Na2SO4 and dried in
vacuo.; Further purification was carried out by flash
chromatography or preparative HPLC when required.
General Procedure 17: Deprotection of Substituted
N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl-
)acetamide
##STR00103##
[0181] General Procedure 17: the acetamide and 1:1 6N HCl: AcOH (5
equiv) was heated to 40.degree. C. for 2 days. Purification: remove
solvent, work up with EtOAc and 1N HCl, washed with brine, dry on
Na.sub.2SO.sub.4, remove solvent. The product was recrystallized in
EtOAc or purified by flash chromatography or preparative HPLC when
required.
General Procedure 20: Deprotection of Substituted
2,2,2-trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
sulfamoyl)phenyl)acetamide
##STR00104##
[0183] General Procedure 20: the acetamide and NH.sub.3 (7M in
MeOH, 5 equiv) was heated to 80.degree. C. for 2 hrs. The reaction
was monitored by LC/MS. Purification: remove solvent, The product
was recrystallized in EtOAc/MeOH or purified by flash
chromatography or preparative HPLC when required.
IV. Assays
[0184] Art-recognized techniques of genetics and molecular biology
are of use to identify compounds that bind to and/or inhibit an
enzyme, such as a tRNA synthetase. Moreover, these techniques are
of use to distinguish whether a compound binds to and/or inhibits a
particular domain of the enzyme. For example, for LeuRS, these
techniques can distinguish whether a compound binds to and/or
inhibits the synthetic domain, the editing domain, or both the
editing and synthetic domains. LeuRS can be obtained from Genscript
(Piscataway, N.J.) and also obtained from Prof. Susan Martinez
(University of Illinois, Champaign, Ill.).
IV. a) LeuRS
[0185] In an exemplary assay, activity of a representative compound
against the editing domain was confirmed. To identify the target of
a novel boron-containing antibacterial compound, mutants in E. coli
showing resistance to the compound were isolated. Characterization
of mutants showed that they have an 32-256 fold increase in
resistance to the compound over wildtype. The mutants were
furthermore shown to be sensitive to various antibacterial agents
with known modes of action, suggesting that the cellular target of
the compound is distinct from the target of the other antibacterial
agents. The leuS gene from the mutants was cloned onto a plasmid
and their resistance was confirmed by MIC. The editing domain from
these mutants were sequenced and the mutations were all located in
the editing domain of this enzyme.
[0186] Assays to determine whether, and how effectively, a
particular compound binds to and/or inhibits the editing domain of
a selected tRNA synthetase are also set forth herein, and
additional assays are readily available to those of skill in the
art. Briefly, in an exemplary assay, an improperly charged tRNA and
a tRNA synthetase that is capable of editing the improperly charged
tRNA are combined. The resulting mixture is contacted with the
putative inhibitor and the degree of editing inhibition is
observed.
[0187] Another assay uses genetics to show that a drug works via
the editing domain. In this assay, the compound is first tested
against a strain of cells over-expressing copies of the tRNA
synthetase gene. The compound's effect on the over-expressing
strain is compared with a control strain to determine whether the
compound is active against the synthetase. If the minimum
inhibitory concentration (MIC) is 2-fold higher in the strain with
extra copies of the synthetase gene than the MIC of the inhibitor
against a wild type cell, a further genetic screen is conducted to
determine whether the increased resistance is due to mutations in
the editing domain. In this second screen, the control strain is
challenged against a high concentration of the inhibitor. The
colonies surviving the challenge are isolated and DNA from these
cells is isolated. The editing domain is amplified using a
proof-reading PCR enzyme and the appropriate primers. The PCR
product can be purified using standard procedures. The sequence
amplified mutant DNA is compared to wild-type. If the mutant DNA
bears mutations in the editing domain, such results would suggest
that the compound binds to the editing domain and affects the
editing function of the molecule through this domain.
[0188] Generally, the compounds to be tested are present in the
assays in ranges from about 1 pM to about 100 mM, preferably from
about 1 pM to about 1 .mu.M. Other compounds range from about 1 nM
to about 100 nM, preferably from about 1 nM to about 1 .mu.M.
[0189] The effects of the test compounds upon the function of the
enzymes can also be measured by any suitable physiological change.
When the functional consequences are determined using intact cells
or animals, one can also measure a variety of effects such as
transmitter release, hormone release, transcriptional changes to
both known and uncharacterized genetic markers, changes in cell
metabolism such as cell growth or pH changes, and changes in
intracellular second messengers such as Ca.sup.2+, or cyclic
nucleotides.
[0190] Utilizing the assays set forth herein and others readily
available in the art, those of skill in the art will be able to
readily and routinely determine other compounds and classes of
compounds that operate to bind to and/or inhibit the editing domain
of tRNA synthetases.
[0191] In another aspect, the invention provides a method for
identifying a compound which binds to an editing domain of a tRNA
synthetase comprising: a) contacting said editing domain with a
test compound under conditions suitable for binding; and b)
detecting binding of said test compound to said editing domain. In
an exemplary embodiment, detecting binding of said compound
comprises use of at least one detectable element, isotope, or
chemical label attached to said compound. In an exemplary
embodiment, the element, isotope or chemical label is detected by a
fluorescent, luminescent, radioactive, or absorbance readout. In an
exemplary embodiment, the contacting of said test compound with
said editing domain also includes further contacting said test
compound and said editing domain with a member selected from AMP
and a molecule with a terminal adenosine. In an exemplary
embodiment, the tRNA synthetase is derived from leucyl tRNA
synthetase. In an exemplary embodiment, the tRNA synthetase is
derived from a mutated tRNA synthetase, wherein said mutated tRNA
synthetase comprises amino acid mutations in an editing domain. In
another exemplary embodiment, wherein said editing domain of a tRNA
synthetase comprises the amino acid sequence of a peptide sequence
described herein.
[0192] In another aspect, the invention provides a method for
identifying a compound which binds to an editing domain of a tRNA
synthetase, said assay comprising: a) contacting said editing
domain of a tRNA synthetase with said compound under conditions
suitable for binding of said compound with said editing domain of a
tRNA synthetase; b) comparing a biological activity of said editing
domain of a tRNA synthetase contacting said compound to said
biological activity when not contacting said compound; and c)
identifying said compound as binding to said editing domain of a
tRNA synthetase if said biological activity of said editing domain
of a tRNA synthetase is reduced when contacting said compound. In
an exemplary embodiment, the biological activity is hydrolysis of
noncognate amino acid. In another exemplary embodiment, the
hydrolysis of said noncognate amino acid is detected through the
use of one or more labels. In another exemplary embodiment, the
labels include a radiolabel, a fluorescent marker, an antibody, or
a combination thereof. In another exemplary embodiment, said labels
can be detected using spectroscopy. In another exemplary
embodiment, said editing domain of a tRNA synthetase is derived
from leucyl tRNA synthetase.
[0193] In another aspect, the invention provides a method of
generating a tRNA molecule with a noncognate amino acid comprising:
a) creating or isolating a mutated tRNA synthetase with altered
amino acid editing domains; and b) contacting a tRNA molecule with
said mutated tRNA synthetase and a noncognate amino acid. In
another exemplary embodiment, the mutated tRNA synthetase contains
one or more amino acid mutations in an editing domain. In another
exemplary embodiment, the mutated tRNA synthetase is unable to bind
with a compound of the invention. In another exemplary embodiment,
the mutated tRNA synthetase is unable to bind with a compound
described herein, or a pharmaceutically acceptable salt thereof. In
another exemplary embodiment, the mutated tRNA synthetase is unable
to bind with a compound according to a formula described herein, or
a pharmaceutically acceptable salt thereof.
[0194] In another aspect, the invention provides a composition that
comprises one or more tRNA molecules attached to noncognate amino
acids, wherein said tRNA molecules are synthesized using one or
more mutated tRNA synthetases isolated from a microorganism or a
cell line derived from a microorganism. In an exemplary embodiment,
the microorganism is a bacteria. In an exemplary embodiment,
wherein said mutated tRNA synthetases contain amino acid mutations
in their editing domains.
V. Amino Acid and Nucleotide Sequences Used in Assays
[0195] Amino acid and nucleotide sequences of use in the invention
are published in references described and incorporated by reference
herein, such as U.S. patent application Ser. Nos. 12/142,692 and
U.S. Pat. Pubs. US20060234981, US20070155699 and US20070293457.
VI. Methods
[0196] In another aspect, the compounds of the invention can be
utilized to inhibit an enzyme. In another aspect, the compounds of
the invention and/or combinations of the invention exhibit potency
against microorganisms, such as bacteria, and therefore have the
potential to kill and/or inhibit the growth of microorganisms. In
another aspect, the compounds of the invention and/or combinations
of the invention exhibit potency against microorganisms, such as
bacteria, and therefore have the potential to achieve therapeutic
efficacy in the animals described herein.
VI. LeuRS--
[0197] In an exemplary embodiment, the compounds of the invention
exhibit the ability of inhibiting the editing domain of tRNA
synthetases, such as leucyl tRNA synthetase, of microorganisms,
such as bacteria, and therefore have the potential to be used as
editing domain inhibitors of microorganism tRNA synthetases.
[0198] According to another aspect of the invention, a method for
binding to and/or inhibiting the editing domain of a tRNA
synthetase is provided which comprises contacting a tRNA synthetase
with a compound of the invention that inhibits the editing domain
under conditions in which the tRNA synthetase interacts with its
substrate to form an aminoacyl adenylate intermediate and,
preferably, to form a charged tRNA. Such conditions are known to
those skilled in the art. In an exemplary embodiment, the compound
has a structure according to a formula described herein. In an
exemplary embodiment, the compound is described herein, or a salt,
hydrate or solvate thereof, or a combination thereof. In an
exemplary embodiment, the invention provides a compound described
herein, or a salt, hydrate or solvate thereof. In an exemplary
embodiment, the invention provides a compound described herein, or
a salt thereof. In an exemplary embodiment, the invention provides
a compound described herein, or a salt thereof. The tRNA synthetase
is contacted with an amount of compound of the invention sufficient
to result in a detectable amount of tRNA synthetase inhibition.
This method can be performed on a tRNA synthetase that is contained
within an organism or which is outside an organism. In an exemplary
embodiment, the method is performed on a tRNA synthetase that is
contained within a microorganism or a microbial cell that is in, or
on the surface of, an animal. In an exemplary embodiment, the
animal is a human. The method results in a decrease in the amount
of charged tRNA produced by the tRNA synthetase that has an
inhibited editing domain. In an exemplary embodiment, the
inhibition takes place in a cell, such as a microorganism cell. In
another exemplary embodiment, the microorganism cell is a bacteria.
In another exemplary embodiment, the tRNA synthetase is leucyl tRNA
synthetase.
[0199] In an exemplary embodiment, the invention provides a method
of inhibiting conversion of a tRNA molecule into a charged tRNA
molecule. The method involves contacting a tRNA synthetase with a
compound of the invention effective to inhibit activity of an
editing domain of said tRNA synthetase, under conditions sufficient
to inhibit said activity, thereby inhibiting said conversion. In an
exemplary embodiment, the compound of the invention is a compound
described herein, or a pharmaceutically acceptable salt thereof. In
an exemplary embodiment, the inhibition occurs within a cell, and
the cell is a microorganism cell. In another exemplary embodiment,
the microorganism cell is a bacteria. In another exemplary
embodiment, the microorganism cell is a bacteria which is described
herein. In another exemplary embodiment, the enzyme is a leucyl
tRNA synthetase of a bacteria described herein. In another
exemplary embodiment, the tRNA synthetase is leucyl tRNA
synthetase. In another exemplary embodiment, the compound has a
K.sub.D, synthesis of greater than 100 .mu.M against a synthetic
domain of said tRNA synthetase.
[0200] In certain embodiments, the mechanism of action of a
compound of the invention is to inhibit the conversion of a tRNA
molecule into a charged tRNA molecule by binding to and/or
inhibiting at least the editing domain of the synthetase. The
compounds of use in this method may also inhibit or otherwise
interact with the synthetic domain (e.g., the active site of the
synthetic domain). In a presently preferred embodiment, the editing
domain is inhibited selectively in the presence of the synthetic
domain. In a preferred embodiment, the synthetic domain is
essentially uninhibited, while the editing domain is inhibited at
least 50%, preferably at least 60%, more preferably at least 70%,
still more preferably, at least 80% and even still more preferably
at least 90% of the activity of the tRNA synthetase. In another
preferred embodiment, the synthetic domain is inhibited by at most
50%, preferably at most 30%, preferably at most 20%, 10%,
preferably at most 8%, more preferably at most 5%, still more
preferably, at most 3% and even still more preferably at most 1%.
Inhibition of the editing domain produces a decrease in the amount
of the properly charged tRNA which results in retardation or
cessation of cell growth and division.
[0201] In another exemplary embodiment, the ratio of a minimum
concentration of said compound inhibiting said editing domain to a
minimum concentration of said compound inhibiting said synthetic
domain of said tRNA synthetase, represented as K.sub.D,
edit/K.sub.D, synthesis, is less than one. In another exemplary
embodiment, the K.sub.D, edit/K.sub.D, synthesis of the compound is
a member selected from less than 0.5, less than 0.1 and less than
0.05.
VI. a) Inhibiting Microorganism Growth or Killing
Microorganisms
[0202] The compounds of the invention and/or combinations of the
invention exhibit potency against microorganisms, such as bacteria,
and therefore have the potential to treat, and/or prevent a
microorganism infection, or kill and/or inhibit the growth of
microorganisms.
[0203] In a further aspect, the invention provides a method of
treating and/or preventing a microorganism infection, or a method
of killing and/or inhibiting the growth of a microorganism, said
method comprising: contacting said microorganism with an effective
amount of a compound of the invention, thereby killing and/or
inhibiting the growth of the microorganism. In a further aspect,
the invention provides a method of treating and/or preventing a
microorganism infection, or a method of killing and/or inhibiting
the growth of a microorganism, said method comprising: contacting
said microorganism with an effective amount of a combination of the
invention, thereby killing and/or inhibiting the growth of the
microorganism.
[0204] In a further aspect, the invention provides a method of
treating a bacterial infection comprising adminstering to an animal
suffering from the infection an effective amount of a compound of
the invention or a combination of the invention, or a
pharmaceutically acceptable salt thereof, thereby treating the
bacterial infection. In an exemplary embodiment, the invention
provides a method of treating a bacterial infection comprising
adminstering to an animal suffering from the infection an effective
amount of a compound of the invention, or a pharmaceutically
acceptable salt thereof, and an effective amount of an antibiotic,
or a pharmaceutically acceptable salt thereof, thereby treating the
bacterial infection.
[0205] In a further aspect, the invention provides a method of
preventing a bacterial infection comprising adminstering to an
animal a prophylactic amount of a compound of the invention or a
combination of the invention, or a pharmaceutically acceptable salt
thereof, thereby treating the bacterial infection. In an exemplary
embodiment, the invention provides a method of preventing a
bacterial infection comprising adminstering to an animal a
prophylactic amount of a compound of the invention, or a
pharmaceutically acceptable salt thereof.
[0206] In an exemplary embodiment, the microorganism is a bacteria.
In an exemplary embodiment, the compound or combination is
described herein, or a salt, prodrug, hydrate or solvate thereof,
or a combination thereof. In an exemplary embodiment, the invention
provides a compound or combination described herein, or a salt,
hydrate or solvate thereof. In an exemplary embodiment, the
invention provides a compound or combination described herein, or a
prodrug thereof. In an exemplary embodiment, the invention provides
a compound or combination described herein, or a salt thereof. In
another exemplary embodiment, the compound or combination of the
invention is a compound or combination described herein, or a
pharmaceutically acceptable salt thereof. In another exemplary
embodiment, the compound or compound of the combination is
described by a formula listed herein, or a pharmaceutically
acceptable salt thereof. In an exemplary embodiment, the compound
is part of a combination described herein. In an exemplary
embodiment, the compound is part of a pharmaceutical formulation
described herein. In another exemplary embodiment, the contacting
occurs under conditions which permit entry of the compound into the
organism. Such conditions are known to one skilled in the art and
are described herein.
[0207] In another aspect, the microorganism is inside, or on the
surface of an animal. In an exemplary embodiment, the animal is
selected from the group consisting of human, cattle, deer,
reindeer, goat, honey bee, pig, sheep, horse, cow, bull, dog,
guinea pig, gerbil, rabbit, cat, camel, yak, elephant, ostrich,
otter, chicken, duck, goose, guinea fowl, pigeon, swan, and turkey.
In another exemplary embodiment, the animal is a human.
[0208] In an exemplary embodiment, the microorganism infection is
treated and or prevented, or the microorganism is killed or its
growth is inhibited, through oral administration of the compound of
the invention and/or the combination of the invention. In an
exemplary embodiment, the microorganism infection is treated and or
prevented, or the microorganism is killed or its growth is
inhibited through intravenous administration of the compound of the
invention and/or the combination of the invention.
[0209] In an exemplary embodiment, the microorganism is a
bacterium. In an exemplary embodiment, an infection is caused by
and/or associated with a microorganism, particularly a bacterium.
In an exemplary embodiment, the bacterium is a gram-positive
bacteria. In another exemplary embodiment, the gram-positive
bacterium is selected from the group consisting of Staphylococcus
species, Streptococcus species, Bacillus species, Mycobacterium
species, Corynebacterium species (Propionibacterium species),
Clostridium species, Actinomyces species, Enterococcus species and
Streptomyces species. In another exemplary embodiment, the
gram-positive bacterium is selected from the group consisting of
Propionibacterium acnes, Staphylococcus aureus, Staphylococcus
epidermidis, Staphylococcus saprophyticus, Staphylococcus
haemolyticus, Streptococcus pyogenes, Streptococcus agalactiae,
Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus
faecium, Bacillus anthracis, Mycobacterium avium-intracellulare,
Mycobacterium tuberculosis, Acinetobacter baumanii, Corynebacterium
diphtheria, Clostridium perfringens, Clostridium botulinum,
Clostridium tetani, and Clostridium difficile. In another exemplary
embodiment, the gram-positive bacterium is selected from the group
consisting of Staphylococcus aureus, Staphylococcus epidermidis,
Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus
faecalis, Enterococcus faecium, Clostridium difficile and
Propionibacter acnes. In another exemplary embodiment, the
bacterium is a gram-negative bacterium. In another exemplary
embodiment, the gram-negative bacterium is selected from the group
consisting of Acinetobacter species, Neisseria species, Pseudomonas
species, Brucella species, Agrobacterium species, Bordetella
species, Escherichia species, Shigelia species, Yersinia species,
Salmonella species, Klebsiella species, Enterobacter species,
Haemophilus species, Pasteurella species, Streptobacillus species,
spirochetal species, Campylobacter species, Vibrio species,
Helicobacter species, Bacteroides species, Citrobacter species,
Proteus species, Providencia species, Serratia species,
Stenotrophomonas species and Burkholderia species. In another
exemplary embodiment, the gram-negative bacterium is selected from
the group consisting of Acinetobacter species, Pseudomonas species,
Escherichia species, Klebsiella species, Enterobacter species,
Bacteroides species, Citrobacter species, Proteus species,
Providencia species, Serratia species, Stenotrophomonas species and
Burkholderia species. In another exemplary embodiment, the
gram-negative bacterium is selected from the group consisting of
Neisseria gonorrhoeae, Neisseria meningitidis, Pseudomonas
aeruginosa, Legionella pneumophila, Escherichia coli, Yersinia
pestis, Haemophilus influenzae, Helicobacter pylori, Campylobacter
fetus, Campylobacter jejuni, Vibrio cholerae, Vibrio
parahemolyticus, Trepomena pallidum, Actinomyces israelii,
Rickettsia prowazekii, Rickettsia rickettsii, Chlamydia
trachomatis, Chlamydia psittaci, Brucella abortus, Agrobacterium
tumefaciens, Francisella tularensis, Klebsiella pneumoniae,
Enterobacter cloacae, Acinetobacter baumannii, Bacteroides
fragilis, Citrobacter freundii, Proteus mirabilis, Providencia
stuartii, Serratia marcescens, Stenotrophomonas maltophilia and
Burkholderia cepacia. In another exemplary embodiment, the
gram-negative bacterium is selected from the group consisting of
Pseudomonas aeruginosa, Escherichia coli, Haemophilus influenzae,
Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter
baumannii, Bacteroides fragilis, Citrobacter freundii, Proteus
mirabilis, Providencia stuartii, Serratia marcescens,
Stenotrophomonas maltophilia and Burkholderia cepacia. In another
exemplary embodiment, the gram-negative bacterium is selected from
the group consisting of Enterobacter aerogenes, Enterobacter
cloacae, Enterobacter sakazakii, Escherichia coli, Klebsiella
pneumoniae, Proteus mirabilis, Serratia marcescens and Citrobacter
freundii. In another exemplary embodiment, the gram-negative
bacterium is a Providencia spp. In another exemplary embodiment,
the gram-negative bacterium is an Enterobacter spp.
[0210] In another exemplary embodiment, the bacterium is a
Pseudomonas species. In another exemplary embodiment, the bacterium
is Pseudomonas aeruginosa. In another exemplary embodiment, the
bacterium is selected from the group consisting of Pseudomonas
aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia
and Burkholderia cepacia. In another exemplary embodiment, the
bacterium is Acinetobacter baumannii. In another exemplary
embodiment, the bacterium is Stenotrophomonas maltophilia. In
another exemplary embodiment, the bacterium is Burkholderia
cepacia. In another exemplary embodiment, the bacterium is
Acinetobacter species. In another exemplary embodiment, the
bacterium is Acinetobacter anitratus. In another exemplary
embodiment, the bacterium is selected from the group consisting of
Enterobacter aerogenes, Enterobacter cloacae, Enterobacter
sakazakii, E. coli, K. pneumoniae , P. mirabilis, Serratia
marcescens, Citrobacter freundii and Providencia spp. In another
exemplary embodiment, the bacterium is selected from the group
consisting of Enterobacter aerogenes, Enterobacter cloacae,
Enterobacter sakazakii, E. coli, K. pneumoniae, P. mirabilis,
Serratia marcescens, Citrobacter freundii, Providencia spp., S.
aureus, S. pneumonia, S. pyogenes, E. faecalis, and E. faecium. In
another exemplary embodiment, the bacterium is selected from the
group consisting of Pseudomonas aeruginosa, Acinetobacter
baumannii, Stenotrophomonas maltophilia, Burkholderia cepacia. In
another exemplary embodiment, the bacterium is selected from the
group consisting of S. aureus, S. pneumonia, S. pyogenes, E.
faecalis, and E. faecium. In another exemplary embodiment, the
bacterium is selected from the group consisting of Viridans group
Strep. In another exemplary embodiment, the bacterium is selected
from the group consisting of Strep. mitis, Strep. mutans, Strep.
oxalis, Strep. sanguis, Strep. sobrinus and Strep. millari. In
another exemplary embodiment, the bacterium is S. pneumonia. In
another exemplary embodiment, the bacterium is H. influenzae. In
another exemplary embodiment, the bacterium is S. aureus. In
another exemplary embodiment, the bacterium is M. catarrhalis. In
another exemplary embodiment, the bacterium is M. pneumoniae. In
another exemplary embodiment, the bacterium is L. pneumoniae. In
another exemplary embodiment, the bacterium is C. pneumoniae. In
another exemplary embodiment, the bacterium is S. pyogenes. In
another exemplary embodiment, the bacterium is an anaerobe. In
another exemplary embodiment, the bacterium is an Alcaligenes
species. In another exemplary embodiment, the bacterium is a B.
cepacia. In another exemplary embodiment, the bacterium is selected
from the group consisting of Enterobacter cloacae, Escherichia
coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia
stuartii, Serratia marcescens, and Citrobacter freundii. In another
exemplary embodiment, the bacterium is resistant to methicillin. In
another exemplary embodiment, the bacterium is
methicillin-resistant staphylococcus aureus. In another exemplary
embodiment, the bacterium is selected from the group consisting of
Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus
aureus, Mycobacterium catarrhalis, Mycobacterium pneumoniae,
Legionella pneumophila and Chlamydia pneumoniae. In another
exemplary embodiment, the bacterium is selected from the group
consisting of Enterobacter cloacae, Escherichia coli, Klebsiella
pneumoniae, Proteus mirabilis, Serratia marcescens, Citrobacter
freundii, Providencia stuartii, Pseudomonas aeruginosa,
Acinetobacter baumannii, Stenotrophomonas maltophilia, Burkholderia
cepacia, Staphylococcus aureus, Streptococcus pneumoniae,
Streptococcus pyogenes, Enterococcus faecalis, and Enterococcus
faecium. In another exemplary embodiment, the bacterium is selected
from the group consisting of Staphylococcus aureus, Staphylococcus
epidermidis, Staphylococcus haemolyticus, Streptococcus pyogenes,
Streptococcus agalactiae and Streptococcus pneumoniae.
[0211] In an exemplary embodiment, the microorganism is a
bacterium, which is selected from the group consisting of acid-fast
bacteria, including Mycobacterium species; bacilli, including
Bacillus species, Corynebacterium species (also Propionibacterium)
and Clostridium species; filamentous bacteria, including
Actinomyces species and Streptomyces species; bacilli, such as
Pseudomonas species, Brucella species, Agrobacterium species,
Bordetella species, Escherichia species, Shigella species, Yersinia
species, Salmonella species, Klebsiella species, Enterobacter
species, Haemophilus species, Pasteurella species, and
Streptobacillus species; spirochetal species, Campylobacter
species, Vibrio species; and intracellular bacteria including
Rickettsiae species and Chlamydia species.
VI. b) Microorganism Infection
[0212] The compounds of the invention and/or combinations of the
invention exhibit potency against microorganisms, such as bacteria,
and therefore have the potential to be used to treat and/or prevent
a micororganism infection, such as a bacterial infection.
[0213] In a further aspect, the invention provides a method of
treating a bacterial infection comprising adminstering to an animal
suffering from the infection an effective amount of a compound of
the invention, or a pharmaceutically acceptable salt thereof,
thereby treating the bacterial infection. In an exemplary
embodiment, the invention provides a method of treating a bacterial
infection comprising adminstering to an animal suffering from the
infection an effective amount of a compound of the invention, or a
pharmaceutically acceptable salt thereof, and an effective amount
of an antibiotic, or a pharmaceutically acceptable salt thereof,
thereby treating the bacterial infection.
[0214] In a further aspect, the invention provides a method of
preventing a bacterial infection comprising adminstering to an
animal a prophylactic amount of a compound of the invention, or a
pharmaceutically acceptable salt thereof, thereby treating the
bacterial infection. In an exemplary embodiment, the invention
provides a method of preventing a bacterial infection comprising
adminstering to an animal a prophylactic amount of a compound of
the invention, or a pharmaceutically acceptable salt thereof, and
an effective amount of an antibiotic, or a pharmaceutically
acceptable salt thereof, thereby treating the bacterial
infection.
VI. c) Diseases
[0215] The compounds of the invention and/or combinations of the
invention exhibit potency against microorganisms, such as bacteria,
and therefore have the potential to achieve therapeutic efficacy in
the animals described herein.
[0216] In another aspect, the invention provides a method of
treating and/or preventing a disease. In an exemplary embodiment,
the method includes administering to the animal a therapeutically
effective amount of a compound of the invention, sufficient to
treat and/or prevent the disease. In an exemplary embodiment, the
method includes administering to the animal a therapeutically
effective amount of a combination of the invention, sufficient to
treat and/or prevent the disease. In an exemplary embodiment, the
compound of the invention or the combination of the invention can
be used in human or veterinary medical therapy, particularly in the
treatment or prophylaxis of bacterial-associated disease. In an
exemplary embodiment, the compound is described herein, or a salt,
prodrug, hydrate or solvate thereof, or a combination thereof. In
an exemplary embodiment, the invention provides a compound
described herein, or a prodrug thereof. In an exemplary embodiment,
the invention provides a compound described herein, or a salt,
hydrate or solvate thereof. In an exemplary embodiment, the
invention provides a compound described herein, or a salt thereof.
In another exemplary embodiment, the compound of the invention is a
compound described herein, or a pharmaceutically acceptable salt
thereof. In an exemplary embodiment, the compound is a compound
described herein, or a pharmaceutically acceptable salt thereof. In
an exemplary embodiment, the compound is according to a formula
described herein, or a pharmaceutically acceptable salt thereof. In
an exemplary embodiment, the compound is part of a combination
described herein. In an exemplary embodiment, the compound is part
of a pharmaceutical formulation described herein. In another
exemplary embodiment, the animal is selected from the group
consisting of human, cattle, deer, reindeer, goat, honey bee, pig,
sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat,
camel, yak, elephant, ostrich, otter, chicken, duck, goose, guinea
fowl, pigeon, swan, and turkey. In another exemplary embodiment,
the animal is a human. In another exemplary embodiment, the animal
is selected from the group consisting of a human, cattle, goat,
pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat,
chicken and turkey. In another exemplary embodiment, the disease is
a systemic disease. In another exemplary embodiment, the disease is
a topical disease.
[0217] In an exemplary embodiment, the disease is treated through
oral administration of a compound of the invention and/or a
combination of the invention. In an exemplary embodiment, the
disease is treated through intravenous administration of a compound
of the invention and/or a combination of the invention.
[0218] Systemic Diseases
[0219] In another aspect, the invention provides a method of
treating a systemic disease. The method involves contacting an
animal with a compound of the invention and/or a combination of the
invention.
[0220] In an exemplary embodiment, the disease is selected from the
group consisting of candidiasis, aspergillosis, coccidioidomycosis,
cryptococcosis, histoplasmosis, blastomycosis,
paracoccidioidomycosis, zygomycosis, phaeohyphomycosis and
rhinosporidiosis.
[0221] In another exemplary embodiment, the disease is associated
with infection by a Gram-positive bacteria. In an exemplary
embodiment, the disease is associated with a Staphylococcus
species. In another exemplary embodiment, the disease is selected
from the group consisting of pneumonia, gastroenteritis, toxic
shock syndrome, community acquired pneumonia (CAP), meningitis,
septic arthritis, urinary tract infection, bacteremia,
endocarditis, osteomylitis, skin and skin-structure infection. In
an exemplary embodiment, the disease is associated with a
Streptococcus species. In another exemplary embodiment, the disease
is selected from the group consisting of strep throat, skin
infections, necrotizing fasciitis, toxic shock syndrome, pneumonia,
otitis media and sinusitis. In an exemplary embodiment, the disease
is associated with an Actinomyces species. In another exemplary
embodiment, the disease is actinomycosis. In an exemplary
embodiment, the disease is associated with a Norcardia species. In
another exemplary embodiment, the disease is pneumonia. In an
exemplary embodiment, the disease is associated with a
Corynebacterium species. In another exemplary embodiment, the
disease is diptheria. In an exemplary embodiment, the disease is
associated with a Listeria species. In another exemplary
embodiment, the disease is meningitis. In an exemplary embodiment,
the disease is associated with a Bacillus species. In another
exemplary embodiment, the disease is anthrax or food poisoning. In
an exemplary embodiment, the disease is associated with a
Clostridium species. In another exemplary embodiment, the disease
is selected from the group consisting of botulism, tetanus, gas
gangrene and diarrhea. In an exemplary embodiment, the disease is
associated with a Mycobacterium species. In another exemplary
embodiment, the disease is tuberculosis or leprosy.
[0222] In another exemplary embodiment, the disease is associated
with infection by a Gram-negative bacteria. In an exemplary
embodiment, the disease is associated with a Neisseria species. In
another exemplary embodiment, the disease is selected from the
group consisting of meningitis, gonorrhea, otitis extema and
folliculitis. In an exemplary embodiment, the disease is associated
with an Escherichia species. In another exemplary embodiment, the
disease is selected from the group consisting of diarrhea, urinary
tract infections, meningitis, sepsis and HAP. In an exemplary
embodiment, the disease is associated with a Shigella species. In
another exemplary embodiment, the disease is selected from the
group consisting of diarrhea, bacteremia, endocarditis, meningitis
and gastroenteritis. In an exemplary embodiment, the disease is
associated with a Salmonella species. In another exemplary
embodiment, the disease is selected from the group consisting of
typhoid fever, supsis, gastroenteritis, endocarditis, sinusitis and
meningitis. In an exemplary embodiment, the disease is associated
with a Yersinia species. In another exemplary embodiment, the
disease is selected from the group consisting of typhoid fever,
bubonic plague, enteric fever and gastroenteritis. In an exemplary
embodiment, the disease is associated with a Klebsiella species. In
another exemplary embodiment, the disease is sepsis or urinary
tract infection. In an exemplary embodiment, the disease is
associated with a Proteus species. In another exemplary embodiment,
the disease is an urinary tract infection. In an exemplary
embodiment, the disease is associated with an Enterobacter species.
In another exemplary embodiment, the disease is a hospital-acquired
infection. In an exemplary embodiment, the disease is associated
with a Serratia species. In another exemplary embodiment, the
disease is selected from the group consisting of a urinary tract
infection, skin and skin-structure infection and pneumonia. In an
exemplary embodiment, the disease is associated with a Vibrio
species. In another exemplary embodiment, the disease is cholera or
gastroenteritis. In an exemplary embodiment, the disease is
associated with a Campylobacter species. In another exemplary
embodiment, the disease is gastroenteritis. In an exemplary
embodiment, the disease is associated with a Helicobacter species.
In another exemplary embodiment, the disease is chronic gastritis.
In an exemplary embodiment, the disease is associated with a
Pseudomonas species. In another exemplary embodiment, the disease
is selected from the group consisting of pneumonia, osteomylitis,
burn-wound infections, sepsis, UTIs, endocarditis, otitis and
corneal infections. In an exemplary embodiment, the disease is
associated with a Bacteroides species. In another exemplary
embodiment, the disease is periodontal disease or aspriation
pneumonia. In an exemplary embodiment, the disease is associated
with a Haemophilus species. In another exemplary embodiment, the
disease is selected from the group consisting of meningitis,
epiglottitis, septic arthritis, sepsis, chancroid and vaginitis. In
an exemplary embodiment, the disease is associated with a
Bordetella species. In another exemplary embodiment, the disease is
Whooping cough. In an exemplary embodiment, the disease is
associated with a Legionella species. In another exemplary
embodiment, the disease is pneumonia or pontiac fever. In an
exemplary embodiment, the disease is associated with a Francisella
species. In another exemplary embodiment, the disease is tularemia.
In an exemplary embodiment, the disease is associated with a
Brucella species. In another exemplary embodiment, the disease is
brucellosis. In an exemplary embodiment, the disease is associated
with a Pasteurella species. In another exemplary embodiment, the
disease is a skin infection. In an exemplary embodiment, the
disease is associated with a Gardnerella species. In another
exemplary embodiment, the disease is vaginitis. In an exemplary
embodiment, the disease is associated with a Spirochetes species.
In another exemplary embodiment, the disease is syphilis or Lyme
disease. In an exemplary embodiment, the disease is associated with
a Chlamydia species. In another exemplary embodiment, the disease
is chlamydia. In an exemplary embodiment, the disease is associated
with a Rickettsiae species. In another exemplary embodiment, the
disease is Rocky Mountain spotted fever or typhus.
[0223] In an exemplary embodiment, the disease is associated with
Mycoplasma pneumoniae. In another exemplary embodiment, the disease
is tracheobronchitis or walking pneumonia. In an exemplary
embodiment, the disease is associated with Ureaplasma urealyticum.
In another exemplary embodiment, the disease is urethritis. In
another exemplary embodiment, the disease is pyelonephritis. In
another exemplary embodiment, the disease is an intra-abdominal
infection. In another exemplary embodiment, the disease is febrile
neutropenia. In another exemplary embodiment, the disease is a
pelvic infection. In another exemplary embodiment, the disease is
bacteraemia. In another exemplary embodiment, the disease is
septicaemia.
[0224] In another exemplary embodiment, the disease is community
acquired pneumonia (CAP). In another exemplary embodiment, the
disease is sinusitis. In another exemplary embodiment, the disease
is a urinary tract infection. In another exemplary embodiment, the
disease is a skin and skin-structure infection. In another
exemplary embodiment, the disease is pyelonephritis. In another
exemplary embodiment, the disease is intra-abdominal infection. In
another exemplary embodiment, the disease is an acute pelvic
infection. In another exemplary embodiment, the disease is
tonsillitis.
[0225] In another exemplary embodiment, the disease is chronic
obstructive pulmonary disease. In an exemplary embodiment, the
disease is an acute exacerbaton of chronic obstructive pulmonary
disease. In an exemplary embodiment, the disease is chronic
obstructive pulmonary disease. In an exemplary embodiment, the
disease is pharyngitis. In an exemplary embodiment, the disease is
tonsillitis. In an exemplary embodiment, the disease is Acute
Exacerbation of Chronic Bronchitis (AECB). In an exemplary
embodiment, the disease is cervicitis. In an exemplary embodiment,
the disease is genital ulcer disease.
[0226] In an exemplary embodiment, for any of the methods described
herein, the animal is selected from the group consisting of human,
cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow,
bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant,
ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan,
and turkey. In another exemplary embodiment, for any of the methods
described herein, the animal is selected from the group consisting
of a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea
pig, gerbil, rabbit, cat, chicken and turkey. In another exemplary
embodiment, for any of the methods described herein, the animal is
a human.
[0227] In an exemplary embodiment, for any of the methods described
herein, a compound of the invention, a combination of the
invention, a compound described herein or a pharmaceutically
acceptable salt thereof, or combination described herein, and/or a
pharmaceutical formulation described herein can be used.
VII. Pharmaceutical Formulation
[0228] In another aspect, the invention provides a pharmaceutical
formulation comprising: a) a compound of the invention; and b) a
pharmaceutically acceptable excipient. In another aspect, the
invention provides a pharmaceutical formulation comprising: a) a
combination of the invention; and b) a pharmaceutically acceptable
excipient. In an exemplary embodiment, the compound is according to
a formula described herein. In an exemplary embodiment, the
compound is according to an example described herein. In an
exemplary embodiment, the compound of the invention in the
pharmaceutical formulation is a compound described herein. In an
exemplary embodiment, the compound of the invention in the
pharmaceutical formulation is a pharmaceutically acceptable salt of
a compound described herein.
[0229] In an exemplary embodiment, the compound of the invention is
present in the pharmaceutical formulation in an amount of between
about 0.0001% to about 60% (w/w). In an exemplary embodiment, the
amount is between about 0.01% to about 10% (w/w). In an exemplary
embodiment, the amount is between about 0.1% to about 10% (w/w). In
an exemplary embodiment, the amount is between about 0.25% to about
6% (w/w). In an exemplary embodiment, the amount is between about
0.5% to about 5% (w/w). In an exemplary embodiment, the amount is
between about 0.1% and about 1.0% (w/w). In an exemplary
embodiment, the amount is between about 1.0% and about 2.0% (w/w).
In an exemplary embodiment, the amount is between about 2.0% and
about 3.0% (w/w). In an exemplary embodiment, the amount is between
about 3.0% and about 4.0% (w/w). In an exemplary embodiment, the
amount is between about 4.0% and about 5.0% (w/w).
[0230] The pharmaceutical formulations of the invention can take a
variety of forms adapted to the chosen route of administration.
Those skilled in the art will recognize various synthetic
methodologies that may be employed to prepare non-toxic
pharmaceutical formulations incorporating the compounds described
herein. Those skilled in the art will recognize a wide variety of
non-toxic pharmaceutically acceptable solvents that may be used to
prepare solvates of the compounds of the invention, such as water,
ethanol, propylene glycol, mineral oil, vegetable oil and
dimethylsulfoxide (DMSO).
[0231] The pharmaceutical formulation of the invention may be
administered orally, topically, intraperitoneally, parenterally, by
inhalation or spray or rectally in unit dosage forms containing
conventional non-toxic pharmaceutically acceptable carriers,
adjuvants and vehicles. It is further understood that the best
method of administration may be a combination of methods. Oral
administration in the form of a pill, capsule, elixir, syrup,
lozenge, troche, or the like is particularly preferred. The term
parenteral as used herein includes subcutaneous injections,
intradermal, intravascular (e.g., intravenous), intramuscular,
spinal, intrathecal injection or like injection or infusion
techniques. In an exemplary embodiment, the pharmaceutical
formulation is administered orally. In an exemplary embodiment, the
pharmaceutical formulation is administered intravenously. In an
exemplary embodiment, the pharmaceutical formulation is
administered topically. In an exemplary embodiment, the
pharmaceutical formulation is administered in a topically effective
dose. In an exemplary embodiment, the pharmaceutical formulation is
administered in a cosmetically effective dose. In an exemplary
embodiment, the pharmaceutical formulation is administered in an
orally effective dose.
[0232] The pharmaceutical formulations containing compounds of the
invention are preferably in a form suitable for oral use, for
example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsion, hard or
soft capsules, or syrups or elixirs.
[0233] Compositions intended for oral use may be prepared according
to any method known in the art for the manufacture of
pharmaceutical formulations, and such compositions may contain one
or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents and preserving agents in
order to provide pharmaceutically elegant and palatable
preparations. Tablets may contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients
that are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia; and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed.
[0234] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0235] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing
or wetting agents, which may be a naturally-occurring phosphatide,
for example, lecithin, or condensation products of an alkylene
oxide with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
[0236] Oily suspensions may be formulated by suspending the active
ingredients in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide palatable oral preparations. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0237] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0238] Pharmaceutical formulations of the invention may also be in
the form of oil-in-water emulsions and water-in-oil emulsions. The
oily phase may be a vegetable oil, for example olive oil or arachis
oil, or a mineral oil, for example liquid paraffin or mixtures of
these. Suitable emulsifying agents may be naturally-occurring gums,
for example gum acacia or gum tragacanth; naturally-occurring
phosphatides, for example soy bean, lecithin, and esters or partial
esters derived from fatty acids and hexitol; anhydrides, for
example sorbitan monooleate; and condensation products of the said
partial esters with ethylene oxide, for example polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening and
flavoring agents.
[0239] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative, and
flavoring and coloring agents. The pharmaceutical formulations may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known art using those suitable dispersing or wetting agents and
suspending agents, which have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic 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 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
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
[0240] The composition of the invention may also be administered in
the form of suppositories, e.g., for rectal administration of the
drug. These compositions can be prepared by mixing the drug with a
suitable non-irritating excipient that is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
are cocoa butter and polyethylene glycols.
[0241] Alternatively, the compositions can be administered
parenterally in a sterile medium. The drug, depending on the
vehicle and concentration used, can either be suspended or
dissolved in the vehicle. Advantageously, adjuvants such as local
anesthetics, preservatives and buffering agents can be dissolved in
the vehicle.
[0242] For administration to non-human animals, the composition
containing the therapeutic compound may be added to the animal's
feed or drinking water. Also, it will be convenient to formulate
animal feed and drinking water products so that the animal takes in
an appropriate quantity of the compound in its diet. It will
further be convenient to present the compound in a composition as a
premix for addition to the feed or drinking water. The composition
can also added as a food or drink supplement for humans.
[0243] Dosage levels of the order of from about 5 mg to about 250
mg per kilogram of body weight per day and more preferably from
about 25 mg to about 150 mg per kilogram of body weight per day,
are useful in the treatment of the above-indicated conditions. The
amount of active ingredient that may be combined with the carrier
materials to produce a unit dosage form will vary depending upon
the condition being treated and the particular mode of
administration. Unit dosage forms will generally contain between
from about 1 mg to about 500 mg of an active ingredient.
[0244] Frequency of dosage may also vary depending on the compound
used and the particular disease treated. However, for treatment of
most disorders, a dosage regimen of 4 times daily or less is
preferred. It will be understood, however, that the specific dose
level for any particular patient will depend upon a variety of
factors including the activity of the specific compound employed,
the age, body weight, general health, sex, diet, time of
administration, route of administration and rate of excretion, drug
combination and the severity of the particular disease undergoing
therapy.
[0245] In an exemplary embodiment, the unit dosage form contains
from about 1 mg to about 800 mg of a compound of the invention. In
an exemplary embodiment, the unit dosage form contains from about 1
mg to about 500 mg of an active ingredient. In an exemplary
embodiment, the unit dosage form contains from about 100 mg to
about 800 mg of a compound of the invention. In an exemplary
embodiment, the unit dosage form contains from about 200 mg to
about 500 mg of a compound of the invention. In an exemplary
embodiment, the unit dosage form contains from about 500 mg to
about 800 mg of a compound of the invention. In an exemplary
embodiment, the unit dosage form contains from about 1 mg to about
100 mg of a compound of the invention. In an exemplary embodiment,
the unit dosage form contains from about 10 mg to about 100 mg of a
compound of the invention. In an exemplary embodiment, the unit
dosage form contains from about 50 mg to about 100 mg of a compound
of the invention. In an exemplary embodiment, the unit dosage form
contains from about 25 mg to about 75 mg of a compound of the
invention. In an exemplary embodiment, the unit dosage form
contains from about 40 mg to about 60 mg of a compound of the
invention. In an exemplary embodiment, the unit dosage form
contains from about 75 mg to about 200 mg of a compound of the
invention. In an exemplary embodiment, the unit dosage form
contains from about 1 mg to about 5 mg of a compound of the
invention. In an exemplary embodiment, the unit dosage form
contains from about 10 mg to about 25 mg of a compound of the
invention. In an exemplary embodiment, the unit dosage form
contains from about 50 mg to about 350 mg of a compound of the
invention. In an exemplary embodiment, the unit dosage form
contains from about 200 mg to about 400 mg of a compound of the
invention.
[0246] In an exemplary embodiment, the daily dosage contains from
about 1 mg to about 800 mg of a compound of the invention. In an
exemplary embodiment, the daily dosage contains from about 1 mg to
about 500 mg of an active ingredient. In an exemplary embodiment,
the daily dosage contains from about 100 mg to about 800 mg of a
compound of the invention. In an exemplary embodiment, the daily
dosage contains from about 200 mg to about 500 mg of a compound of
the invention. In an exemplary embodiment, the daily dosage
contains from about 500 mg to about 800 mg of a compound of the
invention. In an exemplary embodiment, the daily dosage contains
from about 1 mg to about 100 mg of a compound of the invention. In
an exemplary embodiment, the daily dosage contains from about 10 mg
to about 100 mg of a compound of the invention. In an exemplary
embodiment, the daily dosage contains from about 50 mg to about 100
mg of a compound of the invention. In an exemplary embodiment, the
daily dosage contains from about 75 mg to about 200 mg of a
compound of the invention. In an exemplary embodiment, the daily
dosage contains from about 1 mg to about 5 mg of a compound of the
invention. In an exemplary embodiment, the daily dosage contains
from about 10 mg to about 25 mg of a compound of the invention. In
an exemplary embodiment, the daily dosage contains from about 50 mg
to about 350 mg of a compound of the invention. In an exemplary
embodiment, the daily dosage contains from about 200 mg to about
400 mg of a compound of the invention.
[0247] Preferred compounds of the invention will have desirable
pharmacological properties that include, but are not limited to,
oral bioavailability, low toxicity, low serum protein binding and
desirable in vitro and in vivo half-lives. Penetration of the blood
brain barrier for compounds used to treat CNS disorders is
necessary, while low brain levels of compounds used to treat
peripheral disorders are often preferred.
[0248] The amount of the composition required for use in treatment
will vary not only with the particular compound selected but also
with the route of administration, the nature of the condition being
treated and the age and condition of the patient and will
ultimately be at the discretion of the attendant physician or
clinician.
VII. a) Testing
[0249] Preferred compounds for use in the pharmaceutical
formulations described herein will have certain pharmacological
properties. Such properties include, but are not limited to, low
toxicity, low serum protein binding and desirable in vitro and in
vivo half-lives. Assays may be used to predict these desirable
pharmacological properties. Assays used to predict bioavailability
include transport across human intestinal cell monolayers,
including Caco-2 cell monolayers. Serum protein binding may be
predicted from albumin binding assays. Such assays are described in
a review by Oravcova et al. (1996, J. Chromat. B677: 1-27).
[0250] Toxicity and therapeutic efficacy of such compounds can be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., for determining the LD50 (the dose
lethal to 50% of the population) and the ED.sub.50 (the dose
therapeutically effective in 50% of the population). The dose ratio
between toxic and therapeutic effects is the therapeutic index and
it can be expressed as the ratio between LD.sub.50 and ED.sub.50.
Compounds that exhibit high therapeutic indices are preferred. The
data obtained from these cell culture assays and animal studies can
be used in formulating a range of dosage for use in humans. The
dosage of such compounds lies preferably within a range of
circulating concentrations that include the ED.sub.50 with little
or no toxicity. The dosage can vary within this range depending
upon the unit dosage form employed and the route of administration
utilized. The exact formulation, route of administration and dosage
can be chosen by the individual physician in view of the patient's
condition. (See, e.g. Fingl et al., 1975, in "The Pharmacological
Basis of Therapeutics", Ch. 1, p. 1).
VII. b) Administration
[0251] In general, the compounds prepared by the methods, and from
the intermediates, described herein will be administered in a
therapeutically or cosmetically effective amount by any of the
accepted modes of administration for agents that serve similar
utilities. It will be understood, however, that the specific dose
level for any particular patient will depend upon a variety of
factors including the activity of the specific compound employed,
the age, body weight, general health, sex, diet, time of
administration, route of administration, and rate of excretion,
drug combination, the severity of the particular disease undergoing
therapy and the judgment of the prescribing physician. The drug can
be administered from once or twice a day, or up to 3 or 4 times a
day.
[0252] Usual patient dosages for systemic administration range from
0.1 to 1000 mg/day, preferably, 1-500 mg/day, more preferably
10-200 mg/day, even more preferably 100-200 mg/day. Stated in terms
of patient body surface areas, usual dosages range from 50-91
mg/m.sup.2/day.
[0253] The amount of the compound in a pharmaceutical formulation
can vary within the full range employed by those skilled in the
art. Typically, the pharmaceutical formulation will contain, on a
weight percent (wt %) basis, from about 0.01-10 wt % of the drug
based on the total formulation, with the balance being one or more
suitable pharmaceutical excipients. Preferably, the compound is
present at a level of about 0.1-3.0 wt %, more preferably, about
1.0 wt %.
[0254] Exemplary embodiments are summarized herein below.
[0255] In an exemplary embodiment, the invention is a compound
having a structure which is a member selected from the group
consisting of:
##STR00105##
wherein R.sup.5 is H or halogen; each R.sup.a2, R.sup.a3, R.sup.a4,
R.sup.a5 and R.sup.a6 is independently selected from the group
consisting of H, --OR.sup.10, --NR.sup.10R.sup.11, --SR.sup.10,
--S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --C(O)R.sup.10, --C(O)OR.sup.10,
--C(O)NR.sup.10R.sup.11, nitro, cyano, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl, wherein each R.sup.10
and each R.sup.11 is independently selected from the group
consisting of H, nitro, halogen, cyano, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl; with the proviso that
R.sup.10 and R.sup.11, together with the atoms to which they are
attached, are optionally combined to form a 5- to 7-membered
substituted or unsubstituted heterocycloalkyl ring; with the
proviso that when R.sup.5 is H, at least two members selected from
the group consisting of R.sup.a2, R.sup.a3, R.sup.a4, R.sup.a5 and
R.sup.a6 are not H; with the proviso that when the structure is
according to formula (I), and R.sup.5 is H, at least one member
selected from the group consisting of R.sup.a2, R.sup.a3, R.sup.a4,
R.sup.a5 and R.sup.a6 is not a member selected from the group
consisting of H, halogen, unsubstituted alkyl and halosubstituted
alkyl; with the proviso that R.sup.a2 and R.sup.a3, together with
the atoms to which they are attached, are optionally joined to form
a 4 to 8 membered ring; with the proviso that R.sup.a3 and
R.sup.a4, together with the atoms to which they are attached, are
optionally joined to form a 4 to 8 membered ring; with the proviso
that R.sup.a4 and R.sup.a5, together with the atoms to which they
are attached, are optionally joined to form a 4 to 8 membered ring;
with the proviso that R.sup.a5 and R.sup.a6, together with the
atoms to which they are attached, are optionally joined to form a 4
to 8 membered ring; or a salt, hydrate or solvate thereof.
[0256] In an exemplary embodiment, according to any of the above
paragraphs,
##STR00106##
wherein R.sup.5 is H or halogen; one of R.sup.a2, R.sup.a3,
R.sup.a5 and R.sup.a6 is halogen or --NHC(O)OR.sup.30 or alkyl
substituted with --C(O)OR.sup.30 or alkyl substituted with
--S(O).sub.2R.sup.30 or alkyl substituted with halogen or alkyl
substituted with hydroxy or alkyl substituted with cyano or alkyl
substituted with --NHC(O)OR.sup.30 or alkyl substituted with
unsubstituted oxazolyl or alkyl substituted with alkyl substituted
oxazolyl or alkyl substituted with unsubstituted oxadiazolyl or
alkyl substituted with alkyl substituted oxadiazolyl or alkyl
substituted with --C(O)NHR.sup.35, wherein R.sup.30 is
unsubstituted alkyl and R.sup.35 is unsubstituted alkyl or
unsubstituted cycloalkyl, and the remaining members of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 are H, R.sup.10 and R.sup.11 are
independently selected from the group consisting of H, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0257] In an exemplary embodiment, according to any of the above
paragraphs, wherein R.sup.5 is H or halogen; one of R.sup.a2,
R.sup.a3, R.sup.a5 and R.sup.a6 is halogen or --NHC(O)OR.sup.30 or
alkyl substituted with --C(O)OR.sup.30 or alkyl substituted with
--S(O).sub.2R.sup.30 or alkyl substituted with halogen or alkyl
substituted with hydroxy or alkyl substituted with cyano or alkyl
substituted with --NHC(O)OR.sup.30 or alkyl substituted with
--C(O)NHR.sup.35, wherein R.sup.30 is unsubstituted alkyl and
R.sup.35 is unsubstituted alkyl or unsubstituted cycloalkyl, and
the remaining members of R.sup.a2, R.sup.a3, R.sup.a5 and R.sup.a6
are H, R.sup.10 and R.sup.11 are independently selected from the
group consisting of H, substituted or unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
[0258] In an exemplary embodiment, according to the above
paragraph, the compound has a structure which is selected from the
group consisting of
##STR00107##
[0259] In an exemplary embodiment, according to any of the above
paragraphs, the compound has a structure which is selected from the
group consisting of
##STR00108##
[0260] In an exemplary embodiment, according to any of the above
paragraphs, the compound has a structure which is selected from the
group consisting of
##STR00109##
[0261] In an exemplary embodiment, according to any of the above
paragraphs, the compound has a structure which is selected from the
group consisting of
##STR00110##
[0262] In an exemplary embodiment, according to any of the above
paragraphs, the compound has a structure which is selected from the
group consisting of
##STR00111##
[0263] In an exemplary embodiment, according to any of the above
paragraphs, the compound has a structure which is selected from the
group consisting of
##STR00112##
[0264] In an exemplary embodiment, according to any of the above
paragraphs, the compound has a structure which is selected from the
group consisting of
##STR00113##
[0265] In an exemplary embodiment, according to any of the above
paragraphs, the compound has a structure which is selected from the
group consisting of
##STR00114##
[0266] In an exemplary embodiment, according to any of the above
paragraphs, wherein R.sup.a2 or R.sup.a6 is selected from the group
consisting of OR.sup.10, --NR.sup.10R.sup.11, cyano, halogen,
substituted or unsubstituted alkyl and substituted or unsubstituted
heteroaryl, wherein each R.sup.10 and each R.sup.11 is
independently selected from the group consisting of H, nitro,
halogen, cyano, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0267] In an exemplary embodiment, according to any of the above
paragraphs, wherein R.sup.a2 or R.sup.a6 is selected from the group
consisting of F, Cl, Br, I, OCH.sub.3, OH, CH.sub.3,
CH.sub.2CH.sub.3, NHC(O)NH.sub.2, NHC(O)NHR.sup.16,
--NR.sup.10R.sup.11, cyano, halogen, substituted or unsubstituted
alkyl and substituted or unsubstituted heteroaryl, wherein R.sup.16
is selected from the group consisting of unsubstituted alkyl,
substituted or unsubstituted heteroalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
[0268] In an exemplary embodiment, according to any of the above
paragraphs, wherein R.sup.a2 or R.sup.a6 is selected from the group
consisting of cyano, F, Cl, Br, I, OCH.sub.3, OH, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CH(CH.sub.3).sub.2, CH.sub.2CH.sub.2Br,
CH.sub.2CH.sub.2OH, CH.sub.2OH, CH.sub.2NH.sub.2, NH.sub.2,
NHC(O)NH.sub.2, NHC(O)NHCH.sub.3, NHC(O)NHCH.sub.2CH.sub.3,
NHC(O)OCH.sub.3, NHC(O)OCH.sub.2CH.sub.3,
NHC(O)OCH(CH.sub.3).sub.2, NHC(O)OCH.sub.2CH(CH.sub.3).sub.2,
NHC(O)CH.sub.2OH, NHC(O)CH.sub.2NH.sub.2,
NHC(O)CH.sub.2N(CH.sub.3).sub.2, NHC(O)CF.sub.3, NHC(O)CH.sub.3,
NHC(O)OCH.sub.2CFH.sub.2, NHC(O)OR.sup.30, NHC(O)CH.sub.2OR.sup.31,
NHC(O)OCH.sub.2R.sup.31, NHC(O)O(CH.sub.2).sub.2OCH.sub.3,
NHC(O)R.sup.32, CH.sub.2C(O)OH, CH.sub.2C(O)OCH.sub.3,
CH.sub.2C(O)OCH.sub.2CH.sub.3, CH.sub.2C(O)NH.sub.2,
CH.sub.2C(O)NHCH.sub.3, CH.sub.2C(O)NHCH.sub.2CH.sub.3,
CH.sub.2C(O)NH(CH.sub.2).sub.2CH.sub.3,
CH.sub.2C(O)NH(CH.sub.2).sub.3CH.sub.3, NHCH.sub.2R.sup.33, wherein
R.sup.30 is cyclohexyl, R.sup.31 is phenyl, R.sup.32 is pyridinyl,
and R.sup.33 is heteroaryl.
[0269] In an exemplary embodiment, according to any of the above
paragraphs, the compound has a structure which is
##STR00115##
[0270] In an exemplary embodiment, according to any of the above
paragraphs, the compound has a structure which is
##STR00116##
wherein R.sup.a6 is F or Cl or Br.
[0271] In an exemplary embodiment, according to any of the above
paragraphs, the compound has a structure which is
##STR00117##
wherein R.sup.a6 is F or Cl or Br.
[0272] In an exemplary embodiment, according to any of the above
paragraphs, R.sup.5 is H.
[0273] In an exemplary embodiment, according to any of the above
paragraphs, R.sup.5 is F.
[0274] In an exemplary embodiment, according to any of the above
paragraphs, R.sup.a6 is Cl.
[0275] In an exemplary embodiment, the invention is a combination
comprising a) a compound according to any of the above paragraphs,
or a pharmaceutically acceptable salt thereof; and b) at least one
therapeutic agent.
[0276] In an exemplary embodiment, the invention is a
pharmaceutical formulation comprising a) a compound according to
any of the above paragraphs or a combination according to any of
the above paragraphs, or a pharmaceutically acceptable salt
thereof; and b) a pharmaceutically acceptable excipient.
[0277] In an exemplary embodiment, according to any of the above
paragraphs, the formulation is a unit dosage form.
[0278] In an exemplary embodiment, according to any of the above
paragraphs, the formulation is an oral unit dosage form or a
topical unit dosage form.
[0279] In an exemplary embodiment, the invention is a method of
killing or inhibiting the growth of a bacteria comprising:
contacting said bacteria with an effective amount of a compound or
a combination according to any of the above paragraphs, or a
pharmaceutically acceptable salt thereof, thereby killing or
inhibiting the growth of the bacteria.
[0280] In an exemplary embodiment, the invention is a method of
treating a bacterial infection comprising: administering to an
animal suffering from said infection an effective amount of a
compound or a combination according to any of the above paragraphs,
or a pharmaceutically acceptable salt thereof, thereby treating the
bacterial infection.
[0281] In an exemplary embodiment, according to any of the above
paragraphs, the animal is a human.
[0282] In an exemplary embodiment, the invention is a use of a
compound or a combination according to any of the above paragraphs,
or a pharmaceutically acceptable salt thereof, in the manufacture
of a medicament for the treatment and/or prophylaxis of bacterial
infection.
[0283] In an exemplary embodiment, the invention is a method of
inhibiting the editing domain of a t-RNA synthetase, comprising:
contacting the synthetase with an effective amount of a compound
described herein, or a pharmaceutically-acceptable salt thereof,
thereby inhibiting the synthetase.
[0284] The invention is further illustrated by the Examples that
follow. The Examples are not intended to define or limit the scope
of the invention.
EXAMPLES
[0285] Proton NMR are recorded on Varian AS 300 spectrometer and
chemical shifts are reported as .delta. (ppm) down field from
tetramethylsilane. Mass spectra are determined on Micromass Quattro
II.
Example 1
N-(5-Chloro-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzenesulfo-
namide
##STR00118##
[0286] 5-Chloro-6-nitro-3H-benzo[c][1,2]oxaborol-1-ol
[0287] To a solution of concentration HNO.sub.3 (75 mL) at
-60.degree. C. was added 5-chloro-3H-benzo[c][1,2]oxaborol-1-ol
(2.5 g, 14.84 mmol) portion-wise and the resulting solution stirred
at -30.degree. C. over a period of 3 h. The reaction was then
poured into crushed ice and the precipitate that formed was
filtered, washed with cold water and vacuum dried generating 2.62 g
(82%) of the title compound as a tan color powder. .sup.1H NMR (400
MHz, DMSO-d.sub.6+D.sub.2O) .delta. (ppm): 8.30 (s, 1H), 7.86 (s,
1H), 5.07 (s, 2H).
6-Amino-5-chloro-3H-benzo[c][1,2]oxaborol-1-ol; hydrochloride
[0288] To a solution of
5-chloro-6-nitro-3H-benzo[c][1,2]oxaborol-1-ol (2.5 g, 11.7 mmol)
in 70 mL of methanol and 20 mL of 2M NH.sub.3 in MeOH was added
Raney Ni (1.0 g). The vessel was charged with a hydrogen atmosphere
at 50 psi for 4 h. The reaction mixture was then filtered, washed
with methanol and the combined filtrate evaporated in vacuo. To the
residue was added diethyl ether (20 mL) and then evaporated to
dryness twice affording. The material was then dissolved in minimum
amount of THF and 4M HCl in dioxane was added. After 4 h at room
temperature, the precipitate that formed was filtered, washed with
diethyl ether and dried in vacuo generating 2.3 g (89%) of the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O)
.delta. (ppm): 7.43 (s, 1H), 7.40 (s, 1H), 4.84 (s, 2H); MS (ESI)
m/z=183 (M+1, positive).
N-(5-Chloro-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzenesulfo-
namide
[0289] To a solution of
6-amino-5-chloro-3H-benzo[c][1,2]oxaborol-1-ol; hydrochloride (0.30
g, 1.36 mmol) in 25 mL of anhydrous pyridine was added
benzenesulfonyl chloride (0.175 ml, 1.36 mmol) and the resulting
yellowish solution heated to 50.degree. C. overnight under nitrogen
atmosphere. Pyridine was removed in vacuo and the residue treated
with 30 mL of 2N HCl. The resulting suspension was sonicated for 30
minutes and the fine precipitate that formed was filtered. The
precipitate was re-crystallized from an EtOAc (20 mL) and MeOH (0.2
mL) mixture.
[0290] The resulting crystals were heated in water and the
subsequent suspension was lyophilized producing 0.135 g (30%) of
the title compound as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 9.97 (s, 1H), 9.36 (s, 1H), 7.68-7.65
(m, 3H), 7.63-7.59 (m, 1H), 7.54-7.50 (m, 2H), 7.44 (s, 1H), 4.90
(s, 2H); MS (ESI) m/z=322 (M-1, negative); HPLC purity: 97.78%
(MaxPlot 200-400 nm), 98.53% (220 nm); Anal. Calcd for
C.sub.13H.sub.11BClNO.sub.4S: C, 48.26%; H, 3.43%; N, 4.33. Found:
C, 47.98%; H, 3.48%; N, 4.45.
N-(5-Chloro-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-nitro-benz-
enesulfonamide
##STR00119##
[0292] To a solution of
6-amino-5-chloro-3H-benzo[c][1,2]oxaborol-1-ol; hydrochloride (0.30
g, 1.36 mmol) in 20 mL of anhydrous pyridine was added
4-nitro-benzenesulfonyl chloride (0.302 g, 1.36 mmol) and the
resulting reddish solution heated to 50.degree. C. overnight under
nitrogen atmosphere. Pyridine was removed in vacuo and the residue
treated with 30 mL of 2N HCl. The solid that formed was filtered
and washed with water and dried in vacuo. The material obtained was
recrystallized twice from methanol. The crystals were then
suspended in 20 mL of H.sub.2O and sonicated for 4 h at 70.degree.
C. to form a fine white suspension which was lyophilized generating
0.107 g (21%) of the title compound as a white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 10.43 (s, 1H), 9.38 (s, 1H),
8.37 (d, J=8.8 Hz, 2H), 7.90 (d, J=9.2 Hz, 2H), 7.60 (s, 1H), 7.50
(s, 1H), 4.91 (s, 2H); MS (ESI) m/z=367 (M-1, negative); HPLC
purity: 98.66% (MaxPlot 200-400 nm), 99.13% (220 nm).
4-Amino-N-(5-chloro-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benz-
enesulfonamide; hydrochloride
##STR00120##
[0294] To a solution of
N-(5-chloro-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-nitro-ben-
zenesulfonamide (0.402 g, 1.09 mmol) in methanol (100 ml) was added
5 mL of 2N NH.sub.3 in MeOH and the resulting solution was added
Raney Ni (0.1 g). The vessel was charged with hydrogen at 50 psi
for 2 h. The reaction mixture was filtered, washed with methanol
and the combined filtrate evaporated to dryness. Diethyl ether was
added to the residue and evaporated twice to form a powdery
material. This was dissolved in 5 mL of anhydrous THF and to it was
added 10 mL of 1M HCl in ether solution. The precipitate that
formed was sonicated for 1 h and filtered. Purification was
accomplished by Preparative HPLC generating 15 mg (3%) of the title
compound as a tan solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6+D.sub.2O) .delta. (ppm): 7.64 (brs, 1H), 7.41 (brs,
1H), 7.31-7.27 (m, 2H), 6.55-6.51 (m, 2H), 4.86 (s, 2H); MS (ESI)
m/z=337 (M-1, negative); HPLC purity: 95.77% (MaxPlot 200-400 nm);
96.71% (220 nm).
N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfona-
mide
##STR00121##
[0296] General Procedure 1: Starting Materials
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and benzenesulfonyl
chloride. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.15 (s,
1H), 9.25 (bs., 1H), 7.70 (m, 2H), 7.64 (m, 2H), 7.53 (m, 2H), 7.21
(d, J=7.6 Hz, 1H), 4.89 (s, 2H). MS (ESI): m/z=306.1 (M-H,
negative).
3-Fluoro-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benze-
nesulfonamide
##STR00122##
[0298] General Procedure 1: Starting Materials
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 3-fluoro
benzenesulfonyl chloride. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 10.27 (s, 1H), 9.30 (s., 1H), 7.62 (m, 2H), 7.52 (m,
3H), 7.24 (d, J=10.4 Hz, 1H), 4.91 (s, 2H). MS (ESI): m/z=324.1
(M-H, negative).
2-Fluoro-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benze-
nesulfonamide
##STR00123##
[0300] General Procedure 1: Starting Materials
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 2-fluoro
benzenesulfonyl chloride. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 10.36 (s, 1H), 9.29 (s., 1H), 7.67 (m, 3H), 7.45 (t,
J=8.4, 2.4 Hz, 1H), 7.31 (t, J=8 Hz, 1H), 7.23 (d, J=10 Hz, 1H),
4.91 (s, 2H). MS (ESI): m/z=324.1 (M-H, negative).
N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(trifluorom-
ethoxy)benzenesulfonamide
##STR00124##
[0302] General Procedure 1: Starting Materials
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and
2-trifluoromethoxy benzenesulfonyl chloride. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.27 (s, 1H), 9.29 (s., 1H), 7.81 (d,
J=8 Hz, 1H), 7.77 (dm, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.56 (d, J=8
Hz, 1H), 7.49 (d, J=10 Hz, 1H), 7.23 (d, J=10.4 Hz, 1H), 4.91 (s,
2H). MS (ESI): m/z=390.1 (M-H, negative).
2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)b-
enzamide
##STR00125##
[0304] 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (0.33 g, 2
mmol), 2-cyanobenzene-1-sulfonyl chloride (0.52 g, 2.56 mmol),
pyridine (1 mL), dichloromethane (5 mL), 0.degree. C.-rt, O/N.
Purification: remove solvent, work up with EtOAc and 3N HCl, washed
with brine, dry on Na.sub.2SO.sub.4, remove solvent. The title
compound was purified by preparative HPLC to give a white powder:
yield 116 mg (17%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
11.25 (s, 1H), 9.71 (s, 1H), 9.47 (br. s., 1H), 9.09 (s, 1H), 7.94
(m, 2H), 7.67 (m, 1H), 7.55 (m, 3H), 5.04 (s, 2H). MS (ESI):
m/z=351.0 (M+H, positive).
N-(4-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)phenyl)acetamide
##STR00126##
[0306] General Procedure 1: Starting Materials
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and
4-acetamidobenzene-1-sulfonyl chloride. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.33 (s, 1H), 9.99 (s, 1H), 9.33 (s.,
1H), 7.79 (d, J=8.4 Hz, 2H), 7.61 (m, 3H), 7.20 (d, J=10 Hz, 1H),
4.89 (s, 2H), 2.06 (s, 3H). MS (ESI): m/z=363.0 (M-H,
negative).
N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-nitrobenzen-
esulfonamide
##STR00127##
[0308] General Procedure 1: Starting Materials
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and
4-nitrobenzenesulfonyl chloride. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.53 (s, 1H), 9.33 (s., 1H), 8.40 (dd,
J=6.8, 0.8 Hz, 2 H), 7.95 (dd, J=6.8, 2.0 Hz, 2H), 7.61 (d, J=7.6
Hz, 1H), 7.25 (d, J=10 Hz, 1H), 4.91 (s, 2H). MS (ESI): m/z=351.0
(M-H, negative).
N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-aminobenzen-
esulfonamide
##STR00128##
[0310]
N-(4-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)s-
ulfamoyl)phenyl)acetamide (0.2 g, 0.59 mmol), 6N HCl (3 mL), AcOH
(3 mL) was heated to 40.degree. C. for 2 days. Purification: remove
solvent, work up with EtOAc and 1N HCl, washed with brine, dry on
Na.sub.2SO.sub.4, remove solvent. The title compound was
recrystallized in EtOAc to give a light-yellow solid as product:
yield 53.1 mg (29%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 9.58 (s, 1H), 9.28 (s, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.32 (d,
J=8 Hz, 2H), 7.18 (d, J=10 Hz, 1H), 6.52 (d, J=8.4 Hz, 2H), 5.95
(s, 2H), 4.89 (s, 2H); MS (ESI): m/z=321.0 (M-H, negative).
2-Cyano-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzen-
esulfonamide
##STR00129##
[0312] General Procedure 1: Starting Materials
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and
2-cyanobenzene-1-sulfonyl chloride. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.55 (s, 1H), 9.33 (s., 1H), 8.09 (dd,
J=7.2, 1.6 Hz, 1H), 7.87 (m, 3H), 7.62 (d, J=8 Hz, 1H), 7.25 (d,
J=10 Hz, 1H), 4.92 (s, 2H). MS (ESI): m/z=331.1 (M-H,
negative).
2-(Aminomethyl)-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-y-
l)benzenesulfonamide
##STR00130##
[0314]
2-cyano-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl-
)benzenesulfonamide (0.16 g, 1 mmol), Raney Ni (2 equiv w/w), 2.0 M
NH.sub.3 in EtOH (5 mL), and absolute EtOH (20 mL/1 g) was shaken
under an atmosphere of H.sub.2 (40-50 psi) for 3 h at rt.
Purification: The resultant mixture was filtered through a pad of
Celite and washed with EtOH. The filtrate was concentrated in vacuo
to give the free amine. The title compound was purified by
preparative HPLC to give a white powder: yield 23 mg (13%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.40 (s, 1H), 9.33 (bs.,
1H), 8.24 (b, 3H), 7.73 (m, 2H), 7.64 (d, J=7.6 Hz, 2H), 7.55 (dd,
J=8, 1.2 Hz, 1H), 7.23 (d, J=10.4 Hz, 1H), 4.92 (s, 2H), 4.36 (d,
J=5.2 Hz, 2H). MS (ESI): m/z=337.0 (M+H, positive).
2,6-Difluoro-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)b-
enzenesulfonamide
##STR00131##
[0316] General Procedure 1: Starting Materials
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and 2,6-fluoro
benzenesulfonyl chloride. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 10.66 (s, 1H), 9.32 (s., 1H), 7.68 (m, 2H), 7.27 (m,
3H), 4.93 (s, 2H). MS (ESI): m/z=342.1 (M-H, negative).
N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-sul-
fonamide
##STR00132##
[0318] General Procedure 1: Starting Materials
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and
pyridine-2-sulfonyl chloride. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 10.28 (s, 1H), 9.28 (s., 1H), 8.73 (d, J=4.8 Hz, 1H),
8.04 (dt, J=7.6, 1.6 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.66 (m, 2H),
7.22 (d, J=10.4 Hz, 1H), 4.90 (s, 2H). MS (ESI): m/z=309.1 (M+H,
positive).
5-Nitro-pyridine-2-sulfonic acid
(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide
##STR00133##
[0319] 5-Nitro-pyridine-2-sulfonyl chloride
[0320] To an ice-cold solution of 5-nitro-pyridine-2-thiol (1.27 g,
8.13 mmol) in 1N aqueous HCl (25 mL) and acetic acid (5 mL) was
vigorously bubbled chlorine (gas) for 15 min, followed by nitrogen
for 5 min. the solid was collected by filtration, washed with cold
1N aqueous HCl and water and dried in vacuo: yield 842 mg (47%).
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 9.60 (d, J=2.0 Hz,
1H), 8.84 (dd, J=8.6, 2.3 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H).
5-Nitro-pyridine-2-sulfonic acid
(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide
[0321] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol
(0.2 g, 1.34 mmol), MeCN (4 mL), pyridine (0.22 mL, 2.69 mmol), and
5-nitro-pyridine-2-sulfonyl chloride (0.3 g, 1.34 mmol).
Purification by filtration from water and wash with water and ethyl
acetate generated 380 mg (84%) of the title compound as an orange
solid. mp 211-213.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 10.85 (s, 1H), 9.45 (d, J=2.2 Hz, 1H), 9.22 (s, 1H),
8.78 (dd, J=8.6, 2.5 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 7.52 (s, 1H),
7.34-7.15 (m, 2H), 4.88 (s, 2H); MS (ESI) m/z=334 (M-1, negative);
HPLC purity: 93.99% (MaxPlot 200-400 nm), 93.92% (220 nm).
5-Amino-pyridine-2-sulfonic acid
(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide;
hydrochloride
##STR00134##
[0323] A mixture of 5-Nitro-pyridine-2-sulfonic acid
(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (1.51 g,
4.51 mmol)) and 10% Pd on carbon (1.51 g, 1:1 w/w substrate to
catalyst) in THF (30 mL) and methanol (135 mL) was shaken under an
atmosphere of H.sub.2 (40 psi) in a Parr shaker. Once the reaction
was complete (30 min), the mixture was filtered through Celite. The
filtrate was concentrated in vacuo and the residue dissolved in
acetonitrile--water, washed with ethyl ether and lyophilized to
provide the title compound as a yellow solid: yield 827 mg (60%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.10 (s, 1H), 9.17
(br. s., 1H), 7.90 (d, J=2.5 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.47
(s, 1H), 7.27-7.13 (m, 2H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 6.17 (br.
s., 2H), 4.86 (s, 2H); MS (ESI): m/z=304 (M-1, negative); HPLC
purity: 95.56% (MaxPlot 200-400 nm), 95.55% (220 nm).
4-Amino-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridi-
ne-2-sulfonamide
##STR00135##
[0325] General Procedure 3: Starting Materials
N-(2-(N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamo-
yl)pyridin-4-yl)acetamide, 6N HCl and AcOH. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 10.34 (s, 1H), 9.30 (bs, 1H), 8.03 (d,
J=6 Hz, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.24 (m, 2H), 7.04 (d, J=2.4
Hz, 1H), 6.59 (dd, J=5.6, 2.4 Hz, 1H), 6.82 (bs, 2H), 4.89 (s, 2H);
MS (ESI): m/z=306.1 (M+H, positive).
6-Amino-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridi-
ne-3-sulfonamide
##STR00136##
[0327] To a stirred solution of 6-aminopyridine-3-sulfonyl chloride
(251 mg, 1.30 mmol) and
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (218 mg, 1.30 mmol)
in 5 mL of ACN was added pyridine (210 uL, 2.6 mmol) dropwise. The
reaction mixture was stirred at room temperature for 16 hours.
After quenched with water, the solvent was removed in vacuo. The
residue was extracted with ethyl acetate three times, and washed
with water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, and concentrated to give a yellow residue. The
crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM
30.times.50 mm column) to give 135 mg of the title compound as a
white solid. MS calcd for (C.sub.12H.sub.11BFN.sub.3O.sub.4S):
323.1, MS found (ESI negative): (M-H).sup.-=322.1. .sup.1H NMR
(DMSO-d.sub.6) .delta. (ppm): 9.80 (s, 1H), 9.20 (bs, 1H), 8.06 (s,
1H), 7.50 (d, 1H), 7.55 (d, 1H), 7.17 (d, 1H), 6.45 (d, 1H), 4.84
(s, 2H).
N-[6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methyl--
pyridin-3-yl]-acetamide
##STR00137##
[0328] 2-Benzylsulfanyl-3-methyl-5-nitro-pyridine
[0329] To a solution of phenyl-methanethiol (4.12 mL, 31.87 mmol)
in THF (25 mL) was added K.sub.2CO.sub.3 (5.20 g, 37.66 mmol) and
the resulting suspension was heated at 60.degree. C. for 30 min. A
solution of 2-chloro-3-methyl-5-nitro-pyridine (5.00 g, 28.97 mmol)
in THF (10 mL) was added dropwise and the mixture was heated to
reflux. After ON, the mixture was cooled and the volatiles were
removed in vacuo. The residue was treated with ethyl acetate and
water. The layers were separated and the aqueous layer was
extracted twice with ethyl acetate and the combined organic layer
was washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. Purification was accomplished by
Biotage.RTM. (SP4, Silica gel 100 g SNAP.TM. column, eluting with
75%-100% DCM in hexanes) produced 5.83 g (77%) of the title
compound as a pale yellow solid. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 9.15 (d, J=2.0 Hz, 1H), 8.08 (s, 1H),
7.42 (d, J=7.4 Hz, 2H), 7.39-7.18 (m, 3H), 4.55 (s, 2H), 2.33 (s,
3H).
6-Benzylsulfanyl-5-methyl-pyridin-3-ylamine
[0330] To a solution of 2-benzylsulfanyl-3-methyl-5-nitro-pyridine
(1.4 g, 5.38 mmol) in ethanol (20 mL) and water (5 mL) was added
iron powder (3 g, 53.8 mmol) and concentrated HCl (0.25 mL). The
mixture was heated to reflux for 2 h. After cooling to room
temperature, the insoluble material was removed by filtration
through Celite.RTM. and washed with 4:1 ethanol-water. The filtrate
was concentrated in vacuo and the pH adjusted to -8 with 20%
aqueous NaOH. The mixture was extracted with DCM (2.times.) and the
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo generating
1.26 g (quantitative) of the title compound that was used in the
next step without further purification. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 7.89 (d, J=2.3 Hz, 1H), 7.43-7.13 (m,
7H), 6.76 (d, J=2.0 Hz, 1H), 4.38 (s, 2H), 2.15 (s, 3H); MS (ESI)
m/z=231 (M+1, positive).
N-(6-Benzylsulfanyl-5-methyl-pyridin-3-yl)-acetamide
[0331] To a solution of 6-benzylsulfanyl-5-methyl-pyridin-3-ylamine
(1.24 g, 5.38 mmol) in THF (10 mL) at 0.degree. C. was added
triethylamine (1.12 mL, 8.07 mmol). After 10 min, acetic anhydride
(0.763 mL, 8.07 mmol) was added. The ice bath was removed. After
overnight, slightly acidic water (dilute HCl) was added and the
mixture was extracted with ethyl acetate. The organic layer was
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo generating 1.02 g (70%) of the title compound
that was used in the next step without further purification.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.31 (s, 1H), 7.77
(s, 1H), 7.40 (d, J=7.4 Hz, 2H), 7.35-7.17 (m, 3H), 7.08 (br. s.,
1H), 4.45 (s, 2H), 2.23 (s, 3H), 2.19 (s, 3H).
5-Acetylamino-3-methyl-pyridine-2-sulfonyl chloride
[0332] Through a solution of
N-(6-benzylsulfanyl-5-methyl-pyridin-3-yl)-acetamide (1.02 g, 3.75
mmol) in DCM (25 mL) and water (5 mL) cooled in an ice bath was
vigorously bubbled chlorine for 15 min. After 15 min of additional
stirring, nitrogen was bubbled through the reaction mixture for 30
min. The layers were separated and the organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo generating
1.142 g of the title compound as yellow oil that was used in the
next step without further purification.
N-[6-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methyl--
pyridin-3-yl]-acetamide
[0333] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol
(558 mg, 3.75 mmol), pyridine (0.606 mL, 7.49 mmol), acetonitrile
(10 mL) and 5-acetylamino-3-methyl-pyridine-2-sulfonyl chloride
(3.75 mmol). The residue was repeatedly washed with DCM and after
drying in vacuo 0.714 g (53% for 2 steps) of the title compound was
isolated as a red powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 10.43 (s, 1H), 10.42 (s, 1H), 9.19 (br. s., 1H), 8.56
(d, J=1.7 Hz, 1H), 8.01 (s, 1 H), 7.52 (s, 1H), 7.25 (s, 2H), 4.88
(s, 2H), 2.53 (s, 3H), 2.08 (s, 3H); MS (ESI) m/z=362 (M+1,
positive); HPLC purity: 97.65% (MaxPlot 200-400 nm), 97.61% (220
nm).
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-methylpyridi-
ne-2-sulfonamide
##STR00138##
[0335] To a solution of
N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-met-
hylpyridin-3-yl)acetamide (592 mg, 1.64 mmol) in 1,4-dioxane (30
mL) was added 6 M HCl (10 mL), and the mixture was stirred at
100.degree. C. for 4 h. The pH was adjusted to 7 with aqueous NaOH,
and the mixture was extracted with ethyl acetate. The organic layer
was washed with water and brine and dried on anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was triturated with small amount of ethyl acetate to give
5-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-methylpyrid-
ine-2-sulfonamide (60 mg, 11%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm) 2.37 (s, 3H), 4.85 (s, 2H), 5.98 (br s, 2H), 6.71 (d,
J=1.5 Hz, 1H), 7.20 (s, 2H), 7.45 (s, 1H), 7.66 (d, J=2.2 Hz, 1H),
9.15 (s, 1H), 10.1 (s, 1H).
5-Amino-3-methyl-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6--
yl)pyridine-2-sulfonamide
##STR00139##
[0337] General Procedure 1:
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (485 mg, 3 mmol),
3-methyl-5-(2,2,2-trifluoroacetamido)pyridine-2-sulfonyl chloride
(302 mg, 1 mmol), pyridine (400 mg, 5 mmol), rt, 0.5 hour. Removed
solvent, the crude was dissolved in MeOH (5 ml), treated with
ammonia (2 ml, 7N in MeOH), heated at 100.degree. C. for 2 hours in
a sealed tube. After cooled down to rt, concentrated, the result
solid was purified by prep HPLC (SunFire Prep C18 OBD 5 uM
30.times.50 mm column). Title compound was obtained as white
powder. MS calcd for (C.sub.13H.sub.13BN.sub.3O.sub.4FS): 337.13,
MS found (ESI negative): (M-H).sup.-=336.1. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 9.77 (s, 1H), 7.66 (d, J=2.4 Hz, 1H),
7.64 (s, 1H), 7.18 (d, J=10.4 Hz, 1H), 6.74 (d, J=2 Hz, 1H), 4.87
(s, 2H), 2.33 (s, 3H).
5-Amino-3-ethyl-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridin-
e-2-sulfonamide
##STR00140##
[0338] Tert-butyl pyridin-2-ylcarbamate
[0339] Into a 500-mL round-bottom flask were placed a solution of
pyridin-2-amine (30 g, 319.15 mmol, 1.00 equiv) in tetrahydrofuran
(200 mL) and (Boc).sub.2O (83.5 g, 383.03 mmol, 1.20 equiv). The
resulting solution was heated to reflux overnight. The resulting
mixture was cooled and concentrated under vacuum. The residue was
applied onto a silica gel column and eluted with ethyl
acetate/petroleum ether (1:20). This resulted in 15.5 g (24%) of
tert-butyl pyridin-2-ylcarbamate as a white solid.
Tert-butyl 3-ethylpyridin-2-ylcarbamate
[0340] Into a 500-mL 3-necked round-bottom flask was placed a
solution of tert-butyl pyridin-2-ylcarbamate (15.5 g, 79.90 mmol,
1.00 equiv) in tetrahydrofuran (200 mL). This was followed by the
addition of n-BuLi (2.5M, 70.4 mL, 2.20 equiv) dropwise with
stirring at -78.degree. C. The reaction mixture was stirred 2 h at
-78.degree. C., then added iodoethane (18.72 g, 120.00 mmol, 1.50
equiv) dropwise with stirring at -78.degree. C. The resulting
solution was stirred overnight at room temperature, then quenched
by the addition of 50 mL of NH.sub.4Cl solution. The resulting
mixture was extracted with 3.times.50 ml, of ethyl acetate. The
organic layers were combined, washed with 1.times.30 mL of brine,
dried and concentrated under vacuum. The residue was applied onto a
silica gel column and eluted with ethyl acetate/petroleum ether
(1:20-1:10). This resulted in 6.5 g (35%) of tert-butyl
3-ethylpyridin-2-ylcarbamate as a light yellow solid.
3-Ethylpyridin-2-amine
[0341] Into a 50-mL round-bottom flask was placed a solution of
tert-butyl 3-ethylpyridin-2-ylcarbamate (6 g, 27.03 mmol, 1.00
equiv) in DCM/CF.sub.3COOH (30/10 mL) and stirred overnight at room
temperature. The resulting solution was diluted with 10 mL of
water, then adjusted to pH 9-10 with sodium hydroxide solution. The
resulting solution was extracted with 2.times.20 mL of
dichloromethane. The organic layers were combined, washed with
1.times.20 mL of brine, dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with ethyl acetate/petroleum ether (1:5).
This resulted in 3 g (86%) of 3-ethylpyridin-2-amine as a yellow
solid.
3-Ethyl-5-nitropyridin-2-amine
[0342] Into a 50-mL 3-necked round-bottom flask was placed a
solution of 3-ethylpyridin-2-amine (1 g, 8.20 mmol, 1.00 equiv) in
sulfuric acid (4.8 mL), then added a mixture of HNO.sub.3 (0.7 ml)
and sulfuric acid (0.7 ml) dropwise at 0-5.degree. C. The resulting
solution was stirred overnight at room temperature. LCMS showed the
reaction was completed. The reaction mixture was used in the next
step directly without further work up.
3-Ethyl-5-nitropyridin-2-ol
[0343] Into a 50-mL 3-necked round-bottom flask was placed a
solution of 3-ethyl-5-nitropyridin-2-amine (.about.800 mg, 4.79
mmol, 1.00 equiv) in sulfuric acid and HNO.sub.3, then added
HNO.sub.3 (0.7 mL) dropwise at below 40.degree. C. The resulting
mixture was poured into 20 ml water and heated to 120.degree. C.
until no N.sub.2 evolution. The reaction mixture was cooled with a
water/ice bath. The isolated solid was collected by filtration and
washed with 10 ml of water. This resulted in 0.7 g (83%) of
3-ethyl-5-nitropyridin-2-ol as a light yellow solid.
2-Chloro-3-ethyl-5-nitropyridine
[0344] A solution of 3-ethyl-5-nitropyridin-2-ol (500 mg, 2.98
mmol, 1.00 equiv) in POCl.sub.3 (10 mL) was heated to reflux for 5
hr. The reaction mixture was cooled and concentrated under vacuum.
The residue was diluted with 10 mL of water, then adjusted to pH
8-9 with sodium bicarbonate solution. The resulting solution was
extracted with 2.times.20 mL of ether. The organic layers were
combined, dried over anhydrous sodium sulfate and concentrated
under vacuum. This resulted in 0.5 g (86%) of
2-chloro-3-ethyl-5-nitropyridine as a yellow oil.
2-(Benzylthio)-3-ethyl-5-nitropyridine
[0345] Into a 50-mL round-bottom flask were placed a solution of
phenylmethanethiol (370 mg, 2.98 mmol, 1.10 equiv) in
tetrahydrofuran (50 mL) and potassium carbonate (482 mg, 3.49 mmol,
1.30 equiv), then added a solution of
2-chloro-3-ethyl-5-nitropyridine (500 mg, 2.69 mmol, 1.00 equiv) in
tetrahydrofuran (10 mL) dropwise with stirring. The resulting
solution was heated to reflux overnight. The resulting mixture was
cooled and concentrated under vacuum. The residue was diluted with
20 mL of water, then extracted with 4.times.20 mL of ethyl acetate.
The organic layers were combined, washed with 1.times.20 mL of
brine, dried over anhydrous sodium sulfate and concentrated under
vacuum. The residue was applied onto a silica gel column and eluted
with ethyl acetate/petroleum ether (1:100). This resulted in 0.65 g
(84%) of 2-(benzylthio)-3-ethyl-5-nitropyridine as a yellow
solid.
6-(Benzylthio)-5-ethylpyridin-3-amine
[0346] Into a 50-mL round-bottom flask were placed a solution of
2-(benzylthio)-3-ethyl-5-nitropyridine (650 mg, 2.37 mmol, 1.00
equiv) in ethanol/H.sub.2O (10/2.5 mL), Fe (1.33 g, 23.75 mmol,
10.00 equiv) and HCl (0.125 mL). The resulting mixture was heated
to reflux for 2 hr. The reaction mixture was cooled and filtered.
The filtrate was concentrated under vacuum. This resulted in 0.53 g
(87%) of 6-(benzylthio)-5-ethylpyridin-3-amine as a yellow oil.
N-(6-(Benzylthio)-5-ethylpyridin-3-yl)acetamide
[0347] Into a 50-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen were placed a
solution of 6-(benzylthio)-5-ethylpyridin-3-amine (530 mg, 2.17
mmol, 1.00 equiv) in tetrahydrofuran (5 mL) and triethylamine (320
mg, 3.17 mmol, 1.50 equiv). This was followed by the addition of
Ac.sub.2O (320 mg, 3.14 mmol, 1.50 equiv) dropwise with stirring at
0.degree. C. The resulting solution was stirred for 3 h at room
temperature, then concentrated under vacuum. The residue was
diluted with 5 mL of water, then extracted with 2.times.10 mL of
ethyl acetate. The organic layers were combined, washed with
1.times.5 mL of brine, dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with ethyl acetate/petroleum ether (1:5).
This resulted in 0.45 g (69%) of
N-(6-(benzylthio)-5-ethylpyridin-3-yl)acetamide as a yellow
solid.
5-Acetamido-3-ethylpyridine-2-sulfonyl chloride
[0348] Into a 50-mL 3-necked round-bottom flask was placed a
solution of N-(6-(benzylthio)-5-ethylpyridin-3-yl)acetamide (450
mg, 1.57 mmol, 1.00 equiv) in DCM/H.sub.2O (10/2 mL). The solution
was cooled in an ice bath, then slowly bubbled Cl.sub.2 into the
reaction mixture for 15 min. The reaction mixture was stirred for
additional 15 min. Nitrogen was then bubbled into the reaction
mixture for 30 min to remove any excess Cl.sub.2. The reaction
mixture was diluted with DCM. The separated organic layer was dried
over Na.sub.2SO.sub.4 and concentrated under vacuum. This resulted
in 0.4 g (92%) of 5-acetamido-3-ethylpyridine-2-sulfonyl chloride
as a yellow oil.
N-(5-ethyl-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl-
)pyridin-3-yl)acetamide
[0349] Into a 50-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen were placed a
solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (200 mg, 1.34
mmol, 1.00 equiv) in CH.sub.3CN (15 mL), potassium carbonate (575
mg, 4.17 mmol, 3.00 equiv) and
5-acetamido-3-ethylpyridine-2-sulfonyl chloride (400 mg, 1.53 mmol,
1.10 equiv). The resulting solution was stirred for 1 h at
0.degree. C. The reaction was then quenched by the addition of 5 mL
of water. The resulting mixture was concentrated under vacuum. The
residue was diluted with 20 mL of water, then adjusted to pH 6 with
2N HCl. The resulting solution was extracted with 3.times.20 ml, of
ethyl acetate. The organic layers were combined, dried and
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with dichloromethane/methanol (30:1). This
resulted in 345 mg (65%) of
N-(5-ethyl-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)pyridin-3-yl)acetamide as a yellow solid.
5-Amino-3-ethyl-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridin-
e-2-sulfonamide
[0350] Into a 100-mL round-bottom flask was placed a solution of
N-(5-ethyl-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)pyridin-3-yl)acetamide (345 mg, 0.92 mmol, 1.00 equiv) in
tetrahydrofuran (20 mL) and HCl (10%, 20 mL). The resulting
solution was stirred overnight at 60.degree. C. The reaction
mixture was cooled and concentrated under vacuum. The crude product
(200 mg) was purified by Prep-HPLC with the following conditions:
Column, SunFire C18, 19.times.150 mm, Sum; Mobile phase, water
(with 0.05% TFA) and acetonitrile; Grident: 25% acetonitrile up to
45% in 6 min, then up to 100% in 0.1 min); Detector, UV 254 nm.
This resulted in 139.8 mg (46%) of
5-amino-3-ethyl-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridi-
ne-2-sulfonamide as a white solid. LC-MS-(ES, m/z): 334
[M+H].sup.+. H-NMR-(DMSO-d6, 300 MHz, ppm): 10.149 (1H, s), 7.179
(1H, s), 7.696-7.688 (1H, d, J=2.8), 7.501 (1H, s), 7.235 (2H, s),
6.37 (2H, s), 6.804-6.796 (1H, d, J=2.4), 6.012 (2H, s), 4.876 (2H,
s), 2.879-2.805 (2H, m), 1.157-1.107 (3H, m).
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-isopropylpyr-
idine-2-sulfonamide
##STR00141##
[0351] Methyl 2-aminonicotinate
[0352] Into a 250-mL round-bottom flask was placed a solution of
2-aminonicotinic acid (15 g, 108.70 mmol, 1.00 equiv) in methanol
(100 mL), then added thionyl chloride (38.5 g, 326.27 mmol, 3.00
equiv) dropwise at 0.degree. C. The resulting solution was stirred
overnight at 70.degree. C. in an oil bath. The resulting mixture
was cooled and concentrated under vacuum. The residue was diluted
with 30 mL of water, then adjusted to pH 7-8 with NaHCO.sub.3
solution. The resulting solution was extracted with 3.times.40 mL
of ethyl acetate. The organic layers were combined, dried over
anhydrous sodium sulfate and concentrated under vacuum. The crude
product was purified by re-crystallization from ether. This
resulted in 8 g (42%) of methyl 2-aminonicotinate as a white
solid.
2-(2-Aminopyridin-3-yl)propan-2-ol
[0353] Into a 250-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen was placed a
solution of methyl 2-aminonicotinate (8 g, 52.63 mmol, 1.00 equiv)
in tetrahydrofuran (100 mL). This was followed by the addition of
methylmagnesium bromide (70 mL, 4.00 equiv) dropwise with stirring
at -20.degree. C. The resulting solution was stirred for 2.5 h at
room temperature, then quenched by the addition of 60 mL of
NH.sub.4Cl solution. The resulting solution was extracted with
3.times.50 ml, of ethyl acetate. The organic layers were combined,
dried over anhydrous sodium sulfate and concentrated under vacuum.
This resulted in 6.6 g (73%) of 2-(2-aminopyridin-3-yl)propan-2-ol
as a white solid.
3-Isopropylpyridin-2-amine
[0354] A mixture of 2-(2-aminopyridin-3-yl)propan-2-ol (6 g, 39.47
mmol, 1.00 equiv), P (3.67 g, 118.39 mmol, 3.00 equiv) and HI (30
mL) was stirred overnight at 150.degree. C. in an oil bath. The
reaction mixture was cooled and filtered. The filtrate was washed
with 3.times.10 mL of ether. The aqueous layer was adjusted to pH
6-7 with ammonia. The resulting solution was extracted with
3.times.10 mL of ethyl acetate. The organic layers were combined,
dried over anhydrous sodium sulfate and concentrated under vacuum.
The residue was applied onto a silica gel column and eluted with
ethyl acetate/petroleum ether (1:3). This resulted in 4.6 g (77%)
of 3-isopropylpyridin-2-amine as a white solid.
3-Isopropyl-5-nitropyridin-2-ol
[0355] Into a 100-mL round-bottom flask was placed a solution of
3-isopropylpyridin-2-amine (4.6 g, 33.82 mmol, 1.00 equiv) in
sulfuric acid (22 mL). This was followed by the addition of mixture
of sulfuric acid (3.2 mL) and HNO.sub.3 (3.2 mL) dropwise with
stirring at 5.degree. C. The resulting solution was stirred
overnight at 30.degree. C. in an oil bath. A second batch of
HNO.sub.3 (3.2 mL) was added dropwise with stirring at below
40.degree. C. The reaction mixture was then poured into 40 ml of
water and heated to 120.degree. C. The reaction mixture was cooled
rapidly by placing in an ice-bath and by adding ice directly to the
reaction mixture. The isolated solid was collected by filtration.
This resulted in 3.1 g (46%) of 3-isopropyl-5-nitropyridin-2-ol as
a yellow solid.
2-Chloro-3-isopropyl-5-nitropyridine
[0356] A solution of 3-isopropyl-5-nitropyridin-2-ol (100 mg, 0.55
mmol, 1.00 equiv) in POCl.sub.3 (10 mL) was stirred for 4 h at
100.degree. C. in an oil bath. The resulting mixture was cooled and
concentrated under vacuum. The residue was diluted with ice water
and adjusted to pH 7 with sodium hydroxide solution. The resulting
solution was extracted with 3.times.20 mL of ether. The organic
layers were combined, dried over anhydrous sodium sulfate and
concentrated under vacuum. This resulted in 96 mg (79%) of
2-chloro-3-isopropyl-5-nitropyridine as a red oil.
2-(Benzylthio)-3-isopropyl-5-nitropyridine
[0357] Into a 50-mL round-bottom flask was placed a solution of
phenylmethanethiol (70 mg, 0.56 mmol, 1.10 equiv) in
tetrahydrofuran (10 mL), then added potassium carbonate (90 mg,
0.65 mmol, 1.30 equiv). The resulting mixture was stirred for 30
min at 60.degree. C. in an oil bath. This was followed by the
addition of a solution of 2-chloro-3-isopropyl-5-nitropyridine (100
mg, 0.50 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) dropwise with
stirring. The resulting solution was stirred for an additional 3 h
at 70.degree. C. in an oil bath. The resulting mixture was cooled
and concentrated under vacuum. The residue was diluted with 10 mL
of water, then extracted with 3.times.10 mL of ethyl acetate. The
organic layers were combined, dried over anhydrous sodium sulfate
and concentrated under vacuum. The residue was applied onto a
silica gel column and eluted with PE/EtOAc (80:1). This resulted in
0.089 g (55%) of 2-(benzylthio)-3-isopropyl-5-nitropyridine as a
yellow oil.
6-(Benzylthio)-5-isopropylpyridin-3-amine
[0358] A mixture of 2-(benzylthio)-3-isopropyl-5-nitropyridine (2.5
g, 8.68 mmol, 1.00 equiv), ethanol (50 mL), water (12 mL), Fe (4.86
g, 86.79 mmol, 10.00 equiv) and HCl (0.75 mL) was stirred for 2 h
at 100.degree. C. in an oil bath. The reaction mixture was cooled
to room temperature and filtered. The filtrate was diluted with
EtOH/H.sub.2O(4:1), then concentrated under vacuum. The residual
solution was adjusted to pH 8 with sodium hydroxide solution (20%).
The resulting solution was extracted with 2.times.40 mL of
dichloromethane. The organic layers were combined, washed with
2.times.20 ml, of brine, dried over anhydrous sodium sulfate and
concentrated under vacuum. This resulted in 2.1 g (86%) of
6-(benzylthio)-5-isopropylpyridin-3-amine as a yellow oil.
N-(6-(Benzylthio)-5-isopropylpyridin-3-yl)acetamide
[0359] Into a 100-mL round-bottom flask was placed a solution of
6-(benzylthio)-5-isopropylpyridin-3-amine (2.1 g, 8.14 mmol, 1.00
equiv) in tetrahydrofuran (20 mL) and triethylamine (1.23 g, 12.18
mmol, 1.50 equiv), then added acetic anhydride (1.24 g, 12.16 mmol,
1.50 equiv) at 0.degree. C. The resulting solution was stirred
overnight at room temperature. The reaction was then quenched by
the addition of 10 mL of HCl (4M). The resulting solution was
extracted with 3.times.20 mL of ethyl acetate. The organic layers
were combined, washed with 1.times.20 mL of brine, dried over
anhydrous sodium sulfate and concentrated under vacuum. This
resulted in 2.15 g (77%) of
N-(6-(benzylthio)-5-isopropylpyridin-3-yl)acetamide as a yellow
oil.
5-Acetamido-3-isopropylpyridine-2-sulfonyl chloride
[0360] Cl.sub.2 gas was bubbled into a solution of
N-(6-(benzylthio)-5-isopropylpyridin-3-yl)acetamide (2.1 g, 7.00
mmol, 1.00 equiv) in DCM (50 mL) and water (10 mL) for 15 min at
0.degree. C. The resulting solution was stirred for 15 min at room
temperature, then bubbled with N.sub.2 for 30 min at 0.degree. C.
The resulting solution was extracted with 2.times.10 mL of
dichloromethane. The organic layers were combined, dried over
anhydrous sodium sulfate and concentrated under vacuum. The crude
product was purified by re-crystallization from hexane. This
resulted in 1.9 g (85%) of
5-acetamido-3-isopropylpyridine-2-sulfonyl chloride as a yellow
solid.
N-{6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]-5-(propan-2--
yl)pyridin-3-yl}acetamide
[0361] Into a 50-mL 3-necked round-bottom flask were placed a
solution of 5-acetamido-3-isopropylpyridine-2-sulfonyl chloride (1
g, 3.62 mmol, 1.10 equiv) in MeCN (10 mL) and potassium carbonate
(1.36 g, 9.86 mmol, 3.00 equiv). The resulting mixture was stirred
for 10 min at 0.degree. C., then added a solution of
6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (490 mg, 3.29 mmol, 1.00
equiv) in MeCN (5 mL) dropwise with stirring at 0.degree. C. The
resulting solution was stirred for an additional 30 min at room
temperature, then concentrated under vacuum. The residue was
diluted with 10 mL of water, then adjusted to pH 6 with HCl. The
resulting solution was extracted with 3.times.20 mL of ethyl
acetate. The organic layers were combined, dried over anhydrous
sodium sulfate and concentrated under vacuum. The residue was
applied onto a silica gel column and eluted with
dichloromethane/methanol (100:1). This resulted in 1.03 g (73%) of
N-{6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]-5-(propan-2-
-yl)pyridin-3-yl}acetamide as a yellow solid.
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-isopropylpyr-
idine-2-sulfonamide
[0362] A solution of
N-{6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]-5-(propan-2-
-yl)pyridin-3-yl}acetamide (1 g, 2.57 mmol, 1.00 equiv) in
tetrahydrofuran (50 mL) and HCl (50 mL, 10%) was stirred overnight
at 60.degree. C. in an oil bath. The resulting mixture was cooled
and concentrated under vacuum. The crude product (350 mg) was
purified by prep-HPLC with the following conditions: Column,
SunFire C18, Sum, 19.times.150 mm; Mobile phase, water (with 0.1%
formic acid) and methanol; Gradient, 30% methanol up to 60% in 7
min, up to 100% in 2 min, down to 30% in 3 min; Detector, UV 220
& 254 nm. This resulted in 0.11 g (12%) of
5-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-isopropylpy-
ridine-2-sulfonamide as a white solid. LC-MS (ES, m/z): 348
[M+H].sup.+. .sup.1H-NMR (300 MHz, DMSO-d6, ppm): 9.176 (1H, s),
10.145 (1H, s), 7.679 (1H, d, J=2.4 Hz), 7.515 (1H, s), 7.272 (2H,
m), 6.948 (1H, d, J=2.4 Hz), 5.969 (2H, s), 4.879 (2H, s), 3.794
(1H, m), 1.135 (6H, d, J=6.9 Hz).
2-Chloro-N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-ni-
trobenzenesulfonamide
##STR00142##
[0364] General Procedure 1: Starting Materials
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and
2-chloro-4-nitrobenzene-1-sulfonyl chloride. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.73 (s, 1H), 9.28 (bs., 1H), 8.51 (d,
J=2.4 Hz, 1H), 8.28 (dd, J=8.8, 2.0 Hz, 1H), 8.09 (d, J=8.8 Hz,
1H), 7.62 (d, J=8.0 Hz, 1H), 7.27 (d, J=10 Hz, 1H), 4.92 (s, 2H).
MS (ESI): m/z=385.0 (M-H, negative).
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluorome-
thyl)pyridine-2-sulfonamide
##STR00143##
[0365] 5-Nitro-3-(trifluoromethyl)pyridin-2-ol
[0366] Into a 500-mL 3-necked round-bottom flask was placed
3-(trifluoromethyl)pyridin-2-ol (10 g, 61.35 mmol, 1.00 equiv),
then added sulfuric acid (98%) (40 mL) dropwise with stirring at
0.degree. C. This was followed by the addition of HNO.sub.3 (50 mL)
dropwise with stirring at 0.degree. C. The resulting solution was
stirred overnight at 40.degree. C. The reaction was quenched by the
addition of 500 mL of water, then extracted with 3.times.200 mL of
ether. The organic layers were combined, dried and concentrated
under vacuum. This resulted in 6.5 g (51%) of
5-nitro-3-(trifluoromethyl)pyridin-2-ol as a white solid.
2-Chloro-5-nitro-3-(trifluoromethyl)pyridine
[0367] Into a 250-mL round-bottom flask was placed a solution of
5-nitro-3-(trifluoromethyl)pyridin-2-ol (5 g, 24.04 mmol, 1.00
equiv) in POCl.sub.3 (270.5 g) and PCl.sub.5 (14 g, 67.31 mmol,
2.80 equiv). The resulting solution was stirred for 2 h at
120.degree. C. The reaction was then cooled and quenched by the
addition of 800 mL of water/ice. The pH value of the solution was
adjusted to 9 with sodium carbonate solution (60%). The resulting
solution was extracted with 2.times.200 mL of dichloromethane. The
organic layers were combined, dried over anhydrous sodium sulfate
and concentrated under vacuum. This resulted in 3.1 g (57%) of
2-chloro-5-nitro-3-(trifluoromethyl)pyridine as a yellow solid.
2-(Benzylthio)-5-nitro-3-(trifluoromethyl)pyridine
[0368] Into a 100-mL 3-necked round-bottom flask was placed a
solution of phenylmethanethiol (2 g, 16.13 mmol, 1.10 equiv) in
tetrahydrofuran (50 mL), then added potassium carbonate (1.6 g,
11.59 mmol, 1.30 equiv). The resulting solution was stirred for 30
min at 60.degree. C. This was followed by the addition of a
solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 8.85
mmol, 1.00 equiv) in tetrahydrofuran (10 mL) dropwise with stirring
at 60.degree. C. The resulting solution was refluxed overnight. The
reaction mixture was cooled and concentrated under vacuum. The
residue was applied onto a silica gel column and eluted with ethyl
acetate/petroleum ether (1:20). This resulted in 1.9 g (68%) of
2-(benzylthio)-5-nitro-3-(trifluoromethyl)pyridine as a yellow
solid.
6-(Benzylthio)-5-(trifluoromethyl)pyridin-3-amine
[0369] Into a 250-mL round-bottom flask were placed a solution of
2-(benzylthio)-5-nitro-3-(trifluoromethyl)pyridine (2.1 g, 6.69
mmol, 1.00 equiv) in ethanol (50 mL), Fe (3.7 g, 66.07 mmol, 10.00
equiv) and acetic acid (5 mL). The resulting mixture was refluxed
for 3 h. The reaction mixture was cooled and filtered. The filtrate
was concentrated under vacuum. The residue was applied onto a
silica gel column and eluted with dichloromethane/methanol (100:1).
This resulted in 1.8 g (95%) of
6-(benzylthio)-5-(trifluoromethyl)pyridin-3-amine as a yellow
solid.
N-(6-(benzylthio)-5-(trifluoromethyl)pyridin-3-yl)-2,2,2-trifluoroacetamid-
e
[0370] Into a 100-mL round-bottom flask was placed a solution of
6-(benzylthio)-5-(trifluoromethyl)pyridin-3-amine (1.8 g, 6.34
mmol, 1.00 equiv) in dichloromethane (50 mL), then added TEA (1.3
g, 12.87 mmol, 2.00 equiv). This was followed by the addition of
(CF.sub.3CO).sub.2O (2 g, 9.52 mmol, 1.50 equiv) dropwise with
stirring at 0.degree. C. The resulting solution was stirred for 30
min at room temperature, then quenched by the addition of 100 mL of
water. The resulting solution was extracted with 3.times.100 mL of
dichloromethane. The organic layers were combined, dried and
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with ethyl acetate/petroleum ether (1:20).
This resulted in 2.0 g (83%) of
N-(6-(benzylthio)-5-(trifluoromethyl)pyridin-3-yl)-2,2,2-trifluoroacetami-
de as a white solid.
5-(2,2,2-Trifluoroacetamido)-3-(trifluoromethyl)pyridine-2-sulfonyl
chloride
[0371] Into a 100-mL 3-necked round-bottom flask was placed a
solution of
N-(6-(benzylthio)-5-(trifluoromethyl)pyridin-3-yl)-2,2,2-trifluoroacetami-
de (700 mg, 1.84 mmol, 1.00 equiv) in dichloromethane (17.5 mL) and
water (3.5 mL). Cl.sub.2 gas was bubbled into the reaction mixture
at 0.degree. C. The resulting solution was stirred for 15 min at
0-5.degree. C. The reaction mixture was dried over anhydrous sodium
sulfate and concentrated under vacuum. This resulted in 650 mg
(crude) of
5-(2,2,2-trifluoroacetamido)-3-(trifluoromethyl)pyridine-2-sulfonyl
chloride as a yellow solid.
2,2,2-Trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)s-
ulfamoyl)-5-(trifluoromethyl)pyridin-3-yl)acetamide
[0372] Into a 100-mL 3-necked round-bottom flask were placed a
solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (250 mg, 1.68
mmol, 1.00 equiv) in CH.sub.3CN (20 mL) and potassium carbonate
(926 mg, 6.71 mmol, 4.00 equiv). This was followed by the addition
of a solution of
5-(2,2,2-trifluoroacetamido)-3-(trifluoromethyl)pyridine-2-sulfonyl
chloride (716 mg, 2.01 mmol, 1.20 equiv) in CH.sub.3CN (10 mL)
dropwise with stirring at 0.degree. C. The resulting solution was
stirred for 30 min at room temperature, then concentrated under
vacuum. The residue was diluted with 50 mL of water, then adjusted
to pH 6 with HCl (1 mol/L). The resulting solution was extracted
with 3.times.100 mL of ethyl acetate. The organic layers were
combined, dried and concentrated under vacuum. The residue was
applied onto a silica gel column and eluted with
dichloromethane/methanol (50:1). This resulted in 400 mg (crude) of
2,2,2-trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
sulfamoyl)-5-(trifluoromethyl)pyridin-3-yl)acetamide as a yellow
solid.
5-Amino-N-(1-hydroxy-1,-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluoromet-
hyl)pyridine-2-sulfonamide
[0373] Into a 100-mL round-bottom flask was placed a solution of
2,2,2-trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
sulfamoyl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (300 mg, 0.64
mmol, 1.00 equiv) in tetrahydrofuran (50 mL), then added potassium
carbonate (aq) (40 mL). The resulting mixture was stirred overnight
at 40.degree. C., then concentrated under vacuum. The residue was
diluted with 50 mL of water, then adjusted to pH 7 with HCl (1
mol/L). The resulting solution was extracted with 3.times.100 mL of
ethyl acetate. The organic layers were combined, dried and
concentrated under vacuum. The collected fractions were combined
and concentrated under vacuum. The crude product (400 mg) was
purified by Prep-HPLC with the following conditions: Column,
SunFire C18, 19.times.150 mm, Sum; Mobile phase, water (with 0.1%
TFA) and MeOH; Gradient: 40% MeOH up to 70% in 10 min). This
resulted in 109.5 mg (46%) of
5-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(trifluorom-
ethyl)pyridine-2-sulfonamide as a yellow solid. The compound
exhibited a melting point of 157-159.degree. C. LC-MS-(ES, m/z):
374 [M+H].sup.+. .sup.1H NMR-(300 MHz, DMSO-d6): 4.894 (2H, s),
6.598 (2H, s), 7.278-7.332 (3H, d, 16.2 Hz), 7.548 (1H, s), 8.022
(1H, s), 9.206 (1H, s), 10.432 (1H, s).
5-Amino-3-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl-
)pyridine-2-sulfonamide hydrochloride
##STR00144##
[0374] 2-Methoxynicotinonitrile
[0375] A solution of 2-chloronicotinonitrile (20 g, 144.93 mmol,
1.00 equiv) and MeONa (15.7 g, 290.74 mmol, 2.00 equiv) in methanol
(300 mL) was stirred overnight at room temperature. The resulting
mixture was concentrated under vacuum. The residue was diluted with
500 mL of water, then extracted with 3.times.200 mL of
dichloromethane. The organic layers were combined, dried and
concentrated under vacuum. This resulted in 17 g (88%) of
2-methoxynicotinonitrile as a white solid.
2-Hydroxynicotinonitrile
[0376] A solution of 2-methoxynicotinonitrile (10 g, 74.63 mmol,
1.00 equiv) in HBr/AcOH (20 mL) was stirred for 30 min at
70.degree. C. The reaction mixture was cooled and filtered. The
filter cake was washed with 2.times.200 mL of ether. This resulted
in 7.5 g (50%) of 2-hydroxynicotinonitrile hydrobromide as a yellow
solid.
2-Hydroxy-5-nitronicotinonitrile
[0377] Into a 1000-mL 3-necked round-bottom flask was placed a
solution of 2-hydroxynicotinonitrile hydrobromide (100 g, 500.00
mmol, 1.00 equiv) in acetic anhydride (250 mL). This was followed
by the addition of a solution of fuming nitric acid (35 mL) in
acetic anhydride (65 mL) dropwise with stirring at 0.degree. C. The
resulting solution was stirred for 30 min at room temperature, then
quenched by the addition of 500 mL of ether. The isolated solid was
collected by filtration and washed with 3.times.50 mL of ether.
This resulted in 39 g (47%) of 2-hydroxy-5-nitronicotinonitrile as
a yellow solid.
2-Chloro-5-nitronicotinonitrile
[0378] Into a 1000-mL round-bottom flask were placed
2-hydroxy-5-nitronicotinonitrile (40 g, 242.42 mmol, 1.00 equiv),
POCl.sub.3 (845 g) and PCl.sub.5 (141 g, 677.88 mmol, 2.80 equiv).
The resulting solution was heated to reflux for 3 h. The reaction
mixture was cooled and quenched by the addition of 2000 mL of
water/ice.
[0379] The pH value of the solution was adjusted to 8 with
potassium carbonate solution, then it was extracted with
3.times.200 mL of dichloromethane. The organic layers were
combined, dried and concentrated under vacuum. This resulted in 40
g (90%) of 2-chloro-5-nitronicotinonitrile as a yellow solid.
2-(Benzylthio)-5-nitronicotinonitrile
[0380] Into a 1000-mL 4-necked round-bottom flask were placed a
solution of 2-chloro-5-nitronicotinonitrile (40 g, 218.58 mmol,
1.00 equiv) in tetrahydrofuran (500 mL) and potassium carbonate
(39.2 g, 284.06 mmol, 1.30 equiv). The resulting mixture was
stirred for 30 min at 60.degree. C., then added phenylmethanethiol
(30 g, 241.94 mmol, 1.10 equiv) dropwise. The resulting solution
was then heated to reflux overnight. The resulting mixture was
cooled and concentrated under vacuum. The residue was applied onto
a silica gel column and eluted with ethyl acetate/petroleum ether
(1:50-1:10). This resulted in 43 g (73%) of
2-(benzylthio)-5-nitronicotinonitrile as a yellow solid.
5-Amino-2-(benzylthio)nicotinonitrile
[0381] Into a 2000-mL 4-necked round-bottom flask were placed a
solution of 2-(benzylthio)-5-nitronicotinonitrile (50 g, 184.50
mmol, 1.00 equiv) in ethanol (1000 mL) and Fe (103 g, 1.84 mol,
10.00 equiv). This was followed by the addition of AcOH (66.4 g,
1.11 mol, 6.00 equiv) dropwise with stirring. The resulting
solution was heated to reflux for 5 h. The reaction mixture was
cooled and filtered. The filtrate was concentrated under vacuum.
The residue was applied onto a silica gel column and eluted with
dichloromethane/methanol (100:1). This resulted in 36 g (81%) of
5-amino-2-(benzylthio)nicotinonitrile as a yellow solid.
Methyl 6-(benzylthio)-5-cyanopyridin-3-ylcarbamate
[0382] Into a 500-mL round-bottom flask was placed a solution of
5-amino-2-(benzylthio)nicotinonitrile (24 g, 99.59 mmol, 1.00
equiv) in pyridine (250 mL). This was followed by the addition of
methyl carbonochloridate (10.3 g, 109.57 mmol, 1.10 equiv) dropwise
with stirring at 0.degree. C. The resulting solution was stirred
for 1 h at room temperature, then it was concentrated under vacuum.
The residue was diluted with 200 ml, of water. The resulting
solution was extracted with 3.times.100 mL of ethyl acetate. The
organic layers were combined, dried and concentrated under vacuum.
The residue was applied onto a silica gel column and eluted with
ethyl acetate/petroleum ether (1:20-1:5). This resulted in 25 g
(84%) of methyl 6-(benzylthio)-5-cyanopyridin-3-ylcarbamate as a
yellow solid.
Methyl 6-(chlorosulfonyl)-5-cyanopyridin-3-ylcarbamate
[0383] Chlorine gas was bubbled slowly into a solution of methyl
6-(benzylthio)-5-cyanopyridin-3-ylcarbamate (5 g, 16.72 mmol, 1.00
equiv) in dichloromethane (75 mL) and water (25 mL) at 0.degree. C.
for 5 minutes. The resulting solution was stirred for 15 min at
0.degree. C. The separated organic layer was dried over anhydrous
sodium sulfate and concentrated under vacuum. This resulted in 4.8
g (crude) of methyl 6-(chlorosulfonyl)-5-cyanopyridin-3-ylcarbamate
as a yellow solid.
Methyl
5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfa-
moyl)pyridin-3-ylcarbamate
[0384] Into a 250-mL round-bottom flask were placed a solution of
6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (2.98 g, 20.00 mmol, 1.00
equiv) in CH.sub.3CN (50 mL) and potassium carbonate (11.1 g, 80.43
mmol, 4.00 equiv). This was followed by the addition of a solution
of methyl 6-(chlorosulfonyl)-5-cyanopyridin-3-ylcarbamate (6.6 g,
23.91 mmol, 1.20 equiv) in CH.sub.3CN (10 mL) dropwise with
stirring at 0.degree. C. The resulting solution was stirred for 1 h
at room temperature, then it was concentrated under vacuum. The
residue was adjusted to pH 4-6 with HCl (10%), then extracted with
3.times.50 mL of ethyl acetate. The organic layers were combined,
dried and concentrated under vacuum. The residue was applied onto a
silica gel column and eluted with dichloromethane/methanol
(100:1-50:1). This resulted in 5 g (64%) of the title compound as a
yellow solid.
Methyl
5-(aminomethyl)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6--
yl)sulfamoyl)pyridin-3-ylcarbamate
[0385] A mixture of methyl
5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)p-
yridin-3-ylcarbamate (3 g, 7.73 mmol, 1.00 equiv) and Raney Ni (6
g, 103.45 mmol, 13.38 equiv) in NH.sub.3 solution (2M in methanol,
100 mL) was stirred for 3 h at room temperature under a hydrogen
atmosphere. The solid was filtered out. The filtrate was
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with dichloromethane/methanol (20:1-5:1).
This resulted in 1.8 g (59%) of the title compound as a yellow
solid.
5-Amino-3-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl-
)pyridine-2-sulfonamide
[0386] Into a 100-mL round-bottom flask was placed a solution of
methyl
5-(aminomethyl)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sul-
famoyl)pyridin-3-ylcarbamate (600 mg, 1.53 mmol, 1.00 equiv) in
ethanol (10 mL), then added a solution of potassium hydroxide (171
mg, 3.05 mmol, 2.00 equiv) in water (10 mL). The resulting solution
was stirred for 1 h at 90.degree. C. The reaction mixture was
cooled and adjusted to pH 7 with HCl (10%). The resulting mixture
was concentrated under vacuum. This resulted in 500 mg (crude) of
5-amino-3-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-y-
l)pyridine-2-sulfonamide as a yellow solid.
Tert-butyl
(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
sulfamoyl)pyridin-3-yl)methylcarbamate
[0387] Into a 50-mL round-bottom flask was placed a solution of
5-amino-3-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-y-
l)pyridine-2-sulfonamide (300 mg, 0.90 mmol, 1.00 equiv) and
Boc.sub.2O (392 mg, 1.80 mmol, 2.00 equiv) in methanol (10 mL),
then added a solution of potassium carbonate (211 mg, 1.53 mmol,
2.00 equiv) in water (20 mL). The resulting solution was stirred
for 2 h at room temperature. Then it was adjusted to pH 7 with HCl
(10%). The resulting solution was extracted with 3.times.20 mL of
ethyl acetate. The organic layers were combined, dried and
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with ethyl acetate/petroleum ether
(20:1-5:1). This resulted in 301 mg (75%) of the title compound as
a yellow solid.
5-Amino-3-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl-
)pyridine-2-sulfonamide hydrochloride
[0388] HCl gas was bubbled slowly into a solution of tert-butyl
(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-
pyridin-3-yl)methylcarbamate (300 mg, 0.69 mmol, 1.00 equiv) in
methanol (30 mL) for 30 min at room temperature. The resulting
mixture was concentrated under vacuum. The residue was washed with
1.times.20 mL of ether. This resulted in 126 mg (47%) of the title
compound as a yellow solid. LC-MS-(ES, m/z): 335 [M+H].sup.+.
.sup.1H-NMR-(300 MHz, DMSO-d6, ppm): 4.165-4.355 (m, 4H), 4.888 (s,
2H), 6.952-6.960 (d, J=2.4 Hz, 1H), 7.086 (s, 1H), 7.249-7.253 (d,
J=1.2 Hz, 2H), 7.425 (s, 1H), 7.532 (s, 1H), 7.840-7.848 (d, J=2.4
Hz, 1H), 8.414 (s, 2H), 10.365 (s, 1H).
Tert-butyl
(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
sulfamoyl)pyridin-3-yl)methylcarbamate
##STR00145##
[0390] Into a 50-mL round-bottom flask was placed a solution of
5-amino-3-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-y-
l)pyridine-2-sulfonamide (300 mg, 0.90 mmol, 1.00 equiv) and
Boc.sub.2O (392 mg, 1.80 mmol, 2.00 equiv) in methanol (10 mL),
then added a solution of potassium carbonate (211 mg, 1.53 mmol,
2.00 equiv) in water (20 mL). After stirred for 2 h at room
temperature, the reaction mixture was adjusted to pH 7 with HCl
(10%). The resulting solution was extracted with 3.times.20 mL of
ethyl acetate. The organic layers were combined, dried and
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with ethyl acetate/petroleum ether
(20:1-5:1). This resulted in 301 mg (75%) of the title compound as
a yellow solid. LC-MS-(ES, m/z): 435 [M+H].sup.+. .sup.1H-NMR-(300
MHz, DMSO-d6, ppm): 1.418 (m, 9H), 4.405-4.427 (d, J=6.6 Hz, 2H),
4.877 (s, 1H), 6.205 (s, 2H), 6.838 (s, 1H), 7.237 (s, 3H), 7.499
(s, 1H), 7.703-7.711 (d, J=2.4 Hz, 1H), 9.185 (s, 1H), 10.220 (s,
1H).
5-Amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)ni-
cotinic acid
##STR00146##
[0392] Into a 50-mL round-bottom flask were placed a solution of
methyl
2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-
-trifluoroacetamido)nicotinate (100 mg, 0.22 mmol, 1.00 equiv) in
tetrahydrofuran/H.sub.2O (1:1, 20 mL) and lithium hydroxide hydrate
(91 mg, 2.17 mmol, 10.00 equiv). The resulting solution was stirred
overnight at room temperature. The reaction progress was monitored
by LCMS. The resulting solution was washed with 20 mL of ethyl
acetate. The aqueous layer was adjusted to pH 5-6 with HCl (4
mol/L). The resulting solution was extracted with 3.times.20 mL of
ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate and concentrated under vacuum. The crude product was
purified by re-crystallization from ethyl ether. This resulted in
30 mg (39.5%) of the title compound as a yellow solid. LC-MS-(ES,
m/z): 350 [M+H].sup.+. .sup.1H-NMR-(300 MHz, DMSO-d6, ppm): 13.38
(s, 1H), 10.15 (s, 1H), 9.17 (s, 1H), 7.88-7.87 (d, J=2.4 Hz, 1H),
7.48-7.47 (d, J=1.2 Hz, 1H), 7.28-7.20 (m, 2H), 6.94-6.93 (d, J=2.7
Hz, 1H), 6.32 (s, 2H), 4.87 (s, 2H).
5-Amino-N-ethyl-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulf-
amoyl)nicotinamide
##STR00147##
[0393] 2-Chloro-5-nitronicotinic acid
[0394] A solution of 2-hydroxy-5-nitrobenzoic acid (6.5 g, 35.52
mmol, 1.00 equiv) in phosphoryl trichloride (112.4 g, 739.47 mmol,
20.82 equiv) was stirred for 4 h at 120.degree. C. in an oil bath.
The resulting mixture was cooled and concentrated under vacuum. The
residue was diluted with 20 mL of THF, then added dropwise to 50 mL
of water/ice. The resulting solution was adjusted to pH 4-5 with
saturated NaHCO.sub.3 solution, followed by extraction with
3.times.30 mL of tetrahydrofuran/Et.sub.2O (1:2). The organic
layers were combined, dried over anhydrous sodium sulfate and
concentrated under vacuum. This resulted in 4.5 g (63%) of
2-chloro-5-nitronicotinic acid as a yellow solid.
2-(Benzylthio)-5-nitronicotinic acid
[0395] Into a 500-mL round-bottom flask were placed a solution of
phenylmethanethiol (3 g, 24.19 mmol, 1.08 equiv) in tetrahydrofuran
(200 mL) and potassium carbonate (7 g, 50.72 mmol, 2.27 equiv). The
resulting solution was stirred for 30 min at room temperature. This
was followed by the addition of 2-chloro-5-nitrobenzoic acid (4.5
g, 22.39 mmol, 1.00 equiv) in several batches. The resulting
solution was heated to reflux overnight in an oil bath. The
reaction mixture was cooled and concentrated under vacuum. The
residue was diluted with 100 mL of water and adjusted to pH 5-6
with HCl (4 mol/L). The resulting solution was extracted with
2.times.200 mL of ethyl acetate. The organic layers were combined,
dried over anhydrous sodium sulfate and concentrated under vacuum.
This resulted in 5.7 g (88%) of 2-(benzylthio)-5-nitrobenzoic acid
as a yellow solid.
Methyl 2-(benzylthio)-5-nitronicotinate
[0396] Into a 250-mL round-bottom flask was placed a solution of
2-(benzylthio)-5-nitronicotinic acid (5.7 g, 19.66 mmol, 1.00
equiv) in methanol (100 mL), then added sulfuryl dichloride (28 g,
235.29 mmol, 11.97 equiv). The resulting solution was heated to
reflux overnight in an oil bath. The reaction mixture was cooled to
room temperature with an ice water bath. The isolated solid was
collected by filtration. This resulted in 4 g (67%) of methyl
2-(benzylthio)-5-nitronicotinate as a yellow solid.
Methyl 5-amino-2-(benzylthio)nicotinate
[0397] Into a 250-mL round-bottom flask were placed a solution of
methyl 2-(benzylthio)-5-nitronicotinate (4 g, 13.16 mmol, 1.00
equiv) in ethanol (100 mL) and iron (7.4 g, 132.14 mmol, 10.04
equiv), then added acetic acid (4.7 g, 78.33 mmol, 5.95 equiv). The
resulting mixture was heated to reflux for 30 min in an oil bath.
The reaction mixture was cooled and filtered. The filter cake was
washed with 3.times.50 mL of methanol. The filtrate was
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with ethyl acetate/petroleum ether (2:1). The
collected fractions were combined and concentrated under vacuum.
This resulted in 4.6 g (crude) of methyl 5-amino-2-(benzylthio)
nicotinate as a brown oil.
Methyl 2-(benzylthio)-5-(2,2,2-trifluoroacetamido)nicotinate
[0398] Into a 250-mL 3-necked round-bottom flask was placed a
solution of methyl 5-amino-2-(benzylthio)nicotinate (3.6 g, 13.14
mmol, 1.00 equiv) in dichloromethane (60 mL) and TEA (2.6 g, 25.74
mmol, 1.96 equiv). This was followed by the addition of TFAA (4.1
g, 19.52 mmol, 1.49 equiv) dropwise with stirring at 0.degree. C.
The resulting solution was stirred for 2.5 h at room temperature.
The reaction was then quenched by the addition of 50 mL of water.
The resulting solution was extracted with 2.times.50 mL of
dichloromethane. The organic layers were combined, dried and
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with ethyl acetate/petroleum ether (1:7). The
collected fractions were combined and concentrated under vacuum.
This resulted in 3.2 g (66%) of methyl
2-(benzylthio)-5-(2,2,2-trifluoroacetamido) nicotinate as a white
solid.
Methyl
2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido)nicotinate
[0399] Chlorine gas was bubbled slowly into a solution of methyl
2-(benzylthio)-5-(2,2,2-trifluoroacetamido) nicotinate (3.2 g, 8.65
mmol, 1.00 equiv) in DCM/H.sub.2O (2:1, 40 mL) for 15 min. Excess
chlorine gas was removed by bubbling nitrogen gas through the
reaction solution for 15 minutes. The resulting solution was
extracted with 2.times.50 mL of dichloromethane. The organic layers
were combined, dried over anhydrous sodium sulfate and concentrated
under vacuum. The crude product was directly used in the next
step.
Methyl
2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5--
(2,2,2-trifluoroacetamido)nicotinate
[0400] Into a 50-mL 3-necked round-bottom flask were placed a
solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (1 g, 6.71 mmol,
0.93 equiv) in acetonitrile (20 mL) and potassium carbonate (3.7 g,
26.81 mmol, 3.72 equiv). This was followed by the addition of a
solution of methyl 2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido)
nicotinate (2.5 g, 7.20 mmol, 1.00 equiv) in acetonitrile (5 mL)
dropwise with stirring at 0.degree. C. The resulting solution was
stirred for 2 h at room temperature, then it was concentrated under
vacuum. The residue was diluted with 50 mL of H.sub.2O, then it was
adjusted to pH 5-6 with HCl (4 mol/L). The resulting solution was
extracted with 2.times.100 mL of ethyl acetate. The organic layers
were combined, dried over anhydrous sodium sulfate and concentrated
under vacuum. The residue was applied onto a silica gel column and
eluted with ethyl acetate/petroleum ether (1:3). The collected
fractions were combined and concentrated under vacuum. This
resulted in 2.3 g (70%) of the title compound as a yellow
solid.
5-Amino-N-ethyl-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulf-
amoyl)nicotinamide
[0401] Into a 100-mL round-bottom flask was placed a solution of
methyl
2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-
-trifluoroacetamido)nicotinate (500 mg, 1.09 mmol, 1.00 equiv) in
ethanol (40 mL), then added a solution of ethanamine in H.sub.2O
(70% wt, 2 mL). The resulting solution was heated to reflux for 30
min in an oil bath. The reaction progress was monitored by LC-MS.
Once reaction was completed, the reaction mixture was cooled and
concentrated under vacuum. The crude product (300 mg) was purified
by Prep-HPLC with the following conditions: Column, SunFire Prep
C.sub.18, Sum, 19.times.150 mm; Mobile phase, water (with 0.1%
formic acid) and CH.sub.3CN; Gradient, 25% CH.sub.3CN up to 35% in
4 min, up to 100% in 1.5 min; Detector, UV 220 & 254 nm. This
resulted in 0.12 g (29%) of the title compound as a light yellow
solid. LC-MS-(ES, m/z): 377 [M+H].sup.+. .sup.1H-NMR-(300 MHz,
DMSO-d6, ppm): 9.75 (s, 1H), 9.17 (s, 1H), 8.37-8.33 (t, J=5.4 Hz,
1H), 7.83-7.82 (d, J=2.4 Hz, 1H), 7.48 (s, 1H), 7.31-7.21 (m, 2H),
6.83-6.82 (d, J=1.8 Hz, 1H), 6.27 (s, 2H), 4.88 (s, 2H), 3.28-3.19
(m, 2H), 2.52-2.51 (t, J=1.8 Hz, 3H).
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-4H-
-1,2,4-triazol-3-yl)pyridine-2-sulfonamide
##STR00148##
[0402]
N-(6-(Benzylthio)-5-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide
[0403] Into a 250-mL round-bottom flask was placed a solution of
5-amino-2-(benzylthio)nicotinonitrile (3.5 g, 14.52 mmol, 1.00
equiv) in dichloromethane (50 mL) and TEA (3 g, 29.70 mmol, 2.05
equiv). This was followed by the addition of trifluoroacetic
anhydride (4.8 g, 22.86 mmol, 1.57 equiv) dropwise with stirring at
0.degree. C. After stirred for 1 h at room temperature, the
resulting mixture was diluted with 20 ml, of water. The separated
organic layer was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with ethyl acetate/petroleum ether (1:20).
This resulted in 4 g (82%) of
N-(6-(benzylthio)-5-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide as
a yellow solid.
3-Cyano-5-(2,2,2-trifluoroacetamido)pyridine-2-sulfonyl
chloride
[0404] Chlorine gas was bubbled into a solution of
N-(6-(benzylthio)-5-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide (4
g, 11.87 mmol, 1.00 equiv) in dichloromethane (100 mL) and water
(20 mL) for 15 min. Then nitrogen is bubbled through the reaction
mixture for 30 min. The organic layer was dried over anhydrous
sodium sulfate and concentrated under vacuum. This resulted in 4 g
of 3-cyano-5-(2,2,2-trifluoroacetamido) pyridine-2-sulfonyl
chloride as light red oil.
N-(5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl-
)pyridin-3-yl)-2,2,2-trifluoroacetamide
[0405] Into a 250-mL 3-necked round-bottom flask were placed a
solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (1.5 g, 10.07
mmol, 0.88 equiv) in acetonitrile (50 mL) and potassium carbonate
(6.5 g, 47.10 mmol, 4.11 equiv). This was followed by the addition
of a solution of 3-cyano-5-(2,2,2-trifluoroacetamido)
pyridine-2-sulfonyl chloride (4 g, 11.46 mmol, 1.00 equiv, 90%) in
acetonitrile (40 mL) dropwise with stirring at 0.degree. C. The
resulting solution was stirred for 30 min at room temperature, then
it was diluted with 30 mL of water. The resulting solution was
extracted with 3.times.50 ml, of ethyl acetate. The organic layers
were combined, dried over anhydrous sodium sulfate and concentrated
under vacuum. The residue was applied onto a silica gel column and
eluted with ethyl acetate/petroleum ether (1:51:1). This resulted
in 2.6 g (51%) of the title compound as a yellow solid.
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-4H-
-1,2,4-triazol-3-yl)pyridine-2-sulfonamide
[0406] Into a 100-mL round-bottom flask were placed a solution of
N-(5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)pyridin-3-yl)-2,2,2-trifluoroacetamide (500 mg, 1.12 mmol, 1.00
equiv, 95%) in ethanol (50 mL), acetohydrazide (870 mg, 11.76 mmol,
10.54 equiv) and EtONa (240 mg, 3.53 mmol, 3.17 equiv). The
resulting solution was heated to reflux for 3 days. The reaction
progress was monitored by LC-MS. Once the reaction was completed,
the resulting mixture was cooled and concentrated under vacuum. The
residue was applied onto a silica gel column and eluted with
dichloromethane/methanol (100:1). This resulted in 127.2 mg (29%)
of
5-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-4-
H-1,2,4-triazol-3-yl)pyridine-2-sulfonamide as a light yellow
solid. LC-MS (ES, m/z): 387 [M+H].sup.+. .sup.1H-NMR--(300 MHz,
DMSO-d6, ppm): 14.053 (s, 1H), 10.355 (s, 1H), 9.188 (s, 1H), 7.816
(s, 1H), 7.518 (s, 1H), 7.282-7.261 (d, 3H), 6.274 (s, 2H), 4.893
(s, 2H).
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-1,-
3,4-oxadiazol-2-yl)pyridine-2-sulfonamide
##STR00149##
[0407] 2-Chloro-5-nitronicotinic acid
[0408] Into a 250-mL round-bottom flask was placed
2-hydroxy-5-nitrobenzoic acid (15 g, 81.97 mmol, 1.00 equiv), then
added phosphoryl trichloride (90.9 g, 598.03 mmol, 7.30 equiv). The
resulting solution was heated to reflux for 4 h in an oil bath. The
resulting mixture was cooled and concentrated under vacuum. The
residue was diluted with 20 mL of tetrahydrofuran, then quenched by
the addition of 50 mL of water/ice. The pH value of the solution
was adjusted to 4-5 with saturated NaHCO.sub.3 solution. The
resulting solution was extracted with 3.times.30 mL of
tetrahydrofuran/Et.sub.2O (1:2). The organic layers were combined,
dried over anhydrous sodium sulfate and concentrated under vacuum.
This resulted in 8.6 g (52%) of 2-chloro-5-nitrobenzoic acid as a
yellow solid.
2-(Benzylthio)-5-nitronicotinic acid
[0409] Into a 500-mL round-bottom flask was placed a solution of
phenylmethanethiol (7 g, 56.45 mmol, 1.33 equiv) in tetrahydrofuran
(200 mL), then added potassium carbonate (13.5 g, 97.83 mmol, 2.31
equiv). The reaction mixture was stirred for 30 min at room
temperature. This was followed by the addition of
2-chloro-5-nitrobenzoic acid (8.6 g, 42.36 mmol, 1.00 equiv) in
several batches. The resulting solution was heated to reflux
overnight in an oil bath. The resulting mixture was cooled and
concentrated under vacuum. The residue was diluted with 100 mL of
water and was adjusted to pH 5-6 with HCl (4 mol/L). The resulting
solution was extracted with 2.times.200 mL of ethyl acetate. The
organic layers were combined, dried over anhydrous sodium sulfate
and concentrated under vacuum. This resulted in 10 g (81%) of
2-(benzylthio)-5-nitrobenzoic acid as a brown solid.
2-(2-(Benzylthio)-5-nitropyridin-3-yl)-5-methyl-1,3,4-oxadiazole
[0410] Into a 250-mL round-bottom flask were placed
2-(benzylthio)-5-nitronicotinic acid (8 g, 27.59 mmol, 1.00 equiv),
acetohydrazide (10.2 g, 137.84 mmol, 5.00 equiv) and phosphoryl
trichloride (85.2 mL). The resulting solution was heated to reflux
for 2 h in an oil bath. The resulting mixture was cooled and
concentrated under vacuum. The residue was diluted with 50 mL of
tetrahydrofuran, then quenched by the addition of 150 mL of
water/ice. The pH value of the solution was adjusted to 9-10 with
saturated NaHCO.sub.3 solution. The resulting solution was
extracted with 2.times.100 mL of ethyl acetate. The organic layers
were combined, dried and concentrated under vacuum. The residue was
applied onto a silica gel column and eluted with ethyl
acetate/petroleum ether (1:6). The collected fractions were
combined and concentrated under vacuum. This resulted in 4 g (44%)
of 2-(2-(benzylthio)-5-nitropyridin-3-yl)-5-methyl-1,3,4-oxadiazole
as a yellow solid.
6-(Benzylthio)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-amine
[0411] Into a 500-mL round-bottom flask were placed a solution of
2-(2-(benzylthio)-5-nitropyridin-3-yl)-5-methyl-1,3,4-oxadiazole (4
g, 12.20 mmol, 1.00 equiv) in ethanol (150 mL) and iron (6.8 g,
121.43 mmol, 9.96 equiv). This was followed by the addition of a
solution of acetic acid (4.4 g, 73.33 mmol, 6.01 equiv) in ethanol
(50 mL) dropwise while the reaction mixture was heated to reflux.
The resulting solution was refluxed for 30 min in an oil bath, then
it was cooled. The solid was filtered out. The filtrate was
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with dichloromethane/methanol (1:10). The
collected fractions were combined and concentrated under vacuum.
This resulted in 1.6 g (44%) of
6-(benzylthio)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-amine as
a brown solid.
5-Amino-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-2-sulfonyl
chloride
[0412] Into a 50-mL 3-necked round-bottom flask was placed a
solution of
6-(benzylthio)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-amine
(850 mg, 2.85 mmol, 1.00 equiv) in DCM/H.sub.2O (2:1, 30 mL). This
was followed by the addition of dichloromethane saturated with
chlorine gas (15 mL) dropwise with stirring at 0.degree. C. After
stirred for 30 minutes at 0.degree. C. in a water/ice bath, the
reaction mixture was diluted with DCM. The separated organic layer
was dried and concentrated under vacuum. The crude solid was
directly used in the next step.
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-1,-
3,4-oxadiazol-2-yl)pyridine-2-sulfonamide
[0413] Into a 50-mL 3-necked round-bottom flask were placed a
solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (350 mg, 2.35
mmol, 0.98 equiv) in acetonitrile (20 mL) and potassium carbonate
(1.2 g, 8.70 mmol, 3.62 equiv). This was followed by the addition
of a solution of
5-amino-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-2-sulfonyl
chloride (660 mg, 2.40 mmol, 1.00 equiv, crude) in acetonitrile (5
mL) dropwise with stirring at 0.degree. C. The resulting solution
was stirred for 2 h at room temperature. The reaction progress was
monitored by LC-MS. The resulting mixture was concentrated under
vacuum. The residue was diluted with 50 mL of H.sub.2O, then
adjusted to pH 5-6 with HCl (4 mol/L). The resulting solution was
extracted with 2.times.100 mL of ethyl acetate. The organic layers
were combined, dried over anhydrous sodium sulfate and concentrated
under vacuum. The crude product (300 mg) was purified by Prep-HPLC
with the following conditions: Column, SunFire Prep C.sub.18, Sum,
19.times.100 mm; Mobile phase, water (with 0.1% formic acid) and
CH.sub.3CN; Gradient, 20% CH.sub.3CN up to 40% in 6 min; Detector,
UV 254 nm. This resulted in 120 mg (13%) of
5-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-1-
,3,4-oxadiazol-2-yl)pyridine-2-sulfonamide as a light-yellow solid.
LC-MS-(ES, m/z): 388 [M+H].sup.+. .sup.1H-NMR-(300 MHz, DMSO-d6,
ppm): 10.29 (s, 1H), 9.19 (s, 1H), 8.06-8.05 (d, J=2.4 Hz, 1H),
7.46 (s, 1H), 7.26-7.17 (m, 2H), 7.10-7.09 (d, J=2.7 Hz, 1H), 6.53
(s, 2H), 4.89 (s, 2H), 3.55 (s, 3H).
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-1,-
2,4-oxadiazol-3-yl)pyridine-2-sulfonamide
##STR00150##
[0414]
2,2,2-Trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-
-6-yl)sulfamoyl)-5-(N-hydroxycarbamimidoyl)pyridin-3-yl)acetamide
[0415] Into a 100-mL round-bottom flask were placed a solution of
N-(5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)pyridin-3-yl)-2,2,2-trifluoroacetamide (2 g, 4.46 mmol, 1.00
equiv, 95%) in methanol (50 mL), NH.sub.2OH.HCl (1 g, 14.49 mmol,
3.25 equiv) and TEA (2 g, 19.80 mmol, 4.44 equiv). The resulting
solution was stirred for 3 h at room temperature, then it was
concentrated under vacuum. The residue was dissolved in 50 mL of
EtOAc. The resulting mixture was washed with 1.times.20 mL of
water. The organic layer was dried over anhydrous sodium sulfate
and concentrated under vacuum. This resulted in 2.1 g (92%) of the
title compound as a yellow solid.
2,2,2-Trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)s-
ulfamoyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)acetamide
[0416] Into a 50-mL round-bottom flask was placed a solution of
2,2,2-trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
sulfamoyl)-5-(N-hydroxycarbamimidoyl)pyridin-3-yl)acetamide (2.1 g,
4.12 mmol, 1.00 equiv, 90%) in AcOH (30 mL) and acetic anhydride (1
g, 9.80 mmol, 2.38 equiv). The resulting solution was stirred for 4
h at 100.degree. C. The resulting mixture was cooled and
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with dichloromethane/methanol (100:1). This
resulted in 0.8 g (36%) of the title compound as a yellow
solid.
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(5-methyl-1,-
2,4-oxadiazol-3-yl)pyridine-2-sulfonamide
[0417] Into a 100-mL round-bottom flask were placed a solution of
2,2,2-trifluoro-N-(6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
sulfamoyl)-5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl)acetamide
(400 mg, 0.75 mmol, 1.00 equiv, 90%) in methanol/H.sub.2O (50:1, 50
mL) and potassium carbonate (200 mg, 1.45 mmol, 1.94 equiv). The
resulting solution was stirred for 4 days at room temperature. The
reaction progress was monitored by LC-MS. Once reaction was
completed, the reaction mixture was adjusted to pH 7 with AcOH. The
resulting mixture was concentrated under vacuum. The crude product
(200 mg) was purified by Prep-HPLC with the following conditions:
Column, Atlantis T3, Sum, 19.times.150 mm; Mobile phase, water
(with 0.05% TFA) and CH.sub.3CN; Gradient, 20% CH.sub.3CN up to 23%
in 3 min, hold at 23% for 9 min, up to 100% in 0.1 min, hold at
100% for 1.9 min; Detector, UV 220 nm. This resulted in 70.2 mg
(24%) of the title compound as a white solid. LC-MS-(ES, m/z): 388
[M+H].sup.+. .sup.1H-NMR-- (300 MHz, DMSO-d6, ppm): 10.109 (s, 1H),
9.115 (s, 1H), 8.011 (s, 1H), 7.470 (s, 1H), 7.229 (s, 2H), 7.006
(s, 1H), 6.441 (s, 2H), 4.887 (s, 2H), 2.693 (s, 3H).
5-Amino-3-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridi-
ne-2-sulfonamide
##STR00151##
[0418] 2-(Benzylthio)-3-chloro-5-nitropyridine
[0419] Into a 250-mL round-bottom flask was placed a solution of
phenylmethanethiol (7.1 g, 57.26 mmol, 1.10 equiv) in
tetrahydrofuran (40 mL) and potassium carbonate (9.34 g, 67.68
mmol, 1.30 equiv). The resulting solution was stirred for 30 min at
60.degree. C. in an oil bath. This was followed by the addition of
a solution of 2,3-dichloro-5-nitropyridine (10 g, 52.08 mmol, 1.00
equiv) in tetrahydrofuran (20 mL) dropwise with stirring. The
resulting solution was refluxed for an additional 4 h. The reaction
mixture was then cooled and quenched by the addition of 30 mL of
water. The resulting solution was extracted with 50 mL of ethyl
acetate. The organic layers were combined, washed with brine, dried
and concentrated under vacuum. This resulted in 14.6 g (95%) of
2-(benzylthio)-3-chloro-5-nitropyridine as a brown solid.
6-(Benzylthio)-5-chloropyridin-3-amine
[0420] Into a 250-mL round-bottom flask were placed a solution of
2-(benzylthio)-3-chloro-5-nitropyridine (7 g, 25.00 mmol, 1.00
equiv) in ethanol (140 mL) and water (35 mL), Fe (14 g, 250.00
mmol, 10.00 equiv) and HCl (3.5 mL). The resulting mixture was
heated to reflux for 2 h in an oil bath. The reaction mixture was
cooled and filtered. The filtrate was concentrated under vacuum.
The residue was diluted with water and adjusted to pH 8 with sodium
hydroxide solution (20%). The resulting solution was extracted with
3.times.50 mL of dichloromethane. The organic layers were combined,
dried over anhydrous sodium sulfate and concentrated under vacuum.
This resulted in 6 g (92%) of
6-(benzylthio)-5-chloropyridin-3-amine as red oil.
N-(6-(benzylthio)-5-chloropyridin-3-yl)acetamide
[0421] To a 100-mL round-bottom flask was added a solution of
6-(benzylthio)-5-chloropyridin-3-amine (6 g, 24.00 mmol, 1.00
equiv) in tetrahydrofuran (60 mL) and triethylamine (3.6 g, 35.64
mmol, 1.50 equiv). The resulting solution was stirred for 10 min.
Then acetic anhydride (3.7 g, 36.27 mmol, 1.50 equiv) was added.
The resulting solution was stirred for 7 h at room temperature. The
reaction was then quenched by the addition of 5 mL of HCl (2M). The
resulting solution was extracted with 3.times.50 mL of ethyl
acetate. The organic layers were combined, washed with brine, dried
over anhydrous sodium sulfate and concentrated under vacuum. The
residue was applied onto a silica gel column and eluted with ethyl
acetate/petroleum ether (1:2). This resulted in 5.7 g (77%) of
N-(6-(benzylthio)-5-chloropyridin-3-yl)acetamide as a yellow
solid.
5-Acetamido-3-chloropyridine-2-sulfonyl chloride
[0422] A 250-mL 3-necked round-bottom flask was added a solution of
N-(6-(benzylthio)-5-chloropyridin-3-yl)acetamide (2 g, 6.85 mmol,
1.00 equiv) in DCM (50 mL) and water (10 mL). The resulting
solution was vigorously bubbled with Cl.sub.2 gas for 15 min at
0.degree. C. The resulting solution was extracted with 2.times.30
mL of dichloromethane. The organic layers were combined, dried over
anhydrous sodium sulfate and concentrated under vacuum. This
resulted in 1.63 g (86%) of 5-acetamido-3-chloropyridine-2-sulfonyl
chloride as a yellow solid.
N-{5-chloro-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyri-
din-3-yl}acetamide
[0423] Into a 50-mL round-bottom flask were placed a solution of
6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (200 mg, 1.34 mmol, 1.00
equiv) in CH.sub.3CN (10 mL),
5-acetamido-3-chloropyridine-2-sulfonyl chloride (400 mg, 1.49
mmol, 1.10 equiv) and potassium carbonate (648 mg, 4.70 mmol, 3.50
equiv). The resulting solution was stirred for 1 min at room
temperature, then quenched by the addition of 10 mL of water. The
pH value of the solution was adjusted to 6 with HCl. The resulting
solution was extracted with 3.times.20 mL of ethyl acetate. The
organic layers were combined, dried over anhydrous sodium sulfate
and concentrated under vacuum. This resulted in 500 mg (98%) of
N-{5-chloro-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyr-
idin-3-yl}acetamide as a yellow solid.
5-Amino-3-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridi-
ne-2-sulfonamide
[0424] Into a 50-mL round-bottom flask was placed a solution of
N-{5-chloro-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyr-
idin-3-yl}acetamide (500 mg, 1.31 mmol, 1.00 equiv) in
tetrahydrofuran (25 mL) and HCl (10%, 25 mL). The resulting
solution was heated to reflux overnight. The resulting mixture was
cooled and concentrated under vacuum. The crude product (500 mg)
was purified by prep-HPLC with the following conditions: Column,
SunFire C18, 19.times.150 mm, Sum; Mobile phase, water (with 0.05%
TFA) and methanol; Gradient: 30% methanol up to 50% in 6 min, up to
100% in 1 min, down to 30% in 1 min; Detector, UV 254 nm and 220
nm. This resulted in 102 mg (23%) of
5-amino-3-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyrid-
ine-2-sulfonamide as a white solid. LC-MS-(ES, m/z): 340
[M+H].sup.+. .sup.1H-NMR-(300 MHz, CD.sub.3OD, ppm): 7.78 (1H, d,
J=2.4 Hz), 7.43 (1H, s), 7.30 (2H, m), 7.02 (1H, d, J=2.4 Hz), 4.99
(2H, s).
5-Amino-3-bromo-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridin-
e-2-sulfonamide
##STR00152##
[0425] 2-(Benzylthio)-3-bromo-5-nitropyridine
[0426] Into a 250-mL round-bottom flask were placed a solution of
phenylmethanethiol (2.89 g, 23.31 mmol, 1.10 equiv) in
tetrahydrofuran (40 mL) and potassium carbonate (3.8 g, 27.54 mmol,
1.30 equiv). The resulting mixture was stirred for 30 min at
60.degree. C., then added a solution of
3-bromo-2-chloro-5-nitropyridine (5 g, 21.19 mmol, 1.00 equiv) in
tetrahydrofuran (20 mL) dropwise with stirring. The resulting
solution was refluxed overnight, then cooled and quenched by the
addition of 30 mL of water. The resulting solution was extracted
with 50 mL of ethyl acetate. The organic layers were combined,
washed with brine, dried and concentrated under vacuum. This
resulted in 6 g (83%) of 2-(benzylthio)-3-bromo-5-nitropyridine as
a yellow solid.
6-(Benzylthio)-5-bromopyridin-3-amine
[0427] Into a 250-mL round-bottom flask were placed a solution of
2-(benzylthio)-3-bromo-5-nitropyridine (6 g, 18.52 mmol, 1.00
equiv) in ethanol (120 mL) and water (30 mL), Fe (10.3 g, 183.93
mmol, 10.00 equiv) and HCl (2.5 mL, 1.00 equiv). The resulting
mixture was heated to reflux for 2 h in an oil bath. The reaction
mixture was cooled and filtered. The filtrate was concentrated
under vacuum to remove most of EtOH. The residual solution was
adjusted to pH 8 with sodium hydroxide solution (20%). The
resulting solution was extracted with 3.times.50 mL of
dichloromethane. The organic layers were combined, dried over
anhydrous sodium sulfate and concentrated under vacuum. This
resulted in 4.2 g (74%) of 6-(benzylthio)-5-bromopyridin-3-amine as
a red oil.
N-(6-(Benzylthio)-5-bromopyridin-3-yl)acetamide
[0428] To a 100-mL round-bottom flask was added a solution of
6-(benzylthio)-5-bromopyridin-3-amine (4.2 g, 14.29 mmol, 1.00
equiv) in tetrahydrofuran (42 mL) and triethylamine (2.15 g, 21.29
mmol, 1.50 equiv), then added acetic anhydride (2.17 g, 21.27 mmol,
1.50 equiv) at 0.degree. C. The resulting solution was stirred for
7 h at room temperature, then quenched by the addition of 5 mL of
HCl (2M). The resulting solution was extracted with 3.times.50 mL
of ethyl acetate. The organic layers were combined, washed with
brine, dried over anhydrous sodium sulfate and concentrated under
vacuum. The residue was applied onto a silica gel column and eluted
with ethyl acetate/petroleum ether (1:2). This resulted in 4.1 g
(81%) of N-(6-(benzylthio)-5-bromopyridin-3-yl)acetamide as a
yellow solid.
5-Acetamido-3-bromopyridine-2-sulfonyl chloride
[0429] Cl.sub.2 gas was bubbled into a solution of
N-(6-(benzylthio)-5-bromopyridin-3-yl)acetamide (1.5 g, 4.46 mmol,
1.00 equiv) in DCM 37.5 mL) and water (7.5 mL) for 15 min at
0.degree. C. The resulting solution was extracted with 2.times.30
mL of dichloromethane. The organic layers were combined, dried over
anhydrous sodium sulfate and concentrated under vacuum. This
resulted in 1.5 g(crude) of 5-acetamido-3-bromopyridine-2-sulfonyl
chloride as a yellow solid.
N-{5-bromo-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyrid-
in-3-yl}acetamide
[0430] Into a 50-mL round-bottom flask was placed a solution of
6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (200 mg, 1.34 mmol, 1.00
equiv) in CH.sub.3CN (20 mL),
5-acetamido-3-bromopyridine-2-sulfonyl chloride (460 mg, 1.47 mmol,
1.10 equiv) and potassium carbonate (648 mg, 4.70 mmol, 3.50
equiv). The resulting solution was stirred for 30 min at room
temperature, then quenched by the addition of 10 mL of water. The
pH value of the solution was adjusted to 6 with HCl. The resulting
solution was extracted with 3.times.20 mL of ethyl acetate. The
organic layers were combined, dried over anhydrous sodium sulfate
and concentrated under vacuum. This resulted in 500 mg (crude) of
N-{5-bromo-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyri-
din-3-yl}acetamide as a red oil.
5-Amino-3-bromo-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridin-
e-2-sulfonamide
[0431] A solution of
N-{5-bromo-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyri-
din-3-yl}acetamide (500 mg, 1.18 mmol, 1.00 equiv) in
tetrahydrofuran (25 mL) and HCl (10%, 25 mL) was heated to reflux
overnight in an oil bath. The resulting solution was cooled and
extracted with 3.times.25 mL of ethyl acetate. The organic layers
were combined, dried over anhydrous calcium chloride and
concentrated under vacuum. The crude product (350 mg) was purified
by prep-HPLC with the following conditions: Column, SunFire C18,
19.times.150 mm, 5 um; Mobile phase, water (with 0.1% formic acid)
and methanol; Gradient, 30% methanol up to 80% in 8 min; Detector,
UV 254 nm. This resulted in 200 mg (43%) of
5-amino-3-bromo-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridi-
ne-2-sulfonamide as a light yellow solid. LC-MS (ES, m/z): 386
[M+H].sup.+. .sup.1H-NMR (DMSO-d6, 300 MHz, ppm): 10.31 (1H, s),
9.21 (1H, s), 7.81 (1H, d, J=2.1 Hz), 7.51 (1H, s), 7.22 (3H, m),
6.37 (2H, s), 4.88 (2H, s).
6-Amino-4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridi-
ne-3-sulfonamide
##STR00153##
[0432] N-(5-(benzylthio)-4-fluoropyridin-2-yl)acetamide
[0433] Into a 50-mL round-bottom flask was placed a solution of
N-(5-(benzylthio)-4-chloropyridin-2-yl)acetamide (2.8 g, 9.59 mmol,
1.00 equiv) in DMSO (10 mL), KF (4 g, 68.97 mmol, 7.19 equiv) and
Me.sub.4NCl (50 mg). The resulting solution was stirred for 4 days
at 130.degree. C. in an oil bath. The reaction mixture was then
cooled and quenched by the addition of 20 mL of water. The
resulting solution was extracted with 3.times.20 mL of ethyl
acetate. The organic layers were combined, dried over anhydrous
sodium sulfate and concentrated under vacuum. The residue was
applied onto a silica gel column and eluted with ethyl
acetate/hexane (1/15.about.1/5). This resulted in 0.3 g (crude) of
N-(5-(benzylthio)-4-fluoropyridin-2-yl)acetamide as a white
solid.
6-Acetamido-4-fluoropyridine-3-sulfonyl chloride
[0434] Chlorine gas was bubbled slowly into a solution of
N-(5-(benzylthio)-4-fluoropyridin-2-yl)acetamide (160 mg, 0.58
mmol, 1.00 equiv) in dichloromethane (5 mL) and water (1 mL) cooled
at 0.degree. C. in an ice bath for 10 min. The reaction mixture was
then bubbled with nitrogen for 30 min. The reaction was then
quenched by the addition of 5 mL of water. The resulting solution
was extracted with 2.times.10 mL of dichloromethane. The organic
layers were combined, dried over anhydrous sodium sulfate and
concentrated under vacuum. This resulted in 100 mg (crude) of
6-acetamido-4-fluoropyridine-3-sulfonyl chloride as a yellow
solid.
N-(4-fluoro-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)pyridin-2-yl)acetamide
[0435] Into a 50-mL 3-necked round-bottom flask was placed a
solution of 6-acetamido-4-fluoropyridine-3-sulfonyl chloride (100
mg, 0.40 mmol, 1.00 equiv) in CH.sub.3CN (10 mL), then added
6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (86 mg, 0.58 mmol, 1.00
equiv) and potassium carbonate (320 mg, 2.32 mmol, 4.00 equiv). The
resulting mixture was stirred for 1 h at 0.degree. C. in an
ice/salt bath. The pH value of the solution was adjusted to 6 with
HCl (10%), followed by extraction with 3.times.10 mL of ethyl
acetate. The organic layers were combined, dried over anhydrous
sodium sulfate and concentrated under vacuum. The residue was
applied onto a silica gel column and eluted with DCM/MeOH (1:20).
This resulted in 0.05 g (32%) of
N-(4-fluoro-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamo-
yl)pyridin-2-yl)acetamide as a white solid.
6-Amino-4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridi-
ne-3-sulfonamide
[0436] A solution of
N-(4-fluoro-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamo-
yl)pyridin-2-yl)acetamide (200 mg, 0.55 mmol, 1.00 equiv) in
tetrahydrofuran (5 mL) and HCl (5 mL, 35%) was stirred for 1.5 h at
60.degree. C. in an oil bath. The resulting mixture was cooled and
concentrated under vacuum. The residue was purified by
preparative-HPLC with the following conditions: Column, SunFire
Prep C18, 5 um, 19.times.100 mm; Mobile phase, water (with 0.1%
formic acid) and CH.sub.3CN; Gradient, CH.sub.3CN starting from 20%
and increasing to 28% in 6 min, then to 100% in 1 min, decreasing
to 20% in 1 min; Detector, UV 220 nm. This resulted in 43.8 mg
(25%) of
6-amino-4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyrid-
ine-3-sulfonamide as a white solid. LC-MS-(ES, m/z): 324
[M+H].sup.+. .sup.1H-NMR (300 MHz, DMSO-d6, ppm): 4.886 (2H, s),
6.158-6.201 (1H, d, J=12.9 Hz), 7.15-7.21 (3H, m), 7.26-7.30 (1H,
m), 7.492-7.498 (1H, d, J=1.8 Hz), 8.188-8.225 (1H, d, J=11.1 Hz),
9.237 (1H, s), 10.306 (1H, s).
6-Amino-4-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridi-
ne-3-sulfonamide
##STR00154##
[0437] 4-Chloro-5-iodopyridin-2-amine
[0438] Into a 100-mL round-bottom flask were placed a solution of
4-chloropyridin-2-amine (5.9 g, 46.09 mmol, 1.00 equiv) in
N,N-dimethylformamide (30 mL) and NIS (13.35 g, 59.33 mmol, 1.30
equiv). The resulting solution was stirred overnight at room
temperature, then quenched by the addition of 10 mL of
Na.sub.2S.sub.2O.sub.3 solution. The resulting solution was
extracted with 3.times.50 mL of ethyl acetate. The organic layers
were combined, dried over anhydrous sodium sulfate and concentrated
under vacuum. The crude product was re-crystallized from
ether/hexane in the ratio of 1:1. This resulted in 11 g (crude) of
4-chloro-5-iodopyridin-2-amine as a yellow solid.
5-(Benzylthio)-4-chloropyridin-2-amine
[0439] Sodium (480 mg, 20.87 mmol, 1.50 equiv) was added to
methanol (20 mL) in portions. The resulting solution was stirred
for 1 hr at reflux. Then added Cu (360 mg, 5.62 mmol, 0.30 equiv),
phenylmethanethiol (2.81 g, 22.66 mmol, 1.20 equiv) and
4-chloro-5-iodopyridin-2-amine (4.8 g, 18.90 mmol, 1.00 equiv). The
resulting mixture was heated to reflux for an additional 6 h. The
reaction mixture was then cooled and quenched by the addition of
H.sub.2O. The resulting solution was extracted with 3.times.30 ml
of ethyl acetate. The organic layers combined, dried and
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with EtOAc:PE (1/10). This resulted in 5 g
(crude) of 5-(benzylthio)-4-chloropyridin-2-amine as a yellow
solid.
N-(5-(benzylthio)-4-chloropyridin-2-yl)acetamide
[0440] Into a 100-mL 3-necked round-bottom flask was placed a
solution of 5-(benzylthio)-4-chloropyridin-2-amine (4.5 g, 18.00
mmol, 1.00 equiv) in acetic anhydride (9.6 g) and triethylamine
(9.59 g, 94.95 mmol, 5.00 equiv). The resulting solution was
stirred for 3 h at 60.degree. C. in an oil bath. The resulting
mixture was cooled and concentrated under vacuum. The residue was
applied onto a silica gel column and eluted with ethyl
acetate/petroleum ether (1/20). This resulted in 2 g (crude) of
N-(5-(benzylthio)-4-chloropyridin-2-yl)acetamide as a white
solid.
6-Acetamido-4-chloropyridine-3-sulfonyl chloride
[0441] Chlorine gas was bubbled slowly into a solution of
N-(5-(benzylthio)-4-chloropyridin-2-yl)acetamide (1.07 g, 3.65
mmol, 1.00 equiv) in dichloromethane (25 mL) and water (5 mL) for
10 min at 0.degree. C. in an ice/salt bath. The reaction mixture
was then bubbled with nitrogen gas for 20 min and stirred for 10
min at 0.degree. C. in an ice/salt bath. The resulting solution was
diluted with water, followed by extraction with 2.times.50 mL of
dichloromethane. The organic layers were combined, dried over
anhydrous sodium sulfate and concentrated under vacuum. The crude
product was used in the next step directly without further
purification.
N-(4-chloro-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)pyridin-2-yl)acetamide
[0442] Into a 100-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen were placed
6-amino-3H-benzo[c][1,2]oxaborol-1-ol (546 mg, 3.66 mmol, 1.00
equiv), a solution of potassium carbonate (2.02 g, 14.64 mmol, 4.00
equiv) in CH.sub.3CN (20 mL) at 0.degree. C. This was followed by
the addition of 6-acetamido-4-chloropyridine-3-sulfonyl chloride (1
g, 3.72 mmol, 1.00 equiv). The resulting solution was stirred for 1
h at room temperature, then quenched by the addition of water. The
pH value of the solution was adjusted to 6 with HCl (1M), then
extracted with ethyl acetate. The organic layers were combined,
dried over anhydrous sodium sulfate and concentrated under vacuum.
The residue was applied onto a silica gel column and eluted with
dichloromethane/methanol (1:20). This resulted in 500 mg (28%) of
the title compound as a white solid.
6-Amino-4-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridi-
ne-3-sulfonamide
[0443] A solution of
N-(4-chloro-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamo-
yl)pyridin-2-yl)acetamide (300 mg, 0.79 mmol, 1.00 equiv) in
tetrahydrofuran (10 mL) and HCl (10 mL, 10%) was heated to reflux
for 3 h in an oil bath. The resulting mixture was cooled and
concentrated under vacuum to remove THF. The residual mixture was
cooled with an ice bath. The isolated solid was collected by
filtration. This resulted in 0.2 g (73%) of
6-amino-4-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-
-yl)pyridine-3-sulfonamide as a white solid. LC-MS-(ES, m/z):
340[M+H].sup.+. .sup.1H NMR-(400 MHz, DMSO-d6, ppm): 4.77 (2H, s),
6.63 (1H, s), 7.20-7.29 (2H, m), 7.50 (1H, s), 8.38 (1H, s), 10.36
(1H, s).
5-Amino-3-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridin-
e-2-sulfonamide
##STR00155##
[0444] 2-Nitro-1,3-dioxopropan-2-ide
[0445] Into a 250-mL 3-necked round-bottom flask was placed a
solution of NaNO.sub.2 (10.2 g, 147.83 mmol, 3.78 equiv) in water
(10 mL). This was followed by the addition of a solution of
(E)-2,3-dibromo-4-oxobut-2-enoic acid (10 g, 39.06 mmol, 1.00
equiv) in ethanol (10 mL) dropwise with stirring at 54.degree. C.
over 18 min. The resulting solution was stirred for 30 min at
54.degree. C. The reaction mixture was cooled to 5.degree. C. and
filtered. The filter cake was washed with 60 mL of ethanol. The
filtrate was concentrated under vacuum. This resulted in 5 g
(crude) of 2-nitro-1,3-dioxopropan-2-ide as a yellow solid.
2-Hydroxy-5-nitronicotinonitrile
[0446] Into a 500-mL 3-neck-round-bottom flask was placed a
solution of 2-nitro-1,3-dioxopropan-2-ide (31.4 g, 225.90 mmol,
1.00 equiv) in water (400 mL). This was followed by the addition of
2-cyanoacetamide (16.4 g, 195.24 mmol, 0.91 equiv) at 20.degree. C.
To this was added N,N,N-triethylbenzenaminium hydroxide (7 g, 35.90
mmol, 0.16 equiv) at 20.degree. C. The resulting solution was
stirred for 30 min at 30.degree. C. The reaction mixture was cooled
to 0.degree. C. with an ice/salt bath. The isolated solid was
collected by filtration and purified by re-crystallization from
H.sub.2O (20 mL). This resulted in 4 g (10%) of
2-hydroxy-5-nitronicotinonitrile as a yellow solid.
2-Chloro-5-nitronicotinonitrile
[0447] A solution of 2-hydroxy-5-nitronicotinonitrile (10 g, 60.61
mmol, 1.00 equiv) in POCl.sub.3 (122.6 g) and PCl.sub.5 (35 g,
168.27 mmol, 2.80 equiv) was stirred for 2 h at 120.degree. C. The
reaction mixture was cooled and quenched by the addition of 800 mL
of water/ice. The pH value of the solution was adjusted to >7
with sodium carbonate solution (60%). The resulting solution was
extracted with 2.times.200 mL of dichloromethane. The organic
layers were combined, dried and concentrated under vacuum. This
resulted in 10.1 g (91%) of 2-chloro-5-nitronicotinonitrile as a
yellow solid.
2-(Benzylthio)-5-nitronicotinonitrile
[0448] Into a 100-mL 3-necked round-bottom flask was placed a
solution of phenylmethanethiol (1.4 g, 11.29 mmol, 1.10 equiv) in
tetrahydrofuran (40 mL), then added potassium carbonate (1.9 g,
13.77 mmol, 1.30 equiv). The resulting mixture was stirred for 30
min at 60.degree. C. This was followed by the addition of a
solution of 2-chloro-5-nitronicotinonitrile (1.9 g, 10.38 mmol,
1.00 equiv) in tetrahydrofuran (10 mL) dropwise with stirring at
60.degree. C. The resulting solution was refluxed overnight. The
resulting mixture was cooled and concentrated under vacuum. The
residue was applied onto a silica gel column and eluted with ethyl
acetate/petroleum ether (1:50). This resulted in 1.9 g (61%) of
2-(benzylthio)-5-nitronicotinonitrile as a yellow solid.
5-Amino-2-(benzylthio)nicotinonitrile
[0449] A mixture of 2-(benzylthio)-5-nitronicotinonitrile (3.9 g,
14.39 mmol, 1.00 equiv), ethanol (100 mL), Fe (8.1 g, 144.64 mmol,
10.00 equiv) and acetic acid (10 mL) was refluxed for 3 h. The
reaction mixture was cooled and filtered. The filtrate was
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with dichloromethane/methanol (100:1). This
resulted in 3.4 g (98%) of 5-amino-2-(benzylthio)nicotinonitrile as
a yellow solid.
N-(6-(benzylthio)-5-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide
[0450] Into a 100-mL round-bottom flask was placed a solution of
5-amino-2-(benzylthio)nicotinonitrile (3.4 g, 14.11 mmol, 1.00
equiv) in dichloromethane (50 mL) and TEA (2.8 g, 27.72 mmol, 2.00
equiv). This was followed by the addition of (CF.sub.3C0).sub.2O
(4.4 g, 20.95 mmol, 1.50 equiv) dropwise with stirring at 0.degree.
C. The resulting solution was stirred for 15 min at 0-5.degree. C.,
then quenched by the addition of 100 mL of water. The resulting
solution was extracted with 3.times.100 mL of dichloromethane. The
organic layers were combined, and concentrated under vacuum. The
residue was applied onto a silica gel column and eluted with ethyl
acetate/petroleum ether (1:20). This resulted in 3.5 g (74%) of
N-(6-(benzylthio)-5-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide as
a white solid.
3-Cyano-5-(2,2,2-trifluoroacetamido) pyridine-2-sulfonyl
chloride
[0451] Cl.sub.2 (gas) was bubbled into a solution of
N-(6-(benzylthio)-5-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide
(3.37 g, 10.00 mmol, 1.00 equiv) in dichloromethane (75 mL) and
water (15 mL) at 0.degree. C. in 15 min. The resulting solution was
stirred for 15 min at room temperature, then dried over anhydrous
sodium sulfate and concentrated under vacuum. This resulted in 3.0
g (96%) of 3-cyano-5-(2,2,2-trifluoroacetamido) pyridine-2-sulfonyl
chloride as a yellow oil.
N-(5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl-
)pyridin-3-yl)-2,2,2-trifluoroacetamide
[0452] Into a 100-mL round-bottom flask were placed a solution of
6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (200 mg, 1.34 mmol, 1.00
equiv) in CH.sub.3CN (50 mL) and potassium carbonate (741 mg, 5.37
mmol, 4.00 equiv). This was followed by the addition of a solution
of 3-cyano-5-(2,2,2-trifluoroacetamido) pyridine-2-sulfonyl
chloride (504 mg, 1.61 mmol, 1.20 equiv) in CH.sub.3CN (10 mL)
dropwise with stirring at 0.degree. C. The resulting solution was
stirred for 30 min at room temperature, then concentrated under
vacuum. The residue was diluted with 50 mL of water, then adjusted
to pH 6 with HCl (1 mol/L). The resulting solution was extracted
with 3.times.100 mL of ethyl acetate. The organic layers were
combined, dried and concentrated under vacuum. The residue was
applied onto a silica gel column and eluted with
dichloromethane/methanol (100:1-50:1). This resulted in 300 mg
(crude) of
N-(5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)pyridin-3-yl)-2,2,2-trifluoroacetamide as a yellow solid.
5-Amino-3-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridin-
e-2-sulfonamide
[0453] Into a 250-mL round-bottom flask was placed a solution of
N-(5-cyano-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)pyridin-3-yl)-2,2,2-trifluoroacetamide (300 mg, 0.70 mmol, 1.00
equiv) in methanol (50 mL), then added potassium carbonate solution
(50 mL). The resulting solution was stirred for 18 h at room
temperature, then concentrated under vacuum. The residue was
diluted with 50 mL of water. The pH value of the solution was
adjusted to 7 with HCl (1 mol/L). The resulting solution was
extracted with 2.times.100 mL of ethyl acetate. The organic layers
were combined, dried and concentrated under vacuum. The residue was
washed with 1.times.10 mL of methanol and dried. This resulted in
104 mg (43%) of
5-amino-3-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridi-
ne-2-sulfonamide as a yellow solid. The compound exhibited a
melting point of 234-237.degree. C. LC-MS (ES, m/z): 331
[M+H].sup.+. .sup.1H-NMR (300 MHz, DMSO-d6): 4.898 (2H, s), 6.639
(2H, s), 7.236-7.287 (2H, m), 7.485-7.489 (1H, d, J=1.2 Hz),
8.085-8.092 (1H, d, J=2.1 Hz), 9.201 (1H, s), 10.484 (1H, s).
6-Amino-4-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridin-
e-3-sulfonamide
##STR00156##
[0454] 2-(4-Methoxybenzylamino)isonicotinonitrile
[0455] Into a 500-mL round-bottom flask were placed a solution of
2-chloroisonicotinonitrile (11.0 g, 79.71 mmol, 1.00 equiv) in
pyridine (250 mL), (4-methoxyphenyl)methanamine (12.4 g, 90.51
mmol, 1.14 equiv) and sodium bicarbonate (15.0 g, 178.57 mmol, 2.20
equiv). The resulting mixture was heated to reflux overnight in an
oil bath. The resulting mixture was cooled and concentrated under
vacuum. The crude product was purified by re-crystallization from
EtOAc. This resulted in 7.5 g (crude) of
2-(4-methoxybenzylamino)isonicotinonitrile as a yellow solid.
2-Aminoisonicotinonitrile
[0456] A solution of 2-(4-methoxybenzylamino)isonicotinonitrile
(3.59 g, 15.08 mmol, 1.00 equiv) in trifluoroacetic acid (40 mL)
was stirred for 3 h at 60.degree. C. The resulting mixture was
cooled and concentrated under vacuum. The residue was diluted with
water, then adjusted to pH 9-10 with potassium carbonate solution.
The resulting solution was extracted with ethyl acetate. The
organic layers were combined, dried and concentrated under vacuum.
The residue was applied onto a silica gel column and eluted with
ethyl acetate/petroleum ether (1/4). This resulted in 1.8 g (crude)
of 2-aminoisonicotinonitrile as a yellow solid.
2-Amino-5-iodoisonicotinonitrile
[0457] Into a 100-mL round-bottom flask was placed a solution of
2-aminoisonicotinonitrile (1.8 g, 15.13 mmol, 1.00 equiv) in
N,N-dimethylformamide (20 mL), then added NIS (4.42 g, 19.64 mmol,
1.30 equiv). The resulting solution was stirred overnight at room
temperature, then quenched by the addition of 30 mL of
Na.sub.2S.sub.2O.sub.3 solution. The resulting solution was
extracted with 3.times.15 mL of ethyl acetate. The organic layers
were combined, dried over anhydrous sodium sulfate and concentrated
under vacuum. The residue was applied onto a silica gel column and
eluted with ethyl acetate/petroleum ether (1/10). This resulted in
2.6 g (70%) of 2-amino-5-iodoisonicotinonitrile as a yellow
solid.
2-Amino-5-(benzylthio)isonicotinonitrile
[0458] Sodium (101 mg, 4.39 mmol, 1.20 equiv) was added to methanol
(15 mL) and stirred for 20 min at room temperature. Then added Cu
(80 mg, 1.25 mmol, 0.30 equiv), phenylmethanethiol (610 mg, 4.92
mmol, 1.20 equiv) and 2-amino-5-iodoisonicotinonitrile (1.0 g, 4.08
mmol, 1.00 equiv). The resulting solution was heated to reflux for
an additional 6 h. The reaction mixture was cooled with a water
bath, then diluted with 100 ml of water. The resulting solution was
extracted with 3.times.50 ml of ethyl acetate. The organic layers
were combined, dried over anhydrous sodium sulfate and concentrated
under vacuum. The residue was applied onto a silica gel column and
eluted with EA:PE (1:10). This resulted in 0.2 g (20%) of
2-amino-5-(benzylthio)isonicotinonitrile as a yellow solid.
N-(5-(benzylthio)-4-cyanopyridin-2-yl)acetamide
[0459] A solution of 2-amino-5-(benzylthio)isonicotinonitrile (2 g,
8.30 mmol, 1.00 equiv) in acetic anhydride (4 g) and triethylamine
(4 g, 39.60 mmol, 5.00 equiv) was stirred for 5 h at 60.degree. C.
in an oil bath. The resulting mixture was cooled and concentrated
under vacuum. The residue was applied onto a silica gel column and
eluted with ethyl acetate/petroleum ether (1:20). This resulted in
2.2 g (94%) of N-(5-(benzylthio)-4-cyanopyridin-2-yl)acetamide as a
light yellow solid.
4-Acetamido-6-cyanopyridine-3-sulfonyl chloride
[0460] Chlorine gas was bubbled slowly into a solution of
N-(5-(benzylthio)-2-cyanopyridin-4-yl)acetamide (665 mg, 2.35 mmol,
1.00 equiv) in dichloromethane (15 mL) and water (5 mL) cooled at
0.degree. C. in a water/ice bath for 10 min. The reaction was then
quenched by the addition of 10 mL of water. The resulting solution
was extracted with 2.times.10 mL of dichloromethane. The organic
layers were combined, dried over anhydrous sodium sulfate and
concentrated under vacuum. This resulted in 0.6 g (crude) of
4-acetamido-6-cyanopyridine-3-sulfonyl chloride as a yellow
solid.
N-(4-cyano-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl-
)pyridin-2-yl)acetamide
[0461] Into a 50-mL 3-necked round-bottom flask was placed a
solution of 4-acetamido-6-cyanopyridine-3-sulfonyl chloride (600
mg, 1.00 equiv, crude) in CH.sub.3CN (10 mL), then added
6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (305 mg, 2.05 mmol, 1.00
equiv) and potassium carbonate (276 mg, 2.00 mmol, 4.00 equiv). The
resulting mixture was stirred for 1 h at 0.degree. C. in a
water/ice bath. The pH value of the solution was adjusted to 6 with
HCl (10%), then it was extracted with 3.times.10 mL of ethyl
acetate. The organic layers were combined, dried over anhydrous
sodium sulfate and concentrated under vacuum. This resulted in 0.2
g (crude) of
N-(4-cyano-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)pyridin-2-yl)acetamide as a white solid.
6-Amino-4-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridin-
e-3-sulfonamide
[0462] A solution of
N-(4-cyano-5-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)pyridin-2-yl)acetamide (500 mg, 1.34 mmol, 1.00 equiv) in
tetrahydrofuran (10 mL) and HCl (10%, 10 mL) was stirred for 3 h at
60.degree. C. in an oil bath. The resulting mixture was cooled and
concentrated under vacuum. The crude product (0.4 g) was purified
by preparative-HPLC with the following conditions: Column, SunFire
Prep C18, Sum, 19.times.150 mm; Mobile phase, water (with 0.05%
TFA) and CH.sub.3CN; Gradient, MeCN starting at 25%, increasing to
34% in 6 min, then to 100% in 1.5 min; Detector, uv 220&254 nm.
This resulted in 0.2 g (45%) of
6-amino-4-cyano-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6--
yl)pyridine-3-sulfonamide as a white solid. LC-MS-(ES, m/z): 331
[M+H].sup.+. .sup.1H-NMR-(300 MHz, DMSO-d6, ppm): 4.901 (2H, s),
6.825 (1H, s), 7.181-7.321 (2H, m), 7.479 (1H, s), 8.406 (1H, s),
9.250 (1H, s), 10.414 (1H, s).
Benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)sulfa-
moyl)pyridin-3-ylcarbamate
##STR00157##
[0463] 2-Hydroxy-5-nitronicotinic acid
[0464] Into a 2000-mL 4-necked round-bottom flask was placed a
solution of 2-hydroxynicotinic acid (98 g, 705.04 mmol, 1.00 equiv)
in sulfuric acid (280 mL). This was followed by the addition of
HNO.sub.3 (70 mL) dropwise with stirring. The resulting solution
was stirred for 5 h at 50.degree. C. The reaction was then cooled
and quenched by the addition of 2000 mL of water/ice. The solid was
collected by filtration and dried in an oven under reduced
pressure. This resulted in 100 g (69%) of
2-hydroxy-5-nitronicotinic acid as a yellow solid.
2-Chloro-5-nitronicotinic acid
[0465] A solution of 2-hydroxy-5-nitronicotinic acid (100 g, 543.48
mmol, 1.00 equiv) in POCl.sub.3 (250 mL) was heated to reflux for 3
hr. The resulting mixture was cooled and concentrated under vacuum.
The residue was then quenched by the addition of 2000 mL of
water/ice. The resulting solution was extracted with 4.times.300 mL
of ethyl acetate and 2.times.300 mL of THF/Et.sub.2O (1:1). The
organic layers were combined, washed with 1.times.1000 mL of brine,
dried over anhydrous sodium sulfate and concentrated under vacuum.
This resulted in 115 g (crude) of 2-chloro-5-nitronicotinic acid as
a yellow solid.
2-(Benzylthio)-5-nitronicotinic acid
[0466] Into a 3000-mL 4-necked round-bottom flask was placed a
solution of phenylmethanethiol (77.65 g, 626.21 mmol, 1.00 equiv)
in tetrahydrofuran (1800 mL), then added potassium carbonate
(180.69 g, 1.31 mol, 2.30 equiv). The resulting mixture was heated
to reflux for 1 hr. This was followed by the addition of a solution
of 2-chloro-5-nitronicotinic acid (115 g, 569.31 mmol, 1.00 equiv)
in tetrahydrofuran (400 mL) in portions. The resulting solution was
refluxed for an additional 5 h. The reaction mixture was then
cooled and quenched by the addition of 1000 mL of water. The pH
value of the solution was adjusted to 3-4 with HCl (12 mol/L). The
resulting solution was extracted with 3.times.1500 mL of ethyl
acetate. The organic layers were combined, washed with 1.times.1000
mL of brine, dried over anhydrous sodium sulfate and concentrated
under vacuum. The residue was washed with 3.times.500 mL of
petroleum ether and dried. This resulted in 130 g (72%) of
2-(benzylthio)-5-nitronicotinic acid as a yellow solid.
Tert-butyl 2-(benzylthio)-5-nitropyridin-3-ylcarbamate
[0467] Into a 3000-mL 4-necked round-bottom flask were placed a
solution of 2-(benzylthio)-5-nitronicotinic acid (130 g, 448.28
mmol, 1.00 equiv) in tert-butanol (1500 mL), triethylamine (58.86
g, 582.77 mmol, 1.30 equiv) and DPPA (147.9 g, 537.82 mmol, 1.20
equiv). The resulting solution was heated to reflux overnight. The
reaction mixture was cooled and concentrated under vacuum. The
residue diluted with 2000 ml, of water, then adjusted to pH 8 with
sodium carbonate. The resulting solution was diluted with 2000 ml
of H.sub.2O and 500 ml of EtOAc. The isolated solid was collected
by filtration and dried. This resulted in 148 g (82%) of tert-butyl
2-(benzylthio)-5-nitropyridin-3-ylcarbamate as a yellow solid.
Tert-butyl 5-amino-2-(benzylthio)pyridin-3-ylcarbamate
[0468] Into a 3000-mL 4-necked round-bottom flask were placed a
solution of tert-butyl 2-(benzylthio)-5-nitropyridin-3-ylcarbamate
(125 g, 346.26 mmol, 1.00 equiv) in methanol (1500 mL) and H.sub.2O
(150 mL), Fe (116.3 g, 2.08 mol, 6.00 equiv) and NH.sub.4Cl (110.1
g, 2.08 mol, 6.00 equiv). The resulting mixture was heated to
reflux overnight. The reaction mixture was cooled and filtered. The
filtrate was concentrated under vacuum. The solid was collected by
filtration, washed 2 times with 500 ml of water and dried in an
oven under reduced pressure. This resulted in 120 g (crude) of
tert-butyl 5-amino-2-(benzylthio)pyridin-3-ylcarbamate as a yellow
solid.
Tert-butyl
5-(benzylcarbamoyl-amino-2-(benzylthio)pyridin-3-ylcarbamate
[0469] Into a 3000-mL 4-necked round-bottom flask was placed a
solution of tert-butyl 5-amino-2-(benzylthio)pyridin-3-ylcarbamate
(120 g, 362.54 mmol, 1.00 equiv) in tetrahydrofuran/H.sub.2O (1:1,
2 L), then added sodium carbonate (57.6 g, 538.3 mmol, 1.30 equiv).
This was followed by the addition of Cbz-Cl (74 g, 435.29 mmol,
1.20 equiv) dropwise with stirring at 0.degree. C. The resulting
solution was stirred overnight at room temperature. The reaction
was then quenched by the addition of 500 mL of NH.sub.4Cl solution.
The resulting solution was extracted with 3.times.500 mL of ethyl
acetate. The organic layers were combined, dried over anhydrous
sodium sulfate and concentrated under vacuum. The residue was
applied onto a silica gel column and eluted with ethyl
acetate/petroleum ether (1:20-1:10). This resulted in 102 g (58%)
of the title compound as a yellow solid.
Benzyl 5-(tert-butyl
carbamoylamino)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)sul-
famoyl)pyridin-3-ylcarbamate
[0470] Into a 500-mL round-bottom flask was placed a solution of
tert-butyl
5-(benzylcarbamoyl-amino-2-(benzylthio)pyridin-3-ylcarbamate (10 g,
21.51 mmol, 1.00 equiv) in acetic acid (150 mL) and water (70 mL),
then added NCS (11.4 g, 85.71 mmol, 3.99 equiv). After stirred for
30 min at room temperature, the reaction mixture was extracted with
2.times.200 mL of ethyl acetate. The organic layers were combined,
washed with 1.times.200 mL of water. The organic layer was diluted
with 200 ml of water, then added potassium carbonate solution till
pH 8 was reached. The separated organic layer was washed with
1.times.100 mL of brine, dried over sodium sulfate and concentrated
under vacuum. This resulted in 9 g (76%) of benzyl 5-(tert-butyl
carbamoylamino)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)sul-
famoyl)pyridin-3-ylcarbamate as a yellow oil. The product was used
in the next step directly.
Benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)sulfa-
moyl)pyridin-3-ylcarbamate
[0471] A solution of benzyl 5-(tert-butyl
carbamoylamino)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)sul-
famoyl)pyridin-3-ylcarbamate (74 g, 126.90 mmol, 1.00 equiv, 95%)
in DCM/CF.sub.3COOH (400/100 mL) was stirred for 5 h at room
temperature. The reaction was quenched by the addition of 500 mL of
water. The pH value of the solution was adjusted to 8-9 with
potassium carbonate solution. The solid was collected by
filtration. The filtrate was extracted with 500 mL of
dichloromethane. The filter cake and aqueous layer were combined.
The resulting solution was adjusted to pH 4-5 with HCl (6N), then
extracted with 2.times.200 mL of ethyl acetate. All the organic
layers were combined, washed with 100 mL of brine, dried over
sodium sulfate and concentrated under vacuum. The residue was
applied onto a silica gel column and eluted with DCM:MeOH
(100:1-50:1). This resulted in 44.36 g (79%) of the title compound
as a light yellow solid. The compound exhibited a melting point of
174-176.degree. C. LC-MS (ES, m/z): 455 [M+H].sup.+. .sup.1H-NMR
(300 MHz, DMSO-d6, ppm): 10.30 (s, 1H), 10.12 (s, 1H), 9.20 (s,
1H), 7.80 (s, 1H), 7.73-7.80 (m, 7H), 7.19-7.26 (m, 2H), 6.19 (s,
2H), 5.16-5.19 (d, J=9 Hz, 2H), 4.88 (s, 2H).
3,5-Diamino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)pyridine-2--
sulfonamide
##STR00158##
[0473] A mixture of Palladium carbon (0.2 g) and benzyl
N-5-amino-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoyl]pyrid-
in-3-ylcarbamate (900 mg, 1.98 mmol, 1.00 equiv) in methanol (20
mL) was stirred overnight at room temperature under a hydrogen
atmosphere. The solid was filtered out. The filtrate was
concentrated under vacuum. The residue was applied onto a silica
gel column with dichloromethane/methanol (20/1). The crude product
(500 mg) was purified by prep-HPLC with the following conditions:
Column, SunFire C18, Sum, 19.times.100 mm; Mobile phase: water and
acetonitrile; Gradient: 10% acetonitrile up to 50% in 7 min;
Detector, UV 254 nm. This resulted in 75.7 mg (12%) of
3,5-diamino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)pyridine-2-
-sulfonamide as a white solid. LC-MS-(ES, m/z): 321 [M+H].sup.+.
.sup.1H-NMR-(300 MHz, DMSO-d6, ppm): 9.17 (1H, s), 7.46 (1H, s),
7.19-7.20 (3H, d, J=3 Hz), 6.11-6.12 (1H, d, J=3 Hz), 5.80-5.82
(4H, d, J=6 Hz), 4.87 (2H, s).
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(ureidomethy-
l)pyridine-2-sulfonamide
##STR00159##
[0474] Methyl
6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(ureid-
omethyl)pyridin-3-ylcarbamate
[0475] Into a 100-mL round-bottom flask was placed a solution of
methyl
5-(aminomethyl)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sul-
famoyl)pyridin-3-ylcarbamate (1 g, 2.55 mmol, 1.00 equiv) in AcOH
(20 mL), then added a solution of KOCN (200 mg, 2.47 mmol, 1.10
equiv) in H.sub.2O (20 mL). The resulting solution was stirred
overnight at room temperature. The resulting mixture was
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with DCM:MeOH (100:1-20:1). This resulted in
400 mg (36%) of the title compound as a yellow solid.
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(ureidomethy-
l)pyridine-2-sulfonamide
[0476] Into a 100-mL round-bottom flask was placed a solution of
methyl
6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(ureid-
omethyl)pyridin-3-ylcarbamate (300 mg, 0.69 mmol, 1.00 equiv) in
ethanol (10 mL), then added a solution of potassium hydroxide (77
mg, 1.38 mmol, 2.00 equiv) in water (10 mL). The resulting solution
was stirred for 1 h at 90.degree. C. The reaction mixture was
cooled and adjusted to pH 7 with HCl (10%). The resulting mixture
was concentrated under vacuum. The residue was applied onto a
silica gel column and eluted with ethyl acetate/petroleum ether
(1:20-3:1). The crude product (400 mg) was purified by Prep-HPLC
with the following conditions: Column, SunFire Prep C.sub.18,
19.times.150 mm, Sum; Mobile phase, water (with 0.05% TFA) and
CH.sub.3CN; Gradient, 10% CH.sub.3CN up to 28% in 6 min, up to 100%
in 1.5 min, down to 10% in 1.5 min; Detector, UV 254 nm. This
resulted in 167.9 mg (64%) of the title compound as a white solid.
LC-MS (ES, m/z): 378 [M+H].sup.+. .sup.1H-NMR (300 MHz, DMSO-d6,
ppm): 4.426-4.446 (d, J=6 Hz, 2H), 4.878 (s, 2H), 5.720 (s, 2H),
6.163 (s, 2H), 6.376-6.417 (t, 1H), 6.905-6.913 (d, J=2.4 Hz, 1H),
7.237-7.241 (d, J=1.2 Hz, 2H), 7.515 (s, 1H), 7.700-7.708 (d, J=2.4
Hz, 1H), 9.235 (s, 1H), 10.219 (s, 1H).
5-Amino-3-(3-ethylureido)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6--
yl)pyridine-2-sulfonamide
##STR00160##
[0477] Benzyl
5-(3-ethylureido)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)s-
ulfamoyl)pyridin-3-ylcarbamate
[0478] Into a 30-mL sealed tube were placed a solution of Benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)p-
yridin-3-ylcarbamate (500 mg, 1.10 mmol, 1.00 equiv) in
tetrahydrofuran (15 mL) and isocyanatoethane (800 mg, 11.27 mmol,
10.00 equiv). The resulting solution was stirred overnight at
70.degree. C. The reaction was then cooled and quenched by the
addition of 3 mL of methanol. The resulting mixture was
concentrated under vacuum. This resulted in 0.5 g (52%) of crude
benzyl
5-(3-ethylureido)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)s-
ulfamoyl)pyridin-3-ylcarbamate as light yellow oil which was used
in the next step directly without further purification.
5-Amino-3-(3-ethylureido)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6--
yl)pyridine-2-sulfonamide
[0479] A mixture of benzyl
5-(3-ethylureido)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)s-
ulfamoyl)pyridin-3-ylcarbamate (500 mg, 0.57 mmol, 1.00 equiv, 60%)
and Pd/C (500 mg, 41.67 mmol, 72.92 equiv) in methanol (20 mL) was
stirred overnight at room temperature under a hydrogen atmosphere.
The solid was filtered out. The filtrate was concentrated under
vacuum. The crude product (200 mg) was purified by Prep-HPLC with
the following conditions: Column, SunFire Prep C18, Sum,
19.times.100 mm; Mobile phase, water (with 0.1% formic acid) and
CH.sub.3CN; This resulted in 33.4 mg (15%) of the title compound as
a white solid (m.p. 195-197.degree. C.). LC-MS (ES, m/z): 392
[M+H].sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, ppm): 10.28 (s,
1H), 9.14 (s, 1H), 8.41 (s, 1H), 7.75-7.76 (d, 1H, J=4 Hz), 7.48
(s, 2H), 7.37 (s, 1H), 7.24 (s, 2H), 6.08 (s, 2H), 4.88 (s, 2H),
3.04-3.09 (m, 2H), 1.04-1.07 (m, 3H).
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(methylsulfo-
namido)pyridine-2-sulfonamide
##STR00161##
[0480] Benzyl 5-amino-6-(benzylthio)pyridin-3-ylcarbamate
[0481] A solution of tert-butyl
5-(benzyloxycarbonylamino)-2-(benzylthio)pyridin-3-ylcarbamate
(4.65 g, 10.00 mmol, 1.00 equiv) in DCM (40 mL) and TFA (10 mL) was
stirred overnight at room temperature. The reaction was quenched by
the addition of 10 mL of water and then adjusted to pH 8-9 with
sodium hydroxide solution. The resulting solution was extracted
with 2.times.20 mL of dichloromethane. The organic layers were
combined, dried and concentrated under vacuum. The residue was
applied onto a silica gel column and eluted with ethyl
acetate/petroleum ether (1:10-1:5). This resulted in 3.5 g (96%) of
benzyl 5-amino-6-(benzylthio)pyridin-3-ylcarbamate as a yellow
solid.
Benzyl
6-(benzylthio)-5-(methylsulfonamido)pyridin-3-ylcarbamate
[0482] Into a 50-mL round-bottom flask was placed a solution of
benzyl 5-amino-6-(benzylthio)pyridin-3-ylcarbamate (1.5 g, 4.11
mmol, 1.00 equiv) in pyridine (10 mL). This was followed by the
addition of methanesulfonyl chloride (560 mg, 4.91 mmol, 1.20
equiv) dropwise with stirring at 0.degree. C. The resulting
solution was stirred for 3 h at room temperature. Then it was
concentrated under vacuum. The residue was diluted with 30 mL of
EtOAc and washed with 1.times.20 mL of 1N HCl and 1.times.10 mL of
brine. The organic layer was dried over anhydrous sodium sulfate
and concentrated under vacuum. This resulted in 1.2 g (66%) of
benzyl 6-(benzylthio)-5-(methylsulfonamido)pyridin-3-ylcarbamate as
a yellow solid.
2-Hydroxy-5-nitronicotinonitrile
[0483] Chlorine gas was bubbled slowly into a solution of benzyl
6-(benzylthio)-5-(methylsulfonamido)pyridin-3-ylcarbamate (660 mg,
1.49 mmol, 1.00 equiv) in DCM (10 mL) and water (2 mL) for 5 min at
0-5.degree. C. The resulting solution was stirred for 30 min at
0-5.degree. C., then it was diluted with water (10 mL) and DCM (20
mL). The separated organic layer was dried over sodium sulfate and
concentrated under vacuum. This resulted in 600 mg (48%) of benzyl
6-(chlorosulfonyl)-5-(methylsulfonamido)pyridin-3-ylcarbamate as a
yellow solid.
2-Chloro-5-nitronicotinonitrile
[0484] Into a 50-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen were placed a
solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (213.4 mg, 1.43
mmol, 1.00 equiv) in CH.sub.3CN (15 mL) and potassium carbonate
(592.8 mg, 4.30 mmol, 3.00 equiv). This was followed by the
addition of a solution of benzyl
6-(chlorosulfonyl)-5-(methylsulfonamido)pyridin-3-ylcarbamate (600
mg, 0.86 mmol, 1.00 equiv, 60%) in CH.sub.3CN (5 mL) dropwise with
stirring at 0.degree. C. The resulting solution was stirred for 30
min at room temperature, then quenched by the addition of 10 mL of
water. The resulting mixture was concentrated under vacuum. The
residual solution was adjusted to pH 4 with 6N HCl, then extracted
with 3.times.20 ml, of ethyl acetate. The organic layers were
combined, washed with 2.times.10 mL of brine, dried over anhydrous
sodium sulfate and concentrated under vacuum. The residue was
applied onto a silica gel column and eluted with
dichloromethane/methanol (100:1-50:1). This resulted in 640 mg
(76%) of benzyl
6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-
-(methylsulfonamido)pyridin-3-ylcarbamate as a yellow solid.
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(methylsulfo-
namido)pyridine-2-sulfonamide
[0485] A mixture of benzyl
6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(methy-
lsulfonamido)pyridin-3-ylcarbamate (840 mg, 1.58 mmol, 1.00 equiv)
and Palladium carbon (1 g, 83.33 mmol, 52.78 equiv) in methanol (20
mL) was stirred overnight at room temperature under a hydrogen
atmosphere. The solid was filtered out. The filtrate was
concentrated under vacuum. The crude product (300 mg) was purified
by Prep-HPLC with the following conditions: Column, SunFire Prep
C18, 5 um, 19.times.100 mm; Mobile phase, water (with 0.1% formic
acid) and CH.sub.3CN; Gradient, 20% CH.sub.3CN up to 40% in 6 min,
up to 100% in 1 min, down to 20% in 1 min; Detector, UV 220 &
254 nm. This resulted in 200.3 mg (32%) of the title compound as a
white solid (m.p. 209-210.degree. C.). LC-MS-(ES, m/z): 399
[M+H].sup.+. .sup.1H-NMR-- (300 MHz, DMSO-d6, ppm): 10.46 (s, 1H),
9.23 (s, 1H), 8.88 (s, 1H), 7.67 (s, 1H), 7.50 (s, 1H), 7.18-7.29
(m, 2H), 7.03-7.04 (d, 1H, J=3 Hz), 6.43 (s, 2H), 4.89 (s, 2H),
3.03 (s, 3H).
5-Amino-3-(5-aminopyridin-2-ylamino)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]-
oxaborol-6-yl)pyridine-2-sulfonamide
##STR00162##
[0486] Benzyl
6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(5-nit-
ropyridin-2-ylamino)pyridin-3-ylcarbamate
[0487] Into a 50-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen were placed a
solution of benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)p-
yridin-3-ylcarbamate (500 mg, 1.02 mmol, 1.00 equiv, 93%) in
1,4-dioxane (20 mL), 2-chloro-5-nitropyridine (210 mg, 1.33 mmol,
1.20 equiv), Pd.sub.2(dba).sub.3 (20 mg, 0.02 mmol, 0.02 equiv),
Xantphos (40 mg, 0.07 mmol, 0.06 equiv) and potassium carbonate
(215 mg, 1.56 mmol, 1.40 equiv). The resulting mixture was stirred
for 3 h at 80.degree. C. in an oil bath. The resulting mixture was
cooled and concentrated under vacuum. The residue was applied onto
a silica gel column and eluted with ethyl acetate/petroleum ether
(1:1). This resulted in 520 mg (71%) of the title compound as a
yellow solid.
5-Amino-3-(5-aminopyridin-2-ylamino)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]-
oxaborol-6-yl)pyridine-2-sulfonamide
[0488] A mixture of benzyl
6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(5-nit-
ropyridin-2-ylamino)pyridin-3-ylcarbamate (520 mg, 0.72 mmol, 1.00
equiv, 80%) and Palladium carbon (10%, 500 mg) in methanol (50 mL)
was stirred for 12 h at room temperature under a hydrogen
atmosphere. The solid was filtered out. The filtrate was
concentrated under vacuum. The crude product (362 mg) was purified
by Prep-HPLC with the following conditions: Column, SunFire Prep
C18, 5 um, 19.times.150 mm; Mobile phase: water and CH.sub.3CN;
Gradient, 15% CH.sub.3CN up to 30% in 8 min, up to 100% in 2 min;
Detector, UV 220 & 254 nm. This resulted in 103.6 mg (35%) of
the title compound as a brown solid. LC-MS (ES, m/z): 413
[M+H].sup.+. .sup.1H-NMR (300 MHz, DMSO-d6, ppm): 10.24 (1H, s),
9.18 (1H, s), 8.21 (1H, s), 7.66 (1H, d, J=2.7 Hz), 7.51 (1H, s),
7.41 (2H, d, J=2.1 Hz), 7.36 (2H, d, J=2.1 Hz), 6.99 (1H, m), 5.98
(2H, s), 5.05 (2H, m), 4.84 (2H, s).
5-Amino-3-(5-cyanopyridin-2-ylamino)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]-
oxaborol-6-yl)pyridine-2-sulfonamide
##STR00163##
[0489] Benzyl
5-(5-cyanopyridin-2-ylamino)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxab-
orol-6-yl)sulfamoyl)pyridin-3-ylcarbamate
[0490] Into a 50-mL 3-necked round-bottom flask were placed a
solution of benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulf-
amoyl)pyridin-3-ylcarbamate (400 mg, 0.88 mmol, 1.00 equiv) in
dioxane (25 mL), 6-chloronicotinonitrile (146 mg, 1.06 mmol, 1.20
equiv), potassium carbonate (170 mg, 1.23 mmol, 1.40 equiv),
Pd.sub.2(dba).sub.3 (16 mg, 0.02 mmol, 0.02 equiv) and Xantphos (30
mg, 0.05 mmol, 0.06 equiv). The resulting solution was stirred for
1 h at 90.degree. C., then it was cooled and concentrated under
vacuum. The residue was applied onto a silica gel column and eluted
with ethyl acetate. This resulted in 450 mg (87%) of the title
compound as an orange solid.
5-Amino-3-(5-cyanopyridin-2-ylamino)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]-
oxaborol-6-yl)pyridine-2-sulfonamide
[0491] A mixture of benzyl
5-(5-cyanopyridin-2-ylamino)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxab-
orol-6-yl)sulfamoyl)pyridin-3-ylcarbamate (450 mg, 0.81 mmol, 1.00
equiv) and Pd(OH).sub.2/C (450 mg, 2.25 mmol, 1.00 equiv) in
ethanol/EtOAc(10/10 mL) was stirred for 4.5 h at room temperature
under a hydrogen atmosphere. The solid was filtered out. The
filtrate was concentrated under vacuum. The crude product (300 mg)
was purified by Prep-HPLC with the following conditions: Column,
SunFire Prep C18, Sum, 19.times.150 mm; Mobile phase, water (with
0.05% TFA) and CH.sub.3CN; Gradient, 22% CH.sub.3CN up to 42% in 6
min, up to 100% in 1 min; Detector, UV 220 & 254 nm. This
resulted in 160 mg (47%) of the title compound as a white solid.
LC-MS (ES, m/z): 423 [M+H].sup.+. .sup.1H-NMR (DMSO-d6, 300 MHz,
ppm): 10.23 (s, 1H), 9.14 (s, 1H), 8.95 (s, 1H), 8.50 (J=2.1 Hz, d,
1H), 7.94 (J=2.4, 8.7 Hz, dd, 1H), 7.63 (J=2.4 Hz, d, 1H), 7.54
(J=2.1 Hz, d, 1H), 7.44 (s, 1H), 7.14 (d, 2H), 6.90 (J=8.7 Hz, d,
1H), 6.23 (s, 2H), 4.78 (s, 2H).
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(pyrazin-2-y-
lamino)pyridine-2-sulfonamide
##STR00164##
[0492] Benzyl
6-(N-(1-hydroxy-1,3-dihydrobenzok[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(pyra-
zin-2-ylamino)pyridin-3-ylcarbamate
[0493] Into a 50-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen were placed a
solution of
benzyl-N-5-amino-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoy-
l]pyridin-3-ylcarbamate (1000 mg, 2.05 mmol, 1.00 equiv, 93%) in
1,4-dioxane (20 mL), 2-chloropyrazine (301 mg, 2.65 mmol, 1.20
equiv), Pd.sub.2(dba).sub.3 (40 mg, 0.04 mmol, 0.02 equiv),
Xantphos (80 mg, 0.14 mmol, 0.06 equiv) and potassium carbonate
(425 mg, 3.08 mmol, 1.40 equiv). The resulting solution was stirred
for 6 h at 80.degree. C. in an oil bath. Then it was cooled and
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with ethyl acetate/petroleum ether (1:1).
This resulted in 600 mg (44%) of the title compound as a yellow
solid.
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(pyrazin-2-y-
lamino)pyridine-2-sulfonamide
[0494] A mixture of benzyl
6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(pyraz-
in-2-ylamino)pyridin-3-ylcarbamate (600 mg, 0.90 mmol, 1.00 equiv,
80%) and Palladium carbon (500 mg) in methanol (30 mL) was stirred
overnight at room temperature under a hydrogen atmosphere. The
solid was filtered out. The filtrate was concentrated under vacuum.
The crude product (300 mg) was purified by Prep-HPLC with the
following conditions: Column, Atlantis T3, Sum, 19.times.150 mm;
Mobile phase, water (with 0.05% TFA) and CH.sub.3CN; Gradient, 20%
CH.sub.3CN up to 30% in 8 min; Detector, UV 254 nm. This resulted
in 39.6 g (11%) of the title compound as a yellow solid. LC-MS-(ES,
m/z): 399 [M+H].sup.+. .sup.1H-NMR-(300 MHz, DMSO-d6, ppm): 10.26
(1H, s), 9.13 (1H, m), 8.77 (1H, s), 8.23 (1H, s), 8.11 (1H, s),
8.04 (1H, J=2.7 Hz, d), 7.73 (1H, J=2.4 Hz, d), 7.56 (1H, J=2.1 Hz,
d), 7.46 (1H, s), 7.17 (2H, s), 6.21 (2H, m), 4.78 (2H, s).
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(pyrimidin-2-
-ylamino)pyridine-2-sulfonamide
##STR00165##
[0495] Benzyl
6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(pyrim-
idin-2-ylamino)pyridin-3-ylcarbamate
[0496] Into a 50-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen were placed a
solution of
benzyl-N-5-amino-6-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)sulfamoy-
i]pyridin-3-ylcarbamate (800 mg, 1.64 mmol, 1.00 equiv, 93%) in
1,4-dioxane (30 mL), 2-bromopyrimidine (336 mg, 2.11 mmol, 1.20
equiv), Pd.sub.2(dba).sub.3 (40 mg, 0.04 mmol, 0.02 equiv),
Xantphos (80 mg, 0.14 mmol, 0.06 equiv) and sodium
2-methylpropan-2-olate (338 mg, 3.52 mmol, 2.00 equiv). The
resulting mixture was stirred for 6 h at 110.degree. C. in an oil
bath, then it was cooled and concentrated under vacuum. The residue
was applied onto a silica gel column and eluted with ethyl
acetate/petroleum ether (1:1). This resulted in 500 mg (46%) of the
title compound as a yellow solid.
5-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(pyrimidin-2-
-ylamino)pyridine-2-sulfonamide
[0497] A mixture of benzyl
6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(pyrim-
idin-2-ylamino)pyridin-3-ylcarbamate (500 mg, 0.75 mmol, 1.00
equiv, 80%) and palladium on carbon (500 mg) in methanol (50 mL)
was stirred overnight at room temperature under a hydrogen
atmosphere. The solid was filtered out. The filtrate was
concentrated under vacuum. The residue was applied onto a silica
gel column and eluted with methanol/DCM (1/10). This resulted in
80.9 mg (27%) of the title compound as a light yellow solid.
LC-MS-(ES, m/z): 399 [M+H].sup.+. .sup.1H-NMR-(300 MHz, DMSO-d6,
ppm): 10.36 (1H, s), 9.37 (1H, s), 9.18 (1H, s), 8.52 (2H, J=5.1
Hz, d), 8.11 (1H, J=2.4 Hz, d), 7.56 (1H, J=2.4 Hz, d), 7.50 (1H,
s), 7.20 (2H, J=1.5 Hz, d), 6.99 (1H, m), 6.25 (2H, s), 4.82 (2H,
s).
Methyl
5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfa-
moyl)pyridin-3-ylcarbamate
##STR00166##
[0499] Methyl chloroformate (1.23 g, 13 mmol) was added to the
solution of benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulf-
amoyl)pyridin-3-ylcarbamate (820 mg, 1.8 mmol) in THF (12 ml) at
rt. Stirring was kept for 2 days. Removed solvent, diluted with
EtOAc (100 ml), washed with water (20 ml.times.2) and brine (20
ml.times.2), dried over Na.sub.2SO.sub.4. Concentrated to give off
white solid. The mixture of the crude and Pd/C (500 mg, 10 wt %) in
MeOH (20 ml), was degassed with Nitrogene, then placed under
hydrogen atmosphere at 50 psi for 4 hours. The catalyst was
filtered with a pad of Celite, washed with MeOH (100 ml), the
solution was then concentrated. The crude was purified by prep HPLC
(SunFire Prep C18 OBD 5 uM 30.times.50 mm column). The title
compound was obtained as white powder. MS calcd for
(C.sub.14H.sub.15BN.sub.4O.sub.6S): 378.169, MS found (ESI
negative): (M-H).sup.-=377.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 10.35 (s, 1H), 9.19 (s, 1H), 8.95 (s, 1H), 7.59 (d,
J=2.4 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.46 (d, J=1.6 Hz, 1H), 7.23
(d, J=8 Hz, 1H), 7.14 (dd, J=8.4 Hz, 1H), 6.32 (bs, 2H), 4.86 (s,
2H), 3.64 (s, 3H).
Ethyl
5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfam-
oyl)pyridin-3-ylcarbamate
##STR00167##
[0501] Ethyl chloroformate (570 mg, 3.5 mmol) was added to the
solution of benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulf-
amoyl)pyridin-3-ylcarbamate (227 mg, 0.5 mmol) in THF (8 ml) at rt.
Stirring was kept for 2 days. Removed solvent, diluted with EtOAc
(100 ml), washed with water (20 ml.times.2) and brine (20
ml.times.2), dried over Na.sub.2SO.sub.4. Concentrated to give off
white solid. The mixture of the crude and Pd/C (100 mg, 10 wt %) in
MeOH (20 ml), was degassed with Nitrogene, then placed under
hydrogen atmosphere at 50 psi for 4 hours. The catalyst was
filtered with a pad of Celite, washed with MeOH (100 ml), the
solution was then concentrated. The crude was purified by prep HPLC
(SunFire Prep C18 OBD 5 uM 30.times.50 mm column). The title
compound was obtained as white powder, yield 91 mg. MS calcd for
(C.sub.15H.sub.17BN.sub.4O.sub.6S): 392.195, MS found (ESI
negative): (M-H).sup.-=391.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 10.35 (s, 1H), 8.90 (s, 1H), 7.62 (d, J=2.4 Hz, 1H),
7.57 (d, J=2.4 Hz, 1H), 7.46 (d, J=2 Hz, 1H), 7.23 (d, J=8 Hz, 1H),
7.14 (dd, J=8 Hz, 1H), 4.83 (s, 2H).
2-Fluoroethyl
5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)p-
yridin-3-ylcarbamate
##STR00168##
[0503] General Procedure 4 and 5: Starting material--benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)p-
yridin-3-ylcarbamate and 2-fluoroethyl carbonochloridate.
Preparative HPLC was applied for the purification and give the
title compound as white powder yield 108 mg. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 10.40 (s, 1H), 9.19 (bs, 1H), 9.05 (s,
1H), 7.61 (m, 2H), 7.47 (d, J=1.6 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H),
7.18 (dd, J=8.0, 2 Hz, 1H), 6.38 (bs, 2H), 4.87 (s, 2H), 4.71 (t,
J=4 Hz, 2H), 4.59 (t, J=4 Hz, 2H), 4.36 (t, J=4 Hz, 2H), 4.29 (t,
J=4 Hz, 2H); MS (ESI) m/z=409.1 (M-H, negative).
2-Hydroxyethyl
5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)p-
yridin-3-ylcarbamate
##STR00169##
[0505] 2-Benzyloxyethyl chloroformate (2.7 ml, 15 mmol) was added
to the solution of benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)p-
yridin-3-ylcarbamate (910 mg, 2 mmol) in THF (20 ml) at rt.
Stirring was kept for 2 days. Removed solvent, diluted with EtOAc
(200 ml), washed with water (20 ml.times.2) and brine (20
ml.times.2), dried over Na.sub.2SO.sub.4. Concentrated to give off
white solid. The mixture of the crude and Pd/C (500 mg, 10 wt %) in
MeOH (20 ml), was degassed with nitrogen, then placed under
hydrogen atmosphere at 50 psi for 4 hours. The catalyst was
filtered with a pad of Celite, washed with MeOH (100 ml), the
solution was then concentrated. The crude was purified by prep HPLC
(SunFire Prep C18 OBD 5 uM 30.times.50 mm column). MS calcd for
(C.sub.15H.sub.17BN.sub.4O.sub.7S): 408.09, MS found (ESI
negative): (M-H).sup.-=407.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 10.39 (s, 1H), 8.96 (s, 1H), 7.64 (d, J=2.4 Hz, 1H),
7.57 (d, J=2.4 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.24 (d, J=8.4 Hz,
1H), 7.16 (dd, J=8.4 Hz, 1H), 4.86 (s, 2H), 4.06 (t, J=4.8 Hz, 2H),
3.58 (t, J=4.8 Hz, 2H).
2-(Benzyloxy)ethyl
5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)p-
yridin-3-ylcarbamate
##STR00170##
[0507] 2-Benzyloxyethyl chloroformate (2.7 ml, 15 mmol) was added
to the solution of benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)p-
yridin-3-ylcarbamate (910 mg, 2 mmol) in THF (20 ml) at rt.
Stirring was kept for 2 days. Removed solvent, diluted with EtOAc
(200 ml), washed with water (20 ml.times.2) and brine (20
ml.times.2), dried over Na.sub.2SO.sub.4. Concentrated to give off
white solid. The mixture of the crude and Pd/C (500 mg, 10 wt %) in
MeOH (20 ml), was degassed with Nitrogen, then placed under
hydrogen atmosphere at 50 psi for 4 hours. The catalyst was
filtered with a pad of Celite, washed with MeOH (100 ml), the
solution was then concentrated. The crude was purified by prep HPLC
(SunFire Prep C18 OBD 5 uM 30.times.50 mm column). MS calcd for
(C.sub.22H.sub.23BN.sub.4O.sub.7S): 498.14, MS found (ESI
negative): (M-H).sup.-=497.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 10.39 (s, 1H), 9.00 (s, 1H), 7.62 (d, J=2.4 Hz, 1H),
7.58 (d, J=2.4 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.35-7.25 (m, 5H),
7.22 (d, J=8.4 Hz, 1H), 7.16 (dd, J=8.4 Hz, 1H), 4.84 (s, 2H), 4.51
(s, 2H), 4.22 (t, J=6 Hz, 2H), 3.64 (t, J=4.8 Hz, 2H).
Propyl
5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfa-
moyl)pyridin-3-ylcarbamate
##STR00171##
[0509] Allyl chloroformate (5 ml, 48 mmol) was added to the
solution of benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulf-
amoyl)pyridin-3-ylcarbamate (910 mg, 2 mmol) in THF (50 ml) at rt.
Stirring was kept for 2 days. Removed solvent, diluted with EtOAc
(300 ml), washed with water (40 ml.times.2) and brine (40
ml.times.2), dried over Na.sub.2SO.sub.4. Concentrated to give off
white solid. The mixture of the crude (1.62 g, 3 mmol) and Pd/C
(900 mg, 10 wt %) in MeOH (30 ml), was degassed with Nitrogen, then
placed under hydrogen atmosphere at 50 psi for 4 hours. The
catalyst was filtered with a pad of Celite, washed with MeOH (100
ml), the solution was then concentrated. The crude was purified by
prep HPLC (SunFire Prep C18 OBD 5 uM 30.times.50 mm column). MS
calcd for (C.sub.16H.sub.19BN.sub.4O.sub.6S): 406.11, MS found (ESI
negative): (M-H).sup.-=405.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 10.34 (s, 1H), 9.17 (s, 1H), 8.92 (s, 1H), 7.62 (d,
J=2 Hz, 1H), 7.57 (d, J=2 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.24 (d,
J=8.4 Hz, 1H), 7.15 (dd, J=8 Hz, 1H), 6.30 (s, 2H), 4.86 (s, 2H),
4.00 (t, J=6.4 Hz, 2H), 1.61 (m, 2H), 0.88 (t, J=7.2 Hz, 3H).
Isobutyl
5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sul-
famoyl)pyridin-3-ylcarbamate-
##STR00172##
[0511] General Procedure 4 and 5: Starting Material compound benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)p-
yridin-3-ylcarbamate and isobutyl carbonochloridate. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 10.36 (s, 1H), 9.20 (bs,
1H), 8.96 (s, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H),
7.47 (d, J=2.4 Hz, 1H), 7.24 (d, J=8 Hz, 1H), 7.16 (dd, J=8.0, 2
Hz, 1H), 4.87 (s, 2H), 3.86 (d, J=6.8 Hz, 2H), 1.91 (m, 1H), 0.89
(d, J=6.8 Hz, 6H); MS (ESI) m/z=419.1 (M-H, negative).
Hexyl
5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfam-
oyl)pyridin-3-ylcarbamate
##STR00173##
[0513] Hexyl chloroformate (2.45 ml, 15 mmol) was added to the
solution of benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulf-
amoyl)pyridin-3-ylcarbamate (910 mg, 2 mmol) in THF (20 ml) at rt.
Stirring was kept for 2 days. Removed solvent, diluted with EtOAc
(100 ml), washed with water (20 ml.times.2) and brine (20
ml.times.2), dried over Na.sub.2SO.sub.4. Concentrated to give off
white solid. The mixture of the crude and Pd/C (100 mg, 10 wt %) in
MeOH (20 ml), was degassed with nitrogen, then placed under
hydrogen atmosphere at 50 psi for 4 hours. The catalyst was
filtered with a pad of Celite, washed with MeOH (100 ml), the
solution was then concentrated. The crude was purified by prep HPLC
(SunFire Prep C18 OBD 5 uM 30.times.50 mm column). The title
compound was obtained as white powder. MS calcd for
(C.sub.19H.sub.25BN.sub.4O.sub.6S): 448.16, MS found (ESI
negative): (M-H).sup.-=447.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 10.30 (s, 1H), 9.11 (br, 1H), 8.86 (s, 1H), 7.57 (d,
J=2 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.40 (s, 1H), 7.18 (d, J=8 Hz,
1H), 7.08 (dd, J=8 Hz, 1H), 6.26 (br, 2H), 4.81 (s, 2H), 3.98 (t,
J=6.8 Hz, 2H), 1.53 (m, J=6.4 Hz, 2H), 1.22 (s, 6H), 0.81 (t, J=6.8
Hz, 3H).
Cyclopentyl
5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)p-
yridin-3-ylcarbamate
##STR00174##
[0515] General Procedure 4 and 5: Starting Materials. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 10.35 (s, 1H), 9.20 (bs,
1H), 8.84 (s, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H),
7.47 (s, 1H), 7.24 (d, J=8 Hz, 1H), 7.15 (dd, J=8, 2 Hz, 1H), 6.32
(bs, 2H), 5.03 (m, 1H), 4.88 (s, 2H), 1.84 (m, 2H), 1.65 (m, 4H),
1.57 (m, 2H); S (ESI) m/z=431.1 (M-H, negative).
Cyclohexyl
5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)s-
ulfamoyl)pyridin-3-ylcarbamate
##STR00175##
[0517] Cyclohexyl chloroformate (2.44 g, 15 mmol) was added to the
solution of benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)p-
yridin-3-ylcarbamate (910 mg, 2 mmol) in THF (12 ml) at rt.
Stirring was kept for 2 days. Removed solvent, diluted with EtOAc
(200 ml), washed with water (20 ml.times.2) and brine (20
ml.times.2), dried over Na.sub.2SO.sub.4. Concentrated to give off
white solid. The mixture of the crude and Pd/C (500 mg, 10 wt %) in
MeOH (20 ml), was degassed with Nitrogene, then placed under
hydrogen atmosphere at 50 psi for 4 hours. The catalyst was
filtered with a pad of Celite, washed with MeOH (100 ml), the
solution was then concentrated. The crude was purified by prep HPLC
(SunFire Prep C18 OBD 5 uM 30.times.50 mm column). The title
compound was obtained as light yellow powder. MS calcd for
(C.sub.19H.sub.23BN.sub.4O.sub.6S): 446.28, MS found (ESI
negative): (M-H).sup.-=445.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 10.35 (s, 1H), 9.18 (bs, 1H), 8.73 (s, 1H), 7.64 (d,
J=2.4 Hz, 1H), 7.57 (d, J=2 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.23
(d, J=8 Hz, 1H), 7.14 (dd, J=8.4 Hz, 1H), 6.30 (bs, 2H), 4.86 (s,
2H), 3.65 (s, 2H), 1.90-1.20 (m, 9H).
Phenyl
5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfa-
moyl)pyridin-3-ylcarbamate
##STR00176##
[0519] Phenyl chloroformate (1.8 ml, 14 mmol) was added to the
solution of benzyl
5-amino-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulf-
amoyl)pyridin-3-ylcarbamate (910 mg, 2 mmol) in THF (20 ml) at rt.
Stirring was kept for 2 days. Removed solvent, diluted with EtOAc
(100 ml), washed with water (20 ml.times.2) and brine (20
ml.times.2), dried over Na.sub.2SO.sub.4. Concentrated and got off
white solid. The crude was treated with HBr (in acetic acid, 5 ml),
stirred at r.t. for 4 hours, concentrated. The residue was
dissolved in DMSO then purified by prep HPLC (SunFire Prep C18 OBD
5 uM 30.times.50 mm column). The title compound was obtained as off
white powder, yield 240 mg. MS calcd for
(C.sub.19H.sub.17BN.sub.4O.sub.6S): 440.10, MS found (ESI
positive): (M+H).sup.+=441.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 10.41 (s, 1H), 9.35 (s, 1H), 9.21 (s, 1H), 7.63 (d,
J=1.6 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.50 (s, 1H), 7.42 (t, J=8
Hz, 2H), 7.26 (m, 3H), 7.19 (d, J=7.6 Hz, 2H), 6.36 (s, 2H), 4.87
(s, 2H).
N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy
benzenesulfonamide
##STR00177##
[0521] General Procedure 1: Starting Materials
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and
4-methoxybenzenesulfonyl chloride. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 9.97 (s, 1H), 9.32 (s., 1H), 7.64 (m,
3H), 7.21 (d, J=10 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 4.89 (s, 2H),
3.80 (s, 3H). MS (ESI): m/z=336.0 (M-H, negative).
N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-hydroxybenz-
enesulfonamide
##STR00178##
[0523]
N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-meth-
oxybenzenesulfonamide (0.2 g, 0.59 mmol), DCM (5 mL), was added
boron tribromide 1M solution in DCM (1.7 ml, 1.78 mmol) at
0.degree. C. overnight. Purification: ice was added and worked up
with EtOAc; preparative HPLC was applied for the purification and
give product as white powder yield 5 mg (1%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 10.41 (s, 1H), 9.81 (s, 1H)), 9.29 (s,
1H), 7.64 (d, J=7.6 Hz, 1H), 7.51 (d, J=8 Hz, 2H), 7.20 (d, J=10
Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 4.89 (s, 2H); MS (ESI): m/z=322.0
(M-H, negative).
5-Hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)pyridine-2-su-
lfonamide
##STR00179##
[0524] 2-Benzylsulfanyl-5-methoxy-pyridine
[0525] To a solution of 2-bromo-5-methoxy-pyridine (2.0 g, 10.6
mmol) in THF (20 mL) at -78.degree. C. was added n-BuLi (1.6 M in
hexane, 6.65 mL, 10.64 mmol). After 20 min, dibenzyldisulfide (3.15
g, 12.7 mmol) was added and the mixture was stirred for 1 h in an
ice bath and 1 h at ambient temperature. Saturated aqueous ammonium
chloride was added and the mixture was extracted with ethyl
acetate. The organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Partial
purification was accomplished by flash silica gel column
chromatography (Biotage.RTM., 15-40% ethyl acetate in hexanes
gradient) resulting in 1.086 g of the title compound that was used
without further purification in the next step.
5-Methoxy-pyridine-2-sulfonyl chloride
[0526] Through a solution of 2-benzylsulfanyl-5-methoxy-pyridine
(1.086 g) in DCM (25 mL) and water (5 mL) at 0.degree. C. was
bubbled chlorine for 15 min. The mixture was stirred for 15 min
before bubbling nitrogen for 15 min. The organic layer was
separated, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo providing the 1.039 g (47% over 2 steps) of the title
compound that was directly used in the next step without further
purification. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.43
(d, J=2.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.66 (dd, J=9.0, 2.7 Hz,
1H), 4.00 (s, 3H).
5-Methoxy-pyridine-2-sulfonic acid
(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide
[0527] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol
(0.400, 2.68 mmol), pyridine (0.434 mL, 5.37 mmol), acetonitrile
(10 mL), and 5-methoxy-pyridine-2-sulfonyl chloride (1.039 g, 2.68
mmol). Purification was accomplished by Biotage.RTM. silica gel
chromatography (50 g SNAP.TM. column, eluting with 2-25% MeOH in
DCM gradient) followed by lyophilizing from an acetonitrile-water
mixture produced 0.691 g (80%) of the title compound. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 10.39 (s, 1H), 9.20 (s, 1H),
8.37 (d, J=2.7 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.58-7.47 (m, 2H),
7.36 (d, J=4.7 Hz, 1H), 7.31-7.16 (m, 1H), 4.87 (s, 2H), 3.87 (s,
3H).
5-Hydroxy-pyridine-2-sulfonic acid
(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide
[0528] To a solution of 5-methoxy-pyridine-2-sulfonic acid
(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-amide (0.690 g,
2.16 mmol) in DCM (35 mL) at 0.degree. C. was added BBr.sub.3 (1 M
in DCM, 8.62 mL, 8.62 mmol). After 3 h, the ice bath was removed
and after an additional 3 h at room temperature more BBr.sub.3 (1 M
in DCM, 2.16 mL, 2.16 mmol) was added. After overnight, the mixture
was poured into crushed ice. After the ice melted the solid was
collected by filtration, washed with water and dried in vacuo
generating 291 mg of crude material. The organic layer of the
filtrate was separated and dried in vacuo producing another 321 mg
of crude material. The two fractions (291 mg and 321 mg) were
combined, dissolved in 10% MeOH in EtOAc and dried in vacuo
producing 585 mg of crude material. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 10.94 (s, 1H). 10.28 (s, 1H), 9.83 (s,
1H), 9.20 (bs, 1H), 8.16 (d, J=2.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H),
7.47 (s, 1H), 7.24 (m, 3H), 4.86 (s, 2H); MS (ESI) m/z=305.0 (M-H,
negative).
N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-3-methyl-be-
nzenesulfonamide
##STR00180##
[0530] To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.25
g, 1.34 mmol) in anhydrous pyridine (30 mL) at 5.degree. C. was
added 4-methoxy-3-methyl-benzenesulfonyl chloride (0.29 g, 1.34
mmol). After overnight at room temperature, the volatiles were
removed in vacuo. The residue was treated with H.sub.2O (80 mL) and
sonicated for 4 h. The fine precipitate that formed was filtered,
washed with water and dried in vacuo generating 0.22 g (48%) as a
yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm):
10.06 (brs, 1H), 9.21 (s, 1H), 7.56-7.53 (m, 2H), 7.48 (d, J=1.6
Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.17 (dd, J=8.2, 1.8 Hz, 1H), 7.02
(d, J=9.2 Hz, 1H), 4.87 (s, 2H), 3.81 (s, 3H), 2.13 (s, 3H); MS
(ESI) m/z=332 (M-1, negative); HPLC purity: 97.58% (MaxPlot 200-400
nm), 97.89% (220 nm).
4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-methyl-be-
nzenesulfonamide
##STR00181##
[0532] To a suspension of
N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-3-methyl-b-
enzenesulfonamide (0.80 g, 2.40 mmol) in 100 mL of anhydrous DCM at
5.degree. C. was added 1N solution of BBr.sub.3 in DCM (3 mL). The
resulting solution stirred at room temperature overnight. The
precipitate that formed was filtered, washed with DCM and briefly
dried before suspending in water. The gummy material formed was
extracted into EtOAc, and the organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. This was
further purified through preparative HPLC affording 0.030 g (3%
yield) of the title compound as a white solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 10.33 (brs, 1H), 9.98 (brs, 1H),
9.21 (s, 1H), 7.47 (d, J=2.5 Hz, 2H), 7.5 (d, J=1.9 Hz, 2H), 7.36
(dd, J=8.6, 2.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.14 (dd, J=8.2,
1.8 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 4.85 (s, 2H), 2.07 (s, 3H); MS
(ESI) m/z=318 (M-1, negative); HPLC purity: 99.91% (MaxPlot 200-400
nm), 99.83% (220 nm).
N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-methyl-be-
nzenesulfonamide
##STR00182##
[0534] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol
(721 mg, 3.62 mmol), pyridine (10 mL), and
4-methoxy-2-methyl-benzenesulfonyl chloride (800 mg, 3.62 mmol).
Purification: Column chromatography using 50-70% EtOAc in hexane.
Product was isolated as a light-yellow solid: yield 900 mg (75%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.19 (s, 1H), 9.18
(s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.43 (d, J=1.6 Hz, 1H), 7.24-7.19
(m, 1H), 7.15 (d, J=2.0 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.83 (d,
J=9.0 Hz, 1H), 4.84 (s, 2H), 3.74 (s, 3H), 2.53 (s, 3H); MS (ESI)
m/z=332 (M-1, negative); HPLC purity: 96.93% (MaxPlot 200-400 nm),
97.02% (220 nm).
4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-methyl-be-
nzenesulfonamide
##STR00183##
[0536] To a solution of
N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-methyl-b-
enzenesulfonamide (400 mg, 1.20 mmol) in DCM (10 mL) was added
BBr.sub.3 (1M in DCM, 3.60 mL, 3.6 mmol). After overnight at rt,
water was added and the CH.sub.2Cl.sub.2 layer was separated, dried
over MgSO.sub.4, filtered and concentrated in vacuo. Purification
was accomplished by preparative HPLC generating 140 mg (36%) of the
title compound as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.25 (s, 1H), 10.11 (s, 1H), 9.18 (s,
1H), 7.69 (d, J=8.6 Hz, 1H), 7.43 (s, 1H), 7.20-7.25 (m, 1H),
7.11-7.17 (m, 1H), 6.57-6.70 (m, 2H), 4.86 (s, 2H), 2.48 (s, 3H);
MS (ESI) m/z=318 (M-1, negative); HPLC purity: 99.12% (MaxPlot
200-400 nm), 99.49% (220 nm).
N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-m-
ethylbenzenesulfonamide
##STR00184##
[0538] General Procedure 1: Starting Materials
6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol and
4-methoxy-2-methylbenzene-1-sulfonyl chloride. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 9.95 (s, 1H), 9.30 (s., 1H), 7.67
(d, J=7.6 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.19 (d, J=10.4 Hz, 1H),
6.93 (d, J=2.4 Hz, 1H), 6.80 (dd, J=8.8, 2.8 Hz, 1H), 4.89 (s, 2H),
3.78 (s, 3H), 2.57 (s, 2H). MS (ESI): m/z=350.0 (M-H,
negative).
N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-hydroxy-2-m-
ethylbenzenesulfonamide
##STR00185##
[0540] Boron tribromide (3.4 mL, 3.4 mmol, 1M solution) was added
drop-wise slowly to an ice-cold solution of the
N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2--
methylbenzenesulfonamide (0.4 g, 1.13 mmol) in DCM at 0.degree. C.
The reaction was allowed to stir at r.t. and monitored by LC/MS.
Purification: ice was added slowly to the mixture and worked up
with DCM, the organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 and dried in vacuo. Further purification was
carried out by preparative HPLC to give title product
N-(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-hydroxy-2--
methylbenzene sulfonamide (35 mg, yield: 9.2%) .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 10.26 (bs, 1H), 9.83 (s, 1H),
9.30 (bs, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.19
(d, J=10.4 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.58 (dd, J=8.8, 2.4
Hz, 1H), 4.89 (s, 2H), 2.50 (s, 3H); MS (ESI) m/z=336.1 (M-H,
negative).
2-Hydroxy-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-be-
nzoic acid
##STR00186##
[0542] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol
(200 mg, 1.3 mmol), 5-(chlorosulfonyl)salicylic acid (378 mg, 1.6
mmol), pyridine (0.4 mL, 5.2 mmol), DMSO (2 mL), and MeCN (10 mL)
at rt O/N. 1 M HCl (5 mL) was added and the mixture was
concentrated in vacuo at 40.degree. C. The remaining DMSO solution
was purified by RP-Biotage (10-100% MeOH/0.1% aq TFA). The major
fraction was concentrated in vacuo at 40.degree. C. and then
lyophilized to give the title compound as a white solid: yield; 95
mg (21%). .sup.1H NMR (400 MHz, DMSO-d.sub.6+HCl) .delta. (ppm):
10.24 (s, 1H), 8.08-8.07 (m, 1H), 7.76-7.73 (m, 1H), 7.44-7.43 (m,
1H), 7.23-7.21 (m, 1H), 7.14-7.12 (m, 1H), 7.05-7.03 (m, 1H), 4.83
(s, 2H); MS (ESI) m/z=348 (M-1, negative); HPLC purity: 98.77%
(MaxPlot 200-400 nm), 98.61% (220 nm).
[2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy-p-
henyl]-acetic acid ethyl ester
##STR00187##
[0543] (2-Chlorosulfonyl-5-methoxy-phenyl)-acetic acid ethyl
ester
[0544] Ethyl 3-methoxyphenyl acetate (3.0 mL, 15 mmol) was added
dropwise to chlorosulfonic acid (10 mL, 0.15 mol) at 0.degree. C.
The mixture was allowed to warm to rt and stirred for 3 h. The
mixture was then diluted with H.sub.2O and the precipitate was
isolated by filtration to give the title compound as a white solid:
yield; 2.4 g (52%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.64-7.62 (m, 1H), 6.76-6.73 (m, 2H), 4.00 (q, J=7.0 Hz,
2H), 3.99 (s, 2H), 3.71 (s, 3H), 1.14 (t, J=7.3 Hz, 3H), 4.88 (s,
2H).
[2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy-p-
henyl]-acetic acid ethyl ester
[0545] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol
(750 mg, 5.0 mmol), (2-chlorosulfonyl-5-methoxy-phenyl)-acetic acid
ethyl ester (1.77 g, 6.0 mmol), pyridine (1.5 mL, 20 mmol), DMSO
(5.0 mL), and MeCN (20 mL) at rt O/N. The mixture was concentrated
in vacuo at 40.degree. C. and the remaining DMSO soln was purified
by RP-Biotage (10-100% MeOH/0.1% aq TFA). The major fraction was
concentrated in vacuo, then lyophilized from MeCN/H.sub.2O to give
the title compound as a pale yellow solid: yield; 643 mg (32%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 10.19 (s, 1H),
9.21 (s, 1H), 7.76-7.74 (m, 1H), 7.44-7.43 (m, 1H), 7.25-7.23 (m,
1H), 7.13-7.10 (m, 1H), 6.96-6.92 (m, 2H), 4.87 (s, 2H), 4.05 (q,
J=7.3 Hz, 2H), 4.02 (s, 2H), 4.05 (t, J=7.3 Hz, 3H); MS (ESI)
m/z=404 (M-1, negative); HPLC purity: 93.84% (MaxPlot 200-400 nm),
94.60% (220 nm).
[2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy-p-
henyl]-acetic acid
##STR00188##
[0547] A mixture of
[2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy--
phenyl]-acetic acid ethyl ester (590 mg, 1.5 mmol), LiOH (105 mg,
4.4 mmol), H.sub.2O (10 mL), and MeOH (30 mL) was stirred at rt
O/N. 1 M HCl (5 mL) was added and the mixture was concentrated in
vacuo at 40.degree. C. The residue was purified by RP-Biotage
(10-100% MeOH/0.1% aq TFA). The major fraction was concentrated in
vacuo at 40.degree. C. and then lyophilized to give the title
compound as a white solid: yield; 239 mg (42%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 12.28 (bs, 1H), 10.13 (s, 1H),
9.19 (s, 1H), 7.73-7.71 (m, 1H), 7.43-7.42 (m, 1H), 7.23-7.21 (m,
1H), 7.12-7.11 (m, 1H), 6.93-6.89 (m, 2H), 4.85 (s, 2H), 3.93 (s,
2H), 3.75 (s, 3H); MS (ESI) m/z=378 (M+H, positive); HPLC purity:
98.23% (MaxPlot 200-400 nm), 97.92% (220 nm).
[5-Hydroxy-2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-p-
henyl]-acetic acid
##STR00189##
[0549] 1 M BBr.sub.3 (4.5 mL, 4.5 mmol) was added to a solution of
[2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy--
phenyl]-acetic acid (170 mg, 0.45 mmol) in CH.sub.2Cl.sub.2 (10 mL)
at rt resulting in the formation of a fine suspension. After
stirring at rt O/N the mixture was concentrated in vacuo at
40.degree. C. The residue was purified by RP-Biotage (10-100%
MeOH/0.1% aq TFA). The major fraction was concentrated in vacuo at
40.degree. C. and then lyophilized to give the title compound as a
white solid: yield; 32 mg (20%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 10.34 (s, 1H), 10.07 (s, 1H), 9.20 (s,
1H), 7.65-7.62 (m, 1H), 7.43-7.42 (m, 1H), 7.24-7.22 (m, 1H),
7.13-7.10 (m, 1H), 6.73-6.68 (m, 2H), 4.87 (s, 2H), 3.89 (s, 2H);
MS (ESI) m/z=364 (M+H, positive); HPLC purity: 94.07% (MaxPlot
200-400 nm), 92.99% (220 nm).
N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-hydroxymethyl-4-met-
hoxy-benzenesulfonamide
##STR00190##
[0550] 4-Methoxy-2-methyl-benzenesulfonic acid
[0551] 1-Methoxy-3-methyl-benzene (10.0 g, 81.85 mmol) was added to
H.sub.2SO.sub.4 (conc.) (15 mL) and stirred for 1 h at rt. The
reaction mixture was then poured into cooled brine solution (200
mL). After 30 min, the white solid that precipitated was filtered
and dried to afford the title compound (15.6 g, 94%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 7.62 (d, J=9.2 Hz, 1H),
6.69-6.58 (m, 2H), 3.71 (s, 3H), 2.41 (s, 3H).
5-Methoxy-2-sulfo-benzoic acid
[0552] To a solution of 4-methoxy-2-methyl-benzenesulfonic acid
(15.6 g, 77.13 mmol) in KOH (100 mL, 1.5 M) was heated to
80.degree. C. and KMnO.sub.4 (50.0 g, 316.39 mmol) was added in
portions at the same temperature. After 1 h, the reaction was
cooled and the black solid was removed by filtration through
Celite. The filtrate was concentrated to half of the volume under
reduced pressure and acidified with conc. HCl to pH 1 and cooled in
an ice bath. The white precipitate that formed was collected by
filtration and after drying generated 4.86 g (27%) of the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.77 (d,
J=9.2 Hz, 1H), 7.26 (d, J=3.1 Hz, 1 H), 7.09 (dd, J=9.2, 3.1 Hz,
1H), 3.81 (s, 3H).
5-Methoxy-1,1-dioxo-1H-1.lamda.6-benzo[c][1,2]oxathiol-3-one
[0553] A suspension of 5-methoxy-2-sulfo-benzoic acid (4.86 g,
20.92 mmol) in benzene (50 mL) containing SOCl.sub.2 (2.98 g, 25.11
mmol) was stirred O/N at 80.degree. C. Half of the solvent was
removed under reduced pressure. After cooling in an ice-water bath,
the solid precipitate was filtered and dried generating 4.30 g
(96%) of the title compound. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 7.88 (d, J=9.0 Hz, 1 H), 7.54-7.43 (m, 2H), 3.99 (s,
3H).
5-Methoxy-2-sulfo-benzoic acid methyl ester
[0554] A solution of
5-methoxy-1,1-dioxo-1H-1.lamda..sup.6-benzo[c][1,2]oxathiol-3-one
(4.30 g, 20.07 mmol) in MeOH (20 mL) was stirred at 50.degree. C.
for 2 h. The reaction mixture was then concentrated under reduced
pressure to give a thick liquid that on standing partially
crystallized. Yield 4.20 g, 85%. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.62 (d, J=9.2 Hz, 1H), 6.96 (dd, J=9.2,
3.4 Hz, 1H), 6.77 (d, J=2.2 Hz, 1H), 3.77 (s, 3H), 3.70 (s,
3H).
2-Chlorosulfonyl-5-methoxy-benzoic acid methyl ester
[0555] A mixture of 5-methoxy-2-sulfo-benzoic acid methyl ester
(4.20 g, 17.05 mmol) and PCl.sub.5 (4.26 g, 20.46 mmol) was heated
at 100.degree. C. for 3 h. The volatile component (POCl.sub.3) was
removed under reduced pressure, and the residue was dissolved in
Et.sub.2O. The ethereal solution was washed several times with
ice-water and dried over MgSO.sub.4. Filtration and evaporation of
the solvent afforded the target compound (3.60 g, 80%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 7.62 (d, J=9.4 Hz, 1H), 6.96
(dd, J=9.4, 3.1 Hz, 1H), 6.76 (d, J=2.8 Hz, 1H), 3.77 (s, 3H), 3.69
(s, 3H).
2-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy-be-
nzoic acid methyl ester
[0556] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol
(2.02 g, 13.60 mmol), pyridine (15 mL), and
2-chloro-sulfonyl-5-methoxy-benzoic acid methyl ester (3.60 g,
13.60 mmol). Purification: Column chromatography using 50-70% EtOAc
in hexane. Product was isolated as a light-yellow solid: yield 2.8
g (55%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.91 (s,
1H), 9.22 (s, 1H), 7.74 (d, J=9.4 Hz, 1H), 7.48 (d, J=2.2 Hz, 1H),
7.31-7.24 (m, 1H), 7.22-7.11 (m, 3H), 4.89 (s, 2H), 3.83 (s, 3H),
3.81 (s, 3H), MS (ESI) m/z=376 (M-1, negative).
N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-hydroxymethyl-4-met-
hoxy-benzenesulfonamide
[0557] To a solution in
2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-5-methoxy-b-
enzoic acid methyl ester (1.0 g, 2.65 mmol) and MeOH (0.42 mL, 10.6
mmol) in THF (20 mL) at 0.degree. C. was added LiBH.sub.4 (2.65 mL,
2M in THF). The reaction mixture was stirred for 3 h at rt. Slowly
HCl (1M, 20 mL) was added. After 30 min. the THF was removed in
vacuo. Water and ethyl acetate were added and the organic layer was
separated, dried over MgSO.sub.4, filtered and concentrated in
vacuo generating 800 mg (86%) of the title compound as a white
solid. mp.>280.degree. C. (decomp.); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.18 (s, 1H), 9.21 (s, 1H), 7.76 (d,
J=9.2 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.25-7.23 (m, 2H), 7.14 (dd,
J=8.6, 2.2 Hz, 1H), 6.88 (dd, J=9.2, 3 Hz, 1H), 5.59-5.33 (m, 1H),
4.86 (s, 4H), 3.79 (s, 3H); MS (ESI) m/z=348 (M-1, negative); HPLC
purity: 94.19% (MaxPlot 200-400 nm), 94.30% (220 nm).
2-Aminomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-y-
l)-benzenesulfonamide
##STR00191##
[0558]
2-Bromomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxabo-
rol-6-yl)-benzenesulfonamide
[0559] To a solution of
N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-hydroxymethyl-4-me-
thoxy-benzenesulfonamide (300 mg, 0.86 mmol) in DCM (5 mL) was
added BBr.sub.3 (1M in DCM, 2 mL, 2.0 mmol) and stirred overnight
at rt. The reaction mixture was quenched with H.sub.2O and organic
materials were extracted with CH.sub.2Cl.sub.2 and dried over
MgSO.sub.4. Filtration and evaporation of the solvent afforded the
title compound (200 mg, 58%) as a white solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 10.62 (s, 1H), 10.33 (s, 1H), 9.26
(br. s., 1H), 7.76 (d, J=8.6 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.31
(d, J=8.2 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 7.03 (d, J=2.7 Hz, 1H),
6.84 (dd, J=8.6, 2.3 Hz, 1H), 4.98 (s, 2H), 4.93 (s, 2H); MS (ESI)
m/z=396 and 398 (M-1, negative).
2-Azidomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,
2]oxaborol-6-yl)-benzenesulfonamide
[0560] To a solution of
2-bromomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c]-[1,2]oxaborol-6-
-yl)-benzenesulfonamide (80 mg, 0.20 mmol) in DMF (3.0 mL) was
added NaN.sub.3 (39 mg, 0.60 mmol) and stirred for 3 h at rt. The
reaction mixture was quenched with H.sub.2O and organic materials
were extracted with EtOAc and washed with water, brine and dried
over MgSO.sub.4. Filtration and evaporation of the solvent afforded
the title compound (60 mg, 83%) as a white solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 10.57 (s, 1H), 10.16 (s, 1H), 9.21
(s, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.44 (s, 1H), 7.25 (d, J=7.8 Hz,
1H), 7.14 (d, J=2.0 Hz, 1H), 6.92 (d, J=2.3 Hz, 1H), 6.82-6.72 (m,
1H), 4.87 (s, 2H), 4.75 (s, 2H); MS (ESI) m/z=360 (M-1,
negative).
2-Aminomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-y-
l)-benzenesulfonamide
[0561] To a solution of
2-azidomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]-oxaborol-6-
-yl)-benzenesulfonamide (60 mg, 0.17 mmol) in MeOH (15 mL) was
added Pd/C (60 mg, 10% wet). The reaction mixture was placed under
a hydrogen atmosphere at 30 psi for 1.5 h at rt. The solid catalyst
was removed by filtration through Celite. After evaporation of the
solvent, the crude compound was purified by preparative HPLC
generating 10 mg (18%) of the title compound as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.24 (s, 1H), 7.61
(d, J=8.6 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H),
7.10 (dd, J=8.2, 2.0 Hz, 1H), 6.96 (d, J=2.3 Hz, 1H), 6.68 (dd,
J=8.6, 2.3 Hz, 1H), 4.86 (s, 2H), 4.09 (s, 2H); MS (ESI) m/z=335
(M+1, positive); HPLC purity: 94.52% (MaxPlot 200-400 nm), 94.91%
(220 nm).
N-Butyl-2-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl-
)sulfamoyl)phenyl)acetamide
##STR00192##
[0562] Ethyl
2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-met-
hoxyphenyl)acetate
[0563] To a stirred solution of ethyl
2-(2-(chlorosulfonyl)-5-methoxyphenyl)acetate (9.54 g, 32.6 mmol)
and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (4.86 g, 32.6 mmol) in
400 mL of ACN was added NaHCO.sub.3 (8.22 g, 97.8 mmol). The
reaction mixture was stirred at room temperature for 48 hours. The
reaction mixture was filtered through a pad of silica gel and
washed with ACN. The filtrate was concentrated to give 11.6 g of
the title compound as a yellow solid. MS calcd. for
(C.sub.18H.sub.20BNO.sub.7S): 405.1, MS found (ESI negative):
(M-H).sup.-=404.1
2-(2-(N-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-meth-
oxyphenyl)acetic acid
[0564] To a stirred solution of ethyl
2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-met-
hoxyphenyl)acetate (11.6 g, 28.6 mmol) in 400 mL of MeOH and water
(3:1, v/v) was added LiOH (2.1 g, 85.9 mmol) in portion. The
reaction mixture was stirred at room temperature for 16 hours. More
LiOH (1.0 g, 41.8 mmol) was added, and the reaction mixture was
stirred for additional 4 hours. After MeOH was removed in vacuo,
the residue was dissolved in water and acidified with 6N HCl. The
mixture was extracted with ethyl acetate three times, and washed
with water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, and concentrated to give 8.1 g of the title
compound as an off-white solid. MS calcd for
(C.sub.16H.sub.16BNO.sub.7S): 377.1, MS found (ESI negative):
(M-H).sup.-=376.0.
N-Butyl-2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl-
)-5-methoxyphenyl)acetamide
[0565] To a stirred solution of
2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-met-
hoxyphenyl)acetic acid (1.0 g, 2.65 mmol) and n-butylamine (317 uL,
3.18 mmol) in 20 mL of DMF was added HATU (1.51 g, 3.98 mmol) and
DIEA (1.85 mL, 10.6 mmol). The reaction mixture was stirred at room
temperature for 16 hours. After water was added, the reaction
mixture was extracted with ethyl acetate and washed with water, 1N
HCl and brine. The organic layer was dried over Na.sub.2SO.sub.4
and concentrated to give a yellow residue. The crude residue was
purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30.times.50 mm
column) to give 0.38 g of the title compound as a white solid. MS
calcd for (C.sub.20H.sub.25BN.sub.2O.sub.6S): 432.2, MS found (ESI
negative): (M-H).sup.-=431.1. .sup.1H NMR (DMSO-d.sub.6) .delta.
(ppm): 10.09 (s, 1H), 9.20 (bs, 1H), 8.08 (t, 1H), 7.64 (d, J=8.8
Hz, 1H), 7.43 (s, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz,
1H), 6.95 (s, 1H), 6.87 (d, J=8.8 Hz, 1H), 4.86 (s, 2H), 3.91 (s,
2H), 3.75 (s, 3H), 3.08 (q, 2H), 1.39 (m, 2H), 1.28 (m, 2H), 0.85
(t, 3H).
N-Butyl-2-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl-
)sulfamoyl)phenyl)acetamide
[0566] To a stirred solution of
N-butyl-2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)-5-methoxyphenyl)acetamide (202 mg, 0.467 mmol) in 10 mL of
CH.sub.2Cl.sub.2 at 0.degree. C. was added BBr.sub.3 (1.0 M
solution in CH.sub.2Cl.sub.2, 1.4 mL, 1.4 mmol) dropwise. The
reaction mixture was stirred at room temperature for 16 hours.
After quenched with water, the solvent was removed in vacuo. The
residue was extracted with ethyl acetate three times, and washed
with water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, and concentrated to give an off-white residue.
The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5
uM 30.times.50 mm column) to give 89.4 mg of the title compound as
a white solid. MS calcd for (C.sub.19H.sub.23BN.sub.2O.sub.6S):
418.1, MS found (ESI negative): (M-H).sup.-=417.1. .sup.1H NMR
(DMSO-d.sub.6) .delta. (ppm): 10.33 (bs, 1H), 10.04 (s, 1H), 9.20
(bs, 1H), 8.05 (t, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.22
(d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.77 (s, 1H), 6.64 (d,
J=8.8 Hz, 1H), 4.86 (s, 2H), 3.84 (s, 2H), 3.08 (q, 2H), 1.40 (m,
2H), 1.29 (m, 2H), 0.85 (t, 3H).
N-Ethyl-2-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl-
)sulfamoyl)phenyl)acetamide
##STR00193##
[0567]
N-Ethyl-2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)su-
lfamoyl)-5-methoxyphenyl)acetamide
[0568] To a stirred solution of
2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-met-
hoxyphenyl)acetic acid (1.02 g, 2.71 mmol) and ethylamine (2.0 M
solution in THF, 5.41 mL, 10.82 mmol) in 20 mL of DMF was added
HATU (1.54 g, 4.06 mmol). The reaction mixture was stirred at room
temperature for 2 hours. After water was added, the reaction
mixture was extracted with ethyl acetate and washed with water, 1N
HCl and brine. The organic layer was dried over Na.sub.2SO.sub.4
and concentrated to give a yellow residue. The crude residue was
purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30.times.50 mm
column) to give 0.39 g of the title compound as a white solid. MS
calcd for (C.sub.18H.sub.21BN.sub.2O.sub.6S): 404.1, MS found (ESI
negative): (M-H).sup.-=403.1.
N-Ethyl-2-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl-
)sulfamoyl)phenyl)acetamide
[0569] To a stirred solution of
N-ethyl-2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoy-
l)-5-methoxyphenyl)acetamide (272 mg, 0.673 mmol) in 10 mL of
CH.sub.2Cl.sub.2 at .degree. C. was added BBr.sub.3 (1.0 M solution
in CH.sub.2Cl.sub.2, 2.0 mL, 2.0 mmol) dropwise. The reaction
mixture was stirred at room temperature for 16 hours. After
quenched with water, the solvent was removed in vacuo. The residue
was extracted with ethyl acetate three times, and washed with water
and brine. The organic layer was dried over Na.sub.2SO.sub.4, and
concentrated to give an off-white residue. The crude residue was
purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30.times.50 mm
column) to give 155 mg of the title compound as a white solid. MS
calcd for (C.sub.17H.sub.19BN.sub.2O.sub.6S): 390.1, MS found (ESI
negative): (M-H).sup.-=389.1. .sup.1H NMR (DMSO-d.sub.6) .delta.
(ppm): 10.34 (s, 1H), 10.04 (s, 1H), 9.20 (bs, 1H), 8.07 (t, 1H),
7.56 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.09
(d, J=8.0 Hz, 1H), 6.76 (s, 1H), 6.64 (d, J=8.8 Hz, 1H), 4.86 (s,
2H), 3.83 (s, 2H), 3.11 (q, 2H), 1.03 (t, 3H).
Ethyl
2-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)s-
ulfamoyl)phenyl)acetate
##STR00194##
[0571] To a solution of ethyl
2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-met-
hoxyphenyl)acetate (208 mg, 0.513 mmol) in 10 mL of
CH.sub.2Cl.sub.2 at 0.degree. C. was added BBr.sub.3 (1.0 M
solution in CH.sub.2Cl.sub.2, 1.54 mL, 1.54 mmol) dropwise. The
reaction mixture was stirred at room temperature for 16 hours.
After quenched with water, the solvent was removed in vacuo. The
residue was extracted with ethyl acetate three times, and washed
with water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, and concentrated to give an off-white residue.
The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5
uM 30.times.50 mm column) to give 7 mg of the title compound as a
white solid. MS calcd for (C.sub.17H.sub.18BNO.sub.7S): 391.1, MS
found (ESI negative): (M-H).sup.-=390.1. .sup.1H NMR (DMSO-d.sub.6)
.delta. (ppm): 10.35 (s, 1H), 10.06 (s, 1H), 9.20 (bs, 1H), 7.63
(d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.09 (d,
J=8.0 Hz, 1H), 6.71 (s, 1H), 6.69 (d, 1H), 4.85 (s, 2H), 4.02 (q,
2H), 3.95 (s, 2H), 1.14 (t, 3H).
4-Hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-hydroxy-
ethyl)benzenesulfonamide and
2-(2-bromoethyl)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-
-yl) benzenesulfonamide
##STR00195##
[0572]
N-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-hydroxyeth-
yl)-4-methoxy benzenesulfonamide
[0573] To a solution of
2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-met-
hoxyphenyl)acetic acid (524 mg, 1.39 mmol) in 20 mL of THF was
added borane (1.0 M solution in THF, 5.6 mL, 5.6 mmol). After
quenched with water, the solvent was removed in vacuo. The residue
was extracted with ethyl acetate three times, and washed with water
and brine. The organic layer was dried over Na.sub.2SO.sub.4, and
concentrated to give a white solid. MS calcd for
(C.sub.16H.sub.18BNO.sub.6S): 363.1, MS found (ESI negative):
(M-H).sup.-=362.1.
4-Hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-hydroxy-
ethyl)benzenesulfonamide and
2-(2-bromoethyl)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,
2]oxaborol-6-yl)benzenesulfonamide
[0574] To a solution of
N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-hydroxyethyl)-4--
methoxybenzenesulfonamide (105 mg, 0.289 mmol) in 2 mL of
CH.sub.2Cl.sub.2 at .degree. C. was added BBr.sub.3 (1.0 M solution
in CH.sub.2Cl.sub.2, 1.16 mL, 1.16 mmol) dropwise. The reaction
mixture was stirred at room temperature for 16 hours. After
quenched with water, the solvent was removed in vacuo. The residue
was extracted with ethyl acetate three times, and washed with water
and brine. The organic layer was dried over Na.sub.2SO.sub.4, and
concentrated to give a yellow residue. The crude residue was
purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30.times.50 mm
column) to give 24 mg of
4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-hydrox-
yethyl)benzenesulfonamide and as a white solid and 17 mg of
2-(2-bromoethyl)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol--
6-yl)benzenesulfonamide as a white solid.
Analytical data for
4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-hydrox-
yethyl)benzenesulfonamide
[0575] MS calcd for (C.sub.15H.sub.16BNO.sub.6S): 349.1, MS found
(ESI negative): (M-H).sup.-=348.0. .sup.1H NMR (DMSO-d.sub.6)
.delta. (ppm): 10.25 (s, 1H), 10.13 (s, 1H), 9.19 (bs, 1H), 7.69
(d, J=8.8 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.14 (d,
J=8.4 Hz, 1H), 6.78 (s, 1H), 6.65 (d, J=8.8 Hz, 1H), 4.86 (s, 2H),
3.62 (t, 2H), 3.07 (t, 2H).
Analytical data for
2-(2-bromoethyl)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol--
6-yl)benzenesulfonamide
[0576] MS calcd for (C.sub.15H.sub.15BBrNO.sub.5S): 411.0, MS found
(ESI negative): (M-H).sup.-=410.0. .sup.1H NMR (DMSO-d.sub.6)
.delta. (ppm): 10.39 (s, 1H), 10.24 (s, 1H), 9.20 (bs, 1H), 7.67
(d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.11 (d,
J=8.4 Hz, 1H), 6.78 (s, 1H), 6.69 (d, J=8.8 Hz, 1H), 4.84 (s, 2H),
3.64 (t, 2H), 3.39 (t, 2H).
2-Hydroxy-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-be-
nzoic acid methyl ester
##STR00196##
[0577] 5-Chlorosulfonyl-2-hydroxy-benzoic acid methyl ester
[0578] 2-Hydroxy-benzoic acid methyl ester (5.0 g, 32.8 mmol) was
added drop-wise to chlorosulfonic acid (32.8 g, 0.32 mol) at
0.degree. C. The mixture was allowed to warm to rt, Then heated at
40.degree. C. for 30 min. The mixture was cooled to rt, then poured
into crushed ice and the precipitate was isolated by filtration to
providing 5.2 g (63%) of the title compound as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 8.00 (d, J=2.2
Hz, 1H), 7.68 (dd, J=8.5, 2.2 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 3.86
(s, 3H).
2-Hydroxy-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-be-
nzoicacid methyl ester
[0579] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol
(1.18 g, 7.9 mmol), acetonitrile (40 mL),
5-chlorosulfonyl-2-hydroxy-benzoic acid methyl ester (2.0 g, 7.9
mmol), pyridine (3.15 g, 39.8 mmol). This generated 1.5 g (53%) of
the title compound as a pale yellow solid. A portion (200 mg) of
this material was purified further by reverse-phase preparative
HPLC (gradient of water (0.1% formic acid) and methanol) providing
0.10 g of the title compound as white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 11.02 (s, 1H), 10.17 (s, 1H), 9.22 (s,
1H), 8.12 (d, J=2.3 Hz, 1H), 7.76 (dd, J=8.6, 2.3 Hz, 1H), 7.47 (d,
J=2.0 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.17 (dd, J=8.2, 2.3 Hz,
1H), 7.09 (d, J=9.0 Hz, 1H), 4.88 (s, 2H), 3.86 (s, 3H); MS (ESI)
m/z=364 (M+1, positive); HPLC purity: 99.39% (MaxPlot 200-400 nm),
99.33% (220 nm).
4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-hydroxyme-
thyl-benzenesulfonamide
##STR00197##
[0580] Acetic acid
5-hydroxy-2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-b-
enzyl ester
[0581] A mixture of
2-bromomethyl-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxa-borol-6-
-yl)-benzenesulfonamide (200 mg, 0.5 mmol) and NaOAc (123 mg, 1.50
mmol) in glacial AcOH (5 mL) was heated at 110.degree. C. (bath
temp) for 4 h. The mixture was concentrated in vacuo and the
residue was treated with H.sub.2O and ethyl acetate. The layers
were separated and the organic layer was washed with H.sub.2O,
brine, dried MgSO.sub.4, filtered and concentrated in vacuo.
Purification was accomplished by flash chromatography (70%
EtOAc/hexane) providing 130 mg (69%) of the title compound. This
material was used directly in the next step without further
purification.
4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-hydroxyme-
thyl-benzenesulfonamide
[0582] To a solution of acetic acid
5-hydroxy-2-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-ylsulfamoyl)-b-
enzyl ester (130 mg, 0.34 mmol) in THF (3.0 mL) was added HCl (5
ml, 10%), and the reaction mixture was heated at 60.degree. C. for
3 h. After removal of the solvent, purification was accomplished by
two preparative HPLC (gradient of 10-50% and 15-47% respectively of
acetonitrile in 0.1% aqueous AcOH) affording 29 mg of impure title
compound. MS (ESI) m/z=334 (M-1, negative); HPLC purity 72.22%
(MaxPlot).
4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-hydroxyme-
thyl-benzenesulfonamide
##STR00198##
[0584] To a suspension of lithium aluminum hydride (80 mg, 2.0
mmol) in THF (10 mL) at -10.degree. C. was added solution of
2-hydroxy-5-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-ylsulfamoyl)-ben-
zoic acid methyl ester (0.50 g, 1.3 mmol) in THF (10 mL). The
reaction mixture was allowed to warm to rt. After 3 h, the reaction
mixture was cooled in an ice bath and saturated aq. NH.sub.4Cl
solution (5 mL) was added. The reaction mixture was diluted with
ethyl acetate (100 mL), and the organic layer was separated, washed
with water, brine and dried over Na.sub.2SO.sub.4, decanted and
concentrated under reduced pressure. Purification was accomplished
by preparative HPLC generating 44 mg (9%) of the title compound as
an off-white solid. MS (ESI): m/z=334 (M-1, negative); HPLC purity:
84.44% (MaxPlot 200-400 nm), 82.7% (220 nm).
4-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-methoxy-be-
nzenesulfonamide
##STR00199##
[0586] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol
(0.968 g, 4.31 mmol), MeCN (20 mL), pyridine (1.05 mL, 12.9 mmol),
and 4-fluoro-3-methoxy-benzenesulfonyl chloride (0.674 g, 4.53
mmol). After addition of water and dilute HCl (2 N) the mixture was
concentrated in vacuo to removed MeCN. A small quantity of acetone
was added and the resulting aqueous suspension was heated to remove
the acetone. After cooling to room temperature, the solid was
collected and washed with water. The title compound (1.31 g, 86%)
was obtained as a light red solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 10.25 (s, 1H), 7.52 (d, J=1.9 Hz, 1H),
7.48 (dd, J=7.9, 2.2 Hz, 1H), 7.38 (dd, J=11.1, 8.6 Hz, 1H),
7.31-7.27 (m, 2H), 7.18 (dd, J=8.2, 1.9 Hz, 1H), 4.89 (s, 2H), 3.84
(s, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. (ppm):
-128.56--128.62 (m, 1F); MS (ESI) m/z=336 (M-1, negative); HPLC
purity: 91.37% (MaxPlot 200-400 nm), 91.38% (220 nm); Anal. Calcd
for C.sub.14H.sub.13BFNO.sub.5S.0.25 H.sub.2O: C, 49.22%; H, 3.98%;
N, 4.10%. Found: C, 49.32%; H, 4.44%; N, 3.89%.
4-Fluoro-3-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-be-
nzenesulfonamide
##STR00200##
[0588] To a suspension of
4-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-methoxy-b-
enzenesulfonamide (0.812 g, 2.40 mmol) in DCM (60 mL) was added
BBr.sub.3 (1M in DCM, 40 mL, 40 mmol) and the suspension was heated
to reflux overnight. After consumption of
4-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-3-methoxy-b-
enzenesulfonamide, the reaction was cooled to ambient temperature
and added to methanol chilled in an ice bath. The solution was
concentrated in vacuo and the residue was treated with water and
heated. The hot solution was decanted and then cooled and
lyophilized. Purification was accomplished by preparative reverse
phase HPLC (acetonitrile/water (with 0.1% acetic acid) gradient)
producing 0.089 g (11%) of the title compound as a white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 10.62 (brs, 1H),
10.21 (s, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.37-7.27 (m, 3H), 7.19-7.14
(m, 2H), 4.90 (s, 2H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
(ppm): -129.81--129.87 (m, 1F); MS (ESI) m/z=322 (M-1, negative);
HPLC purity: 93.03% (MaxPlot 200-400 nm), 92.92% (220 nm); Anal.
Calcd for C.sub.13H.sub.11BFNO.sub.5S.0.6 H.sub.2O: C, 46.76%; H,
3.68%; N, 4.19%. Found: C, 46.55%; H, 3.59%; N, 4.46%.
3-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-be-
nzenesulfonamide
##STR00201##
[0590] To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.25
g, 1.34 mmol) in anhydrous pyridine (30 mL) at 5.degree. C. was
added 3-fluoro-4-methoxy-benzenesulfonyl chloride (0.30 g, 1.34
mmol) and the resulting orange solution stirred to room temperature
overnight. The reaction was briefly warmed to 40.degree. C. for 1 h
and then evaporated to dryness in vacuo. The residue was treated
with H.sub.2O (80 mL) and sonicated for 6 h at 60.degree. C. The
resulting fine precipitate was filtered, washed with water and
dried in vacuo generating 0.28 g (62%) of the title compound as a
tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 10.20
(brs, 1H), 9.23 (s, 1H), 7.55-7.48 (m, 3H), 7.31-7.27 (m, 2H), 7.17
(dd, J=8.0, 2.0 Hz, 1H), 4.88 (s, 2H), 3.87 (s, 3H). .sup.19F NMR
(376 MHz, DMSO-d.sub.6) .delta. (ppm): -133.34 (t, J=9.8 Hz, 1F);
MS (ESI) m/z=336 (M-1, negative); HPLC purity: 98.28% (MaxPlot
200-400 nm), 98.29% (220 nm).
3-Fluoro-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-be-
nzenesulfonamide
##STR00202##
[0592] To a suspension of
3-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-b-
enzenesulfonamide (1.0 g, 2.96 mmol) in 100 mL of anhydrous DCM at
5.degree. C. was added 1N solution of BBr.sub.3 in DCM (3 mL). The
resulting solution stirred at room temperature overnight. The
precipitate that formed was filtered, washed with DCM and briefly
dried before suspending in water. The gummy material formed was
extracted into EtOAc, and the organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. This was
further purified through preparative HPLC affording 0.186 g (19%
yield) of the title compound as a white solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 10.96 (brs, 1H), 10.10 (s, 1H),
7.49-7.45 (m, 2H), 7.36 (dd, J=8.8, 1.6 Hz, 1H), 7.26 (d, J=8.4 Hz,
1H), 7.16 (dd, J=8.4, 1.8 Hz, 1H), 7.02 (t, J=8.6 Hz, 1H), 4.88 (s,
2H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. (ppm): -134.62
(t, J=10.2 Hz, 1F); MS (ESI) m/z=322 (M-1, negative); HPLC purity:
95.05% (MaxPlot 200-400 nm), 95.58% (220 nm).
2-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-be-
nzenesulfonamide
##STR00203##
[0593] 2-Fluoro-4-methoxy-benzenesulfonyl chloride and
4-Fluoro-2-methoxy-benzenesulfonyl chloride
[0594] To a solution of 1-fluoro-3-methoxy-benzene (5.0 mL, 43.76
mmol) in DCM (20 mL) cooled to 0.degree. C., was added slowly
chlorosulfonic acid (14.44 mL, 218.8 mmol). The ice bath was then
removed. After 1 h, the mixture was poured into ice and the organic
layer was separated. The aqueous layer was extracted with DCM. The
combined organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The 2.94 g obtained was a 1:1 mixture of
2-fluoro-4-methoxy-benzenesulfonyl chloride and
4-fluoro-2-methoxy-benzenesulfonyl chloride and was used in the
next step without further purification. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.70 (t, J=7.8 Hz, 1H), 7.57 (t, J=8.6
Hz, 1H), 6.86 (dd, J=11.7, 2.3 Hz, 1H), 6.74-6.64 (m, 3H), 3.77 (s,
3H), 3.76 (s, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
(ppm): -109.37--109.42 (m, 1F), -110.35--110.42 (m, 1F).
2-Fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-be-
nzenesulfonamide
[0595] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol
(2.05 g, 13.7 mmol), MeCN (20 mL), pyridine (1.05 mL, 12.9 mmol),
and 1:1 mixture of 2-fluoro-4-methoxy-benzenesulfonyl chloride and
4-fluoro-2-methoxy-benzenesulfonyl chloride (2.94 g, 13.1 mmol).
Purification was accomplished by Biotage.RTM. silica gel column
chromatography (340 g SNAP.TM. cartridge with the sample loaded as
a DCM solution to the sample and air dried, mobile phase was
gradient of ethyl acetate (0.5% AcOH) and hexanes) followed by
dissolving the residue in acetonitrile, adding water, removal of
the acetonitrile in vacuo and lyophilization. Mixed regioisomer
fractions (1.50 g total) were obtained in addition to the 0.78 g
(5%, 2 steps) of the title compound that was obtained as a light
orange solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm):
10.36 (s, 1H), 9.23 (s, 1H), 7.67 (t, J=8.8 Hz, 1H), 7.46 (s, 1H),
7.24 (d, J=8.2 Hz, 1H), 7.17 (dd, J=8.2, 1.6 Hz, 1H), 6.97 (dd,
J=12.1, 2.3 Hz, 1H), 6.84 (dd, J=8.6, 2.3 Hz, 1H), 4.85 (s, 2H),
3.77 (s, 3H) [10 mol % acetic acid also present by .sup.1HNMR];
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. (ppm): -107.6 (dd,
J=11.5, 9.2 Hz, 1F); MS (ESI) m/z=336 (M-1, negative); HPLC purity:
96.86% (MaxPlot 200-400 nm), 96.51% (220 nm); Anal. Calcd for
C.sub.14H.sub.13BFNO.sub.5S.0.1C.sub.2H.sub.4O.sub.2+0.25 H.sub.2O:
C, 49.06%; H, 4.03%; N, 4.03%. Found: C, 48.99%; H, 3.89%; N,
4.18%.
2-Fluoro-4-hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-be-
nzenesulfonamide
##STR00204##
[0597] To a suspension of
2-fluoro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-b-
enzenesulfonamide (0.640 g, 1.90 mmol) in DCM (10 mL) cooled in an
ice bath was added BBr.sub.3 (1M in DCM, 5.7 mL, 5.7 mmol). After 3
h, 5 h and 6 h additional BBr.sub.3 (1M in DCM, 1.9 mL three times
for a combined total of 11.4 mL, 11.4 mmol). After 12 h, the
suspension was poured into ice and stirred vigorously overnight.
The solid was collected by filtration. To this was added water and
enough acetonitrile to dissolve most of the sample. The remaining
dark solid was filtered off and the acetonitrile was removed in
vacuo. The resulting aqueous suspension was heated and sonicated
briefly. After cooling to ambient temperature the solid was
collected by vacuum filtration and was washed with a small amount
of water and air dried. This generated 0.395 g (64%) of the title
compound as an off-white solid. mp 239-241.degree. C. (dec);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 10.89 (br.s,
1H), 10.31 (s, 1H), 9.21 (s, 1H), 7.59 (t, J=8.8 Hz, 1H), 7.47 (d,
J=1.6 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.19 (dd, J=8.2, 2.0 Hz,
1H), 6.68-6.63 (m, 2H), 4.87 (s, 2H) [4 mol % acetonitrile was
present by .sup.1HNMR]; .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.delta. (ppm): -108.31 (t, J=10.3 Hz, 1F); MS (ESI) m/z=322 (M-1,
negative); HPLC purity: 93.25% (MaxPlot 200-400 nm), 93.31% (220
nm); Anal. Calcd for
C.sub.13H.sub.11BFNO.sub.5S.0.04C.sub.2H.sub.3N+0.2H.sub.2O: C,
47.85%; H, 3.54%; N, 4.44%. Found: C, 47.84%; H, 3.51%; N,
4.61%.
2-Chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenz-
enesulfonamide
##STR00205##
[0599] Neat 1-chloro-3-methoxybenzene (3.65 mL, 30 mmol) was put on
an ice-water bath. Chlorosulfonic acid was added drop-wise via
dropping funnel at 0.degree. C., during which the mixture
solidified. Let stir at 0.degree. C. around ten minutes, and
transferred to a beaker of ice water. The mixture was stirred until
all the ice melted, and the product was extracted using ethyl
ether. The organic later was washed two more times with water, then
washed with brine, dried over sodium sulfate, and filtered. The
solvent was removed under slightly reduced pressure to give
2-chloro-4-methoxybenzene-1-sulfonyl chloride (1.7 g, 24%
yield).
[0600] Triethylamine (1.4 mL, 70.5 mmol) was added to a solution of
2-chloro-4-methoxybenzene-1-sulfonyl chloride (1.70 g, 7.05 mmol),
6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (0.745 g, 5 mmol) in
N,N-dimethylformamide (14 mL). The solution was stirred at room
temperature for thirty minutes and was then neutralized to pH 6
using 1 N hydrochloric acid. The solution was the extracted using
ethyl acetate and water. The organic layer was washed four times
with water, then washed with brine, dried over sodium sulfate, and
filtered. The solvent was removed under reduced pressure. The
residue was purified by silica column using Combiflash to give
2-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxyben-
zene sulfonamide (0.828 g, 33% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm) 3.30 (s, 3 H), 4.84 (s, 2H), 6.99 (dd,
J=2.6 Hz, J=9.0 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.19 (d, J=1.9 Hz,
1H), 7.22 (s, 1H), 7.46 (d, J=1.5 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H),
9.19 (s, 1H), 10.39 (s, 1H).
2-Chloro-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide
##STR00206##
[0602] A solution of
2-chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxyben-
zenesulfonamide (0.728 g, 2.06 mmol) in dry dichloromethane (10 mL)
was cooled to -78.degree. C. with acetone-dry ice bath. 1 M
tribromoborane in dichloromethane (6.2 mL) was added drop-wise. The
reaction was stirred in the acetone-dry ice bath and allowed to
warm to room temperature overnight. The solution was then put on an
ice-water bath and was quenched with ice chips. The solvent was
removed under reduced pressure. The residue was extracted using
ethyl acetate and water. The aqueous layer was extracted with ethyl
acetate six times. The organic layers were dried over sodium
sulfate and combined. The solvent was removed under reduced
pressure. The residue was purified by silica column using
Combiflash to give
2-chloro-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ben-
zenesulfonamide (0.098 g, 14% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm) 4.84 (s, 2H), 6.77 (dd, J=2.3 Hz, J=8.6
Hz, 1H), 6.88 (d, J=2.3 Hz, 1H), 7.23-7.16 (m, 2H), 7.44 (d, J=1.5
Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 9.18 (s, 1H), 10.29 (s, 1H), 10.83
(s, 1H).
N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,4-dimethoxy-benzene-
sulfonamide
##STR00207##
[0604] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol
(300 mg, 2.0 mmol), 2,4-dimethoxybenzenesulfonyl chloride (570 mg,
2.4 mmol), Si-pyridine (4.2 g, 6.0 mmol), and MeCN (20 mL) at rt
O/N. Si-amine (1.0 g, 1.8 mmol) was added and the mixture stirred
at rt for 2 h. The mixture was filtered, H.sub.2O was added to the
filtrate, and the resulting soln was concentrated in vacuo at
40.degree. C. until precipitation was observed. The suspension was
decanted and the remaining soln left to stand at rt resulting in
the formation of a precipitate. The precipitate was isolated by
filtration to give the title compound as a yellow solid: yield; 552
mg (78%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 9.82
(s, 1H), 9.19 (s, 1H), 7.64-7.62 (m, 1H), 7.46-7.45 (m, 1H),
7.22-7.16 (m, 2H), 6.63-6.62 (m, 1H), 6.56-6.53 (m, 1H), 4.85 (s,
2H), 3.87 (s, 3H), 3.78 (s, 3H); MS (ESI) m/z=348 (M-1, negative);
HPLC purity: 91.94% (MaxPlot 200-400 nm), 90.96% (220 nm).
2,4-Dihydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzene-
sulfonamide
##STR00208##
[0606] 1 M BBr.sub.3 in CH.sub.2Cl.sub.2 (5.0 mL, 5.0 mmol) was
added to a soln of
N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,4-dimethox-
y-benzenesulfonamide (500 mg, 1.4 mmol) in CH.sub.2Cl.sub.2 (15 mL)
and stirred at rt O/N. H.sub.2O was added and mixture was
concentrated in vacuo at 50.degree. C. The residue was purified by
prep HPLC (20-90% MeCN/0.1% aq HCO.sub.2H) to give the title
compound as a white solid: yield; 41 mg (9%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 7.46-7.44 (m, 2H), 7.18 (s, 2H),
6.29-6.28 (m, 1H), 6.22-6.19 (m, 1H), 4.85 (s, 2H); MS (ESI)
m/z=320 (M-1, negative); HPLC purity: 97.63% (MaxPlot 200-400 nm),
97.59% (220 nm).
N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3,4-dimethoxybenzenesu-
lfonamide
##STR00209##
[0608] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol,
MeCN, pyridine, and 3,4-dimethoxy-benzenesulfonyl chloride. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 10.25 (s, 1H), 7.52 (d,
J=1.9 Hz, 1H), 7.48 (dd, J=7.9, 2.2 Hz, 1H), 7.38 (dd, J=11.1, 8.6
Hz, 1H), 7.31-7.27 (m, 2H), 7.18 (dd, J=8.2, 1.9 Hz, 1H), 4.89 (s,
2H), 3.84 (s, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
(ppm): -128.56--128.62 (m, 1F); MS (ESI) m/z=336 (M-1, negative);
HPLC purity: 91.37% (MaxPlot 200-400 nm), 91.38% (220 nm); Anal.
Calcd for C.sub.14H.sub.13BFNO.sub.5S.0.25 H.sub.2O: C, 49.22%; H,
3.98%; N, 4.10%. Found: C, 49.32%; H, 4.44%; N, 3.89%.
N-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-nitrobenze-
nesulfonamide
##STR00210##
[0610] To a solution of 4-methoxy-2-nitrobenzenesulfonyl chloride
(8.72 g, 34.6 mmol), 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (5.00 g,
33.6 mmol), and triethylamine (5.6 mL, 40.3 mL) in DMF 70 mL was
stirred at room temperature for 1 h. The mixture was poured into
ethyl acetate and water. The organic layer was washed with water
twice and brine and dried on anhydrous sodium sulfate. The solvent
was removed under reduced pressure and the residue was
recrystallized from dichloromethane to give
N-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-nitrobenz-
enesulfonamide (7.23 g, 59%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm) 3.84 (s, 3H), 4.88 (s, 2H), 7.21 (dd, J=8.3, 2.0 Hz,
1H), 7.25-7.32 (m, 2H), 7.49 (d, J=1.6 Hz, 1H), 7.53 (d, J=2.5 Hz,
1H), 7.81 (d, J=8.8 Hz, 1H), 9.22 (s, 1H), 10.4 (s, 1H).
4-Hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-nitrobenze-
nesulfonamide
##STR00211##
[0612] To a solution of
N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-nitrobenz-
enesulfonamide (1.00 g, 2.74 mmol) in dichloromethane (150 mL) was
added boron tribromide (1 M in dichloromethane, 8.2 mL) at
-78.degree. C., and the mixture was stirred for 6 days at room
temperature. Water was added and the mixture was extracted with
dichloromethane. The organic layer was washed with brine and dried
on anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the residue was purified by silica gel column (19:1
dichloromethane/methanol) to give
4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-nitrobenz-
enesulfonamide (290 mg, 30%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm) 4.88 (s, 2H), 7.03 (dd, J=8.8, 2.3 Hz, 1H), 7.16-7.22
(m, 2H), 7.29 (d, J=8.3 Hz, 1H), 7.48 (s, 1H), 7.71 (d, J=8.8 Hz,
1H), 9.21 (s, 1H), 10.3 (s, 1H), 11.4 (s, 1H).
2-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenze-
nesulfonamide
##STR00212##
[0614] A mixture of
N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-nitrobenz-
enesulfonamide (6.00 g, 16.5 mmol) and 10% palladium on charcoal
(1.50 g) in methanol (400 mL) was stirred under hydrogen atmosphere
with a balloon at room temperature for 4 h. The atmosphere was
replaced with nitrogen, and the mixture was filtered through a
Celite pad. The solution was removed under reduced pressure, and
the residue was purified by silica gel column (2:8 hexane/ethyl
acetate) to give
2-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenz-
enesulfonamide (5.09 g, 92%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm) 3.65 (s, 3H), 4.85 (s, 2H), 5.96 (br s, 2H), 6.10
(dd, J=8.8, 2.3 Hz, 1H), 6.21 (d, J=2.3 Hz, 1H), 7.13 (dd, J=8.2,
1.9 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.43
(s, 1H), 9.18 (s, 1H), 10.0 (s, 1H).
2-Amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benze-
nesulfonamide
##STR00213##
[0616] To a solution of
2,2,2-trifluoro-N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxab-
orol-6-yl)sulfamoyl)phenyl)acetamide (2.00 g, 4.81 mmol) in
methanol (40 mL) was added 3 M NaOH (10 mL), and the mixture was
stirred at room temperature for overnight. The pH was adjusted to 7
with 6 M HCl and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and brine and dried on
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the residue was purified by silica gel column (8:1
chloroform/methanol) followed by water-toluene co-boiling to give
2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-
-yl)benzenesulfonamide (1.10 g, 71%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm) 4.85 (s, 2H), 5.83 (br s, 2H), 5.93
(dd, J=8.8, 2.5 Hz, 1H), 6.05 (d, J=2.4 Hz, 1H), 7.11 (dd, J=8.4,
2.2 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.41
(d, J=1.6 Hz, 1H), 9.16 (s, 1H), 9.80 (br s, 1H), 9.92 (br s,
1H).
2,2,2-Trifluoro-N-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)s-
ulfamoyl)-5-methoxyphenyl)acetamide
##STR00214##
[0618] To a solution of
2-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenz-
enesulfonamide (2.01 g, 6.00 mmol) in DMF (15 mL) was added
trifluoroacetic anhydride (1.2 mL, 8.8 mmol), and the mixture was
stirred at room temperature for 1 h. The mixture was poured into
ethyl acetate and water. The organic layer was washed with water
twice and brine and dried on anhydrous sodium sulfate. The solvent
was removed under reduced pressure and the residue was purified by
silica gel column (3:7 hexane/ethyl acetate) to give
2,2,2-trifluoro-N-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
sulfamoyl)-5-methoxyphenyl)acetamide (1.40 g, 54%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm) 3.80 (s, 3H), 4.88 (s, 2H),
6.98 (dd, J=9.0, 2.6 Hz, 1H), 7.07 (dd, J=8.0, 2.0 Hz, 1H), 7.27
(d, J=8.2 Hz, 1H), 7.42 (s, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.66 (d,
J=9.0 Hz, 1H), 9.20 (s, 1H), 10.2 (s, 1H), 10.6 (s, 1H).
2,2,2-Trifluoro-1-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabo-
rol-6-yl)sulfamoyl)phenyl)acetamide
##STR00215##
[0620] To a solution of
2,2,2-trifluoro-N-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
sulfamoyl)-5-methoxyphenyl)acetamide (960 mg, 2.23 mmol) in
dichloromethane (150 mL) was added boron tribromide (1 M in
dichloromethane, 6.0 mL) at -78.degree. C., and the mixture was
stirred for 2 days at room temperature. Water was added and the
precipitates formed were collected by filtration to give
2,2,2-trifluoro-N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxab-
orol-6-yl)sulfamoyl)phenyl)acetamide (155 mg, 17%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm) 4.87 (s, 2H), 6.72 (dd,
J=8.8, 2.6 Hz, 1H), 7.05 (dd. J=8.2, 2.1 Hz, 1H), 7.27 (d, J=8.2
Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.55 (d,
J=8.8 Hz, 1H), 9.19 (s, 1H), 10.1 (s, 1H), 10.5 (s, 1H), 10.8 (s,
1H).
N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sul-
famoyl)phenyl)-2-hydroxyacetamide
##STR00216##
[0621]
N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-
-yl)sulfamoyl)phenyl)-2-chloroacetamide
[0622] A solution of chloro-acetyl chloride (1.65 g, 7.3 mmol) in
DCM was added to a solution of
2-amino-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
benzenesulfonamide (3 g, 7.3 mmol) in DCM and Py (1.734, 21.9 mmol)
at r.t, and stirred overnight. Then the mixture was washed with
brine, dried and concentrated to give product
N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)su-
lfamoyl)phenyl)-2-chloroacetamide (2.4 g, 67%).
2-(5-(Benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,
2]oxaborol-6-yl)sulfamoyl)phenylamino)-2-oxoethyl acetate
[0623] A solution of compound
N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)su-
lfamoyl)phenyl)-2-chloroacetamide (200 mg, 0.41 mmol) and AcOK
(66.5 mg, 0.82 mmol) in DMF (5 mL) was stirred at 50.degree. C.
overnight, then cooled to r.t. The mixture was poured in water and
extracted with DCM, dried and concentrated to give product
2-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)su-
lfamoyl)phenylamino)-2-oxoethyl acetate (200 mg, crude).
N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sul-
famoyl)phenyl)-2-hydroxyacetamide
[0624] A solution of
2-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)su-
lfamoyl)phenylamino)-2-oxoethyl acetate (200 mg, crude) in
CH.sub.3OH and aq. NH.sub.4OH (v/v=1:1) was stirred at r.t
overnight, then the mixture was concentrated and extracted with
DCM, dried and purified by Prep-HPLC (column: Luna 300.times.50.0
mm, 10.mu.; liquid phase: [A-H.sub.2O; B-MeCN+0.025% TFA] B %:
25%-55%, 25 min) to give the title compound (93 mg). .sup.1H NMR:
DMSO-d6 400 MHz .delta. 10.42 (1H, s), 10.23 (1H, s), 9.21 (1H, s),
8.10-8.09 (1H, m), 7.63-706 (1H, m), 7.41-7.35 (5H, m), 7.28-7.26
(1H, m), 7.18-7.16 (1H, m), 6.06-6.03 (1H, m), 5.09 (1H, s), 4.88
(1H, s), 3.95-3.95 (2H, m), 4.72-4.71 (2H, m). ESI-MS m/z 367 (M-H,
negative); HPLC purity: 97.52% (MaxPlot 190-370 nm), 98.83% (220
nm), 99.65% (254 nm).
2-Hydroxy-N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6--
yl)sulfamoyl)phenyl)acetamide
##STR00217##
[0626] A solution of
2-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)su-
lfamoyl)phenylamino)-2-oxoethyl acetate (500 mg, 1 mmol) was
dissolved in CH.sub.3OH and NH.sub.4OH, then the mixture and Pd/C
was stirred under H.sub.2 (50 Psi) overnight. The mixture was
filtrated and the filtrate was concentrated, extracted with DCM.
The organics was dried and purified by Prep-HPLC (column: Luna
300.times.50.0 mm, 10.mu.; liquid phase: [A-H.sub.2O; B-MeCN+0.025%
TFA] B %: 10%-40%, 25 min) to give the title compound (130 mg,
35%). .sup.1H NMR: DMSO-d6 400 MHz .delta. 10.45 (1H, s), 10.35
(1H, s), 10.07 (1H, s), 9.17 (1H, s), 7.89-7.88 (1H, m), 7.51-7.49
(1H, m), 7.39-7.38 (1H, m), 7.26-7.24 (1H, m), 7.16-7.13 (1H, m),
6.52-6.49 (1H, m), 6.00-5.97 (1H, m), 4.87 (2H, s), 3.94-3.92 (2H,
m). ESI-MS m/z 401 (M+Na, positive); HPLC purity: 94.17% (MaxPlot
190-370 nm), 99.76% (220 nm), 100% (254 nm).
2-Amino-N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol--
6-yl)sulfamoyl)phenyl)acetamide
##STR00218##
[0628] A solution of compound
N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)su-
lfamoyl)phenyl)-2-chloroacetamide (500 mg, crude) was dissolved in
CH.sub.3OH and NH.sub.4OH, then the mixture was stirred at
50.degree. C. for 2 hrs. The mixture was adjusted to pH=4,
extracted with DCM, dried and purified by Prep-HPLC (column: Luna
300.times.50.0 mm, 10.mu.; liquid phase: [A-H.sub.2O; B-MeCN+0.025%
TFA] B %: 15%-45%, 25 min) to give the title compound (110 mg).
.sup.1H NMR: DMSO-d6 400 MHz .delta. 10.65 (1H, s), 9.74 (1H, s),
9.2 (1H, s), 8.28 (1H, s), 7.68-7.52 (1H, m), 7.38-7.33 (5H, m),
7.21-7.19 (2H, m), 6.91-6.88 (2H, m), 5.07 (1H, s), 4.84 (1H, s),
4.01 (1H, s). ESI-MS m/z 468 (M+1, positive); HPLC purity: 99.08%
(MaxPlot 190-370 nm), 98.8% (220 nm), 99.02% (254 nm).
2-Amino-N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl-
)sulfamoyl)phenyl)acetamide
##STR00219##
[0630] A solution of
2-amino-N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-
-6-yl)sulfamoyl)phenyl)acetamide (500 mg, crude) was dissolved in
CH.sub.3OH, then the mixture and Pd/C was stirred under H.sub.2 (50
Psi) overnight. The mixture was filtrated and the filtrate was
concentrated, dissolved in DCM, washed with brine. The organics was
dried and purified by Prep-HPLC (column: Luna 300.times.50.0 mm,
10.mu.; liquid phase: [A-H.sub.2O; B-MeCN+0.025% TFA]B %: 5%-35%,
25 min) to give the title compound (100 mg, 35%). .sup.1H NMR:
DMSO-d6 400 MHz .delta.9.21 (1H, s), 7.56-7.54 (1H, m), 7.51-7.50
(1H, m), 7.37-7.36 (1H, m), 7.23-7.21 (1H, m), 7.18-7.17 (1H, m),
6.61-6.58 (1H, m), 4.86 (2H, m), 3.98 (2H, s), 3.94-3.92 (2H, m).
ESI-MS m/z 378 (M+1, positive); HPLC purity: 94.57% (MaxPlot
190-370 nm), 94.11% (220 nm), 94.8% (254 nm).
N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sul-
famoyl)phenyl)-2-(dimethylamino)acetamide
##STR00220##
[0632] A solution of
N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)su-
lfamoyl)phenyl)-2-chloroacetamide (500 mg, 1.07 mmol),
dimethylamine hydrochloride (870 mg, 10.7 mmol) and NMM (1.09 g,
10.7 mmol) was dissolved in CH.sub.3OH. The mixture was stirred at
50.degree. C. overnight. The mixture was adjusted to pH=4, then
concentrated and extracted with DCM. The organics was dried,
concentrated and purified by Prep-HPLC (column: Luna 300.times.50.0
mm, 10.mu.; liquid phase: [A-H.sub.2O; B-MeCN+0.025% TFA] B %:
13%-55%, 25 min) to give the title compound (300 mg, 56.8%).
.sup.1HNMR: DMSO 400 MHz .delta. 10.3 (1H, s), 9.9 (1H, s), 9.21
(1H, s), 7.72-7.47 (1H, m), 7.46-7.36 (7H, m), 7.26-7.24 (1H, m),
7.14-7.11 (1H, m), 7.00-6.97 (1H, m), 5.11 (2H, s), 4.87 (2H, s),
4.23 (2H, s), 2.85 (2H, s). ESI-MS m/z 496 (M+H, positive); HPLC
purity: 96.44% (MaxPlot 190-370 nm), 99.9% (220 nm), 99.84% (254
nm).
2-(Dimethylamino)-N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxa-
borol-6-yl)sulfamoyl)phenyl)acetamide
##STR00221##
[0634] A mixture of
N-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)su-
lfamoyl)phenyl)-2-(dimethylamino)acetamide (130 mg, 0.263 mmol),
Pd/C (0.2 g) in CH.sub.3OH was stirred under H.sub.2 (50 Psi) for 1
hr. Then the mixture was filtrated and the filtrate was
concentrated and purified by Prep-HPLC (column: Luna 300.times.50.0
mm, 10.mu.; liquid phase: [A-H.sub.2O; B-MeCN+0.025% TFA]B %:
3%-43%, 25 min) to give the title compound (100 mg, 94%).
.sup.1HNMR: DMSO-d.sub.6 400 MHz .delta. 10.65 (1H, s), 10.55 (1H,
s), 9.98-9.87 (2H, m), 7.57-7.54 (1H, m), 7.50-7.48 (1H, m),
7.27-7.23 (2H, m), 7.18-7.15 (1H, m), 4.86 (2H, s), 4.30 (2H, s),
2.80 (6H, s). ESI-MS m/z 406 (M+H, positive); HPLC purity: 95.79%
(MaxPlot 190-370 nm), 97.98% (220 nm), 97.83% (254 nm).
N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamo-
yl)phenyl)-2-phenoxyacetamide
##STR00222##
[0636] A solution of
2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide (0.250 g, 0.781 mmol) and 2-phenoxyacetyl chloride
(108 .mu.L, 0.781 mmol) in N,N-dimethylformamide (4 mL) was stirred
at room temperature for two and a half hours. 2-phenoxyacetyl
chloride (32 .mu.L, 0.234 mmol) was again added to the solution,
which was then stirred at room temperature for one hour. The
solution was extracted using ethyl acetate and water. The organic
layer was washed three times with water, then washed with brine,
dried over sodium sulfate, and filtered. The solvent was removed
under reduced pressure. The residue was purified by silica column
using dichloromethane and methanol using 2.5% methanol to 5%
methanol to 10% methanol. The fractions were collected and the
solvent was removed under reduced pressure. Water and toluene were
added and were co-evaporated under reduced pressure to give
N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfam-
oyl)phenyl)-2-phenoxyacetamide (0.196 g, 55% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm) 4.457 (s, 2H), 4.85 (s, 2H),
6.54 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.06-6.70 (m, 3H), 7.12 (s, 2H),
7.33-7.37 (m, 3H), 7.51 (d, J=8.8 Hz, 1H), 9.15 (s, 1H), 10.13 (br
s, 1H), 10.34 (br s, 1 H), 10.51 (br s, 1H).
N-(5-Hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamo-
yl)phenyl)acetamide
##STR00223##
[0638] This compound was made from
2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide and acetic anhydride in a similar way to
N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfam-
oyl)phenyl)-2-phenoxyacetamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm) 2.04 (s, 3H), 4.87 (s, 2H), 6.49 (dd, J=8.8, 2.5 Hz,
1H), 7.09 (dd, J=8.2, 2.1 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.43 (d,
J=1.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 9.05
(s, 1H), 9.20 (s, 1H), 10.2 (s, 1H), 10.4 (s, 1H).
N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamo-
yl)phenyl)nicotinamide
##STR00224##
[0640] This compound was made from
2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide and nicotynoyl chloride in a similar way to
N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfam-
oyl)phenyl)-2-phenoxyacetamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm) 4.73 (s, 2H), 6.56 (dd, J=2.5 Hz, J=8.9 Hz, 1H), 6.99
(dd, J=2.0 Hz, J=8.1 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 7.34 (d,
J=1.7 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.56 (m, 1H), 7.77 (d, J=2.3
Hz, 1H), 8.09 (m, 1H), 8.75 (dd, J=1.5 Hz, J=4.8 Hz, 1H), 8.91 (d,
J=1.9 Hz, 1H), 9.97 (s, 1H), 10.09 (s, 1H), 10.40-10.64 (br s, 1
H).
Ethyl
2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-m-
ethoxyphenylcarbamate
##STR00225##
[0642] This compound was made from
2-amino-4-methoxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide and ethyl chloroformate in a similar way to
N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfam-
oyl)phenyl)-2-phenoxyacetamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm) 1.21 (t, J=7.1 Hz, 3H), 3.75 (s, 3H), 4.07 (q, J=7.1
Hz, 2H), 4.87 (s, 2H), 6.70 (dd, J=9.0, 2.6 Hz, 1H), 7.08 (dd,
J=8.2, 2.1 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H),
7.60 (d, J=9.0 Hz, 1H), 7.64 (d, J=2.5 Hz, 1H), 8.65 (s, 1H), 9.22
(s, 1H), 10.3 (s, 1H).
3-(Ethoxycarbonylamino)-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-
-yl)sulfamoyl)phenyl pivalate
##STR00226##
[0644] To a solution of ethyl
5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl-
)phenylcarbamate (197 mg, 0.503 mmol) in pyridine (3 mL) was added
pivaloyl chloride (0.195 mL, 0.830 mmol), and the mixture was
stirred at room temperature for 24 h. Water was added and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and brine and dried on anhydrous sodium sulfate.
The solvent was removed under reduced pressure and the residue was
purified by silica gel column (55:45 hexane/ethyl acetate) followed
by trituration with isopropyl ether-hexane to give
3-(ethoxycarbonylamino)-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]o-
xaborol-6-yl)sulfamoyl)phenyl pivalate (75 mg, 31%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm) 1.26 (s, 9H), 4.88 (s, 2H),
6.93 (dd, J=8.7, 2.3 Hz, 1H), 7.08 (dd, J=8.0, 2.0 Hz, 1H), 7.28
(d, J=8.2 Hz, 1H), 7.48 (d, J=1.7 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H),
7.82 (d, J=2.2 Hz, 1H), 8.69 (s, 1H), 9.23 (s, 1H), 10.5 (s,
1H).
Ethyl
5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
sulfamoyl)phenylcarbamate
##STR00227##
[0646] A solution of ethyl chloroformate (0.47 g, 4.35 mmol) in DCM
was added to the solution of
2-amino-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
benzene sulfonamide (0.6 g, 1.46 mmol) in DCM and Py (1.5 g, 19
mmol) at r.t, and stirred overnight. Then the mixture was washed
with brine, dried and concentrated, purified by pre-HPLC (column:
Luna 300.times.50.0 mm, 10.mu.; liquid phase: [A-H.sub.2O;
B-MeCN+0.025% TFA] B %: 40%-65%, 25 min) to give the title compound
(120 mg g, 17%). .sup.1HNMR: DMSO-d6 400 MHz .delta. 10.35 (1H, s),
9.30 (1H, s), 8.67 (1H, s), 7.74-7.73 (1H, m), 7.63-7.61 (1H, m),
7.47-7.43 (1H, m), 7.43-7.38 (5H, m), 7.29-7.27 (1H, m), 7.10-7.08
(1H, s), 6.82-6.79 (1H, m), 5.1 (2H, s), 4.89 (1H, s), 4.11-4.05
(2H, m). ESI-MS m/z 481 (M-H, negative); HPLC purity: 95.79%
(MaxPlot 190-370 nm), 97.98% (220 nm), 97.83% (254 nm).
Ethyl
5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulf-
amoyl)phenylcarbamate
##STR00228##
[0648] A solution of
2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide (0.250 g, 0.781 mmol) and ethyl chloroformate (0.38
mL, 4.0 mmol) in N,N-dimethylformamide (3 mL) was stirred overnight
at rt. The solution was extracted using ethyl acetate and water.
The organic layer was washed three times with water, then washed
with brine, dried over sodium sulfate, and filtered. The solvent
was removed under reduced pressure. The residue was purified by
silica column (4:6 hexane/ethyl acetate) followed by
recrystallization from ethyl acetate/hexane to give the desired
product (144 mg, 47% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm) 1.21 (t, J=7.0 Hz, 3H), 4.05 (q, J=7.0 Hz, 2H), 4.87
(s, 2H), 6.46 (dd, J=8.8, 2.4 Hz, 1H), 7.61 (dd, J=8.2, 1.9 Hz,
1H), 7.26 (d, J=8.0 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H), 7.49 (d, J=9.0
Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 8.60 (s, 1H), 9.21 (s, 1H), 10.2
(s, 1H), 10.5 (s, 1H).
Isobutyl
5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)s-
ulfamoyl)phenylcarbamate
##STR00229##
[0650] This compound was made from
2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide and isobutyl chloroformate in a similar way to
N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfam-
oyl)phenyl)-2-phenoxyacetamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm) 0.89 (d, J=6.7 Hz, 6H), 1.88 (sept, J=6.7 Hz, 1H),
3.81 (d, J=6.6 Hz, 2H), 4.87 (s, 2H), 6.47 (dd, J=2.2 Hz, J=8.9 Hz,
1H), 7.07 (dd, J=1.9 Hz, J=8.0 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H),
7.42 (d, J=1.4 Hz, 1H), 7.48-7.53 (m, 2H), 8.65 (br s, 1H), 9.20
(s, 1H), 10.21 (br s, 1H), 10.47 (br s, 1H).
Benzyl
2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5--
methoxyphenylcarbamate
##STR00230##
[0652] This compound was made from
2-amino-4-methoxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide and benzyl chloroformate in a similar way to
N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfam-
oyl)phenyl)-2-phenoxyacetamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm) 3.75 (s, 3H), 4.86 (s, 2H), 5.13 (s, 2H), 6.71 (dd,
J=9.2, 2.5 Hz, 1H), 7.10 (dd, J=8.1, 2.0 Hz, 1H), 7.24 (d, J=8.2
Hz, 1H), 7.32-7.45 (m, 6H), 7.59 (d, J=9.0 Hz, 1H), 7.66 (d, J=2.4
Hz, 1H), 8.81 (s, 1H), 9.21 (s, 1H), 10.4 (s, 1H).
Benzyl
5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sul-
famoyl)phenylcarbamate
##STR00231##
[0654] This compound was made from
2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide and benzyl chloroformate in a similar way to
N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfam-
oyl)phenyl)-2-phenoxyacetamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm) 4.86 (s, 2H), 5.11 (s, 2H), 6.47 (dd, J=8.8, 2.1 Hz,
1H), 7.09 (dd, J=8.2, 1.7 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H),
7.32-7.46 (m, 6H), 7.48 (d, J=8.8 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H),
8.76 (s, 1H), 9.21 (s, 1H), 10.3 (s, 1H), 10.5 (s, 1H).
2-Methoxyethyl
5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl-
)phenylcarbamate
##STR00232##
[0656] This compound was made from
2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide and 2-methoxyethyl chloroformate in a similar way to
N-(5-hydroxy-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfam-
oyl)phenyl)-2-phenoxyacetamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm) 3.54 (t, J=4.5 Hz, 2H), 4.15 (t, J=4.5 Hz, 2H), 4.87
(s, 2H), 6.46 (dd, J=8.8, 2.3 Hz, 1H), 7.09 (dd, J=8.0, 1.9 Hz,
1H), 7.26 (d, J=8.2 Hz, 1H), 7.43 (d, J=1.6 Hz, 1H), 7.47 (d, J=8.8
Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 8.69 (s, 1H), 9.21 (s, 1H), 10.1
(s, 1H), 10.5 (s, 1H).
4-Hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(pyridin-3-
-ylmethylamino)benzenesulfonamide
##STR00233##
[0657]
N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-(py-
ridin-3-ylmethylamino)benzenesulfonamide
[0658] A mixture of nicotinaldehyde (0.5 g, 5.2 mmol),
2-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxybenz-
enesulfonamide (0.5 g, 1.22 mmol) and catalytic amount of
TiCl.sub.4 (1M in DCM) in a solution of DCM (12 mL) was stirred at
r.t. for 2 hrs, then followed by and Na(AcO).sub.3BH (2.12 g, 10
mmol). The mixture was quenched with water then worked up with
EtOAc, H.sub.2O, brine, dried over Na.sub.2SO.sub.4 and dried in
vacuo. Further purification by flash chromatography give product
N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-(pyridin--
3-ylmethylamino) benzenesulfonamide (200 mg, 33.5%).
4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(pyridin-3-
-ylmethylamino)benzenesulfonamide
[0659] General Procedure 16: Starting Materials compound
N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-methoxy-2-(pyridin--
3-ylmethylamino) benzenesulfonamide and boron tribromide 1M
solution in DCM. .sup.1H NMR (400 MHz, DMSO-d.sub.6) (ppm): 10.14
(s, 1H), 9.98 (s, 1H), 9.20 (bs, 1H), 8.62 (s, 1H), 8.54 (d, J=4.8
Hz, 1H), 7.84 (d, J=6.8 Hz, 1H), 7.46 (m, 3H), 7.25 (d, J=8.4 Hz,
1H), 7.15 (dd, J=8.0, 2 Hz, 1H), 6.54 (t, J=5.6 Hz, 1H), 6.02 (dd,
J=8.4, 2 Hz, 1H); 5.89 (d, J=2.0 Hz, 1H), 4.87 (s, 2H), 4.48 (d,
J=6 Hz, 2H); MS (ESI) m/z=410.0 (M-H, negative).
2-((1H-imidazol-2-yl)methylamino)-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobe-
nzo[c][1,2]oxaborol-6-yl)benzenesulfonamide dihydrochloride
##STR00234##
[0661] A mixture of 1H-Imidazole-2-carbaldehyde (0.5 g, 5.2 mmol),
2-amino-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
benzene sulfonamide (0.5 g, 1.22 mmol) and Na(AcO).sub.3BH (2.12 g,
10 mmol) in a solution of CH.sub.3OH/TFA (1:5, 12 mL) was stirred
at 50.degree. C. for 2 hrs. The mixture was quenched with water and
purified by pre-HPLC (column: Luna 300.times.50.0 mm, 10.mu.;
liquid phase: [A-H.sub.2O; B-MeCN+0.025% TFA] B %: 15%-45%, 25 min)
to give the title compound (200 mg, 33.5%). .sup.1HNMR: DMSO 400
MHz .delta. 10.04 (1H, s), 9.19 (1H, s), .delta. 7.65-7.56 (2H, s),
7.48-7.43 (2H, s), 7.33-7.39 (4H, m), 7.22-7.20 (2H, m), 6.64-6.60
(1H, m), 6.37-6.30 (1H, m), 6.27-6.26 (2H, m), 4.99 (1H, s), 4.85
(1H, s), 4.72-4.71 (1H, m). ESI-MS m/z 491 (M+H, positive); HPLC
purity: 98.41% (MaxPlot 190-370 nm), 97.64% (220 nm), 98% (254
nm).
2-((1H-imidazol-2-yl)methylamino)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[-
c][1,2]oxaborol-6-yl)benzenesulfonamide dihydrochloride
##STR00235##
[0662]
2-Amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-y-
l)benzenesulfonamide
[0663] A mixture
4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-nitro
benzenesulfonamide (3.0 g, 6.8 mmol), Pd/C (0.5 g) in CH.sub.3OH
was stirred under H.sub.2 (50 psi) for 2 hrs. Then the mixture was
filtrated and the filtrate was concentrated to give the crude
product
2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide (2.0 g, 91%). .sup.1HNMR: DMSO DMSO-d6 400 MHz
.delta. 9.79 (1H, s), 9.16 (1H, s), 7.41-7.40 (1H, m), 7.30-7.27
(1H, m), 7.21-7.19 (1H, m), 7.12-7.09 (1H, m), 6.04-6.04 (1H, m),
5.19-5.91 (1H, m), 5.86-5.83 (2H, m), 4.84 (2H, s), 4.07-4.06 (2H,
s).
2-((1H-imidazol-2-yl)methylamino)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[-
c][1,2]oxaborol-6-yl)benzenesulfonamide dihydrochloride
[0664] A mixture of 1H-Imidazole-2-carbaldehyde (1.08 g, 10.5
mmol),
2-amino-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide (1.2 g, crude) and Na(AcO).sub.3BH (3.97 g, 20 mmol)
was stirred at 50.degree. C. in CH.sub.3OH/TFA (1:5, 12 M1) for 2
hrs. The mixture was quenched with water and purified by
pre-HPLC(column: Luna 300.times.50.0 mm, 10.mu.; liquid phase:
[A-H.sub.2O; B-MeCN+0.025% TFA] B %: 5%-35%, 25 min) to give the
title compound (350 mg). .sup.1H NMR: DMSO-d6 400 MHz .delta. 10.3
(1H, s), 10.23 (1H, s), 9.3 (1H, s), 7.66-7.60 (1H, s), 7.50 (1H,
m), 7.40-7.30 (1H, m), 6.67-6.64 (1H, m), 6.12-6.09 (1H, m),
6.06-5.99 (1H, m), 4.90 (1H, s), 4.75-4.66 (2H, m), 4.72-4.71 (2H,
m). ESI-MS m/z 401 (M+H, positive); HPLC purity: 94.9% (MaxPlot
190-370 nm), 95.06% (220 nm), 96.71% (254 nm).
Benzyl
4-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-
-yl) sulfamoyl)phenylamino)piperidine-1-carboxylate
##STR00236##
[0665] 4-(Benzyloxy)-2-nitroaniline
[0666] To a solution of 4-amino-3-nitrophenol (50 g, 0.325 mol) and
t-BuOK (36 g, 0.32 mol) in DMF (1 L) was slowly added BnBr (55 g,
0.32 mol) at 0-5.degree. C. Then the mixture was warmed slowly, and
stirred at r.t overnight. The mixture was poured into sat.
NH.sub.4Cl, the suspension was filtrated, and the filtrated cake
was dissloved in DCM, and dried and concentrated to give
4-(benzyloxy)-2-nitroaniline (40 g, 50.5%).
4-(Benzyloxy)-2-nitrobenzene-1-sulfonyl chloride
[0667] 4-Benzyloxy-2-nitroaniline (30 g, 123 mmol) was dissolved in
TFA (400 mL) and concentrated HCl (40 mL). After cooling to
0.degree. C., NaNO.sub.2 (10.6 g, 154 mmol) in H.sub.2O was added
dropwise over 30 min. Once the addition was complete the reaction
was stirred for an additional 5 min. The resulting solution was
poured into AcOH (400 mL), H.sub.2SO.sub.3 (400 mL), and CuCl.sub.2
(8.26 g, 60 mmol) containing a catalytic amount of CuCl (ca. 0.5 g)
at 0.degree. C. After stirring 35 min at room temperature, the
solid material was filtered off and washed with water. This
provided 4-benzyloxy-2-nitrobenzenesulfonyl chloride (14.8 g,
40%).
4-(Benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-nitro
benzenesulfonamide
[0668] To a stirred solution of
6-amino-3H-benzo[c][1,2]oxaborol-1-ol (13.8 g, 0.049 mol, 0.5 eq)
in acetonitrile (300 mL) and NMM (14.8 g, 0.147 mol, 3 eq) was
added a solution of 4-(benzyloxy)-2-nitrobenzene-1-sulfonyl
chloride (30 g, 0.097 mol) in anhydrous acetonitrile (150 mL) at
0-5.degree. C. Then the mixture was stirred at r.t overnight, the
mixture was concentrated and dissolved in DCM and washed with
brine, dried and concentrated, purified by column chromatography to
give product
4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-nitro-
benzenesulfonamide (31 g, 80%).
2-Amino-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,
2]oxaborol-6-yl)benzenesulfonamide
[0669] A mixture
4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-nitro
benzenesulfonamide (2.2 g, 5 mmol), Raney Ni (0.5 g) in CH.sub.3OH
and NH.sub.4OH was stirred under H.sub.2 (30 Psi) for 2 hrs. Then
the mixture was filtrated and the filtrate was dried and
concentrated to give crude product of
2-amino-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
benzenesulfonamide (1.6 g crude). .sup.1HNMR: DMSO DMSO-d6 400 MHz
M0.03 (1H, s), 9.19 (1H, s), .delta. 7.43-7.39 (1H, m), 7.36-7.30
(6H, m), 7.23-7.20 (1H, m), 7.14-7.12 (1H, m), 6.29 (1H, s),
6.19-6.17 (1H, m), 5.96 (2H, s), 4.97 (2H, s), 4.85 (2H, s).
Benzyl
4-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-
-yl)sulfamoyl)phenylamino)piperidine-1-carboxylate
[0670] A mixture of
2-amino-4-(benzyloxy)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
benzenesulfonamide (0.5 g, 1.22 mmol) and Na(AcO).sub.3BH (2.10 g,
10 mol) was stirred at 50.degree. C. in CH.sub.3OH/TFA (1:5) for 2
hrs. The mixture was quenched with water and purified by Prep-HPLC
(column: Luna 300.times.50.0 mm, 10.mu.; liquid phase: [A-H.sub.2O;
B-MeCN+0.025% TFA] B %: 45%-70%, 25 min) to give the title compound
(100 mg, 13.5%). .sup.1HNMR: DMSO-d6 400 MHz .delta. 10.23 (1H, s),
7.62-7.59 (1H, s), 7.33-7.31 (1H, m), 7.21-7.19 (1H, m), 6.38-6.35
(2H, s), 5.79-5.77 (1H, m), 5.20-5.18 (4H, m), 4.96-4.92 (2H, m),
4.00-3.96 (2H, m), 3.68-3.68 (1H, m), 3.09-3.08 (2H, m), 1.88-1.86
(2H, m). ESI-MS m/z 628 (M+H, positive); HPLC purity: 94.34%
(MaxPlot 190-370 nm), 94.74% (220 nm), 96.7% (254 nm).
4-Hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(piperidin-
-4-ylamino)benzenesulfonamide dihydrochloride
##STR00237##
[0672] A mixture of benzyl
4-(5-(benzyloxy)-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)su-
lfamoyl)phenylamino)piperidine-1-carboxylate (0.4 g, crude), Pd/C
(0.5 g) in CH.sub.3OH was stirred under H.sub.2 (50 Psi) for 1 hr.
Then the mixture was filtrated and the filtrate was concentrated to
give the crude product and purified by Prep-HPLC (column: Luna
300.times.50.0 mm, 10.mu.; liquid phase: [A-H.sub.2O; B-MeCN+0.025%
TFA] B %: 2%-32%, 25 min) to give the title compound (100 mg).
.sup.1H NMR: DMSO-d6 400 MHz .delta. 10.25 (1H, s), .delta. 10.08
(1H, s), .delta. 9.20 (1H, s), 8.92 (1H, s), 7.421-7.39 (2H, m),
7.23-7.21 (1H, m), 7.12-7.10 (1H, m), 6.14-6.13 (1H, m), 6.06-6.03
(1H, m), 5.67-5.65 (1H, m), 4.86 (1H, s), 3.58-3.56 (1H, m),
3.27-3.24 (2H, m), 3.02-2.95 (2H, m), 1.99-1.97 (2H, m), 1.68-1.60
(2H, m). ESI-MS m/z 404 (M+H, positive); HPLC purity: 86.77%
(MaxPlot 190-370 nm), 98.57% (220 nm), 99.19% (254 nm).
2-(Benzo[d]oxazol-2-ylamino)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,-
2]oxaborol-6-yl)benzenesulfonamide
##STR00238##
[0674] A mixture of
2-amino-4-methoxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benz-
enesulfonamide (1.00 g, 3.00 mmol) and 2-chlorobenzoxazole (0.453
mL, 4.00 mmol) in DMF (10 mL) was stirred at 120.degree. C. for 3
h. Water was added and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and brine and
dried on anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
(45:55 hexane/ethyl acetate) to give
2-(benzo[d]oxazol-2-ylamino)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaboro-
l-6-yl)-4-methoxybenzene sulfonamide (276 mg, 20%).
[0675] To a solution of
2-(benzo[d]oxazol-2-ylamino)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaboro-
l-6-yl)-4-methoxybenzenesulfonamide (272 mg, 0.537 mmol) in
dichloromethane (20 mL) was added boron tribromide (1 M in
dichloromethane, 1.6 mL) at -78.degree. C., and the mixture was
stirred for overnight allowing to warm to room temperature. Water
was added and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and brine and dried on
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the residue was purified by silica gel column (35:65
hexane/ethyl acetate) and preparative TLC (35:65 hexane/ethyl
acetate) followed by trituration with isopropyl ether-hexane to
give
2-(benzo[d]oxazol-2-ylamino)-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1-
,2]oxaborol-6-yl)benzenesulfonamide (20 mg, 8.5%). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm) 4.61 (s, 2H), 6.5-8.0 (m, 10H),
9.16 (s, 2H), 10.3 (s, 1H), 10.6 (s, 1H).
3,5-Dichloro-4-hydroxy-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-
benzenesulfonamide
##STR00239##
[0677] General Procedure 1: 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol
(150 mg, 1 mmol), 3,5-dichloro-4-hydroxybenzenesulfonyl chloride
(260 mg, 1 mmol), DIPEA (650 mg, 5 mmol), rt, 2 hours.
Purification: prep HPLC (SunFire Prep C18 OBD 5 uM 30.times.50 mm
column). The title compound was obtained as off white powder, yield
156 mg. MS calcd for (C.sub.13H.sub.10BNO.sub.5SCl.sub.2): 374.004,
MS found (ESI negative): (M-H).sup.-=372.0. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 11.41, (bs, 1H), 10.22 (s, 1H), 9.22
(bs, 1H), 7.62 (s, 2H), 7.47 (d, J=2 Hz, 1H), 7.3 (d, J=8 Hz, 1H),
7.18 (d, J=8 Hz, 1H), 4.88 (s, 2H).
N-(1-Hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-2,6-dimethy-
l-benzenesulfonamide
##STR00240##
[0679] General Procedure 1: 6-amino-3H-benzo[c][1,2]oxaborol-1-ol
(0.500 g, 3.36 mmol), MeCN (10 mL), pyridine (0.544 mL, 6.71 mmol),
and 4-methoxy-2,6-dimethyl-benzenesulfonyl chloride (0.788 g, 3.36
mmol, generated according to procedures in US2008/249128). This
produced 1.16 g (99% yield) of material that was used in the next
step without further purification. A small sample (50 mg) was
filtered through a short silica gel column (5% MeOH in DCM as the
mobile phase). The solid obtained was dissolved in a minimum of
acetonitrile, water (acidified with dilute HCl) was added and the
mixture was lyophilized generating 39 mg (77%) of the title
compound as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 10.02 (s, 1H), 9.22 (s, 1H), 7.40 (d, J=1.3 Hz, 1H),
7.25 (d, J=8.3 Hz, 1H), 7.10 (dd, J=8.3, 1.9 Hz, 1H), 6.72 (s, 2H),
4.87 (s, 2H), 3.74 (s, 3H), 2.54 (s, 6H); MS (ESI) m/z=348 (M+1,
positive); HPLC purity: 97.27% (MaxPlot 200-400 nm), 97.12% (220
nm).
4-Hydroxy-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2,6-dimethy-
l-benzenesulfonamide
##STR00241##
[0681] To a suspension of
N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-methoxy-2,6-dimeth-
yl-benzenesulfonamide (0.640 g, 1.90 mmol) in DCM (10 mL) cooled in
an -78.degree. C. bath was added BBr.sub.3 (1M in DCM, 2.16 mL,
2.16 mmol). After 4 h, the -78.degree. C. bath was removed. After 8
h, the solution was cooled to -20.degree. C. and more BBr.sub.3 (1M
in DCM, 0.72 mL, 0.72 mmol) was added. After overnight at ambient
temperature, the reaction was cooled in an ice bath and water was
added. After stirring over the weekend, ethyl acetate was added and
the organic layer was separated and washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification
was accomplished by Biotage.RTM. silica gel chromatography (25 g
SNAP.TM. column, eluting with 2-20% MeOH in DCM), followed by
lyophilization from MeCN/water, reverse-phase preparative HPLC
(MeCN/0.1% aqueous AcOH gradient) and lyophilization generating 80
mg (2%) of the title compound as a white powder. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. (ppm): 9.95 (br.s, 1H), 9.19 (s, 1H),
7.39 (br.s, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.09 (dd, J=8.2, 2.3 Hz,
1H), 6.49 (s, 2H), 4.87 (s, 2H), 2.48 (s, 6H); MS (ESI) m/z=334
(M+1, positive); HPLC purity: 98.97% (MaxPlot 200-400 nm), 99.28%
(220 nm).
4-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2,5-dimethylbe-
nzenesulfonamide
##STR00242##
[0682] N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,
2]oxaborol-6-yl)sulfamoyl)-2,5-dimethylphenyl)acetamide
[0683] General Procedure 1: 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol
(300 mg, 2 mmol), 4-acetylamino-2,5-dimethylbenzenesulfonyl
chloride (500 mg, 1.9 mmol), sodium bicarbonate (504 mg, 6 mmol),
rt, 3 hours. Purification: prep HPLC (SunFire Prep C18 OBD 5 uM
30.times.50 mm column). The title compound was obtained as light
yellow solid. MS calcd for (C.sub.17H.sub.19BN.sub.2O.sub.55):
374.22, MS found (ESI negative): (M-H).sup.-=373.1. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 10.25 (s, 1H), 9.29 (s, 1H),
9.18 (s, 1H), 7.69 (s, 1H), 7.54 (s, 1H), 7.45 (d, J=2 Hz, 1H),
7.22 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 4.85 (s, 2H), 2.16
(s, 3H), 2.04 (s, 3H).
4-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2,5-dimethylbe-
nzenesulfonamide
##STR00243##
[0685]
N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-
-2,5-dimethylphenyl)acetamide (530 mg, 1.4 mmol) was mixed with
acetic acid (20 ml), HCl (6N, 2 ml), heated at 100.degree. C. for 3
hours. Removed solvent, and purified by prep HPLC (SunFire Prep C18
OBD 5 uM 30.times.50 mm column). The title compound was obtained as
white powder, yield 280 mg. MS calcd for
(C.sub.15H.sub.17BN.sub.2O.sub.4S): 332.18, MS found (ESI
negative): (M-H).sup.-=331.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. (ppm): 9.89 (s, 1H), 7.45 (s, 1H), 7.41 (d, J=1.6 Hz, 1H),
7.18 (d, J=8 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 4.83 (s, 2H).
4-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2,6-dimethylbe-
nzenesulfonamide
##STR00244##
[0686]
N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-
-3,5-dimethylphenyl)acetamide
[0687] General Procedure 1: Starting Materials
6-amino-3H-benzo[c][1,2]oxaborol-1-ol and
4-acetamido-2,6-dimethylbenzene-1-sulfonyl chloride. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. (ppm): 10.06 (s, 1H), 10.04 (s,
1H), 9.21 (bs, 1H), 7.39 (s, 1H), 7.34 (s, 2H), 7.25 (d, J=8.4 Hz,
1H), 7.09 (dd, J=8, 1.6 Hz, 1H), 4.87 (s, 2H), 2.50 (s, 6H), 2.01
(s, 3H); MS (ESI) m/z=373.1 (M-H, negative).
4-Amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2,6-dimethylbe-
nzenesulfonamide
##STR00245##
[0689] The
N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfam-
oyl)-3,5-dimethylphenyl)acetamide (0.40 g, 1.07 mmol) was added to
1:1 6N HCl: AcOH (10 mL) and heated to 40.degree. C. for 2 days.
The reaction was monitored by LC/MS. Purification: The reaction was
concentrated under vacuum, worked up with EtOAc and 1N HCl, washed
with brine, dry over Na.sub.2SO.sub.4, and evaporated in vacuo. The
product was recrystallized in EtOAc to give title product
4-amino-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2,6-dimethylb-
enzenesulfonamide 195 mg. (yield: 55%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 9.74 (s, 1H), 9.20 (bs, 1H), 7.38 (d,
J=1.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.09 (dd, J=8.4, 2 Hz, 1H),
6.21 (s, 2H), 5.14 (bs, 2H), 4.87 (s, 2H), 2.41 (s, 6H); MS (ESI)
m/z=331.1 (M-H, negative).
Example 2
LeuRS1050 Testing
[0690] Experiments were performed in 96-well microtiter plates,
using 80 .mu.L reaction mixtures containing 50 mM HEPES-KOH (pH
8.0), 30 mM MgCl.sub.2 and 30 mM KCl, 13 .mu.M [.sup.14C]leucine
(306 mCi/mmol, Perkin-Elmer), 15 uM total E. coli tRNA (Roche,
Switzerland), 0.02% (w/v) BSA, 1 mM DTT, 0.2 .mu.M LeuRs and 4 mM
ATP at 30.degree. C. Reactions were started by the addition of 4 mM
ATP. After 7 minutes, reactions were quenched and tRNA was
precipitated by the addition of 50 .mu.L of 10% (w/v) TCA and
transferred to 96-well nitrocellulose membrane filter plates
(Millipore Multiscreen HTS, MSHAN4B50). Each well was then washed
three times with 100 .mu.L of 5% TCA. Filter plates were then dried
under a heat lamp and the precipitated [.sup.14C]leucine
tRNA.sup.Leu were quantified by liquid scintillation counting using
a Wallac MicroBeta Trilux model 1450 liquid scintillation counter
(PerkinElmer, Waltham Mass.).
[0691] To determine the inhibitor concentration which reduces
enzyme activity by 50% (IC.sub.50), increasing concentrations of
inhibitor were incubated with LeuRS enzyme, tRNA and leucine for 20
minutes. Reactions were initiated by the addition of 4 mM ATP and
stopped after 7 minutes then precipitated and counted to quantify
radioactivity.
[0692] Biochemical testing results for exemplary compounds of the
invention are provided in FIG. 1. Units for enzyme activity are
.mu.M.
Example 3
Antibacterial MIC Testing
[0693] All MIC testing of bacteria followed the Clinical and
Laboratory Standards Institute (CLSI) guidelines for antimicrobial
testing of aerobic bacteria (Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically; Approved
Standard--Seventh Edition) (M07-A7) and anaerobic bacteria (Methods
for Antimicrobial Susceptibility Testing of Anaerobic Bacteria;
Approved Standard--Seventh Edition) (M11-A7).
[0694] Antibacterial MIC testing results for exemplary compounds of
the invention are provided in FIG. 1. Units for MIC are
.mu.g/mL.
[0695] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
* * * * *