U.S. patent application number 12/137006 was filed with the patent office on 2009-06-25 for aryl sulfonamides.
This patent application is currently assigned to CHEMOCENTRYX, INC.. Invention is credited to Anita Melikan, Andrew Pennell, Solomon Ungashe, Zheng Wei, J. J. Wright.
Application Number | 20090163498 12/137006 |
Document ID | / |
Family ID | 35428241 |
Filed Date | 2009-06-25 |
United States Patent
Application |
20090163498 |
Kind Code |
A1 |
Ungashe; Solomon ; et
al. |
June 25, 2009 |
Aryl Sulfonamides
Abstract
Compounds are provided that act as potent antagonists of the
CCR9 receptor, and which have been further confirmed in animal
testing for inflammation, one of the hallmark disease states for
CCR9. The compounds are generally aryl sulfonamide derivatives and
are useful in pharmaceutical compositions, methods for the
treatment of CCR9-mediated diseases, and as controls in assays for
the identification of CCR9 antagonists.
Inventors: |
Ungashe; Solomon; (Fremont,
CA) ; Wright; J. J.; (Redwood City, CA) ;
Pennell; Andrew; (San Francisco, CA) ; Wei;
Zheng; (Union City, CA) ; Melikan; Anita; (San
Francisco, CA) |
Correspondence
Address: |
BRINKS HOFER GILSON & LIONE
P.O. BOX 10395
CHICAGO
IL
60610
US
|
Assignee: |
CHEMOCENTRYX, INC.
Mountain View
CA
|
Family ID: |
35428241 |
Appl. No.: |
12/137006 |
Filed: |
June 11, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10846241 |
May 13, 2004 |
7420055 |
|
|
12137006 |
|
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|
|
10716170 |
Nov 17, 2003 |
6939885 |
|
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10846241 |
|
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|
|
60427670 |
Nov 18, 2002 |
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|
Current U.S.
Class: |
514/235.5 ;
514/336; 514/340; 544/131; 546/271.4; 546/282.1 |
Current CPC
Class: |
A61K 31/4545 20130101;
A61P 29/00 20180101; C07D 239/26 20130101; C07D 213/84 20130101;
C07D 417/12 20130101; A61K 31/4439 20130101; A61P 11/06 20180101;
C07D 413/12 20130101; A61P 37/02 20180101; A61P 37/06 20180101;
C07D 409/12 20130101; A61P 35/00 20180101; C07D 241/12 20130101;
C07D 401/12 20130101; A61K 31/443 20130101; C07D 213/50 20130101;
A61P 17/06 20180101; C07D 405/12 20130101; C07D 213/26 20130101;
C07D 213/74 20130101; A61K 45/06 20130101; A61P 19/02 20180101;
A61P 35/02 20180101; A61P 37/08 20180101; A61K 31/4409 20130101;
C07D 213/89 20130101; A61K 31/496 20130101; A61K 31/5377 20130101;
A61K 31/541 20130101; C07D 213/70 20130101; C07D 213/52
20130101 |
Class at
Publication: |
514/235.5 ;
544/131; 546/271.4; 546/282.1; 514/340; 514/336 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 413/12 20060101 C07D413/12; A61K 31/4439
20060101 A61K031/4439; A61K 31/4433 20060101 A61K031/4433; C07D
405/12 20060101 C07D405/12 |
Claims
1. A compound of the formula: ##STR00559##
2. A compound of the formula: ##STR00560##
3. A compound of the formula: ##STR00561##
4. A compound of the formula: ##STR00562##
5. A compound of the formula: ##STR00563##
6. A compound of the formula: ##STR00564##
7. A compound of the formula: ##STR00565##
8. A composition comprising a pharmaceutically acceptable carrier
and a compound according to any of claims 1, 2, 3, 4, 5, 6, or
7.
9. A method for treating a CCR9-mediated condition or disease
comprising administering to a subject a safe and effective amount
of the compound according to any of claims 1, 2, 3, 4, 5, 6 or
7.
10. A method of modulating CCR9 function in a cell, comprising
contacting the cell with a CCR9 modulating amount of the compound
according to any of claims 1, 2, 3, 4, 5, 6 or 7.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
10/846,241, filed May 13, 2004, which application is a continuation
in part of U.S. Ser. No. 10/716,170, filed Nov. 17, 2003, now U.S.
Pat. No. 6,939,885, which application claims priority to U.S.
provisional application Ser. No. 60/427,670, filed Nov. 18, 2002.
The disclosures of these priority applications are incorporated by
reference herein in their entirety.
BACKGROUND OF THE INVENTION
[0002] The present invention provides compounds, pharmaceutical
compositions containing one or more of those compounds or their
pharmaceutically acceptable salts, which are effective in
inhibiting the binding or function of various chemokines, such
TECK, to the CCR9 receptor. As antagonists or modulators for the
CCR9 receptor, the compounds and compositions have utility in
treating inflammatory and immune disorder conditions and
diseases.
[0003] Chemokines are chemotactic cytokines that are released by a
wide variety of cells and attract various types of immune system
cells, such as macrophages, T cells, eosinophils, basophils and
neutrophils, to sites of inflammation (reviewed in Schall,
Cytokine, 3:165-183 (1991), Schall, et al., Curr. Opin. Immunol.,
6:865 873 (1994) and Murphy, Rev. Immun., 12:593-633 (1994)). In
addition to stimulating chemotaxis, other changes can be
selectively induced by chemokines in responsive cells, including
changes in cell shape, transient rises in the concentration of
intracellular free calcium ions ([Ca.sup.2+]), granule exocytosis,
integrin up-regulation, formation of bioactive lipids (e.g.,
leukotrienes) and respiratory burst, associated with leukocyte
activation. Thus, the chemokines are early triggers of the
inflammatory response, causing inflammatory mediator release,
chemotaxis and extravasation to sites of infection or
inflammation.
[0004] T lymphocyte (T cell) infiltration into the small intestine
and colon has been linked to the pathogenesis of Coeliac diseases,
food allergies, rheumatoid arthritis, human inflammatory bowel
diseases (IBD) which include Crohn's disease and ulcerative
colitis. Blocking trafficking of relevant T cell populations to the
intestine can lead to an effective approach to treat human IBD.
More recently, chemokine receptor 9 (CCR9) has been noted to be
expressed on gut-homing T cells in peripheral blood, elevated in
patients with small bowel inflammation such as Crohn's disease and
celiac disease. The only CCR9 ligand identified to date, TECK
(thymus-expressed chemokine) is expressed in the small intestine
and the ligand receptor pair is now thought to play a pivotal role
in the development of IBD. In particular, this pair mediates the
migration of disease causing T cells to the intestine. See for
example, Zaballos, et al., J. Immunol., 162(10):5671-5675 (1999);
Kunkel, et al., J. Exp. Med. 192(5):761-768 (2000); Papadakis, et
al., J. Immunol., 165(9):5069-5076 (2000); Papadakis, et al.,
Gastroenterology, 121(2):246-254 (2001); Campbell, et al., J. Exp.
Med., 195(1):135-141 (2002); Wurbel, et al., Blood, 98(9):2626-2632
(2001); and Uehara, et al., J. Immunol, 168(6):2811-2819
(2002).
[0005] The identification of compounds that modulate the function
of CCR9 represents an attractive new family of therapeutic agents
for the treatment of inflammatory and other conditions and diseases
associated with CCR9 activation, such as inflammatory bowel
disease.
BRIEF SUMMARY OF THE INVENTION
[0006] The present invention is directed to compounds and
pharmaceutically acceptable salts thereof, compositions, and
methods useful in modulating CCR9 chemokine activity. The compounds
and salts thereof, compositions, and methods described herein are
useful in treating or preventing CCR9-mediated conditions or
diseases, including certain inflammatory and immunoregulatory
disorders and diseases.
[0007] In one embodiment, the inventive compounds are of the
formula (I):
##STR00001##
where X, Y and Z are as defined below. Salts of these compounds are
also within the scope of the invention.
[0008] In another aspect, the present invention provides
compositions useful in modulating CCR9 chemokine activity. In one
embodiment, a composition according to the present invention
comprises a compound according to the invention and a
pharmaceutically acceptable carrier or excipient.
[0009] In yet another aspect, the present invention provides a
method of modulating CCR9 function in a cell, comprising contacting
the cell with a therapeutically effective amount of a compound or
composition according to the invention.
[0010] In still another aspect, the present invention provides a
method for modulating CCR9 function, comprising contacting a CCR9
protein with a therapeutically effective amount of a compound or
composition according to the invention.
[0011] In still another aspect, the present invention provides a
method for treating a CCR9-mediated condition or disease,
comprising administering to a subject a safe and effective amount
of a compound or composition according to the invention.
[0012] In addition to the compounds provided herein, the present
invention further provides pharmaceutical compositions containing
one or more of these compounds, as well as methods for the use of
these compounds in therapeutic methods, primarily to treat diseases
associated with CCR9 signaling activity.
BRIEF DESCRIPTION OF THE FIGURE
[0013] FIG. 1 is a graph showing in vivo efficacy for the CCR9
antagonist tested in the examples. Closed triangle: vehicle; Open
circle: CCR9 antagonist of the formula:
##STR00002##
DETAILED DESCRIPTION OF THE INVENTION
General
[0014] The present invention is directed to compounds and salts
thereof, compositions and methods useful in the modulation of
chemokine receptor function, particularly CCR9 function. Modulation
of chemokine receptor activity, as used herein in its various
forms, is intended to encompass antagonism, agonism, partial
antagonism, inverse agonism and/or partial agonism of the activity
associated with a particular chemokine receptor, preferably the
CCR9 receptor. Accordingly, the compounds of the present invention
are compounds which modulate at least one function or
characteristic of mammalian CCR9, for example, a human CCR9
protein. The ability of a compound to modulate the function of
CCR9, can be demonstrated in a binding assay (e.g., ligand binding
or agonist binding), a migration assay, a signaling assay (e.g.,
activation of a mammalian G protein, induction of rapid and
transient increase in the concentration of cytosolic free calcium),
and/or cellular response assay (e.g., stimulation of chemotaxis,
exocytosis or inflammatory mediator release by leukocytes).
ABBREVIATIONS AND DEFINITIONS
[0015] When describing the compounds, compositions, methods and
processes of this invention, the following terms have the following
meanings, unless otherwise indicated.
[0016] "Alkyl" by itself or as part of another substituent refers
to a hydrocarbon group which may be linear, cyclic, or branched or
a combination thereof having the number of carbon atoms designated
(i.e., C.sub.1-8 means one to eight carbon atoms). Examples of
alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,
t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclopentyl,
(cyclohexyl)methyl, cyclopropylmethyl, bicyclo[2.2.1]heptane,
bicyclo[2.2.2]octane, etc. Alkyl groups can be substituted or
unsubstituted, unless otherwise indicated. Examples of substituted
alkyl include haloalkyl, thioalkyl, aminoalkyl, and the like.
[0017] "Alkenyl" refers to an unsaturated hydrocarbon group which
may be linear, cyclic or branched or a combination thereof. Alkenyl
groups with 2-8 carbon atoms are preferred. The alkenyl group may
contain 1, 2 or 3 carbon-carbon double bonds. Examples of alkenyl
groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl,
n-hex-3-enyl, cyclohexenyl, cyclopentenyl and the like. Alkenyl
groups can be substituted or unsubstituted, unless otherwise
indicated.
[0018] "Alkynyl" refers to an unsaturated hydrocarbon group which
may be linear, cyclic or branched or a combination thereof. Alkynyl
groups with 2-8 carbon atoms are preferred. The alkynyl group may
contain 1, 2 or 3 carbon-carbon triple bonds. Examples of alkynyl
groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and
the like. Alkynyl groups can be substituted or unsubstituted,
unless otherwise indicated.
[0019] "Aryl" refers to a polyunsaturated, aromatic hydrocarbon
group having a single ring (bicyclic) or multiple rings (preferably
bicyclic) which can be fused together or linked covalently. Aryl
groups with 6-10 carbon atoms are preferred. Examples of aryl
groups include phenyl and naphthalene-1-yl, naphthalene-2-yl,
biphenyl and the like. Aryl groups can be substituted or
unsubstituted, unless otherwise indicated.
[0020] "Halo" or "halogen", by itself or as part of a substituent
refers to a chlorine, bromine, iodine, or fluorine atom.
Additionally, "haloalkyl", as a substituted alkyl group, refers to
a monohaloalkyl or polyhaloalkyl group, most typically substituted
with from 1-3 halogen atoms. Examples include 1-chloroethyl,
3-bromopropyl, trifluoromethyl and the like.
[0021] "Heterocyclyl" refers to a saturated or unsaturated
non-aromatic group containing at least one heteroatom (typically 1
to 5 heteroatoms) selected from nitrogen, oxygen or sulfur.
Preferably, these groups contain 0-5 nitrogen atoms, 0-2 sulfur
atoms and 0-2 oxygen atoms. More preferably, these groups contain
0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Examples
of heterocycle groups include pyrrolidine, piperidine,
imidazolidine, pyrazolidine, butyrolactam, valerolactam,
imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine,
1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide,
thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone,
3-pyrroline, thiopyran, pyrone, tetrahydrofuran,
tetrahydrothiophene, quinuclidine and the like. Preferred
heterocyclic groups are monocyclic, though they may be fused or
linked covalently to an aryl or heteroaryl ring system.
[0022] Exemplary heterocyclic groups may be represented by formula
(A) below:
##STR00003##
[0023] where formula (A) is attached via a free valence on either
CR.sup.20R.sup.21, CR.sup.22R.sup.23, M.sup.1 or M.sup.2;
[0024] M.sup.1 represents O, NR.sup.24, S(O).sub.I;
[0025] M.sup.2 represents CR.sup.25R.sup.26, O, S(O).sub.I,
NR.sup.24;
[0026] I is 0, 1 or 2;
[0027] j is 1, 2 or 3;
[0028] k is 1, 2 or 3, with the proviso that j+k is 3, 4, or 5;
and
[0029] R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25,
and R.sup.26 are independently selected from the group consisting
of hydrogen, halogen, unsubstituted or substituted C.sub.1-8 alkyl,
unsubstituted or substituted C.sub.2-8 alkenyl, unsubstituted or
substituted C.sub.2-8 alkynyl, --COR.sup.27, --CO.sub.2R.sup.27,
--C(O)NR.sup.27R.sup.28, --NR.sup.27COR.sup.28,
--S(O).sub.2R.sup.28, --S(O).sub.2NR.sup.28R.sup.29,
--NS(O).sub.2R.sup.28R.sup.29--NR.sup.28R.sup.29--OR.sup.28,
--V.sup.1COR.sup.28--V.sup.1COR.sup.28,
--V.sup.1C(O)NR.sup.28R.sup.29, --V.sup.1 NR.sup.28COR.sup.29,
--V.sup.1S(O).sub.2R.sup.28--V.sup.1S(O).sub.2NR.sup.28R.sup.29,
--V.sup.1NS(O).sub.2R.sup.28R.sup.29, --V.sup.1NR.sup.28R.sup.29,
--V.sup.1OR.sup.28, where V.sup.1 is a member selected from the
group consisting of C.sub.1-4 alkylene, C.sub.2-4 alkenylene and
C.sub.2-4 alkynylene, and R.sup.27, R.sup.28 and R.sup.29 are
independently selected from the group consisting of hydrogen or
C.sub.1-8 alkyl, and where the aliphatic portions of each of the
R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25,
R.sup.26, R.sup.27, R.sup.28 and R.sup.29 substituents are
optionally substituted with from one to three members selected from
the group consisting of halogen, --OH, --OR.sup.30,
--OC(O)NHR.sup.30, --OC(O)NR.sup.30R.sup.31, --SH, --SR.sup.30,
--S(O)R.sup.30, --S(O).sub.2R.sup.30, --S(O).sub.2NH.sub.2,
--S(O).sub.2NHR.sup.30, --S(O).sub.2NR.sup.30R.sup.31,
--NHS(O).sub.2R.sup.30, --NR.sup.30S(O).sub.2R.sup.31,
--C(O)NH.sub.2, --C(O)NHR.sup.30, --C(O)NR.sup.30R.sup.31,
--C(O)R.sup.30, --NHC(O)R.sup.30, --NR.sup.30C(O)R.sup.31,
--NHC(O)NH.sub.2, --NR.sup.30C(O)NH.sub.2,
--NR.sup.30C(O)NHR.sup.31, --NHC(O)NHR.sup.30,
--NR.sup.30C(O)NR.sup.30R.sup.31, --NHC(O)NR.sup.30OR.sup.31,
--CO.sub.2H, --CO.sub.2R.sup.30, --NHCO.sub.2R.sup.30,
--NR.sup.30CO.sub.2R.sup.31, --CN, --NO.sub.2, --NH.sub.2,
--NHR.sup.30, --NR.sup.30R.sup.31, --NR.sup.30S(O)NH.sub.2 and
--NR.sup.30S(O).sub.2NHR.sup.31, where R.sup.30 and R.sup.31 are
independently an unsubstituted C.sub.1-6 alkyl. Additionally, any
two of R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25,
R.sup.26 may be combined to form a bridged or spirocyclic ring
system.
[0030] Preferably, the number of
R.sup.20+R.sup.21+R.sup.22+R.sup.23 groups that are other than
hydrogen is 0, 1 or 2. More preferably, R.sup.20, R.sup.21,
R.sup.22, R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are
independently selected from the group consisting of hydrogen,
halogen, unsubstituted or substituted C.sub.1-8 alkyl,
--C(O)R.sup.28, --CO.sub.2R.sup.28, --C(O)NR.sup.28R.sup.29,
--NR.sup.28C(O)R.sup.29, --S(O).sub.2R.sup.28,
--S(O).sub.2NR.sup.28R.sup.29, --NS(O).sub.2R.sup.28R.sup.29,
--NR.sup.28R.sup.29, --OR.sup.28, where R.sup.28 and R.sup.29 are
independently selected from the group consisting of hydrogen,
unsubstituted C.sub.1-8 alkyl and where the aliphatic portions of
each of the R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24,
R.sup.25 and R.sup.26 substituents are optionally substituted with
from one to three members selected from the group consisting of
halogen, --OH, --OR.sup.30, --OC(O)NHR.sup.30,
--OC(O)NR.sup.30R.sup.31, --SH, --SR.sup.30, --S(O)R.sup.30,
--S(O).sub.2R.sup.30, --S(O).sub.2NH.sub.2, --S(O).sub.2NHR.sup.30,
--S(O).sub.2NR.sup.30R.sup.31, --NHS(O).sub.2R.sup.30,
--NR.sup.30S(O).sub.2R.sup.31, --C(O)NH.sub.2, --C(O)NHR.sup.30,
--C(O)NR.sup.30R.sup.31, --C(O)R.sup.30, --NHC(O)R.sup.30,
--NR.sup.30C(O)R.sup.31, --NHC(O)NH.sub.2, --NR.sup.30C(O)NH.sub.2,
--NR.sup.30C(O)NHR.sup.31, --NHC(O)NHR.sup.30,
--NR.sup.30C(O)NR.sup.30R.sup.31, --NHC(O)NR.sup.30R.sup.31,
--CO.sub.2H, --CO.sub.2R.sup.30, --NHCO.sub.2R.sup.30,
--NR.sup.30CO.sub.2R.sup.31, --CN, --NO.sub.2, --NH.sub.2,
--NHR.sup.30, --NR.sup.30R.sup.31, --NR.sup.30S(O)NH.sub.2 and
--NR.sup.30S(O).sub.2NHR.sup.31, where R.sup.30 and R.sup.31 are
independently an unsubstituted C.sub.1-6 alkyl.
[0031] More preferably, R.sup.20, R.sup.21, R.sup.22, R.sup.23,
R.sup.24, R.sup.25, and R.sup.26 are independently hydrogen or
C.sub.1-4alkyl. In another preferred embodiment, at least three of
R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are hydrogen.
[0032] "Heteroaryl" refers to an aromatic group containing at least
one heteroatom. Examples include pyridyl, pyridazinyl, pyrazinyl,
pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl,
cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl,
benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl,
isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl,
thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines,
benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl,
isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,
imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl or thienyl.
Preferred heteroaryl groups are those having at least one aryl ring
nitrogen atom, such as quinolinyl, quinoxalinyl, purinyl,
benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl,
indolyl, quinolyl, isoquinolyl and the like. Preferred 6-ring
heteroaryl systems include pyridyl, pyridazinyl, pyrazinyl,
pyrimidinyl, triazinyl and the like. Preferred 5-ring heteroaryl
systems include isothiazolyl, pyrazolyl, imidazolyl, thienyl,
furyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiadiazolyl, pyrrolyl, thiazolyl and the like.
[0033] Heterocyclyl and heteroaryl can be attached at any available
ring carbon or heteroatom. Each heterocyclyl and heteroaryl may
have one or more rings. When multiple rings are present, they can
be fused together or linked covalently. Each heterocyclyl and
heteroaryl must contain at least one heteroatom (typically 1 to 5
heteroatoms) selected from nitrogen, oxygen or sulfur. Preferably,
these groups contain 0-5 nitrogen atoms, 0-2 sulfur atoms and 0-2
oxygen atoms. More preferably, these groups contain 0-3 nitrogen
atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Heterocyclyl and
heteroaryl groups can be substituted or unsubstituted, unless
otherwise indicated. For substituted groups, the substitution may
be on a carbon or heteroatom. For example, when the substitution is
.dbd.O, the resulting group may have either a carbonyl (--C(O)--)
or a N-oxide (--N.sup.+--O.sup.-) or --S(O)-- or
--S(O).sub.2--.
[0034] Suitable substituents for substituted alkyl, substituted
alkenyl, and substituted alkynyl include halogen, --CN,
--CO.sub.2R', --C(O)R', --C(O)NR'R'', oxo (.dbd.O or --O.sup.-),
--OR, --OC(O)R', --OC(O)NR'R''--NO.sub.2, --NR'C(O)R'',
--NR'''C(O)NR'R'', --NR'R'', --NR'CO.sub.2R'', --NR'S(O).sub.2R''',
--SR', --S(O)R', --S(O).sub.2R', --S(O).sub.2NR'R'', --SiR'R''R''',
--N.sub.3, substituted or unsubstituted C.sub.6-10 aryl,
substituted or unsubstituted 5- to 10-membered heteroaryl, and
substituted or unsubstituted 3- to 10-membered heterocyclyl, in a
number ranging from zero to (2 m'+1), where m' is the total number
of carbon atoms in such radical.
[0035] Suitable substituents for substituted aryl, substituted
heteroaryl and substituted heterocyclyl include halogen, --CN,
--CO.sub.2R', --C(O)R', --C(O)NR'R'', oxo (.dbd.O or --O.sup.-),
--OR', --OC(O)R', --OC(O)NR'R'', --NO.sub.2, --NR'C(O)R'',
--NR'C(O)NR''R''', --NR'R'', --NR'CO.sub.2R'', --NR'S(O).sub.2R'',
--SR', --S(O)R', --S(O).sub.2R', --S(O).sub.2NR'R'',
--NR'--C(NHR'').dbd.NR''', --SiR'R''R''', --N.sub.3, substituted or
unsubstituted C.sub.1-8 alkyl group, substituted or unsubstituted
C.sub.6-10 aryl group, substituted or unsubstituted 5- to
10-membered heteroaryl, and substituted or unsubstituted 3- to
10-membered heterocyclyl, in a number ranging from zero to the
total number of open valences on the aromatic ring system.
[0036] As used above, R', R'' and R''' each independently refer to
a variety of groups including hydrogen, substituted or
unsubstituted C.sub.1-8 alkyl, substituted or unsubstituted
C.sub.2-8 alkenyl, substituted or unsubstituted C.sub.2-8 alkynyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted
aryloxyalkyl. When R' and R'' are attached to the same nitrogen
atom, they can be combined with the nitrogen atom to form a 3-, 4-,
5-, 6-, or 7-membered ring (for example, --NR'R'' includes
1-pyrrolidinyl and 4-morpholinyl).
[0037] Two of the substituents on adjacent atoms of an aryl or
heteroaryl ring may optionally be replaced with a substituent of
the formula -T-C(O)--(CH.sub.2).sub.q--U--, where T and U are
independently --NR''''-, --O--, --CH.sub.2-- or a single bond, and
q is an integer of from 0 to 2. 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--, where A and B are independently
--CH.sub.2--, --O--, --NR''''-, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2NR''''-- or a single bond, and r is an integer of from
1 to 3. 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
--(CH.sub.2).sub.s--X--(CH.sub.2).sub.t--, where s and t are
independently integers of from 0 to 3, and X is --O--, --NR''''-,
--S--, --S(O)--, --S(O).sub.2--, or --S(O).sub.2NR'-. The
substituent R'''' in --NR''''- and --S(O).sub.2NR''''-is selected
from hydrogen or unsubstituted C.sub.1-6 alkyl.
[0038] "Heteroatom" is meant to include oxygen (O), nitrogen (N),
sulfur (S) and silicon (Si).
[0039] "Pharmaceutically acceptable" carrier, diluent, or excipient
is a carrier, diluent, or excipient compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof.
[0040] "Pharmaceutically-acceptable salt" refers to a salt which is
acceptable for administration to a patient, such as a mammal (e.g.,
salts having acceptable mammalian safety for a given dosage
regime). Such salts can be derived from pharmaceutically-acceptable
inorganic or organic bases and from pharmaceutically-acceptable
inorganic or organic acids, depending on the particular
substituents found on the compounds described herein. When
compounds of the present 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. Salts
derived from pharmaceutically-acceptable inorganic bases include
aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,
magnesium, manganic, manganous, potassium, sodium, zinc and the
like. Salts derived from pharmaceutically-acceptable organic bases
include salts of primary, secondary, tertiary and quaternary
amines, including substituted amines, cyclic amines,
naturally-occurring amines and the like, such as arginine, betaine,
caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the like. When
compounds of the present 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. Salts
derived from pharmaceutically-acceptable acids include acetic,
ascorbic, benzenesulfonic, benzoic, camphorsulfonic, citric,
ethanesulfonic, fumaric, gluconic, glucoronic, glutamic, hippuric,
hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic,
malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic,
nicotinic, nitric, pamoic, pantothenic, phosphoric, succinic,
sulfuric, tartaric, p-toluenesulfonic and the like.
[0041] 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, S. M., et
al, "Pharmaceutical Salts", J. Pharmaceutical Science, 1977,
66:1-19). Certain specific compounds of the present invention
contain both basic and acidic functionalities that allow the
compounds to be converted into either base or acid addition
salts.
[0042] The neutral forms of the compounds may be regenerated by
contacting the salt with a base or acid and isolating the parent
compound 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, but otherwise the
salts are equivalent to the parent form of the compound for the
purposes of the present invention.
[0043] "Salt thereof" refers to a compound formed when the hydrogen
of an acid is replaced by a cation, such as a metal cation or an
organic cation and the like. Preferably, the salt is a
pharmaceutically-acceptable salt, although this is not required for
salts of intermediate compounds which are not intended for
administration to a patient.
[0044] In addition to salt forms, the present invention provides
compounds which are in a prodrug form. Prodrugs of the compounds
described herein are those compounds that readily undergo chemical
changes under physiological conditions to provide the compounds of
the present invention. Additionally, prodrugs can be converted to
the compounds of the present invention by chemical or biochemical
methods in an ex vivo environment. For example, prodrugs can be
slowly converted to the compounds of the present invention when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
[0045] "Therapeutically effective amount" refers to an amount
sufficient to effect treatment when administered to a patient in
need of treatment.
[0046] "Treating" or "treatment" as used herein refers to the
treating or treatment of a disease or medical condition (such as a
bacterial infection) in a patient, such as a mammal (particularly a
human or a companion animal) which includes: ameliorating the
disease or medical condition, i.e., eliminating or causing
regression of the disease or medical condition in a patient;
suppressing the disease or medical condition, i.e., slowing or
arresting the development of the disease or medical condition in a
patient; or alleviating the symptoms of the disease or medical
condition in a patient.
[0047] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, both solvated forms and unsolvated forms are
intended to be encompassed within the scope of the present
invention. Certain compounds of the present invention may exist in
multiple crystalline or amorphous forms (i.e., as polymorphs). In
general, all physical forms are equivalent for the uses
contemplated by the present invention and are intended to be within
the scope of the present invention.
[0048] Certain compounds of the present invention possess
asymmetric carbon atoms (optical centers) or double bonds; the
racemates, diastereomers, geometric isomers and individual isomers
(e.g., separate enantiomers) are all intended to be encompassed
within the scope of the present invention. The compounds of the
present 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 (3H), iodine-125
(.sup.125I) or carbon-14 (.sup.14C). All isotopic variations of the
compounds of the present invention, whether radioactive or not, are
intended to be encompassed within the scope of the present
invention.
Compounds that Modulate CCR9 Activity
[0049] The present invention provides compounds that modulate CCR9
activity. Specifically, the invention provides compounds having
anti-inflammatory or immunoregulatory activity. The compounds of
the invention are thought to interfere with inappropriate T-cell
trafficking by specifically modulating or inhibiting a chemokine
receptor function. Chemokine receptors are integral membrane
proteins which interact with an extracellular ligand, such as a
chemokine, and mediate a cellular response to the ligand, e.g.,
chemotaxis, increased intracellular calcium ion concentration, etc.
Therefore, modulation of a chemokine receptor function, e.g.,
interference with a chemokine receptor ligand interaction, will
modulate a chemokine receptor mediated response, and treat or
prevent a chemokine receptor mediated condition or disease.
Modulation of a chemokine receptor function includes both
inducement and inhibition of the function. The type of modulation
accomplished will depend on the characteristics of the compound,
i.e., antagonist or full, partial or inverse agonist.
[0050] Without intending to be bound by any particular theory, it
is believed that the compounds provided herein interfere with the
interaction between a chemokine receptor and one or more cognate
ligands. In particular, it is believed that the compounds interfere
with the interaction between CCR9 and a CCR9 ligand, such as TECK.
Compounds contemplated by the invention include, but are not
limited to, the exemplary compounds provided herein and salts
thereof.
[0051] For example, compounds of this invention act as potent CCR9
antagonists, and this antagonistic activity has been further
confirmed in animal testing for inflammation, one of the hallmark
disease states for CCR9. Accordingly, the compounds provided herein
are useful in pharmaceutical compositions, methods for the
treatment of CCR9-mediated diseases, and as controls in assays for
the identification of competitive CCR9 antagonists.
CCR9 Antagonists as Treatments of Cancer
[0052] In additional to inflammatory diseases, cancers that are
caused by uncontrolled proliferation of T cells may be treated with
a CCR9 antagonist. Certain types of cancer are caused by T cells
expressing chemokine receptor CCR9. For example, thymoma and thymic
carcinoma are diseases in which cancer cells are found in the
tissues of the thymus, an organ where lymphocyte development
occurs. T cells in the thymus, called thymocytes, are known to
express functional CCR9; its ligand is highly expressed in the
thymus. Another example is the acute lymphocytic leukemia (ALL),
also called acute lymphoblastic leukemia and acute, is a common
leukemia, which can occur in children as well as adults. Recent
studies have shown that T cells in patients with ALL selectively
express high level of CCR9 (Quipping Z et al., Cancer Res. 2003, 1;
63(19):6469-77).
[0053] Chemokine receptors have been implicated in cancer. Although
the exact mechanisms of chemokine receptors' involvements have yet
to be full understood, such receptors are known to promote the
growth of cancer cells (proliferation), facilitate the spread of
cancer cells (metastasis) or help them resist program cell death
(apoptosis). For example, CCR9 in a cancer T cell line MOLT-4
provides the cells with a survival signal, allowing them to resist
apoptosis (Youn B S, et al., Apoptosis. 2002 June; 7(3):271-6). In
the cases of thymoma, thymic carcinoma and acute lymphocytic
leukemia, it is likely that CCR9 plays a key in the survival and
proliferation these cells. Thus, blocking the signaling of CCR9
should help prevent their expansion and metastasis.
Compounds of the Invention
[0054] The compounds provided herein have the general formula
(I):
##STR00004##
X Substituents
[0055] X represents from 1 to 5 substituents independently selected
from the group consisting of halogen, substituted or unsubstituted
C.sub.1-8 alkyl, substituted or unsubstituted C.sub.2-8 alkenyl,
substituted or unsubstituted C.sub.2-8 alkynyl, --CN, --NO.sub.2,
--C(O)R.sup.1, --CO.sub.2R.sup.1, --C(O)NR.sup.1R.sup.2,
--OR.sup.1, --OC(O)R.sup.1, --OC(O)NR.sup.1R.sup.2, --NO.sub.2,
--NR.sup.3C(O)R.sup.1, --NR.sup.3C(O)NR.sup.1R.sup.2,
--NR.sup.1R.sup.2, --NR.sup.3CO.sub.2R.sup.1,
--NR.sup.3S(O).sub.2R.sup.1, --SR.sup.1, --S(O)R.sup.1,
--S(O).sub.2R.sup.1, --S(O).sub.2NR.sup.1R.sup.2, substituted or
unsubstituted C.sub.6-10 aryl, substituted or unsubstituted 5- to
10-membered heteroaryl, and substituted or unsubstituted 3- to
10-membered heterocyclyl; [0056] suitable substituted C.sub.1-8
alkyl, substituted C.sub.2-8 alkenyl, or substituted C.sub.2-8
alkynyl may have from 1-5 substituents independently selected from
the group consisting of halogen, --OH, --CN, --NO.sub.2, .dbd.O,
--OC(O)R.sup.1, --OR.sup.1, --C(O)R.sup.1, --C(O)NR.sup.1R.sup.2,
--OC(O)NR.sup.1R.sup.2, --NR.sup.2C(O)R.sup.1,
--NR.sup.1C(O)NR.sup.2R.sup.3, --CO.sub.2R.sup.1,
--NR.sup.1R.sup.2, --NR.sup.2CO.sub.2R.sup.1, --SR.sup.1,
--S(O)R.sup.1, --S(O).sub.2R.sup.1, --S(O).sub.2NR.sup.1R.sup.2,
--NR.sup.1S(O).sub.2R.sup.2, unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl, and unsubstituted or
substituted heterocyclyl; [0057] suitable substituted C.sub.6-10
aryl, substituted 5- to 10-membered heteroaryl, or substituted 3-
to 10-membered heterocyclyl, may have from 1-4 substituents
independently selected from the group consisting of halogen,
unsubstituted C.sub.1-8 alkyl, unsubstituted C.sub.1-8 haloalkyl,
unsubstituted 4- to 7-membered heterocycle, --CN, --NO.sub.2,
--OR.sup.1, .dbd.O, --OC(O)R.sup.1, --CO.sub.2R.sup.1,
--C(O)R.sup.1, --C(O)NR.sup.1R.sup.2, --OC(O)NR.sup.1R.sup.2,
--NR.sup.2C(O)R.sup.1, --NR.sup.1C(O)NR.sup.2R.sup.3,
--NR.sup.1R.sup.2, --NR.sup.2CO.sub.2R.sup.1, --SR.sup.1,
--S(O)R.sup.1, --S(O).sub.2R.sup.1, --S(O).sub.2NR.sup.1R.sup.2,
and --NR.sup.1S(O).sub.2R.sup.1, with the proviso that if X
represents a heterocycle, suitable substituents preferably do not
include another heterocycle; [0058] R.sup.1, R.sup.2 and R.sup.3
are each independently selected from the group consisting of
hydrogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
aryl-C.sub.1-4 alkyl, aryloxy-C.sub.1-4 alkyl, C.sub.6-10 aryl, 5-
to 10-membered heteroaryl, and 3- to 10-membered heterocycle, or
where R.sup.1 and R.sup.2, or R.sup.3 and R.sup.2, or R.sup.1 and
R.sup.3, may together with the atom(s) to which they are attached,
form an substituted or unsubstituted 5-, 6-, or 7-membered ring;
[0059] and where the aliphatic and aromatic portions of R.sup.1,
R.sup.2 and R.sup.3 are optionally further substituted with from 1
to 3 substituents selected from the group consisting of halogen,
--OH, --OR.sup.m, --OC(O)NHR.sup.m, --OC(O)NR.sup.mR.sup.n, --SH,
--SR.sup.m, --S(O)R.sup.m, --S(O).sub.2R.sup.m,
--S(O).sub.2NH.sub.2, --S(O).sub.2NHR.sup.m,
--S(O).sub.2NR.sup.mR.sup.n, --NHS(O).sub.2R.sup.m,
--NR.sup.mS(O).sub.2R.sup.n, --C(O)NH.sub.2, --C(O)NHR.sup.m,
--C(O)N(R.sup.m).sub.2, --C(O)R.sup.m, --NHC(O)R.sup.m,
--NR.sup.mC(O)R.sup.n, --NHC(O)NH.sub.2, --NR.sup.mC(O)NH.sub.2,
--NR.sup.mC(O)NHR.sup.n, --NHC(O)NHR.sup.m,
--NR.sup.oC(O)NR.sup.mR.sup.n, --NHC(O)N(R.sup.m).sub.2,
--CO.sub.2H, --CO.sub.2R.sup.m, --NHCO.sub.2R.sup.m,
--NR.sup.mCO.sub.2R.sup.n, --CN, --NO.sub.2, --NH.sub.2,
--NHR.sup.n, --NR.sup.mR.sup.n, --NR.sup.mS(O)NH.sub.2 and
--NR.sup.mS(O).sub.2NHR.sup.n, where R.sup.m, R.sup.n, and R.sup.o
are each independently unsubstituted C.sub.1-6 alkyl. Y
substituents
[0060] Y represents from 1 to 4 substituents, each independently
selected from the group consisting of halogen, --CN, --NO.sub.2,
--OR.sup.4, --C(O)R.sup.4, --CO.sub.2R.sup.4, --SR.sup.4,
--S(O)R.sup.4, --S(O).sub.2R.sup.4, and unsubstituted or
substituted C.sub.1-4 alkyl; [0061] suitable substituted C.sub.1-4
alkyl may have from 1 to 3 substituents independently selected from
the group consisting of halogen, --OR.sup.4, --CN, --NO.sub.2,
.dbd.O, --OC(O)R.sup.4, --CO.sub.2R.sup.4, --C(O)R.sup.4,
--CONR.sup.4R.sup.5, --OC(O)NR.sup.4R.sup.5, --NR.sup.4C(O)R.sup.5,
--NR.sup.4C(O)NR.sup.5R.sup.6, --NR.sup.4R.sup.5,
--NR.sup.4CO.sub.2R.sup.5, --SR.sup.4, --SOR.sup.4,
--SO.sub.2R.sup.4, --SO.sub.2NR.sup.4R.sup.5, and
--NR.sup.4SO.sub.2R.sup.5; [0062] R.sup.4, R.sup.5 and R.sup.6 are
each independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.6-10
aryl, and 5- to 10-membered heteroaryl; or where R.sup.4 and
R.sup.5, or R.sup.6 and R.sup.4 or R.sup.5 and R.sup.6, together
with the atom to which they are attached, form a substituted or
unsubstituted 5-, 6- or 7-membered ring; [0063] and where the
aliphatic and aromatic portions of R.sup.4, R.sup.5, and R.sup.6
are optionally further substituted with from 1 to 3 substituents
selected from the group consisting of halogen, --OH, --OR.sup.m,
--OC(O)NHR.sup.m, --OC(O)NR.sup.mR.sup.n, --SH, --SR.sup.m,
--S(O)R.sup.m, --S(O).sub.2R.sup.m, --S(O).sub.2NH.sub.2,
--S(O).sub.2NHR.sup.m, --S(O).sub.2NR.sup.mR.sup.n,
--NHS(O).sub.2R.sup.m, --NR.sup.mS(O).sub.2R.sup.n, --C(O)NH.sub.2,
--C(O)NHR.sup.m, --C(O)N(R.sup.m).sub.2, --C(O)R.sup.m,
--NHC(O)R.sup.m, --NR.sup.mC(O)R.sup.n, --NHC(O)NH.sub.2,
--NR.sup.mC(O)NH.sub.2, --NR.sup.mC(O)NHR.sup.n, --NHC(O)NHR.sup.m,
--NR.sup.oC(O)NR.sup.mR.sup.n, --NHC(O)N(R.sup.m).sub.2,
--CO.sub.2H, --CO.sub.2R.sup.m, --NHCO.sub.2R.sup.m,
--NR.sup.mCO.sub.2R.sup.n, --CN, --NO.sub.2, --NH.sub.2,
--NHR.sup.n, --NR.sup.mR.sup.n, --NR.sup.mS(O)NH.sub.2 and
--NR.sup.mS(O).sub.2NHR.sup.n, where R.sup.m, R.sup.n, and R.sup.o
are each independently unsubstituted C.sub.1-6 alkyl.
Linkers
[0064] L is --C(O)--, --S--, --SO-- or --S(O).sub.2--.
Z Substituents
[0065] Z represents either unsubstituted or substituted monocyclic
or bicyclic 5- to 10-membered heteroaryl; unsubstituted or
substituted monocyclic or bicyclic 3- to 10-membered heterocyclyl;
or NR.sup.7R.sup.8.
[0066] When Z is NR.sup.7R.sup.8, R.sup.7 and R.sup.8 are each
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.6-10
aryl, C.sub.1-8 alkylaryl, C.sub.1-8 alkylheteroaryl, 5- to
10-membered heteroaryl and 3- to 10-membered heterocycle, or
R.sup.7 and R.sup.8, may together with the atom(s) to which they
are attached, form an substituted or unsubstituted 5-, 6-, or
7-membered ring; and [0067] where the aliphatic and aromatic
portions of R.sup.7 and R.sup.8 can be substituted with 1 to 3
substituents selected from the group consisting of halogen, --OH,
--OR.sup.m, --OC(O)NHR.sup.m, --OC(O)NR.sup.mR.sup.n, --SH,
--SR.sup.m--S(O)R.sup.m, --S(O).sub.2R.sup.m, --S(O).sub.2NH.sub.2,
--S(O).sub.2NHR.sup.m, --S(O).sub.2NR.sup.mR.sup.n,
--NHS(O).sub.2R.sup.m, --NR.sup.mS(O).sub.2R.sup.n, --C(O)NH.sub.2,
--C(O)NHR.sup.m, --C(O)N(R.sup.m).sub.2, --C(O)R.sup.m,
--NHC(O)R.sup.m, --NR.sup.mC(O)R.sup.n, --NHC(O)NH.sub.2,
--NR.sup.mC(O)NH.sub.2, --NR.sup.mC(O)NHR.sup.n, --NHC(O)NHR.sup.m,
--NR.sup.oC(O)NR.sup.mR.sup.n, --NHC(O)N(R.sup.m).sub.2,
--CO.sub.2H, --CO.sub.2R.sup.m, --NHCO.sub.2R.sup.m,
--NR.sup.mCO.sub.2R.sup.n, --CN, --NO.sub.2, --NH.sub.2,
--NHR.sup.n, --NR.sup.mR.sup.n, --NR.sup.mS(O)NH.sub.2 and
--NR.sup.mS(O).sub.2NHR.sup.n, where R.sup.m, R.sup.n, and R.sup.o
are each independently unsubstituted C.sub.1-6 alkyl.
[0068] When Z is a substituted heteroaryl or substituted
heterocyclyl, it may have from 1 to 5 substituents independently
selected from the group consisting of halogen, unsubstituted or
substituted C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8
alkenyl, unsubstituted or substituted C.sub.2-8 alkynyl, .dbd.O,
--CN, --NO.sub.2, --OR.sup.7, --OC(O)R.sup.7, --CO.sub.2R.sup.7,
--C(O)R.sup.7, --CONR.sup.7R.sup.8, --OC(O)NR.sup.7R.sup.8,
--NR.sup.7C(O)R.sup.8, --NR.sup.7C(O)NR.sup.8R.sup.9,
--NR.sup.7R.sup.8, --NR.sup.7CO.sub.2R.sup.8, --SR.sup.7,
--S(O)R.sup.7, --S(O).sub.2R.sup.7, --SO.sub.2NR.sup.7R.sup.8,
--NR.sup.7SO.sub.2R.sup.8, unsubstituted or substituted C.sub.6-10
aryl, unsubstituted or substituted 5- to 10-membered heteroaryl and
unsubstituted or substituted 3- to 10-membered heterocyclyl; [0069]
suitable substituted C.sub.1-8 alkyl, C.sub.2-8 alkenyl and
C.sub.2-8 alkynyl substituents on Z may have from 1 to 5
substituents independently selected from the group consisting of
halogen, --OR.sup.7, --CN, --NO.sub.2, .dbd.O, --CN, --NO.sub.2,
--OC(O)R.sup.7, --CO.sub.2R.sup.7, --C(O)R.sup.7,
--CONR.sup.7R.sup.8, --OC(O)NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--NR.sup.7C(O)NR.sup.8R.sup.9, --NR.sup.7R.sup.8,
--NR.sup.7CO.sub.2R.sup.8, --SR.sup.7, --S(O)R.sup.7,
S(O).sub.2R.sup.7, --SO.sub.2NR.sup.7R.sup.8,
--NR.sup.7SO.sub.2R.sup.8, unsubstituted or substituted phenyl,
unsubstituted or substituted 5- or 6-membered heteroaryl, or
unsubstituted or substituted 4- to 7-membered heterocyclyl; [0070]
suitable substituted aryl, heteroaryl and heterocyclyl substituents
on Z may have from 1 to 5 substituents independently selected from
the group consisting of halogen, --OR.sup.7, --CN, --NO.sub.2,
.dbd.O, --OC(O)R.sup.7, --OC(O)R.sup.7, --CO.sub.2R.sup.7,
--C(O)R.sup.7, --CONR.sup.7R.sup.8, --OC(O)NR.sup.7R.sup.8,
--NR.sup.7C(O)R.sup.8, --NR.sup.7C(O)NR.sup.8R.sup.9,
--NR.sup.7R.sup.8, --NR.sup.7CO.sub.2R.sup.8, --SR.sup.7,
--SOR.sup.7, --SO.sub.2R.sup.7, --SO.sub.2NR.sup.7R.sup.8,
--NR.sup.7SO.sub.2R.sup.8,unsubstituted 4- to 7-membered
heterocyclyl, unsubstituted C.sub.1-8 alkyl and unsubstituted
C.sub.1-8 haloalkyl; [0071] R.sup.7, R.sup.8 and R.sup.9 are each
independently selected from the group consisting of hydrogen,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.6-10
aryl, 5 to 10 membered heteroaryl and 3- to 10-membered
heterocycle, or R.sup.7 and R.sup.8, or R.sup.8 and R.sup.9, or
R.sup.7 and R.sup.9, may together with the atom(s) to which they
are attached, form a substituted or unsubstituted 5-, 6-, or
7-membered ring, and; [0072] where the aliphatic and aromatic
portions of R.sup.7, R.sup.8 and R.sup.9 are optionally further
substituted with 1 to 3 substituents selected from the group
consisting of halogen, --OH, --OR.sup.m, --OC(O)NHR.sup.m,
--OC(O)NR.sup.mR.sup.n, --SH, --SR.sup.m, --S(O)R.sup.m,
--S(O).sub.2R.sup.m, --S(O).sub.2NH.sub.2, --S(O).sub.2NHR.sup.m,
--S(O).sub.2NR.sup.mR.sup.n, --NHS(O).sub.2R.sup.m,
--NR.sup.mS(O).sub.2R.sup.n, --C(O)NH.sub.2, --C(O)NHR.sup.m,
--C(O)N(R.sup.m).sub.2, --C(O)R.sup.m, --NHC(O)R.sup.m,
--NR.sup.mC(O)R.sup.n, --NHC(O)NH.sub.2, --NR.sup.mC(O)NH.sub.2,
--NR.sup.mC(O)NHR.sup.n, --NHC(O)NHR.sup.m,
--NR.sup.oC(O)NR.sup.mR.sup.n, --NHC(O)N(R.sup.m).sub.2,
--CO.sub.2H, --CO.sub.2R.sup.m, --NHCO.sub.2R.sup.m,
--NR.sup.mCO.sub.2R.sup.n, --CN, --NO.sub.2, --NH.sub.2,
--NHR.sup.n, --NR.sup.mR.sup.n, --NR.sup.mS(O)NH.sub.2 and
--NR.sup.mS(O).sub.2NHR.sup.n, where R.sup.m, R.sup.n, and R.sup.o
are each independently unsubstituted C.sub.1-6 alkyl; [0073] with
the proviso that excluded from the scope of formulae (I,II) are the
following compounds: [0074]
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methyl-benzenesulfonamide
[0075]
N-[4-Chloro-2-(2-trifluoromethyl-pyridine-4-carbonyl)-phenyl]-4-is-
opropoxy-benzenesulfonamide [0076]
4-Chloro-N-[4-chloro-2-(pyridine-2-carbonyl)-phenyl]-benzenesulfonamide
[0077]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesu-
lfonamide [0078]
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
[0079]
4-Isopropoxy-N-[2-(pyridine-4-carbonyl)-4-trifluoromethyl-phenyl]--
benzenesulfonamide [0080]
4-Chloro-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamide
[0081]
4-Ethoxy-N-[2-(pyridine-4-carbonyl)-4-trifluoromethyl-phenyl]-benz-
enesulfonamide [0082]
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesul-
fonamide [0083]
N-[4-Chloro-2-(2-trifluoromethyl-pyrimidine-5-carbonyl)-phenyl]-4-isoprop-
oxy-benzenesulfonamide [0084]
N-[4-Chloro-2-(pyridazine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfona-
mide [0085]
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
[0086]
N-[4-Chloro-2-(6-trifluoromethyl-pyridazine-4-carbonyl)-phenyl]-4--
isopropoxy-benzenesulfonamide [0087]
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-methyl-benzenesulfonamide
[0088]
N-[4-Chloro-2-(pyrimidine-5-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide [0089]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethoxy-benzenesulfonamide
[0090]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethyl-benzenesulfona-
mide [0091]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropyl-benzenesulfonamid-
e [0092]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isobutyl-benzenesul-
fonamide
Known Compounds
[0093] Compounds of the formula (I) where X is methyl when Z is
2-thiophene, 2-(3-hydroxy-1H-indole) or 3-(1-methylpyridinium) are
known, but not as CCR9 antagonists.
[0094] In another embodiment, the present invention provides
compounds of the formula (II) and pharmaceutically acceptable salts
and N-oxides thereof:
##STR00005##
where L and Z are defined as in formula (I);
[0095] X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5 are each
independently selected from the group consisting of hydrogen,
halogen, --CN, --NO.sub.2, --OR.sup.1, --C(O)R.sup.1,
--CO.sub.2R.sup.1, --O(CO)R.sup.1, --OC(O)NR.sup.1R.sup.2,
--SR.sup.1, --SOR.sup.1, --SO.sub.2R.sup.1, --NR.sup.1R.sup.2,
--NR.sup.1C(O)R.sup.2, --NR.sup.1C(O).sub.2R.sup.2,
NR.sup.1(CO)NR.sup.1R.sup.2, unsubstituted or substituted C.sub.1-8
alkyl, unsubstituted or substituted C.sub.2-8 alkenyl,
unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or
substituted C.sub.6-10 aryl, unsubstituted or substituted 5- or
6-membered heteroaryl, and unsubstituted or substituted 4- to
7-membered heterocyclyl, with the proviso that one of X.sup.1,
X.sup.2, X.sup.3, X.sup.4, X.sup.5 is other than hydrogen.
[0096] When X.sup.1, X.sup.2, X.sup.3, X.sup.4, or X.sup.5 is
substituted C.sub.1-8 alkyl, substituted C.sub.2-8 alkenyl and
substituted C.sub.2-8 alkynyl, it may have from 1 to 3 substituents
independently selected from the group consisting of halogen, --CN,
.dbd.O, --OC(O)R.sup.1, --OR.sup.1, --C(O)R.sup.1,
--CONR.sup.1R.sup.2, --NR.sup.2C(O)R.sup.1, --CO.sub.2R.sup.1,
--NR.sup.1R.sup.2, --SR.sup.1, --S(O)R.sup.1, --S(O).sub.2R.sup.1,
--NR.sup.1SO.sub.2R.sup.2, unsubstituted or substituted aryl,
unsubstituted or substituted heterocyclyl, and unsubstituted or
substituted heteroaryl. Preferred substituted C.sub.1-8 alkyl have
from 1 to 3 substituents independently selected from the group
consisting of halogen, --CN, .dbd.O, --OR.sup.1, --C(O)R.sup.1,
--CONR.sup.1R.sup.2, --NR.sup.2C(O)R.sup.1, --CO.sub.2R.sup.1,
--NR.sup.1R.sup.2, --SO.sub.2R.sup.1, unsubstituted or substituted
5- or 6-membered heteroaryl and 5- or 6-membered unsubstituted or
substituted heterocyclyl.
[0097] When X.sup.1, X.sup.2, X.sup.3, X.sup.4, or X.sup.5 is
substituted C.sub.6-10 aryl, substituted 5- or 6-membered
heteroaryl and substituted 4- to 7-membered heterocycle, it may
have from 1 to 3 substituents independently selected from the group
consisting of halogen, --CN, --OR.sup.1, .dbd.O, --OC(O)R.sup.1,
--CO.sub.2R.sup.1, --C(O)R.sup.1, --CONR.sup.1R.sup.2,
--NR.sup.2C(O)R.sup.1, --NR.sup.1R.sup.2, --SR.sup.1,
--S(O)R.sup.1, --S(O).sub.2R.sup.1, --NR.sup.1SO.sub.2R.sup.2,
unsubstituted C.sub.1-8 alkyl, and unsubstituted C.sub.1-8
haloalkyl.
[0098] When X.sup.1, X.sup.2, X.sup.3, X.sup.4, or X.sup.5 is
substituted substituted 5- or 6-membered heteroaryl or substituted
5- or 6-membered heteroaryl, it preferably has from 1 to 3
substituents independently selected from the group consisting of
halogen, --OR.sup.1, --C(O)R.sup.1, --CONR.sup.1R.sup.2,
--NR.sup.2C(O)R.sup.1, --NR.sup.1R.sup.2, --SO.sub.2R.sup.1,
unsubstituted or substituted C.sub.1-8 alkyl, and unsubstituted or
substituted C.sub.1-8 haloalkyl.
[0099] Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are each independently
selected from the group consisting of hydrogen, halogen, --CN,
--NO.sub.2, --OR.sup.4, --C(O)R.sup.4, --SR.sup.4, --CF.sub.3,
--SOR.sup.4, and --SO.sub.2R.sup.4.
[0100] A compound of the present invention can have one the
following formulae:
##STR00006## ##STR00007## ##STR00008## ##STR00009## ##STR00010##
##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015##
##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021##
[0101] Compounds of the present invention are also represented by
the following formula:
##STR00022##
where Ar.sup.2 is selected from the following residues
##STR00023##
[0102] In each of the formula (III-LXXV);
[0103] X.sup.1, X.sup.a and X.sup.b are each independently as
defined for X.sup.1 in formula (II);
[0104] Y.sup.1 and Y.sup.a and Y.sup.b are each independently as
defined for Y.sup.1 in formula (II); and
[0105] Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c are independently
selected from the group consisting of hydrogen, halogen,
substituted or unsubstituted C.sub.1-8 alkyl, substituted or
unsubstituted C.sub.2-8 alkenyl, substituted or unsubstituted
C.sub.2-8 alkynyl, --CN, .dbd.O, --NO.sub.2, --OR.sup.10,
--OC(O)R.sup.10, --CO.sub.2R.sup.10, --C(O)R.sup.10,
--C(O)NR.sup.11R.sup.12, --OC(O)NR.sup.11R.sup.12,
--NR.sup.10C(O)R.sup.11,
--NR.sup.10C(O)NR.sup.11R.sup.12--NR.sup.11R.sup.12,
--NR.sup.10CO.sub.2R.sup.11, --SR.sup.10, --S(O)R.sup.10,
--S(O).sub.2R.sup.10, --S(O).sub.2NR.sup.11R.sup.12,
--NR.sup.10S(O).sub.2R.sup.11, substituted or unsubstituted
C.sub.6-10 aryl, substituted or unsubstituted 5- to 10-membered
heteroaryl and substituted or unsubstituted 3- to 10-membered
heterocyclyl; [0106] suitable substituted C.sub.1-8 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl may have from 1 to 3
substituents independently selected from the group consisting of
halogen, --OR.sup.10, --CN, --NO.sub.2, .dbd.O, --OC(O)R.sup.10,
--CO.sub.2R.sup.10, --C(O)R.sup.10, --C(O)NR.sup.10R.sup.11,
--OC(O)NR.sup.10R.sup.11, --NR.sup.10C(O)R.sup.11,
--NR.sup.10C(O)NR.sup.11R.sup.12, --NR.sup.10R.sup.11,
--NR.sup.10CO.sub.2R.sup.11, --SR.sup.10, --S(O)R.sup.10,
--S(O).sub.2R.sup.10, --S(O).sub.2NR.sup.10R.sup.11,
--NR.sup.10S(O).sub.2R.sup.11, unsubstituted or substituted phenyl,
unsubstituted or substituted 5- or 6-membered heteroaryl, or
unsubstituted or substituted 3- to 6-membered heterocyclyl; [0107]
suitable substituted aryl, heteroaryl and heterocyclyl substituents
may have from 1 to 3 substituents independently selected from the
group consisting of halogen, --OR.sup.10, --CN, --NO.sub.2, .dbd.O,
--OC(O)R.sup.10, --OC(O)R.sup.10, --CO.sub.2R.sup.10,
--C(O)R.sup.10, --C(O)NR.sup.10R.sup.11, --OC(O)NR.sup.10R.sup.11,
--NR.sup.10C(O)R.sup.11,
--NR.sup.10C(O)NR.sup.11R.sup.12--NR.sup.10R.sup.11,
--NR.sup.10CO.sub.2R.sup.11, --SR.sup.10, --S(O)R.sup.10,
--S(O).sub.2R.sup.10, --S(O).sub.2NR.sup.10R.sup.11,
--NR.sup.10S(O).sub.2R.sup.11, unsubstituted 4- to 7-membered ring
heterocyclyl, unsubstituted C.sub.1-8 alkyl and unsubstituted
C.sub.1-8 haloalkyl; [0108] R.sup.10, R.sup.11 and R.sup.12 are
each selected from hydrogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, aryl, heteroaryl, or where R.sup.10 and
R.sup.11, or R.sup.11 and R.sup.12, or R.sup.10 and R.sup.12,
together with the atom(s) to which they are attached, form an
substituted or unsubstituted 5-, 6-, or 7-membered ring; and [0109]
where the aliphatic and aromatic portions of R.sup.10, R.sup.11 and
R.sup.12 are optionally further substituted with from 1 to 3
substituents selected from the group consisting of halogen, --OH,
--OR.sup.m, --OC(O)NHR.sup.m, --OC(O)NR.sup.mR.sup.n, --SH,
--SR.sup.m, --S(O)R.sup.m, --S(O).sub.2R.sup.m,
--S(O).sub.2NH.sub.2, --S(O).sub.2NHR.sup.m,
--S(O).sub.2NR.sup.mR.sup.n, --NHS(O).sub.2R.sup.m,
--NR.sup.mS(O).sub.2R.sup.n, --C(O)NH.sub.2, --C(O)NHR.sup.m,
--C(O)N(R.sup.m).sub.2, --C(O)R.sup.m, --NHC(O)R.sup.m,
--NR.sup.mC(O)R.sup.n, --NHC(O)NH.sub.2, --NR.sup.mC(O)NH.sub.2,
--NR.sup.mC(O)NHR.sup.n, --NHC(O)NHR.sup.m,
--NR.sup.oC(O)NR.sup.mR.sup.n, --NHC(O)N(R.sup.m).sub.2,
--CO.sub.2H, --CO.sub.2R.sup.m, --NHCO.sub.2R.sup.m,
--NR.sup.mCO.sub.2R.sup.n, --CN, --NO.sub.2, --NH.sub.2,
--NHR.sup.n, --NR.sup.mR.sup.n, --NR.sup.mS(O)NH.sub.2, and
--NR.sup.mS(O).sub.2NHR.sup.n, where R.sup.m, R.sup.n, and R.sup.o
are each independently unsubstituted C.sub.1-6 alkyl; with the
proviso that excluded from the scope of formulae (III-LXXV) are the
compounds disclosed in [0056].
[0110] Compounds covered by this invention also include; [0111]
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methyl-benzenesulfonamide
[0112]
N-[4-Chloro-2-(2-trifluoromethyl-pyridine-4-carbonyl)-phenyl]-4-is-
opropoxy-benzenesulfonamide [0113]
4-Chloro-N-[4-chloro-2-(pyridine-2-carbonyl)-phenyl]-benzenesulfonamide
[0114]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesu-
lfonamide [0115]
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
[0116]
4-isopropoxy-N-[2-(pyridine-4-carbonyl)-4-trifluoromethyl-phenyl]--
benzenesulfonamide [0117]
4-Chloro-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamide
[0118]
4-Ethoxy-N-[2-(pyridine-4-carbonyl)-4-trifluoromethyl-phenyl]-benz-
enesulfonamide [0119]
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesul-
fonamide [0120]
N-[4-Chloro-2-(2-trifluoromethyl-pyrimidine-5-carbonyl)-phenyl]-4-isoprop-
oxy-benzenesulfonamide [0121]
N-[4-Chloro-2-(pyridazine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfona-
mide [0122]
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
[0123]
N-[4-Chloro-2-(6-trifluoromethyl-pyridazine-4-carbonyl)-phenyl]-4--
isopropoxy-benzenesulfonamide [0124]
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-methyl-benzenesulfonamide
[0125]
N-[4-Chloro-2-(pyrimidine-5-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide [0126]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethoxy-benzenesulfonamide
[0127]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethyl-benzenesulfona-
mide [0128]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropyl-benzenesulfonamid-
e [0129]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isobutyl-benzenesul-
fonamide.
[0130] The following descriptions and embodiments only refer to
those formulae (I-LXXV) that are applicable (i.e., those formulae
with the applicable substituents).
[0131] In formulae (III-LXXV), U.sub.1 is selected from the group
consisting of CH.sub.2, O, and NR.sup.8, where R.sup.8 is as
defined in formula (I).
[0132] In formulae (III-LXXV), R.sup.8 is as defined in formula
(I). In one preferred embodiment, R.sup.8 is hydrogen or
unsubstituted C.sub.1-6 alkyl.
[0133] In formula (LXXV), J.sub.3, J.sub.4 and J.sub.5 are selected
from the group consisting of CR.sup.30R.sup.31, O, S(O).sub.s,
NR.sup.32, where s is 0, 1 or 2 with the proviso that p+q+r is 3, 4
or 5; and with the proviso that the resulting ring system does not
contain a hydrazine functionality, a peroxide functionality nor a
hydroxylamine derived functionality, and where R.sup.30, R.sup.31
and R.sup.32 are as defined for R.sup.20 in formula (A) in
paragraph [0022]. In one preferred embodiment, R.sup.30, R.sup.31
and R.sup.32 are each independently hydrogen or unsubstituted
C.sub.1-6 alkyl.
[0134] In formula (LXXV), A is CZ', N or N.sup.+--O.sup.-, where Z'
is an Ar.sup.2 substituent, as defined for formula (I),
independently selected from the group consisting of halogen,
substituted or unsubstituted C.sub.1-8 alkyl, substituted or
unsubstituted C.sub.2-8 alkenyl, substituted or unsubstituted
C.sub.2-8 alkynyl, --CN, .dbd.O, --NO.sub.2, --OR.sup.7,
--OC(O)R.sup.7, --CO.sub.2R.sup.7, --C(O)R.sup.7,
--C(O)NR.sup.8R.sup.9, --OC(O)NR.sup.8R.sup.9,
--NR.sup.7C(O)R.sup.8, --NR.sup.7C(O)NR.sup.8R.sup.9,
--NR.sup.8R.sup.9, --NR.sup.7CO.sub.2R.sup.8, --SR.sup.7,
--S(O)R.sup.7, --S(O).sub.2R.sup.7, --S(O).sub.2NR.sup.8R.sup.9,
--NR.sup.7S(O).sub.2R.sup.8, substituted or unsubstituted
C.sub.6-10 aryl, substituted or unsubstituted 5- to 10-membered
heteroaryl and substituted or unsubstituted 3- to 10-membered
heterocyclyl; suitable substituted C.sub.1-8 alkyl, substituted
C.sub.2-8 alkenyl, substituted C.sub.2-8 alkynyl, substituted
C.sub.6-10 aryl, substituted 5- to 10-membered heteroaryl, and
substituted 3- to 10 membered heterocyclyl and R.sup.7, R.sup.8,
and R.sup.9 are as defined for formula (I).
[0135] In formula (LXXV), E is CZ' or N.
[0136] In formula (LXXV), G is O, S, NR.sup.7, where R.sup.7 is as
defined in paragraph [055].
EMBODIMENTS OF THE INVENTION
[0137] In the following embodiments, when one substituent is
specified, the remaining substituents remain as defined during
their first appearance, unless otherwise specified. For example, if
X.sup.1 is defined, then X.sup.2, X.sup.3, X.sup.4, and X.sup.5
remain as defined in formula (II).
[0138] In the following embodiments, the substituents refer to
formula in which they are present. Not all substituents are found
in all formula
Linkers
[0139] In one embodiment of formulae (I) and (II), L is preferably
--C(O)--.
[0140] In another embodiment of formulae (I) and (II), L is
preferably --S--, --S(O)--, or --S(O).sub.2--.
[0141] In another embodiment of formulae (I) and (II), when Z is
substituted or unsubstituted 5-membered heteroaryl, L is preferably
--S--, --S(O)--, or --S(O).sub.2--.
X substituents
[0142] In one embodiment of formula (II), X.sup.1, X.sup.2,
X.sup.3, X.sup.4, X.sup.5 are preferably independently selected
from the group consisting of hydrogen, halogen, --CN, --NO.sub.2,
--OR.sup.1, --C(O)R.sup.1, --SO.sub.2R.sup.1, --NR.sup.1R.sup.2,
unsubstituted or substituted C.sub.1-8 alkyl, unsubstituted or
substituted phenyl, unsubstituted or substituted 5- or 6-membered
heteroaryl, or unsubstituted or substituted 5- or 6-membered
heterocyclyl. More preferably, at least one X substituent is
situated para to the sulfonamido bond as defined in formula (I).
Preferably, either 3 or 4 substituents represented by X.sup.1,
X.sup.2, X.sup.3, X.sup.4, X.sup.5 are hydrogen, and the remaining
1 or 2 substituents are selected from the above group with the
proviso that at least one substituent is other than hydrogen.
[0143] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is a 6-membered hetaryl selected from the
group consisting of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl
and triazinyl.
[0144] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is a substituted or unsubstituted 6-ring
heteroaryl selected from pyrimidinyl and pyridinyl.
[0145] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is a 5-membered heteroaryl systems
selected from the group consisting of isothiazolyl, pyrazolyl,
imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiadiazolyl, pyrrolyl and thiazolyl.
[0146] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is a substituted 5-membered heteroaryl
selected from pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, pyrrolyl, furyl and thienyl. Preferably, at least one
of the substituent on X, X.sup.a, X.sup.b, X.sup.1, X.sup.2,
X.sup.3, X.sup.4 or X.sup.5 is an unsubstituted 5-ring heteroaryl
system selected from pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, pyrrolyl, furyl and thienyl. More preferably, at least
one of the substituent on X, X.sup.a, X.sup.b, X.sup.1, X.sup.2,
X.sup.3, X.sup.4 or X.sup.5 is oxazolyl.
[0147] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is a heterocyclic group represented by
formula (A) as defined in [0022], [0023] and [0024].
[0148] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is a substituted or unsubstituted
heterocyclyl selected from the group including pyrrolidine,
piperidine, imidazolidine, pyrazolidine, butyrolactam,
valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide,
piperidine, 1,4-dioxane, morpholine, thiomorpholine,
thiomorpholine-5-oxide, thiomorpholine-S,S-dioxide, piperazine,
pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran,
and tetrahydrothiophene.
[0149] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is substituted or unsubstituted
heterocyclic group selected from the group consisting of
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
1,3-dioxolanyl, thiomorpholinyl, thiomorpholinyl-S,S-dioxide,
piperazinyl and pyranyl.
[0150] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is a substituted C.sub.1-8 alkyl, where
suitable substituents are as defined for formula (II). Preferably,
the substituent is a substituted or unsubstituted heterocyclic
group of the formula (A) as defined in paragraph [0022], [0023] and
[0024]. More preferably, the substituent is selected from the group
including pyrrolidine, piperidine, imidazolidine, pyrazolidine,
butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane,
phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine,
thiomorpholine-5-oxide, thiomorpholine-S,S-dioxide, piperazine,
pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran,
and tetrahydrothiophene.
[0151] In one embodiment of each of the formulae (I-LXXV), when a
heterocyclic group represented by formula (A) is present, R.sup.20,
R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are
independently hydrogen or C.sub.1-4alkyl. In another preferred
embodiment, at least three of R.sup.20, R.sup.21, R.sup.22,
R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are hydrogen, is 1 or 2,
k is 1 or 2 with the proviso that j+k is 3 or 4. In another
preferred embodiments, at least five of R.sup.20, R.sup.21,
R.sup.22, R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are hydrogen,
j is 1 or 2, k is 1 or 2 with the proviso that j+k is 3 or 4.
[0152] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is a substituted C.sub.1-8 alkyl, where
suitable substituents are as defined for formula (II). In one
preferred embodiment, the substituted C.sub.1-8 alkyl is
substituted with a 5- or 6-membered heteroaryl selected from the
group consisting of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,
triazinyl, isothiazolyl, pyrazolyl, imidazolyl, thienyl, furyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiadiazolyl, pyrrolyl, and thiazolyl. More preferably, the
substituted C.sub.1-8 alkyl is substituted with oxazolyl.
[0153] In one embodiment of each of the formulae (I-LXXV), a
suitable substituent for substituted C.sub.1-8 alkyl (as X,
X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.a, X.sup.b, or
X) can be selected from the group consisting of --CN, --OR.sup.1,
--C(O)R.sup.1, --CO.sub.2R.sup.1, --O(CO)R.sup.1, --SO.sub.2R.sup.1
and halogen.
[0154] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is an unsubstituted C.sub.1-8 alkyl.
[0155] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is t-butyl.
[0156] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is oxazolyl.
[0157] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is morpholinyl.
[0158] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is isopropoxy.
[0159] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is trifluoromethoxy.
[0160] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is --SO.sub.2R.sup.3.
[0161] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is ethyl.
[0162] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is isopropyl.
[0163] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is a cyano, halogen or trifluoromethyl
group.
[0164] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is --C(Me).sub.2CH.sub.2OH.
[0165] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is --C(O)Me.
[0166] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is --(CH.sub.2).sub.2CO.sub.2Me.
[0167] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is isoamyl.
[0168] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is 1-3,dioxolanyl.
[0169] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is furyl.
[0170] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is pyrazolyl.
[0171] In one embodiment of each of the formulae (I-LXXV), at least
one of X.sup.a, X.sup.b, X.sup.1, X.sup.2, X.sup.3, X.sup.4,
X.sup.5 or at least one X is thienyl.
[0172] In one embodiment of paragraphs [0111] to [00108], the
remaining substituents are hydrogen. In another embodiment, the
remaining substituents are selected from the group consisting of
hydrogen, halogen, cyano, or trifluoromethyl.
[0173] In one embodiment of formula (II), at least one of X.sup.1,
X.sup.2, X.sup.3, X.sup.4, and X.sup.5 is other than hydrogen.
[0174] In one embodiment of formula (II), X.sup.1 is other than
hydrogen and at least 2 of X.sup.2, X.sup.3, X.sup.4, and X.sup.5
are hydrogen. Preferably, at least 3 of X.sup.2, X.sup.3, X.sup.4,
and X.sup.5 are hydrogen; more preferably, X.sup.2, X.sup.3,
X.sup.4, and X.sup.5 are hydrogen.
[0175] In one embodiment of each of the formulae (III-LXXV), at
least one of X.sup.1, X.sup.a, and X.sup.b is a substituted or
unsubstituted 5- or 6-membered heteroaryl ring selected from the
group consisting of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,
triazinyl, isothiazolyl, pyrazolyl, imidazolyl, thienyl, furyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiadiazolyl, pyrrolyl, and thiazolyl.
[0176] In one embodiment of each of the formulae (III-LXXV), at
least one of X.sup.1, X.sup.a, and X.sup.b is a substituted or
unsubstituted 5- or 6-membered heterocyclic ring, and the
heterocycle is selected from the group consisting of pyrrolidine,
piperidine, imidazolidine, pyrazolidine, butyrolactam,
valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide,
piperidine, 1,4-dioxane, morpholine, thiomorpholine,
thiomorpholine-5-oxide, thiomorpholine-S,S-dioxide, piperazine,
pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran,
and tetrahydrothiophene.
[0177] In one embodiment of each of the formulae (I-LXXV), at least
one of X, X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.a, and
X.sup.b are independently selected from the group consisting
of:
##STR00024## ##STR00025##
[0178] In one embodiment of each of the formulae (I-LXXV), at least
one of X, X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.a, and
X.sup.b are independently selected from the group consisting
of:
##STR00026##
[0179] In one embodiment for each of the formulae (III-LXXV), one
of X.sup.1 or X.sup.b is selected from the group defined in
paragraphs [091] and [0110], and X.sup.a is selected from the group
consisting of --F, --Cl, --CN or --CF.sub.3. Preferably, one of
X.sup.1 or X.sup.b is selected from the group defined in paragraphs
[091] and [00110], and X.sup.a is hydrogen.
[0180] In one embodiment of each of the formulae (I-LXXV), X,
X.sup.1, X.sup.a, and X.sup.b are independently selected from the
group consisting of hydrogen, halogen, --CN, --NO.sub.2, --OH,
--OR.sup.3 (but not --OMe, --O.sup.iPr, --OEt), --C(O)R.sup.3,
--CO.sub.2R.sup.3, --O(CO)R.sup.3, --OC(O)NR.sup.3R.sup.4,
--SR.sup.3, --S(O)R.sup.3, --NR.sup.3R.sup.3,
--NR.sup.5C(O)R.sup.3, --NR.sup.5C(O).sub.2R.sup.3, unsubstituted
C.sub.1-8 alkyl (but not ethyl, methyl, iso-propyl, isoamyl),
C.sub.1-8 haloalkyl (but not --CF.sub.3), unsubstituted C.sub.2-8
alkenyl, unsubstituted C.sub.2-8 alkynyl, or substituted or
unsubstituted phenyl, with the proviso that at least one
substituent is other than hydrogen.
[0181] In one embodiment of each of the formulae (I-LXXV), X,
X.sup.1, X.sup.a, and X.sup.b are independently selected from the
group consisting hydrogen, --OMe, --O.sup.iPr, --OEt, ethyl,
methyl, iso-propyl, isoamyl, or --CF.sub.3 with the proviso that at
least one substituent is other than hydrogen.
[0182] In one embodiment of each of the formulae (III-LXXV),
X.sup.1, X.sup.a, and X.sup.b are independently selected from the
group consisting of hydrogen, --S(O).sub.2R.sup.3,
--NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5S(O).sub.2R.sup.3,
--S(O).sub.2NR.sup.3R.sup.4, substituted C.sub.1-8 alkyl (but not
C.sub.1-8 haloalkyl), substituted C.sub.2-8 alkenyl, substituted
C.sub.2-8 alkynyl, substituted or unsubstituted 5- or 6-membered
heteroaryl, or substituted or unsubstituted 4- to 7-membered
heterocyclyl, with the proviso that at least one substituent is
other than hydrogen.
[0183] In one embodiment of each of the formulae (III-LXXV),
X.sup.1, X.sup.a, and X.sup.b are independently selected such that
at least one substituent is unsubstituted C.sub.1-8 alkyl.
[0184] In one embodiment of each of the formulae (III-LXXV),
X.sup.1, X.sup.a, and X.sup.b are independently selected from the
group consisting of hydrogen, --NO.sub.2, --OR.sup.3,
--C(O)R.sup.3, --S(O).sub.2R.sup.3, --NR.sup.3R.sup.4, substituted
or unsubstituted C.sub.1-8 alkyl, substituted or unsubstituted
phenyl, substituted or unsubstituted 5- or 6-membered heteroaryl,
or substituted or unsubstituted 5- or 6-membered heterocyclyl.
Preferably, X.sup.a is hydrogen. In another preferred embodiment,
X.sup.a is fluorine, chlorine, --CN, --CF.sub.3.
[0185] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen, and X.sup.b is other than hydrogen.
[0186] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen, and X.sup.1 is other than hydrogen.
[0187] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.1 is C.sub.1-8 alkyl, having 1 to 3
substituents independently selected from the group consisting of
halogen, --CN, .dbd.O, --OC(O)R.sup.3, --OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.4C(O)R.sup.3, --CO.sub.2R.sup.3,
--NR.sup.3R.sup.4, --SR.sup.3, --S(O)R.sup.3, --S(O).sub.2R.sup.3,
--NR.sup.3S(O).sub.2R.sup.4, substituted or unsubstituted phenyl,
and substituted or unsubstituted 5- or 6-membered heteroaryl, and
substituted or unsubstituted 4- to 7-membered heterocycle. In
another embodiment, X.sup.a is halogen, --CF.sub.3, or --CN.
[0188] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.1 is unsubstituted C.sub.1-8 alkyl.
In another embodiment, X.sup.a is halogen, --CF.sub.3, or --CN.
[0189] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.b is C.sub.1-8 alkyl, having 1 to 3
substituents independently selected from the group consisting of
halogen, --CN, .dbd.O, --OC(O)R.sup.3, --OR.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)R.sup.3, --CO.sub.2R.sup.3,
--NR.sup.3R.sup.4, --S(O).sub.2R.sup.3, substituted or
unsubstituted phenyl, and substituted or unsubstituted 5- or
6-membered heteroaryl and substituted or unsubstituted 4- to
7-membered heterocycle. In another embodiment, X.sup.a is halogen,
--CF.sub.3, or --CN.
[0190] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.b is unsubstituted C.sub.1-8 alkyl.
In another embodiment, X.sup.a is halogen, --CF.sub.3, or --CN.
[0191] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.1 is C.sub.6-10 aryl or a heteroaryl,
having from 0 to 3 substituents independently selected from the
group consisting of halogen, --CN, --OR.sup.3, .dbd.O,
--OC(O)R.sup.3, --CO.sub.2R.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)R.sup.3, --NR.sup.3R.sup.4,
--SR.sup.3--S(O)R.sup.3, --S(O).sub.2R.sup.3,
--NR.sup.5S(O).sub.2R.sup.3, and unsubstituted C.sub.1-8 alkyl or
unsubstituted C.sub.1-8 haloalkyl. In other embodiments, X.sup.a is
halogen, --CN, or --CF.sub.3.
[0192] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.b is C.sub.6-10 aryl or a heteroaryl,
having from 0 to 3 substituents independently selected from the
group consisting of halogen, --CN, --OR.sup.3, .dbd.O, --NO.sub.2,
--OC(O)R.sup.3, --CO.sub.2R.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)R.sup.3, --NR.sup.3R.sup.4,
--SR.sup.3, --S(O)R.sup.3, --S(O).sub.2R.sup.3,
--NR.sup.5S(O).sub.2R.sup.3, and unsubstituted C.sub.1-8 alkyl or
unsubstituted C.sub.1-8 haloalkyl. In other embodiments, X.sup.a is
halogen, --CN, or --CF.sub.3.
[0193] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.1 is substituted phenyl, having from
1 to 3 substituents independently selected from the group
consisting of halogen, --OR.sup.3, --NO.sub.2, .dbd.O
--C(O)R.sup.3, --C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)R.sup.3,
--NR.sup.3R.sup.4, --SR.sup.3, --NR.sup.5S(O).sub.2R.sup.3,
--S(O).sub.2R.sup.3, and unsubstituted C.sub.1-8 alkyl or
unsubstituted C.sub.1-8 haloalkyl. In other embodiments, X.sup.a is
halogen, --CN, or --CF.sub.3.
[0194] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.b is phenyl, having from 1 to 3
substituents independently selected from the group consisting of
halogen, --OR.sup.3, .dbd.O, --NO.sub.2, --C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)R.sup.3, --NR.sup.3R.sup.4,
--SR.sup.3, --NR.sup.5S(O).sub.2R.sup.3, --S(O).sub.2R.sup.3, and
unsubstituted C.sub.1-8 alkyl or unsubstituted C.sub.1-8 haloalkyl.
In other embodiments, X.sup.a is halogen, --CN, or --CF.sub.3.
[0195] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.1 is substituted or unsubstituted 5-
or 6-membered heteroaryl, having from 0 to 3 substituents
independently selected from the group consisting of halogen,
--OR.sup.3, --NO.sub.2, .dbd.O--C(O)R.sup.3, --C(O)NR.sup.3R.sup.4,
--NR.sup.5C(O)R.sup.3, --NR.sup.3R.sup.4, --SR.sup.3,
--NR.sup.5S(O).sub.2R.sup.3, --S(O).sub.2R.sup.3, and unsubstituted
C.sub.1-8 alkyl or unsubstituted C.sub.1-8 haloalkyl. In other
embodiments, X.sup.a is selected from halogen, --CN, or
--CF.sub.3.
[0196] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.b is a 5- or 6-membered substituted
or unsubstituted heteroaryl, having from 0 to 3 substituents
independently selected from the group consisting of halogen,
--OR.sup.3, .dbd.O, --NO.sub.2, --C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)R.sup.3, --NR.sup.3R.sup.4,
--SR.sup.3, --NR.sup.5S(O).sub.2R.sup.3, --S(O).sub.2R.sup.3, and
unsubstituted C.sub.1-8 alkyl or unsubstituted C.sub.1-8 haloalkyl.
In other embodiments, X.sup.a is halogen, --CN, or --CF.sub.3.
[0197] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.1 is a 4- to 7-membered heterocyclyl,
having 0 to 3 substituents independently selected from the group
consisting of unsubstituted C.sub.1-8 alkyl, unsubstituted
C.sub.1-8 haloalkyl, --OR.sup.3, --OC(O)R.sup.3, --CO.sub.2R.sup.3,
--C(O)R.sup.3, --C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4,
--NR.sup.5C(O)R.sup.3, --S(O).sub.2R.sup.3, --SR.sup.3 and
--NR.sup.5S(O).sub.2R.sup.3. In other embodiments, X.sup.a is
selected from halogen, --CN, and --CF.sub.3.
[0198] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.b is a 4- to 7-membered heterocyclyl,
having from 0 to 3 substituents independently selected from the
group consisting of unsubstituted C.sub.1-8 alkyl, unsubstituted
C.sub.1-8 haloalkyl, --OR.sup.3, --OH, --NR.sup.5C(O)R.sup.3,
--OC(O)R.sup.3, --CO.sub.2R.sup.3, --C(O)R.sup.3,
--C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4, --S(O).sub.2R.sup.3,
--SR.sup.3 and --NR.sup.5S(O).sub.2R.sup.3. In other embodiments,
X.sup.a is selected from halogen, --CN, and --CF.sub.3.
[0199] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.1 is a 5- or 6-membered heterocyclyl,
having 0 to 2 substituents independently selected from the group
consisting of unsubstituted C.sub.1-8 alkyl or unsubstituted
C.sub.1-8 haloalkyl. In other embodiments, X.sup.a is selected from
halogen, --CN, and --CF.sub.3.
[0200] In one embodiment of each of the formulae (III-LXXV),
X.sup.a is hydrogen and X.sup.b is a 5- or 6-membered heterocyclyl,
having 0 to 2 substituents independently selected from the group
consisting of unsubstituted C.sub.1-8 alkyl or unsubstituted
C.sub.1-8 haloalkyl. In other embodiments, X.sup.a is selected from
halogen, --CN, and --CF.sub.3.
[0201] In one embodiment, in each of formulae (III-LXXV), X.sup.a
is hydrogen and X.sup.b is selected from the group consisting of
--CN, --CF.sub.3, halogen, --OR.sup.3, --S(O).sub.2R.sup.3,
--C(O)R.sup.3, and a substituted or unsubstituted C.sub.1-8 alkyl,
a substituted or unsubstituted 5- or 6-membered heteroaryl, and a
substituted or unsubstituted 4- to 7-membered heterocycle. In other
embodiments, X.sup.a is selected from halogen, --CN, or
--CF.sub.3.
[0202] In one embodiment, in each of formulae (III-LXXV), X.sup.a
is hydrogen and X.sup.1 is selected from the group consisting of
--CN, --CF.sub.3, halogen, --OR.sup.3, --S(O).sub.2R.sup.3,
--C(O)R.sup.3, and a substituted or unsubstituted C.sub.1-8 alkyl,
a substituted or unsubstituted 5- or 6-membered heteroaryl, and a
substituted or unsubstituted 4- to 7-membered heterocycle. In other
embodiments, X.sup.a is selected from halogen, --CN, or
--CF.sub.3.
[0203] In embodiments for each of the formulae (III-LXXV) where
X.sup.1 or X.sup.b is either a substituted C.sub.1-8 alkyl, a
substituted 5- or 6-membered heteroaryl, or a substituted 4- to
7-membered heterocycle, the aromatic or aliphatic portions of
X.sup.1 or X.sup.b may have from 1 to 3 substituents independently
selected from the group consisting of halogen, --CN, .dbd.O,
--OC(O)R.sup.3, --OR.sup.3, --C(O)R.sup.3, --C(O)NR.sup.3R.sup.4,
--NR.sup.5C(O)R.sup.3, --CO.sub.2R.sup.3, --NR.sup.3R.sup.4,
--S(O).sub.2R.sup.3, substituted or unsubstituted phenyl,
substituted or unsubstituted 5- or 6-membered heteroaryl,
substituted or unsubstituted 4- to 7-membered heterocycle.
[0204] In one embodiment of formula (II), X.sup.2, X.sup.3 and
X.sup.5 are hydrogen; X.sup.1 and X.sup.4 are selected from the
group consisting of halogen, --CN, --NO.sub.2, --OH, --OR.sup.3,
--C(O)R.sup.3, --CO.sub.2R.sup.3, --O(CO)R.sup.3,
--OC(O)NR.sup.3R.sup.4, --SR.sup.3, --S(O)R.sup.3,
--S(O).sub.2R.sup.3, --NR.sup.3R.sup.3, --NR.sup.5C(O)R.sup.3,
--NR.sup.5C(O).sub.2R.sup.3, --NR.sup.5C(O)NR.sup.3R.sup.4,
--NR.sup.5S(O).sub.2R.sup.3, --S(O).sub.2NR.sup.3R.sup.4,
substituted or unsubstituted C.sub.1-8 alkyl, substituted or
unsubstituted C.sub.2-8 alkenyl, substituted or unsubstituted
C.sub.2-8 alkynyl, substituted or unsubstituted phenyl, substituted
or unsubstituted 5- or 6-membered heteroaryl, or substituted or
unsubstituted 4- to 7-membered heterocyclyl.
[0205] In one embodiment of formula (II), X.sup.4, X.sup.2, X.sup.3
and X.sup.5 are hydrogen; and X.sup.1 is selected from the group
consisting of halogen, --CN, --NO.sub.2, --OH, --OR.sup.3,
--C(O)R.sup.3, --CO.sub.2R.sup.3, --O(CO)R.sup.3,
--OC(O)NR.sup.3R.sup.4, --SR.sup.3,
--S(O)R.sup.3--S(O).sub.2R.sup.3, --NR.sup.3R.sup.3,
--NR.sup.5C(O)R.sup.3, --NR.sup.5C(O).sub.2R.sup.3,
--NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5S(O).sub.2R.sup.3,
--S(O).sub.2NR.sup.3R.sup.4, substituted or unsubstituted C.sub.1-8
alkyl, substituted or unsubstituted C.sub.2-8 alkenyl, substituted
or unsubstituted C.sub.2-8 alkynyl, substituted or unsubstituted
phenyl, substituted or unsubstituted 5- or 6-membered heteroaryl,
or substituted or unsubstituted 4- to 7-membered heterocyclyl.
[0206] In one embodiment of formulae (II), X.sup.2, X.sup.3 and
X.sup.5 are hydrogen, X.sup.4 is selected from the group consisting
of hydrogen, fluorine, chlorine, --CN and trifluoromethoxy, and
X.sup.1 is selected from the group consisting of --CN, --CF.sub.3,
halogen, --OR.sup.3, --S(O).sub.2R.sup.3, --C(O)R.sup.3, and a
substituted or unsubstituted C.sub.1-8 alkyl, a substituted or
unsubstituted 5- or 6-membered heteroaryl, and a substituted or
unsubstituted 4- to 7-membered heterocycle.
[0207] In embodiments of each of formulae (III-LXXV), X.sup.a and
X.sup.b are hydrogen; and X.sup.1 is selected from the group
consisting of halogen, --CN, --NO.sub.2, --OH, --OR.sup.3,
--C(O)R.sup.3, --CO.sub.2R.sup.3, --O(CO)R.sup.3,
--OC(O)NR.sup.3R.sup.4, --SR.sup.3, --S(O)R.sup.3,
--S(O).sub.2R.sup.3, --NR.sup.3R.sup.3, --NR.sup.5C(O)R.sup.3,
--NR.sup.5C(O).sub.2R.sup.3, --NR.sup.5C(O)NR.sup.3R.sup.4,
--NR.sup.5S(O).sub.2R.sup.3, --S(O).sub.2NR.sup.3R.sup.4,
substituted or unsubstituted C.sub.1-8 alkyl, substituted or
unsubstituted C.sub.2-8 alkenyl, substituted or unsubstituted
C.sub.2-8 alkynyl, substituted or unsubstituted phenyl, substituted
or unsubstituted 5- or 6-membered heteroaryl, and substituted or
unsubstituted 4- to 7-membered heterocyclyl.
[0208] In embodiments of each of formulae (III-LXXV), X.sup.1 and
X.sup.b are hydrogen; and X.sup.a is selected from the group
consisting of halogen, --CN, --NO.sub.2, --OH, --OR.sup.3,
--C(O)R.sup.3, --CO.sub.2R.sup.3, --O(CO)R.sup.3,
--OC(O)NR.sup.3R.sup.4, --SR.sup.3, --S(O)R.sup.3,
--S(O).sub.2R.sup.3, --NR.sup.3R.sup.3, --NR.sup.5C(O)R.sup.3,
--NR.sup.5C(O).sub.2R.sup.3, --NR.sup.5C(O)NR.sup.3R.sup.4,
--NR.sup.5S(O).sub.2R.sup.3, --S(O).sub.2NR.sup.3R.sup.4,
substituted or unsubstituted C.sub.1-8 alkyl, substituted or
unsubstituted C.sub.2-8 alkenyl, substituted or unsubstituted
C.sub.2-8 alkynyl, substituted or unsubstituted phenyl, substituted
or unsubstituted 5- or 6-membered heteroaryl, and substituted or
unsubstituted 4- to 7-membered heterocyclyl.
[0209] In one embodiment in each of formulae (III-LXXV), X.sup.a
and X.sup.b are selected from the group consisting of hydrogen,
fluorine, chlorine, --CN and trifluoromethoxy, and X.sup.1 is
selected from the group consisting of --CN, --CF.sub.3, halogen,
--OR.sup.3, --S(O).sub.2R.sup.3, --C(O)R.sup.3, and substituted or
unsubstituted C.sub.1-8 alkyl, substituted or unsubstituted 5- or
6-membered heteroaryl, and substituted or unsubstituted 4- to
7-membered heterocycle.
[0210] In one preferred embodiment of formula (II), X.sup.2,
X.sup.3 and X.sup.5 are hydrogen, X.sup.4 is selected from the
group consisting of hydrogen, fluorine, chlorine, --CN and
trifluoromethoxy and X.sup.1 is selected from one of the residues
shown below:
##STR00027## ##STR00028##
[0211] with the proviso that at least one of the substituents is
other than hydrogen;
[0212] Y.sup.3 is hydrogen; when Y.sup.1 is chlorine or bromine,
then Y.sup.2 and Y.sup.4 are hydrogen; alternatively when Y.sup.1
is fluorine, then Y.sup.2 and Y.sup.4 are hydrogen or fluorine;
[0213] Ar.sub.2 is selected from the following group consisting
of:
##STR00029## ##STR00030##
[0214] In one preferred embodiment of formula (II), X.sup.2,
X.sup.3 and X.sup.5 are hydrogen, X.sup.4 is selected from the
group consisting of hydrogen, fluorine, chlorine, --CN and
trifluoromethoxy and X.sup.1 is selected from one of the residues
shown below:
##STR00031##
[0215] with the proviso that at least one of the substituents is
other than hydrogen;
[0216] Y.sup.3 is hydrogen; when Y.sup.1 is chlorine or bromine,
then Y.sup.2 and Y.sup.4 are hydrogen; alternatively when Y.sup.1
is fluorine, then Y.sup.2 and Y.sup.4 are hydrogen or fluorine;
and
[0217] Ar.sub.2 is selected from the following group consisting
of:
##STR00032## ##STR00033##
[0218] In one embodiment of each of formulae (III-LXXIV), X.sup.a
is selected from the group consisting of hydrogen, fluorine,
chlorine, --CN and trifluoromethoxy, and X.sup.1 or X.sup.b is
selected from one of the residues shown below.
##STR00034## ##STR00035##
with the proviso that at least one substituent X.sup.1, X.sup.a or
X.sup.b is other than hydrogen;
[0219] Y.sup.1 or Y.sup.b is chlorine, then Y.sup.a is hydrogen; or
alternatively, when Y.sup.1 or Y.sup.b is fluorine, then Y.sup.a is
hydrogen or fluorine; Z.sup.a is hydrogen, and Z.sup.1 or Z.sup.b
are selected from the following group consisting of:
##STR00036##
[0220] In others preferred embodiment, X.sup.1 or X.sup.b is
instead selected from one of the residues shown below.
##STR00037##
[0221] In one embodiment in each of formulae (III-LXXIV), X.sup.a
is selected from the group consisting of hydrogen, fluorine,
chlorine, --CN and trifluoromethoxy, and X.sup.1 or X.sup.b is
selected from one of the residues shown below.
##STR00038## ##STR00039##
[0222] with the proviso that at least one substituent X.sup.1,
X.sup.a or X.sup.b is other than hydrogen; Y.sup.1 or Y.sup.b is
chlorine, then Y.sup.a is hydrogen; or alternatively, when Y.sup.1
or Y.sup.b is fluorine, then Y.sup.a is hydrogen or fluorine; and
Z.sup.1, Z.sup.a and Z.sup.b are all simultaneously hydrogen.
[0223] In others preferred embodiment, X.sup.1 or X.sup.b is
instead selected from one of the residues shown below.
##STR00040##
[0224] In one embodiment of each of the formulae (I-LXXV), X,
X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.a, or X.sup.b
are each independently selected from the group consisting of
hydrogen, --CH.dbd.CH.sub.2, phenylacetylene, t-butyl,
-hydroxybutyl, --C(CH.sub.3).sub.2CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CO.sub.2Me, --OCF.sub.3, --C(O)Me, --SO.sub.2Me,
pyrazole, oxazole, and morpholinyl, with the proviso that at least
one non-hydrogen substituent is present.
[0225] In one embodiment of each of the formulae (I-LXXV), X,
X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.a, or X.sup.b
are each independently selected from the group consisting of
hydrogen, --CF.sub.3, isoamyl, ethyl (Et), i-propyl (.sup.iPr),
--C(CH.sub.3).sub.2CH.sub.2CH.sub.3, --OMe, --O-.sup.iPr, phenyl
(Ph), and --OEt, with the proviso that at least one non-hydrogen
substituent is present.
Y Substituents
[0226] In one embodiment of (II), at least two substituents from
the group Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are hydrogen, with
the proviso that at least one is other than hydrogen. Preferably,
Y.sup.1, Y.sup.2, Y.sup.3 and Y.sup.4 are selected from the group
consisting of halogen, --CN, --NO.sub.2, --CF.sub.3, and
--SO.sub.2R.sup.4, with the proviso that only one or two
substituents are other than hydrogen, and with the proviso that at
least one substituent is halogen. Most preferably, at least one
substituent is a halogen atom located para to the sulfonamide bond
as defined in formula (I).
[0227] In one embodiment of any of formula (I) or (II), when Y,
Y.sup.1, Y.sup.2, Y.sup.3 or Y.sup.4 is substituted alkyl, it
preferably has from 1 to 3 substituents independently selected from
the group consisting of halogen, --OR.sup.4, --CN, --NO.sub.2,
.dbd.O, --OC(O)R.sup.4, --CO.sub.2R.sup.4, --C(O)R.sup.4,
--CONR.sup.4R.sup.5, --NR.sup.4C(O)R.sup.5, --NR.sup.4R.sup.5,
--NR.sup.4, --SR.sup.4, --SOR.sup.4, --SO.sub.2R.sup.4, and
--NR.sup.4SO.sub.2R.sup.5.
[0228] In one embodiment of any of formulae (I) and (II), at least
one of Y, Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 is other
than hydrogen.
[0229] In one embodiment of any of formulae (I) and (II), at least
one of Y, Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4 and Y.sup.5 is
halogen, --CN, --NO.sub.2, --OR.sup.6, --C(O)R.sup.6, --SR.sup.6,
--CF.sub.3, --S(O)R.sup.6, and --S(O).sub.2R.sup.13 and substituted
or unsubstituted C.sub.1-4 alkyl.
[0230] In one embodiment of any of formulae (III-LXXV), one of
Y.sup.1, Y.sup.a and Y.sup.b is hydrogen and the other is not
hydrogen.
[0231] In one embodiment of any of formulae (III-LXXV), Y.sup.1,
Y.sup.a and Y.sup.b represent from 1 to 3 substituents
independently selected from the group consisting of hydrogen,
halogen, --CN, --NO.sub.2, --OR.sup.6, --C(O)R.sup.6, --SR.sup.6,
--CF.sub.3, --S(O)R.sup.6, and --S(O).sub.2R.sup.6 and substituted
or unsubstituted C.sub.1-6 alkyl.
[0232] In one embodiment of any of formulae (III-LXXV), Y.sup.1,
Y.sup.a and Y.sup.b represent from 1 to 3 substituents
independently selected from the group consisting of hydrogen,
halogen, --CN, --NO.sub.2, --CF.sub.3, and --S(O).sub.2Me.
[0233] In one embodiment of any of formulae (III-LXXV), one of
Y.sup.1, Y.sup.a and Y.sup.b is halogen and the other is selected
from the group consisting of hydrogen, halogen, --CN, --NO.sub.2,
--OH, --OR.sup.6, --C(O)R.sup.6, --CO.sub.2R.sup.6, --SR.sup.6,
--S(O)R.sup.6, --S(O).sub.2R.sup.6 and substituted or unsubstituted
C.sub.1-4 alkyl.
[0234] In one embodiment in any of formulae (III-LXXV), one of
Y.sup.1, Y.sup.a and Y.sup.b is substituted alkyl, having from 1 to
3 substituents independently selected from the group consisting of
halogen, --OH, --OR.sup.m, --CN, --NO.sub.2, .dbd.O,
--OC(O)R.sup.m, --CO.sub.2R.sup.m, --C(O)R.sup.m, --C(O)NHR.sup.n,
--C(O)NH.sub.2, --C(O)NR.sup.mR.sup.n, --NR.sup.mC(O)R.sup.n,
--NHC(O)R.sup.n, --NR.sup.mR.sup.n, --NHR.sup.m, --NH.sub.2,
--SR.sup.m, --S(O)R.sup.m, --S(O).sub.2R.sup.m,
--NR.sup.mS(O).sub.2R.sup.n, and --NHS(O).sub.2R.sup.m where
R.sup.m and R.sup.n are each independently unsubstituted C.sub.1-6
alkyl.
[0235] In one embodiment of any of formulae (III-LXXV), Y.sup.1 and
Y.sup.a are each independently selected from the group consisting
of hydrogen, halogen, --CN, --NO.sub.2, --OH, --OR.sup.6,
--C(O)R.sup.6, --CO.sub.2R.sup.6, --SR.sup.6, --S(O)R.sup.6,
--S(O).sub.2R.sup.6, and substituted or unsubstituted C.sub.1-4
alkyl, with the proviso that Y.sup.1 and Y.sup.a cannot both be
hydrogen simultaneously.
[0236] In one embodiment of any of formulae (III-LXXV), Y.sup.1 and
Y.sup.a are each independently hydrogen or halogen, with the
proviso that one of Y.sup.1 and Y.sup.a is halogen. Preferably, one
halogen atom is located para to the sulfonamide bond.
[0237] In one embodiment of any of formulae (III-LXXV), Y.sup.1 or
Y.sup.b is hydrogen and Y.sup.a is chloro, fluoro or bromo; Y.sup.a
is hydrogen and Y.sup.1 or Y.sup.b is chloro, fluoro or bromo;
Y.sup.a and Y.sup.1 or Y.sup.b are both chloro, fluoro, or bromo
(particularly fluoro).
Z Substituents
[0238] In one embodiment of formulae (I) and (II), Z represents an
unsubstituted or substituted 5- or 6-membered heteroaryl. Suitably
substituted 5- or 6-membered heteroaryls may have from 1 to 3
substituents independently selected from the group consisting of
halogen, unsubstituted or substituted C.sub.1-8 alkyl,
unsubstituted or substituted C.sub.2-8 alkenyl, unsubstituted or
substituted C.sub.2-8 alkynyl, .dbd.O, --CN, --NO.sub.2,
--OR.sup.7, --OC(O)R.sup.7, --CO.sub.2R.sup.7, --C(O)R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8, --NR.sup.7R.sup.8,
--SR.sup.7, --SOR.sup.7, --SO.sub.2R.sup.7,
--SO.sub.2NR.sup.7R.sup.8, --NR.sup.7SO.sub.2R.sup.8, unsubstituted
or substituted phenyl, unsubstituted or substituted 5- or
6-membered heteroaryl, and unsubstituted or substituted 4- to
7-membered heterocyclyl. If present, one substituent is preferably
located ortho to one of the heteroatoms in the ring or is an oxygen
atom directly connected to a ring heteroatom (i.e. N-oxide).
[0239] In one embodiment of formulae (I) and (II), Z represents
unsubstituted or substituted 6-membered heteroaryl with up to 3
nitrogen atoms and with from 0 to 3 substituents independently
selected from the group consisting of halogen, unsubstituted or
substituted C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8
alkenyl, unsubstituted or substituted C.sub.2-8 alkynyl, .dbd.O,
--CN, --NO.sub.2, --OR.sup.7, --OC(O)R.sup.7, --CO.sub.2R.sup.7,
--C(O)R.sup.7, --CONR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--NR.sup.7R.sup.8, --SR.sup.7, --S(O)R.sup.7, --S(O).sub.2R.sup.7,
--SO.sub.2NR.sup.7R.sup.8, --NR.sup.7SO.sub.2R.sup.8, unsubstituted
or substituted phenyl, unsubstituted or substituted 5- and
6-membered heteroaryl, and unsubstituted or substituted 4- to
7-membered heterocyclyl.
[0240] In one embodiment of formulae (I) and (II), Z can be any
unsubstituted or substituted chemically allowed regioisomer of
pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like and their
respective N-oxides. In preferred embodiments, Z is pyridinyl with
from 0 to 3 substituents; pyrimidinyl with from 0 to 3
substituents; pyrazinyl with from 0 to 3 substituents; or
pyridazinyl with from 0 to 3 substituents (especially, where one
ring nitrogen has a .dbd.O substituent).
[0241] In one embodiment of formulae (I) and (II), Z represents
unsubstituted or substituted 6-membered heteroaryl with 1 to 2
nitrogen atoms and with 0 or 2 substituents independently selected
from the group consisting of halogen, unsubstituted or substituted
C.sub.1-6 alkyl, .dbd.O, --CN, --NO.sub.2, --OR.sup.7,
--C(O)R.sup.7, --CONR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--NR.sup.7R.sup.8, --SR.sup.7, --SOR.sup.7, --SO.sub.2R.sup.7,
--SO.sub.2NR.sup.7R.sup.8, --NR.sup.7SO.sub.2R.sup.8, unsubstituted
or substituted 5- or 6-membered heteroaryl and a unsubstituted or
substituted 4- to 7-membered heterocyclyl. In this embodiment, Z
can be any chemically allowed regioisomer of pyridyl, pyrimidinyl,
pyridazinyl, pyrazinyl and the like, and their respective
N-oxides.
[0242] When a substituent on Z is substituted C.sub.1-8 alkyl,
substituted C.sub.2-8 alkenyl or substituted C.sub.2-8 alkynyl, it
may have from 1 to 3 substituents independently selected from the
group consisting of halogen, --OR.sup.7, .dbd.O, --CO.sub.2R.sup.7,
--C(O)R.sup.7, --CONR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--NR.sup.7R.sup.8, --SR.sup.7, --SOR.sup.7, --SO.sub.2R.sup.7,
--NR.sup.7SO.sub.2R.sup.8, unsubstituted or substituted phenyl,
unsubstituted or substituted 5- or 6-membered heteroaryl, and
unsubstituted or substituted 4- to 7-membered heterocyclyl. More
preferably, it has from 1 to 3 substituents independently selected
from the group consisting of halogen, --OR.sup.7, .dbd.O,
--C(O)R.sup.7, --CO.sub.2R.sup.7, --CONR.sup.7R.sup.8,
--NR.sup.7C(O)R.sup.8, --NR.sup.7R.sup.8, --SR.sup.7,
--S(O)R.sup.7, --S(O).sub.2R.sup.7, --SO.sub.2NR.sup.7R.sup.8,
--NR.sup.7SO.sub.2R.sup.8, and 4- to 7-membered heterocyclyl.
[0243] When a substituent on Z is substituted phenyl, substituted
5- or 6-membered heteroaryl or substituted 4- to 7-membered
heterocyclyl, it have from 1 to 3 substituents independently
selected from the group consisting of halogen, --OR.sup.7, --CN,
--NO.sub.2, .dbd.O, --OC(O)R.sup.7, --CO.sub.2R.sup.7,
--C(O)R.sup.7, --CONR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.8,
--NR.sup.7R.sup.8, --SR.sup.7, --S(O)R.sup.7, --S(O).sub.2R.sup.7,
--NR.sup.7SO.sub.2R.sup.8, unsubstituted 4- to 7-membered
heterocyclyl, unsubstituted C.sub.1-8 alkyl and unsubstituted
C.sub.1-8 haloalkyl, with the proviso that if the suitable
substituent on residue Z is heterocyclic, substituents on this
heterocycle preferably do not include another heterocycle.
[0244] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted 5- to 10-membered heteroaryl, having 0
to 4 substituents as defined in formula (I).
[0245] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted 3- to 10-membered heterocycle, having
0 to 3 substituents as defined in formula (I).
[0246] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted 3- to 10-membered heterocycle selected
from the group consisting of pyrrolidine, piperidine,
imidazolidine, pyrazolidine, butyrolactam, valerolactam,
imidazolidinone, hydantoin, phthalimide, piperidine, 1,4-dioxane,
morpholine, thiomorpholine, thiomorpholine-S,S-dioxide, piperazine,
pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran,
and tetrahydrothiophene.
[0247] In one embodiment of any of formulae (I) and (II), Z is any
substituted or unsubstituted chemically allowed regioisomers of
pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like and their
respective N-oxides.
[0248] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted 2-pyridyl.
[0249] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted 2-pyridyl-N-oxide.
[0250] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted 3-pyridyl.
[0251] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted 3-pyridyl-N-oxide.
[0252] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted 4-pyridyl.
[0253] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted 4-pyridyl-N-oxide.
[0254] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted pyrazolyl.
[0255] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted imidazolyl.
[0256] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted thiazolyl.
[0257] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted triazolyl.
[0258] In one embodiment of any of formulae (I) and (II), Z is
pyridinyl with from 0 to 3 substituents; pyrimidinyl with from 0 to
3 substituents; pyrazinyl with from 0 to 3 substituents; or
pyridazinyl with from 0 to 3 substituents (especially, where one
ring nitrogen has a .dbd.O substituent).
[0259] In one embodiment of any of formulae (I) and (II), Z is
pyrazolyl with from 0 to 3 substituents; or imidazolyl with from 0
to 3 substituents, or thiazolyl with from 0 to 3 substituents, or
triazolyl with from 0 to 3 substituents.
[0260] In one embodiment in any of the formulae (I) and (II), Z is
substituted or unsubstituted 6-membered heteroaryl with 1 to 2
nitrogen atoms and with 0 to 2 substituents independently selected
from the group consisting of unsubstituted C.sub.1-6 alkyl, .dbd.O,
C.sub.1-6 haloalkyl, --COOH, --NO2, or --OR10. In this embodiment,
Z can be any chemically allowed regioisomer of pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl and the like, and their
respective N-oxides.
[0261] In one embodiment in any of the formulae (I) and (II), Z is
substituted or unsubstituted 6-membered heteroaryl with 1 to 2
nitrogen atoms and with 0 to 2 substituents independently selected
from the group consisting of --CH3, .dbd.O, --CF3, --OCH3. In this
embodiment, Z can be any chemically allowed regioisomer of pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl and the like, and their
respective N-oxides.
[0262] In one embodiment in any of the formulae (I) and (II), Z is
substituted or unsubstituted 6-membered heteroaryl with 1 to 2
nitrogen atoms and with 0 to 2 substituents independently selected
from the group consisting of halogen, substituted C.sub.1-6 alkyl
(but not C.sub.1-6 haloalkyl), unsubstituted or substituted
C.sub.1-6 alkenyl, unsubstituted or substituted C.sub.1-6 alkynyl,
.dbd.O, --CN, --C(O)R.sup.10, --C(O)NR.sup.10R.sup.11,
--NR.sup.10C(O)R.sup.11, --NR.sup.11R.sup.12, --SR.sup.o,
--S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.11R.sup.12--NR.sup.10S(O).sub.2R.sup.11,
--OC(O)R.sup.10, --CO.sub.2R.sup.10 (but not --CO.sub.2H),
--OC(O)NR.sup.11R.sup.12, --NR.sup.10C(O)NR.sup.11R.sup.12,
--NR.sup.10CO.sub.2R.sup.11, unsubstituted or substituted 5- or
6-membered heteroaryl and a unsubstituted or substituted 3- to
7-membered heterocyclyl. Preferred substituents include chlorine,
.dbd.O, --CN, --SCH.sub.3, --SO.sub.2CH.sub.3. In this embodiment,
Z can be any chemically allowed regioisomer of pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl and the like, and their
respective N-oxides.
[0263] In one embodiment in any of the formulae (I) and (II), at
least one substituent on the group Z is cyano.
[0264] In one embodiment in any of the formulae (I) and (II), at
least one substituent on the group Z is --S(O).sub.2R.sup.7. In one
particular embodiment, R.sup.7 is methyl.
[0265] In one embodiment in any of the formulae (I) and (II), at
least one substituent on the group Z is halogen, particularly
chlorine.
[0266] In one embodiment in any of the formulae (I) and (II), at
least one substituent on the group Z is --OR.sup.7. In one
particular embodiment, R.sup.7 is methyl.
[0267] In one embodiment in any of the formulae (I) and (II), at
least one substituent on the group Z is --SR.sup.7. In one
particular embodiment, R.sup.7 is methyl.
[0268] In one embodiment in any of the formulae (I) and (II), at
least one substituent on the group Z is unsubstituted C.sub.1-6
alkyl (in particular methyl) or C.sub.1-6 haloalkyl (in particular
--CF.sub.3).
[0269] In one embodiment in any of the formulae (I) and (II), at
least one substituent on the group Z is substituted C.sub.1-6 alkyl
(preferably not C.sub.1-6 haloalkyl).
[0270] In one embodiment in any of the formulae (I) and (II), no
substituents, except hydrogen, exist on the group Z.
[0271] In one embodiment in any of the formulae (I) and (II), Z is
a substituted or unsubstituted 6-membered heteroaryl with 1 to 2
nitrogen atoms and with 0 to 2 substituents independently selected
from the group consisting of halogen, substituted C.sub.1-6 alkyl
(but not C.sub.1-6 haloalkyl), unsubstituted or substituted
C.sub.1-6 alkenyl, unsubstituted or substituted C.sub.1-6 alkynyl,
.dbd.O, --CN, --C(O)R.sup.10, --C(O)NR.sup.10R.sup.11,
--NR.sup.10C(O)R.sup.11, --NR.sup.11R.sup.12, --SR.sup.10,
--S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.11R.sup.12--NR.sup.10S(O).sub.2R.sup.11,
--OC(O)R.sup.10, --CO.sub.2R.sup.10 (but not --CO.sub.2H),
--OC(O)NR.sup.11R.sup.12, --NR.sup.10C(O)NR.sup.11R.sup.12,
--NR.sup.10CO.sub.2R.sup.11, unsubstituted or substituted 5- or
6-membered heteroaryl and a unsubstituted or substituted 3- to
7-membered heterocyclyl. Preferred substituents include chlorine,
.dbd.O, --CN, --SCH.sub.3, --SO.sub.2CH.sub.3. In this embodiment,
Z can be any chemically allowed regioisomer of pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl and the like, and their
respective N-oxides.
[0272] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted C.sub.6-10 aryl or substituted or
unsubstituted 5- to 10-membered heteroaryl selected from pyridyl,
pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl,
quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,
benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,
benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl,
indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl,
pyrazolopyrimidinyl, imidazopyridines, benzothiazolyl,
benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl,
isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiadiazolyl, pyrrolyl, thiazolyl, furyl or thienyl.
[0273] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted heterocyclic ring system selected from
pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam,
valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide,
piperidine, 1,4-dioxane, morpholine, thiomorpholine,
thiomorpholine-5-oxide, thiomorpholine-S,S-dioxide, piperazine,
pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran or
tetrahydrothiophene. Preferably, Z is selected from substituted and
unsubstituted piperidine, substituted and unsubstituted piperazine,
and substituted and unsubstituted morpholine.
[0274] In one embodiment of any of formulae (I) and (II) when Z is
--NR.sup.7R.sup.8, R.sup.7 is hydrogen and R.sup.8 is preferably
selected from the group consisting of substituted or unsubstituted
C.sub.6-10 aryl, substituted or unsubstituted C.sub.1-8
alkyl(C.sub.1-6)aryl, substituted or unsubstituted C.sub.1-8
alkyl(5 to 10 membered)heteroaryl, and substituted or unsubstituted
5 to 10 membered heteroaryl.
[0275] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted 6-membered heteroaryl selected from
the group consisting of pyridyl, pyridazinyl, pyrazinyl,
pyrimidinyl, and triazinyl.
[0276] In one embodiment of any of formulae (I) and (II), Z is a
substituted or unsubstituted 5-membered heteroaryl selected from
the group consisting of isothiazolyl, pyrazolyl, imidazolyl,
thienyl, furyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiadiazolyl, pyrrolyl, and thiazolyl.
[0277] In one embodiment of any of formulae (I) and (II), Z is a
heterocycle selected from the group consisting of pyrrolidine,
piperidine, imidazolidine, pyrazolidine, butyrolactam,
valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide,
piperidine, 1,4-dioxane, morpholine, thiomorpholine,
thiomorpholine-5-oxide, thiomorpholine-S,S-dioxide, piperazine,
pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran,
and tetrahydrothiophene.
[0278] In one embodiment in any of the formulae (I) and (II), Z is
a heterocyclic group represented by formula (A) as defined in
paragraphs [0022], [0023], and [0024].
[0279] In one embodiment of each of the formulae (I) and (II), at
least one substituent on Z is a heterocyclyl selected from the
group including pyrrolidine, piperidine, imidazolidine,
pyrazolidine, butyrolactam, valerolactam, imidazolidinone,
hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane,
morpholine, thiomorpholine, thiomorpholine-5-oxide,
thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone,
3-pyrroline, thiopyran, pyrone, tetrahydrofuran, or
tetrahydrothiophene.
[0280] In other embodiments of each of the formulae (I) and (II),
when formula (A) is present, R.sup.20, R.sup.21, R.sup.22,
R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are independently
hydrogen or C.sub.1-4alkyl. In another preferred embodiment, at
least three of R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24,
R.sup.25, and R.sup.26 are hydrogen, j is 1 or 2, k is 1 or 2 with
the proviso that j+k is 3 or 4. In another preferred embodiments,
at least five of R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24,
R.sup.25, and R.sup.26 are hydrogen, j is 1 or 2, k is 1 or 2 with
the proviso that j+k is 3 or 4.
[0281] In one embodiment of any of formulae (I) and (II), Z is
monocyclic.
[0282] In one embodiment of any of the formulae (I) and (II),
heterocycle groups as substituents on Z are represented by formula
(A) as defined in [0022], [0023], and [0024].
[0283] In one embodiment of any of the formulae (I) and (II), at
least one substituent on the group Z is a heterocyclyl selected
from the group including pyrrolidine, piperidine, imidazolidine,
pyrazolidine, butyrolactam, valerolactam, imidazolidinone,
hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane,
morpholine, thiomorpholine, thiomorpholine-5-oxide,
thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone,
3-pyrroline, thiopyran, pyrone, tetrahydrofuran, and
tetrahydrothiophene.
[0284] In one embodiment of any of formulae (I) and (II), Z is the
following residue:
##STR00041##
[0285] In another embodiment of any of formulae (I) and (II), Z is
selected from one of the following residues:
##STR00042##
[0286] In another embodiment of any of formulae (I) and (II), Z is
selected from one of the following residues:
##STR00043##
[0287] In another embodiment of any of formulae (I) and (II), Z is
selected from one of the following residues:
##STR00044## ##STR00045##
[0288] In one embodiment of any of formulae (I) and (II), Z has one
or more substituents selected from the group consisting of:
##STR00046##
[0289] with the proviso that at least one substituent is other than
hydrogen. In another embodiment, all substituents on Z are
hydrogen.
[0290] In one embodiment of any of formulae (III-LXXV), Z',
Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c are independently selected
from the group consisting of hydrogen, halogen, substituted or
unsubstituted C.sub.1-8 alkyl, substituted or unsubstituted
C.sub.2-8 alkenyl, substituted or unsubstituted C.sub.2-8 alkynyl,
.dbd.O, --CN, --NO.sub.2, --OR.sup.10, --OC(O)R.sup.10,
--CO.sub.2R.sup.10, --C(O)R.sup.10, --C(O)NR.sup.11R.sup.12,
--NR.sup.10C(O)R.sup.11, --NR.sup.11R.sup.12, --SR.sup.10,
--S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.11R.sup.12, --NR.sup.10S(O).sub.2R.sup.11,
--OC(O)NR.sup.11R.sup.12, --NR.sup.10C(O)NR.sup.11R.sup.12,
substituted or unsubstituted phenyl, substituted or unsubstituted
5- or 6-membered heteroaryl, and substituted or unsubstituted 4- to
7-membered heterocyclyl. If present, one substituent is preferably
located ortho to one of the heteroatoms in the heteroaryl Z ring.
Alternatively, one substituent, .dbd.O, may be directly connected
to a ring heteroatom in the heteroaryl Z ring.
[0291] In one embodiment, any of formulae (III-LXXV), Z', Z.sup.1,
Z.sup.a, Z.sup.b and Z.sup.c are independently selected from the
group consisting of unsubstituted C.sub.1-6 alkyl (not -Me),
.dbd.O, C.sub.1-6 haloalkyl (not --CF.sub.3), --COOH, --NO.sub.2,
or --OR.sup.10 (not --OMe). In this embodiment, Z can be any
chemically allowed regioisomer of pyridyl, pyrimidinyl,
pyridazinyl, pyrazinyl and the like, and their respective
N-oxides.
[0292] In one embodiment, any of formulae (III-LXXV), Z', Z.sup.1,
Z.sup.a, Z.sup.b and Z.sup.c are independently selected from the
group consisting of --CH.sub.3, .dbd.O, --CF.sub.3, --OCH.sub.3. In
this embodiment, Z can be any chemically allowed regioisomer of
pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like, and
their respective N-oxides.
[0293] In one embodiment, any of formulae (III-LXXV), Z', Z.sup.1,
Z.sup.a, Z.sup.b and Z.sup.c are independently selected from the
group consisting of halogen, substituted C.sub.1-6 alkyl (but not
C.sub.1-6 haloalkyl), unsubstituted or substituted C.sub.1-6
alkenyl, unsubstituted or substituted C.sub.1-6 alkynyl, .dbd.O,
--CN, --C(O)R.sup.10, --C(O)NR.sup.10R.sup.11,
--NR.sup.10C(O)R.sup.11, --NR.sup.11R.sup.12, --SR.sup.10,
--S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.11R.sup.12--NR.sup.10S(O).sub.2R.sup.11,
--OC(O)R.sup.10, --CO.sub.2R.sup.10 (but not --CO.sub.2H),
--OC(O)NR.sup.11R.sup.12, --NR.sup.10C(O)NR.sup.11R.sup.12,
--NR.sup.10CO.sub.2R.sup.11, unsubstituted or substituted 5- or
6-membered heteroaryl and a unsubstituted or substituted 4- to
7-membered heterocyclyl. Preferred substituents include chlorine,
.dbd.O, --CN, --SCH.sub.3, --SO.sub.2CH.sub.3. In this embodiment,
Z can be any chemically allowed regioisomer of pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl and the like, and their
respective N-oxides.
[0294] In one embodiment in any of the formulae (III-LXXV), at
least one substituent Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is
cyano.
[0295] In one embodiment in any of the formulae (III-LXXV), at
least one substituent Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is
--S(O).sub.2R.sup.7. In one particular embodiment, R.sup.7 is
methyl.
[0296] In one embodiment in any of the formulae (III-LXXV), at
least one substituent Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is
halogen (in particular chlorine).
[0297] In one embodiment in any of the formulae (III-LXXV), at
least one substituent Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is
--OR.sup.7. In one particular embodiment, R.sup.7 is methyl.
[0298] In one embodiment in any of the formulae (III-LXXV), at
least one substituent Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is
--SR.sup.7. In one particular embodiment, R.sup.7 is methyl.
[0299] In one embodiment in any of the formulae (III-LXXV), at
least one substituent Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is
unsubstituted C.sub.1-6 alkyl (in particular methyl) or C.sub.1-6
haloalkyl (in particular --CF.sub.3).
[0300] In one embodiment in any of the formulae (III-LXXV), at
least one substituent Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is
substituted C.sub.1-6 alkyl (preferably not C.sub.1-6
haloalkyl).
[0301] In one embodiment in any of the formulae (III-LXXV), all
substituents Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c are
hydrogen.
[0302] In one embodiment of any of formulae (III-LXXV), where at
least one of Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c are a
substituted or unsubstituted 4- to 7-membered heterocycle, such
suitable heterocyclic groups are represented by formula (A) as
defined in [0022], [0023], and [0024]. Preferably, R.sup.20,
R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are
independently hydrogen or C.sub.1-4alkyl. In another preferred
embodiment, at least three of R.sup.20, R.sup.21, R.sup.22,
R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are hydrogen, j is 1 or
2, k is 1 or 2 with the proviso that j+k is 3 or 4. In another
preferred embodiments, at least five of R.sup.20, R.sup.21,
R.sup.22, R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are hydrogen,
j is 1 or 2, k is 1 or 2 with the proviso that j+k is 3 or 4.
[0303] In one embodiment of any of formulae (III-LXXV), at least
one of Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is a unsubstituted
or substituted heterocyclyl selected from the group including
pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam,
valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide,
piperidine, 1,4-dioxane, morpholine, thiomorpholine,
thiomorpholine-5-oxide, thiomorpholine-S,S-dioxide, piperazine,
pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran,
and tetrahydrothiophene.
[0304] In one embodiment of any of formulae (III-LXXV), at least
one of Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is a substituted
or unsubstituted 5- or 6-membered heteroaryl selected from the
group consisting of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,
triazinyl, isothiazolyl, pyrazolyl, imidazolyl, thienyl, furyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiadiazolyl, pyrrolyl, and thiazolyl.
[0305] In one embodiment of any of formulae (III-LXXV), when Z',
Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c are substituted C.sub.1-8
alkyl, substituted C.sub.2-8 alkenyl or substituted C.sub.2-8
alkynyl, it preferably has from 1 to 3 substituents independently
selected from the group consisting of halogen, --OH, --OR.sup.10,
.dbd.O, --CO.sub.2R.sup.10, --C(O)R.sup.10,
--C(O)NR.sup.11R.sup.12, --NR.sup.10C(O)R.sup.11,
--NR.sup.11R.sup.12, --SR.sup.10, --S(O)R.sup.10,
--S(O).sub.2R.sup.10, --NR.sup.10S(O).sub.2R.sup.11, substituted or
unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered
heteroaryl, and substituted or unsubstituted 4- to 7-membered
heterocyclyl. More preferably, it has from 1 to 3 substituents
independently selected from the group consisting of halogen, --OH,
--OR.sup.10, .dbd.O, --C(O)R.sup.10, --CO.sub.2R.sup.10,
--C(O)NR.sup.11R.sup.12, --NR.sup.10C(O)R.sup.11,
--NR.sup.11R.sup.12, --SR.sup.10, --S(O)R.sup.10,
--S(O).sub.2R.sup.10, --S(O).sub.2NR.sup.11R.sup.12,
--NR.sup.10S(O).sub.2R.sup.11, and 4- to 7-membered
heterocyclyl.
[0306] In one embodiment of each of the formulae (III-LXXV) when at
least one of Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is a
substituted C.sub.1-8 alkyl, at least one substituent is a
substituted or unsubstituted 4- to 7-membered heterocyclyl
represented by formula (A) as defined in [0022], [0023], and
[0024]. Preferably, R.sup.20, R.sup.21, R.sup.22, R.sup.23,
R.sup.24, R.sup.25, and R.sup.26 are independently hydrogen or
C.sub.1-4alkyl. In another preferred embodiment, at least three of
R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are hydrogen, j is 1 or 2, k is 1 or 2 with the proviso
that j+k is 3 or 4. In another preferred embodiments, at least five
of R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are hydrogen, j is 1 or 2, k is 1 or 2 with the proviso
that j+k is 3 or 4.
[0307] In one embodiment of each of the formulae (III-LXXV) when at
least one of Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is a
substituted C.sub.1-8 alkyl, at least one substituent is selected
from the group including pyrrolidine, piperidine, imidazolidine,
pyrazolidine, butyrolactam, valerolactam, imidazolidinone,
hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane,
morpholine, thiomorpholine, thiomorpholine-5-oxide,
thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone,
3-pyrroline, thiopyran, pyrone, tetrahydrofuran, and
tetrahydrothiophene.
[0308] In one embodiment of each of the formulae (III-LXXV) when at
least one of Z', Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is a
substituted C.sub.1-8 alkyl, at least one substituent is a
substituted or unsubstituted 5- or 6-membered heteroaryl selected
from the group consisting of pyridyl, pyridazinyl, pyrazinyl,
pyrimidinyl, triazinyl, isothiazolyl, pyrazolyl, imidazolyl,
thienyl, furyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiadiazolyl, pyrrolyl, and thiazolyl.
[0309] In one embodiment of the formulae (III-LXXV), Z', Z.sup.1,
Z.sup.a, Z.sup.b or Z.sup.c are selected from one of the following
residues
##STR00047##
with the proviso that at least one of Z', Z.sup.1, Z.sup.a, Z.sup.b
or Z.sup.c are other than hydrogen.
[0310] In one embodiment of the formulae (III-LXXV), Z', Z.sup.1,
Z.sup.a, Z.sup.b or Z.sup.c are each hydrogen.
[0311] In embodiments of the formulae (XVIII, XIX, XX), Z.sup.1,
Z.sup.a, Z.sup.b or Z.sup.c are selected such that the residue Z
(as defined for formula II) is:
##STR00048##
[0312] In embodiments of the formulae (XV-XVII, XXVI, XXV),
Z.sup.1, Z.sup.a, Z.sup.b or Z.sup.c are selected such that the
residue Z (as defined for formula II) is selected from the group
consisting of:
##STR00049##
[0313] In embodiments of the formulae (IX, X, XI, XV, XVI, XVII),
Z.sup.1, Z.sup.a, Z.sup.b or Z.sup.c are selected such that the
residue Z (as defined for formula II) is selected from the group
consisting of:
##STR00050##
[0314] In embodiments of the formulae (III, IV, V, VI, VII, IX, X,
XI, XII, XIII, XIV, XV, XVI, XVIII, XIX, XXII, XXIII, XXV, XL,
XLIII, L, LVI), Z.sup.1, Z.sup.a, Z.sup.b or Z.sup.c are selected
such that the residue Z (as defined for formula II) is selected
from the group consisting of:
##STR00051## ##STR00052##
[0315] In one embodiment of any of formulae (III-LXXV), when Z',
Z.sup.1, Z.sup.a, Z.sup.b and Z.sup.c is substituted heterocyclyl
or heteroaryl, it preferably has from 0 to 2 substituents
independently selected from the group consisting of substituted or
unsubstituted C.sub.1-8 alkyl, --OR.sup.10, --OH, --C(O)R.sup.10,
--C(O)NR.sup.11R.sup.12--NR.sup.11R.sup.12 and
--S(O).sub.2R.sup.10.
[0316] In one embodiment of any of formulae (I-LXXV), Z', Z.sup.1,
Z.sup.a, Z.sup.b, and Z.sup.c are each independently hydrogen,
halogen, --CN, --OR.sup.7, --NR.sup.7R.sup.8, --SR.sup.7 (e.g.,
thiomethyl), --SOR.sup.7, and --SO.sub.2R.sup.7 (e.g.,
methylsulfonyl), unsubstituted or substituted C.sub.1-6 alkoxyl
(e.g., methoxy), unsubstituted or substituted C.sub.1-6 alkyl
(e.g., methyl), unsubstituted or substituted phenyl, or
unsubstituted or substituted 5- or 6-membered heterocyclyl.
[0317] In one embodiment, compounds are represented by the formula
(LXXVI):
##STR00053##
where X represents OCF.sub.3, tert-butyl, ethyl, oxazole,
C(O)CH.sub.3, CN, fluorine, CF.sub.3, isopropoxy, isoamyl, or
hydroxybutyl.
[0318] In one embodiment, compounds are represented by the formula
(LXXVI):
##STR00054##
where X represents isopropyl.
[0319] In one embodiment, compounds are represented by the formula
(LXXVII):
##STR00055##
where X is OCF.sub.3, tert-butyl, ethyl, isopropyl, oxazole,
C(O)CH.sub.3, CN, fluorine, CF.sub.3, isopropoxy, isoamyl, or
hydroxybutyl. Compositions that Modulate CCR9 Activity
[0320] In another aspect, the present invention provides
compositions that modulate CCR9 activity. Generally, the
compositions for modulating chemokine receptor activity in humans
and animals will comprise a pharmaceutically acceptable excipient
or diluent and a compound having the formula provided above as
formula (I).
[0321] The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts. By "pharmaceutically acceptable" it is meant the
carrier, diluent or excipient must be compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof.
[0322] The pharmaceutical compositions for the administration of
the compounds of this invention may conveniently be presented in
unit dosage form and may be prepared by any of the methods well
known in the art of pharmacy. All methods include the step of
bringing the active ingredient into association with the carrier
which constitutes one or more accessory ingredients. In general,
the pharmaceutical compositions are prepared by uniformly and
intimately bringing the active ingredient into association with a
liquid carrier or a finely divided solid carrier or both, and then,
if necessary, shaping the product into the desired formulation. In
the pharmaceutical composition the active object compound is
included in an amount sufficient to produce the desired effect upon
the process or condition of diseases.
[0323] The pharmaceutical compositions containing the active
ingredient may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions and self emulsifications
as described in U.S. Patent Application 20020012680, hard or soft
capsules, or syrups or elixirs. Compositions intended for oral use
may be prepared according to any method known to the art for the
manufacture of pharmaceutical compositions. Such compositions may
contain one or more agents selected from sweetening agents,
flavoring agents, coloring agents and preserving agents in order to
provide pharmaceutically elegant and palatable preparations.
Tablets contain the active ingredient in admixture with other
non-toxic pharmaceutically acceptable excipients which are suitable
for the manufacture of tablets. These excipients may be, for
example, inert diluents such as cellulose, silicon dioxide,
aluminum oxide, calcium carbonate, sodium carbonate, glucose,
mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example PVP, cellulose, PEG,
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 enterically or otherwise 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. They
may also be coated by the techniques described in the U.S. Pat.
Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic
therapeutic tablets for control release.
[0324] Formulations for oral use may also be presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or as soft gelatin capsules where the active ingredient is
mixed with water or an oil medium, for example peanut oil, liquid
paraffin, or olive oil. Additionally, emulsions can be prepared
with a non-water miscible ingredient such as oils and stabilized
with surfactants such as mono-diglycerides, PEG esters and the
like.
[0325] 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,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents 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.
[0326] Oily suspensions may be formulated by suspending the active
ingredient 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 a palatable oral preparation. These compositions may be
preserved by the addition of an anti oxidant such as ascorbic
acid.
[0327] 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.
[0328] The pharmaceutical compositions of the invention may also be
in the form of oil in water 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.
[0329] 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. Oral solutions can be prepared in
combination with, for example, cyclodextrin, PEG and
surfactants.
[0330] The pharmaceutical compositions 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-butane diol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, axed 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.
[0331] The compounds of the present invention may also be
administered in the form of suppositories for rectal administration
of the drug. These compositions can be prepared by mixing the drug
with a suitable non-irritating excipient which 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. Additionally, the
compounds can be administered viaocular delivery by means of
solutions or ointments. Still further, transdermal delivery of the
subject compounds can be accomplished by means of iontophoretic
patches and the like.
[0332] For topical use, creams, ointments, jellies, solutions or
suspensions containing the compounds of the present invention are
employed. As used herein, topical application is also meant to
include the use of mouth washes and gargles.
[0333] The pharmaceutical compositions and methods of the present
invention may further comprise other therapeutically active
compounds as noted herein, such as those applied in the treatment
of the above mentioned pathological conditions.
Methods of Treating CCR9-mediated Conditions or Diseases
[0334] In yet another aspect, the present invention provides
methods of treating or preventing a CCR9-mediated condition or
disease by administering to a subject having such a condition or
disease a therapeutically effective amount of any compound of
formula (I) above. Compounds for use in the present methods include
those compounds according to formula (I), those provided above as
embodiments, those specifically exemplified in the Examples below,
and those provided with specific structures herein. The "subject"
is defined herein to include animals such as mammals, including,
but not limited to, primates (e.g., humans), cows, sheep, goats,
horses, dogs, cats, rabbits, rats, mice and the like. In preferred
embodiments, the subject is a human.
[0335] As used herein, the phrase "CCR9-mediated condition or
disease" and related phrases and terms refer to a condition or
disease characterized by inappropriate, i.e., less than or greater
than normal, CCR9 functional activity. Inappropriate CCR9
functional activity might arise as the result of CCR9 expression in
cells which normally do not express CCR9, increased CCR9 expression
(leading to, e.g., inflammatory and immunoregulatory disorders and
diseases) or decreased CCR9 expression. Inappropriate CCR9
functional activity might also arise as the result of TECK
secretion by cells which normally do not secrete TECK, increased
TECK expression (leading to, e.g., inflammatory and
immunoregulatory disorders and diseases) or decreased TECK
expression. A CCR9-mediated condition or disease may be completely
or partially mediated by inappropriate CCR9 functional activity.
However, a CCR9-mediated condition or disease is one in which
modulation of CCR9 results in some effect on the underlying
condition or disease (e.g., a CCR9 antagonist results in some
improvement in patient well being in at least some patients).
[0336] The term "therapeutically effective amount" means the amount
of the subject compound that will elicit the biological or medical
response of a cell, tissue, system, or animal, such as a human,
that is being sought by the researcher, veterinarian, medical
doctor or other treatment provider.
[0337] Diseases and conditions associated with inflammation, immune
disorders, infection and cancer can be treated or prevented with
the present compounds, compositions, and methods. In one group of
embodiments, diseases or conditions, including chronic diseases, of
humans or other species can be treated with inhibitors of CCR9
function. These diseases or conditions include: (1) allergic
diseases such as systemic anaphylaxis or hypersensitivity
responses, drug allergies, insect sting allergies and food
allergies, (2) inflammatory bowel diseases, such as Crohn's
disease, ulcerative colitis, ileitis and enteritis, (3) vaginitis,
(4) psoriasis and inflammatory dermatoses such as dermatitis,
eczema, atopic dermatitis, allergic contact dermatitis, urticaria
and pruritus, (5) vasculitis, (6) spondyloarthropathies, (7)
scleroderma, (8) asthma and respiratory allergic diseases such as
allergic asthma, allergic rhinitis, hypersensitivity lung diseases
and the like, (9) autoimmune diseases, such as fibromyalagia,
scleroderma, ankylosing spondylitis, juvenile RA, Still's disease,
polyarticular juvenile RA, pauciarticular juvenile RA, polymyalgia
rheumatica, rheumatoid arthritis, psoriatic arthritis,
osteoarthritis, polyarticular arthritis, multiple sclerosis,
systemic lupus erythematosus, type I diabetes, type II diabetes,
glomerulonephritis, and the like, (10) graft rejection (including
allograft rejection), (11) graft-v-host disease (including both
acute and chronic), (12) other diseases in which undesired
inflammatory responses are to be inhibited, such as
atherosclerosis, myositis, neurodegenerative diseases (e.g.,
Alzheimer's disease), encephalitis, meningitis, hepatitis,
nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis,
chronic obstructive pulmonary disease, sinusitis, Behcet's syndrome
and gout, (13) immune mediated food allergies such as Coeliac
(Celiac) disease (14) pulmonary fibrosis and other fibrotic
diseases, and (15) irritable bowel syndrome.
[0338] In another group of embodiments, diseases or conditions can
be treated with modulators and agonists of CCR9 function. Examples
of diseases to be treated by modulating CCR9 function include
cancers, cardiovascular diseases, diseases in which angiogenesis or
neovascularization play a role (neoplastic diseases, retinopathy
and macular degeneration), infectious diseases (viral infections,
e.g., HIV infection, and bacterial infections) and
immunosuppressive diseases such as organ transplant conditions and
skin transplant conditions. The term "organ transplant conditions"
is means to include bone marrow transplant conditions and solid
organ (e.g., kidney, liver, lung, heart, pancreas or combination
thereof) transplant conditions.
[0339] Preferably, the present methods are directed to the
treatment of diseases or conditions selected from inflammatory
bowel disease including Crohn's disease and Ulcerative Colitis,
allergic diseases, psoriasis, atopic dermatitis and asthma,
autoimmune disease such as rheumatoid arthritis and immune-mediated
food allergies such as Coelaic disease.
[0340] Depending on the disease to be treated and the subject's
condition, the compounds and compositions of the present invention
may be administered by oral, parenteral (e.g., intramuscular,
intraperitoneal, intravenous, ICV, intracisternal injection or
infusion, subcutaneous injection, or implant), inhalation, nasal,
vaginal, rectal, sublingual, or topical routes of administration
and may be formulated, alone or together, in suitable dosage unit
formulations containing conventional non toxic pharmaceutically
acceptable carriers, adjuvants and vehicles appropriate for each
rouse of administration. The present invention also contemplates
administration of the compounds and compositions of the present
invention in a depot formulation.
[0341] In the treatment or prevention of conditions which require
chemokine receptor modulation an appropriate dosage level will
generally be about 0.001 to 100 mg per kg patient body weight per
day which can be administered in single or multiple doses.
Preferably, the dosage level will be about 0.01 to about 25 mg/kg
per day; more preferably about 0.05 to about 10 mg/kg per day. A
suitable dosage level may be about 0.01 to 25 mg/kg per day, about
0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within
this range the dosage may be 0.005 to 0.05, 0.05 to 0.5, 0.5 to
5.0, or 5.0 to 50 mg/kg per day. For oral administration, the
compositions are preferably provided in the form of tablets
containing 1.0 to 1000 milligrams of the active ingredient,
particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0,
150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0,
900.0, and 1000.0 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated.
The compounds may be administered on a regimen of 1 to 4 times per
day, preferably once or twice per day.
[0342] It will be understood, however, that the specific dose level
and frequency of dosage for any particular patient may be varied
and will depend upon a variety of factors including the activity of
the specific compound employed, the metabolic stability and length
of action of that compound, the age, body weight, hereditary
characteristics, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity
of the particular condition, and the host undergoing therapy.
[0343] In still other embodiments, the present methods are directed
to the treatment of allergic diseases, where a compound or
composition of the invention is administered either alone or in
combination with a second therapeutic agent, where said second
therapeutic agent is an antihistamine. When used in combination,
the practitioner can administer a combination of the compound or
composition of the present invention and a second therapeutic
agent. Also, the compound or composition and the second therapeutic
agent can be administered sequentially, in any order.
[0344] In yet other embodiments, the present methods are directed
to the treatment of psoriasis where a compound or composition of
the invention is used alone or in combination with a second
therapeutic agent such as a corticosteroid, a lubricant, a
keratolytic agent, a vitamin D.sub.3 derivative, PUVA and
anthralin.
[0345] In other embodiments, the present methods are directed to
the treatment of atopic dermatitis using a compound or composition
of the invention either alone or in combination with a second
therapeutic agent such as a lubricant and a corticosteroid.
[0346] In further embodiments, the present methods are directed to
the treatment of asthma using a compound or composition of the
invention either alone or in combination with a second therapeutic
agent such as a .beta.2-agonist and a corticosteroid.
[0347] The compounds and compositions of the present invention can
be combined with other compounds and compositions having related
utilities to prevent and treat the condition or disease of
interest, such as inflammatory conditions and diseases, including
inflammatory bowel disease, allergic diseases, psoriasis, atopic
dermatitis and asthma, and those pathologies noted above. Selection
of the appropriate agents for use in combination therapies can be
made one of ordinary skill in the art. The combination of
therapeutic agents may act synergistically to effect the treatment
or prevention of the various disorders. Using this approach, one
may be able to achieve therapeutic efficacy with lower dosages of
each agent, thus reducing the potential for adverse side
effects.
[0348] The weight ratio of the compound of the present invention to
the second active ingredient may be varied and will depend upon the
effective dose of each ingredient. Generally, an effective dose of
each will be used. Thus, for example, when a compound of the
present invention is combined with an NSAID the weight ratio of the
compound of the present invention to the NSAID will generally range
from about 1000:1 to about 1:1000, preferably about 200:1 to about
1:200. Combinations of a compound of the present invention and
other active ingredients will generally also be within the
aforementioned range, but in each case, an effective dose of each
active ingredient should be used.
EXAMPLES
[0349] Reagents and solvents used below can be obtained from
commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis.,
USA). .sup.1H-NMR were recorded on a Varian Mercury 400 MHz NMR
spectrometer. Significant peaks are tabulated in the order:
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet) and number of protons. Mass spectrometry results are
reported as the ratio of mass over charge, followed by the relative
abundance of each ion (in parenthesis). In tables, a single m/e
value is reported for the M+H (or, as noted, M-H) ion containing
the most common atomic isotopes. Isotope patterns correspond to the
expected formula in all cases. Electrospray ionization (ESI) mass
spectrometry analysis was conducted on a Hewlett-Packard MSD
electrospray mass spectrometer using the HP1100 HPLC for sample
delivery. Normally the analyte was dissolved in methanol at 0.1
mg/mL and 1 microlitre was infused with the delivery solvent into
the mass spectrometer, which scanned from 100 to 1500 daltons. All
compounds could be analyzed in the positive ESI mode, using
acetonitrile/water with 1% formic acid as the delivery solvent. The
compounds provided below could also be analyzed in the negative ESI
mode, using 2 mM NH.sub.4OAc in acetonitrile/water as delivery
system.
[0350] Compounds within the scope of this invention can be
synthesized as described below, using a variety of reactions known
to the skilled artisan. A sample of useful routes to both the
benzophenone and heteroaryl derived subunits and to fully
elaborated sulfonamide molecules of formula (I) within this claim
are provided below. In the descriptions of the syntheses that
follow, some precursors were obtained from commercial sources.
These commercial sources include Aldrich Chemical Co., Acros
Organics, Ryan Scientific Incorporated, Oakwood Products
Incorporated, Lancaster Chemicals, Sigma Chemical Co., Lancaster
Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, and GFS
Chemicals.
[0351] Compounds of the invention can be prepared using
conventional synthetic methodology. Examples of approaches that may
be taken to synthesize these compounds are shown below.
Nonetheless, one skilled in the art will recognize that alternative
methods may be employed to synthesize the target compounds of this
invention, and that the approaches described within the body of
this document are not exhaustive, but do provide broadly applicable
and practical routes to compounds of interest.
[0352] Certain molecules claimed in this patent can exist in
different enantiomeric and diastereomeric forms and all such
variants of these compounds are within the scope of the
invention.
[0353] The detailed description of the experimental procedures used
to synthesize key compounds in this text lead to molecules that are
described by the physical data identifying them as well as by the
structural depictions associated with them.
[0354] Those skilled in the art will also recognize that during
standard work up procedures in organic chemistry, acids and bases
are frequently used. Salts of the parent compounds are sometimes
produced, if they possess the necessary intrinsic acidity or
basicity, during the experimental procedures described within this
patent.
Preparation of CCR9 Modulators
[0355] The following examples are offered to illustrate, but not to
limit, the claimed invention.
[0356] Additionally, those skilled in the art will recognize that
the molecules claimed in this patent may be synthesized using a
variety of standard organic chemistry transformations.
[0357] Certain general reaction types employed widely to synthesize
target compounds in this invention are summarized in the examples.
Specifically, generic procedures for sulfonamide formation,
pyridine N-oxide formation and 2-aminophenyl-arylmethanone
synthesis via Friedel-Crafts type approaches are given, but
numerous other standard chemistries are described within and were
employed routinely.
[0358] While not intended to be exhaustive, representative
synthetic organic transformations which can be used to prepare
compounds of the invention are included below.
[0359] These representative transformations include; standard
functional group manipulations; reduction such as nitro to amino;
oxidations of functional groups including alcohols and pyridines;
aryl substitutions via IPSO or other mechanisms for the
introduction of a variety of groups including nitrile, methyl and
halogen; protecting group introductions and removals; Grignard
formation and reaction with an electrophile; metal-mediated cross
couplings including but not limited to Buckvald, Suzuki and
Sonigashira reactions; halogenations and other electrophilic
aromatic substitution reactions; diazonium salt formations and
reactions of these species; etherifications; cyclative
condensations, dehydrations, oxidations and reductions leading to
heteroaryl groups; aryl metallations and transmetallations and
reaction of the ensuing aryl-metal species with an electrophile
such as an acid chloride or Weinreb amide; amidations;
esterifications; nuclephilic substitution reactions; alkylations;
acylations; sulfonamide formation; chlorosulfonylations; ester and
related hydrolyses, and the like.
[0360] Compounds of the invention, including those listed in the
table of activities, can be made by the methods and approaches
described in the following experimental section and by the use of
standard organic chemistry transformations well known to those
skilled in the art.
[0361] The following general procedures summarize methodologies
frequently utilized to synthesize the intermediates and compounds
of the invention. Specific examples of the use of these general
methodologies is given in the detailed experimental sections for
individual compounds.
[0362] Additionally, various organic chemistry transformations are
described, as they relate to the synthesis of specific compounds of
the invention. These specific synthetic approaches and
methodologies can also be applied, in a general sense, to access
general classes of compounds claimed in this invention.
[0363] Additionally, it is envisaged that many standard organic
chemistry transformations, well known to those skilled in the art,
including but not limited to those outlined previously in the
introductory comments section to the preparation of CCR9
modulators, can be applied to enable the synthesis of broad classes
of compounds and intermediates of the invention.
General Procedure for the Preparation of
N-Aryl-benzenesulfonamides
##STR00056##
[0365] To the desired aniline (0.5 mmol) dissolved in pyridine and
cooled in an ice-water bath was added a solution of an aryl
sulfonyl chloride (0.5 mmol) dissolved in cold pyridine. The
reaction mixture was then heated to 60.degree. C. with gentle
shaking for 16 h. Evaporation of the solvent with standard workup
followed by either flash chromatography or reversed phase HPLC
yielded the corresponding N-aryl-benzenesulfonamides.
General Procedure for the Synthesis of
(2-Amino-phenyl)-pyridinyl-methanones and
(2-Amino-phenyl)-heteroaryl-methanones
##STR00057##
[0367] To 12.5 mL 1 M BCl.sub.3 (12 mmol, 1.2 eq.) in methylene
chloride stirred at 0.degree. C. was added a solution of the
desired haloaniline (10 mmol, 1.0 eq.) in 15 mL of TCE drop wise
over 20 minutes. After 10 minutes the desired cyanopyridine (11
mmol, 1.1 eq.) was added followed by AlCl.sub.3 (15 mmol, 1.5 eq.).
The reaction was brought to RT, stirred for an hour then heated at
80-90.degree. C. until all of the DCM was distilled off. The
reaction mixture was then refluxed at 160.degree. C. for 4 hours,
cooled to RT and stirred overnight. 10 mL 3 M HCl were carefully
added and the mixture was refluxed at 120.degree. C. for 2-3 hours
while reaction progress was monitored by LC/MS. The crude reaction
was cooled to RT and 100 mL water were added. The crude mixture was
extracted with DCM (2.times.50 mL), the aqueous layer was set aside
and the organic layer was back extracted with 50 mL 1 M HCl (aq.).
All aqueous layers were combined, brought to pH 12 with 3 M NaOH
(aq.) and extracted with DCM (4.times.50 mL). The DCM layer was
dried on Na.sub.2SO.sub.4, filtered and concentrated by rotary
evaporation. The crude product was washed liberally with Et.sub.2O
and dried under vacuum, and further purified by conventional
techniques such as column chromatography when necessary.
Alternate General Procedure (2) for the Synthesis of
(2-Amino-phenyl)-pyridinyl-methanones and
(2-Amino-phenyl)-heteroaryl-methanones
##STR00058##
[0369] To a solution of desired aniline (40 mmol) in 25 mL pyridine
was added 5.3 mL (43.1 mmol) of pivaloyl chloride and the reaction
mixture stirred overnight at room temperature. The mixture was
poured into vigorously stirring 6M HCl, and the solids were
collected by vacuum filtration, washed well with H.sub.2O, and
dried in vacuo.
[0370] 2,2-dimethyl propanamide protected aniline (0.0095 mol) in
dry THF (40 ml) was cooled to -5.degree. C. n-Butyl lithium (24 ml,
1.2 M, 0.0284 mol) was added dropwise and the reaction stirred at
the same temperature for 2 h. The reaction mixture was cooled to
-70.degree. C. and to this was added the desired aryl or heteroaryl
carboxylic acid (0.0142 mol), dissolved in dry THF (10 ml),
dropwise. The mixture was stirred at room temperature for 18 h,
quenched with water and extracted with ethyl acetate. The extract
was washed with brine solution and concentrated. The product was
purified by column using 5-10% of ethyl acetate in pet ether as
eluent.
[0371] Removal of the pivaloyl protecting group form the amino
ketone (0.4 g, 0.0013 mol) in 2 ml of methanol was effected via
addition of potassium hydroxide (0.48 g, 0.00857 mol) in 1.2 ml of
water. The reaction mixture was heated at 70.degree. C. for 6 h,
diluted with water and extracted with ethyl acetate. The extract
was washed with water, brine and concentrated. The crude material
was purified by column chromatography.
[0372] Alternatively, 6N HCl (10 ml) and intermediate pivaloyl
protected aminoketone (1.2 g, 3.755 mmol) were heated at 90.degree.
C. overnight, cooled to room temperature, the reaction mixture
basified by adding saturated sodium bicarbonate solution and
extracted with ether. The organic layer was washed with brine,
dried over sodium sulfate and concentrated. The product was
purified by column chromatography.
Alternate General Procedure (3) for the Synthesis of
(2-Amino-phenyl)-pyridinyl-methanones and
(2-Amino-phenyl)-heteroaryl-methanones
##STR00059##
[0374] Trimethylacetyl chloride was added drop wise to a solution
of desired aniline in dry pyridine and the reaction was stirred
under nitrogen overnight. About half of the pyridine was removed by
rotary evaporation, then the mixture was treated with 6M
hydrochloric acid and extracted with ethyl acetate. The extracts
were washed with saturated aqueous NaHCO.sub.3 and with water, then
were dried (MgSO.sub.4), filtered and concentrated by rotary
evaporation.
[0375] EDC and desired heteroaryl carboxylic acid were stirred in
acetonitrile-THF with N,O-dimethylhydroxylamine hydrochloride and
triethylamine. After stirring overnight at ambient temperature, the
resulting reaction mixture was added to ice water and extracted
with ethyl acetate (3.times.100 mL). The extracts were dried,
filtered, and concentrated.
[0376] To a stirred solution of the pivaloyl protected intermediate
in dry THF was added 2.5M n-butyllithium in hexane at -40.degree.
C. and the mixture was stirred at 0.degree. C. for 2 h. A solution
of the Weinreb amide in dry THF was added dropwise and the reaction
was stirred at ambient temp overnight. The mixture was diluted with
water and extracted with ethyl acetate and the organic layer was
dried (MgSO.sub.4), filtered and concentrated, to yield, after
purification by HPLC or column chromatography, the pivaloyl
protected aminoketone intermediate.
[0377] Deprotection with 70% sulfuric acid was carried out at
75.degree. C. and progress monitored by LC/MS. The reaction was
allowed to cool to ambient temperature, and was washed with
ether-hexane. The acidic aqueous layer was cooled in an ice bath
and aqueous NaOH was added drop wise to basify the mixture. The
product was extracted with ethyl acetate and the extracts were
washed with saturated aqueous NaHCO3 (2.times.100 mL), with
saturated aqueous sodium chloride, dried (MgSO.sub.4), filtered and
concentrated, yielding the desired
(2-Amino-phenyl)-heteroaryl-methanone.
General Procedure for the Synthesis of Sulfonamide
Pyridine-N-Oxides
##STR00060##
[0379] The desired N-Aryl-benzenesulfonamide (250 .mu.mol) was
dissolved in 2 mL DCM and m-CPBA (1.0-1.5 eq) was then added. The
reaction was shaken at RT and monitored by LC-MS. Additional m-CPBA
was added as needed in aliquots until the reaction was complete. In
most cases the reaction required 15-24 h r.times.n time. Standard
workup led to the isolation of crude products, which were purified
by column chromatography.
General Procedure for the Synthesis of Substituted Phenyl Sulfonyl
Chlorides Via Chlorosulfonation
##STR00061##
[0381] The desired benzene derivative (1.4 mmol) was dissolved in
CHCl.sub.3 (15 mL) at 0.degree. C., and to this was added
chlorosulfonic acid (4.2 mmol). After 30 minutes, the reaction
mixture was warmed to room temperature, and additional
chlorosulfonic acid (4.2 mmol) was added. After a further hour, the
reaction mixture was cooled to 0.degree. C., and crushed ice added
to the reaction. The reaction mixture was partitioned between 1M
pH7 phosphate buffer and ether, and the ether layer washed with
saturated aqueous NaCl, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo to yield crude product.
General Procedure for the Synthesis of Substituted Phenyl Sulfonyl
Chlorides Via Diazonium Salt Intermediates
##STR00062##
[0383] The desired aniline (0.0848 mol) was added slowly to
concentrated HCl (109.2 ml), the reaction stirred at room
temperature for 15 min, then cooled to 0.degree. C., sodium nitrite
(6.2 g, 0.1103 mol in 26 ml of water) added dropwise and the
reaction stirred for 15 min.
[0384] Separately, distilled water (0.198 ml) was cooled to
0.degree. C. and thionyl chloride (42.9 g, 0.3605 mol) was added
dropwise, the mixture warmed to and stirred at room temperature for
17 h, then re-cooled to 0.degree. C., and copper (I) chloride
(0.120 g) added in small portions with further stirring for 30 mins
to yield a yellowish green solution (Solution A).
[0385] This Cu(I) solution (A) was added dropwise to the
aniline/HCl solution at -5.degree. C., and stirring continued at
0.degree. C. for 75 min. The reaction mixture was diluted with
chloroform. The organic layer was separated, washed with brine,
dried over sodium sulphate and concentrated in vacuo.
General Procedure for the Synthesis of Heterocyclyl Substituted
Phenylsulfonyl Derivatives
##STR00063##
[0387] The desired bromobenzenesulfonamide derivative (0.22 mmol)
was dissolved in 6 ml anhydrous dioxane, and to this solution was
added potassium phosphate tribasic monohydrate (1.32 mmol),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.032 mmol),
followed by the desired heterocycle (1.1 mmol). The mixture was
purged under nitrogen, and Pd (dba).sub.3 (0.01 mmol) was added.
The reaction mixture was heated overnight at 90.degree. C., cooled,
water (5 mL) added, and extracted with ethyl acetate 3 times. The
combined organic layer was washed with brine, dried over magnesium
sulfate, filtered and concentrated. The crude reaction mixture was
purified using HPLC.
General Procedure for the Synthesis of Heteroaryl Substituted
Phenylsulfonyl Derivatives
##STR00064##
[0389] The desired bromobenzenesulfonamide derivative (0.25 g, 0.55
mmol) was dissolved in 2.5 ml of anhydrous dimethylformamide. To
this solution was added 0.14 g (1.3 mmol) sodium carbonate,
suitable heteroaryl-3-boronic acid (0.68 mmol), and
Pd(PPh.sub.3).sub.4 19 mg (0.014 mmol). The reaction mixture was
heated overnight at 80.degree. C. under a nitrogen atmosphere. The
mixture was quenched with water and extracted 3 times with
dichloromethane. The organic layer was dried over magnesium
sulfate, filtered, and concentrated, and the crude product purified
by flash column chromatography.
Examples of Alternate Approaches Towards the Syntheses of
Functionalized Alkyl Phenyl Sulfonyl Chlorides and Alkylsulfonyl
Phenyl Sulfonyl Chlorides
##STR00065## ##STR00066##
[0390] Examples of alternate approaches towards the synthesis of
(2-Amino-phenyl)-heteroaryl-methanones
##STR00067## ##STR00068## ##STR00069##
[0391] Syntheses of (2-Amino-phenyl)-pyridinyl-methanones and
(2-Amino-phenyl)-heteroaryl-methanones
Synthesis of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone
##STR00070##
[0393] A solution of 4-chloroaniline (2.0 g, 16 mmol) in 30 mL of
TCE was added drop wise to a solution of BCl.sub.3 (1M in DCM) (24
ml, 24 mmol) with ice bath cooling, over a period of 15 min and the
reaction mixture stirred at that temperature for an additional 10
min. 4-Cyanopyridine (2.0 g, 19 mmol) and AlCl.sub.3 (3.0 g, 22
mmol) were added with ice-water cooling. The solution was allowed
to warm to room temperature and stirred for 30 min. The resulting
solution was refluxed at 160.degree. C. for 4 h and stirred at room
temperature overnight. The reaction mixture was then treated with
30 mL of 3N HCl and the mixture was refluxed at 110.degree. C. for
1.5 h. The reaction mixture was allowed to cool down to room
temperature and the solution was adjusted to pH12 with 6N NaOH and
then diluted water and DCM. The resulting two layers were separated
and the aqueous layer was extracted with DCM three times and the
organic layers combined and dried over sodium sulfate. After
removal of the solvent, the resulting solid was washed with ether
to yield (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone (2.8 g,
75%).
Synthesis of (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)
methanone
##STR00071##
[0395] To 20 mL 1M BCl3 (20 mmol, 2.3 eq.) in DCM stirred at
0.degree. C. was added a solution of 1.1 g 4-chloroaniline (8.6
mmol, 1.0 eq.) in 15 mL of TCE drop wise over five minutes. After
10 minutes 1.1 g of 2-cyano-6-methylpyridine (1.1 eq.) were added
to the reaction mixture and after 2 minutes 1.6 g AlCl.sub.3 (12
mmol, 1.4 eq.) was added. After 5 minutes the reaction was brought
to RT, stirred for an hour then heated at 160.degree. C. for 17
hours. 100 mL 3M HCl were added and the reaction is monitored by
LC/MS. After 6 hours the reaction was removed from heat, cooled to
RT and 300 mL water were added. The crude mixture was extracted
with DCM (1.times.500 mL), the aqueous layer was set aside and the
organic layer was back extracted with 300 mL 3M HCl (aq.). All
aqueous layers were combined, brought to pH 11 with 3M NaOH (aq.)
and extracted with DCM. The DCM layer was dried on
Na.sub.2SO.sub.4, filtered and concentrated by rotary evaporation.
Preparatory chromatography afforded the product as a cream colored
solid which was converted to its HCl salt before being
characterized. .sup.1H NMR: .delta. (ppm): 2.83 (s, 3H), 7.32 (d,
J=2.0 Hz, 1H), 7.34 (d, J=1.6 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H),
7.82-7.85 (m, 2H), 7.99 (t, J=7.6 Hz, H), 8.27 (d, J=7.6 Hz, 1H),
10.83 (s, 1H). MS: (M+H)/z=247.0
Synthesis of
(5-chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanol
##STR00072##
[0397] A solution of 1.0 g 2-chloro-5-iodopyridine (4.1 mmol, 1.0
eq.) in 10 mL anhyd. THF was stirred at -40.degree. C. to
-50.degree. C. After five minutes, 2.2 mL of 2.1 M .sup.iPrMgBr/THF
(4.6 mmol, 1.1 eq.) were added drop wise over 1 minute and the
reaction mixture is maintained at -40 to -50.degree. C. for 30
minutes. 1.3 g 2-nitro-5-chlorobenzaldehyde (7.0 mmol, 1.7 eq.) was
then added and the reaction was maintained at -50.degree. C. After
1 hour, the reaction was allowed to warm to -10.degree. C., and
quenched with 50 mL saturated brine after a further fifteen
minutes. The crude product was extracted with EtOAc, dried on
Na.sub.2SO.sub.4 and concentrated by rotary evaporation to yield
desired product. MS: (M+H)/z=298.9
Synthesis of
(5-Chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanone
##STR00073##
[0399] To
(5-Chloro-2-nitro-phenyl)-(6-chloro-pyridin-3-yl)-methanol was
added an excess (ca. 2 eq.) of PDC in DCM. The suspension was
shaken at room temperature overnight. The reaction was monitored by
LC-MS, another 1-2 eq. of PDC was added and the reaction was shaken
for another 6 hours. The crude product was filtered through Celite
and purified by flash chromatography (silica gel, DCM). .sup.1H NMR
(CDCl.sub.3): .delta. (ppm): 7.50 (d, J=2.4 Hz, 1H), 7.79 (d, J=8.0
Hz, 1H), 7.68 & 7.70 (dd, J=8.8 Hz, 2.0 Hz, 1H), 8.09-8.11 (m,
1H), 8.24 (d, J=8.8 Hz, 1H), 8.57 (d, J=2.0 Hz, 1H. MS:
(M+H)/z=296.9
Synthesis of
(2-Amino-5-chloro-phenyl)-(6-chloro-pyridin-3-yl)-methanone
##STR00074##
[0401] 3-(5-chloro-2-nitrophenyl)-pyridinylmethanone was added to a
mixture of concentrated HCl, DMF, SnCl.sub.2 and heated at
130.degree. C. The reaction was monitored by LC/MS and removed from
heat after 2 h. The crude reaction was treated with aq.
K.sub.2CO.sub.3, extracted into DCM and concentrated by rotary
evaporation. The crude product was purified by preparatory
chromatography. MS: (M+H)/z=267.0
Synthesis of N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide
##STR00075##
[0403] To a solution of 4-chloroaniline (5.0 g, 39.2 mmol) in 25 mL
pyridine was added 5.3 mL (43.1 mmol) of pivaloyl chloride and the
reaction mixture stirred overnight at room temperature. The mixture
was poured into vigorously stirring 6M HCl, and the solids were
collected by vacuum filtration, washed well with H.sub.2O, and
dried in vacuo to yield the title compound. 1H NMR (CDCl3) .delta.
7.47 (d, J=9.2 Hz, 2H) 7.30 (s, 1H) 7.27 (d, J=8.8 Hz, 2H) 1.32 (s,
9H) MS (ES) m/z=212.1
Synthesis of
N-[4-chloro-2-(hydroxy-pyridin-3-yl-methyl)-phenyl]-2,2-dimethyl-propiona-
mide
##STR00076##
[0405] N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide (3.0, 14.2
mmol) was dissolved in 15 mL THF in a dry 100 mL flask fitted with
a rubber septa and nitrogen inlet and cooled to 0.degree. C. in ice
water bath for 25 minutes. A solution of 2.5M BuLi in hexane (17.0
mL, 42.6 mmol) was added and the mixture stirred for 45 minutes. To
the thick yellow precipitate that formed was added a solution of
pyridine-3-carboxaldehyde (3.03 g, 28.4 mmol) in 15 mL THF. The ice
bath was removed and the mixture was allowed to stir at room
temperature for 45 minutes and the reaction was quenched with 25 mL
H.sub.2O. The mixture was transferred to a separating funnel, and
the aqueous phase was discarded. The organics were dried in vacuo
to yield product as an orange oil. 1H NMR (CDCl3) .delta. 8.85 (m,
1H) 8.54 (m, 1H) 8.42 (m, 1H) 8.10 (dd, J=8.8 Hz, 2.8 Hz, 1H) 7.50
(d, J=8.0 Hz, 1H) 7.31 (m, 1H) 7.23 (m, 1H) 7.10 (m, 1H) 5.85 (m,
1H) 1.70 (d, 1H) 1.08 (s, 9H); MS (ES) m/z=319.1 (MH).sup.+
Synthesis of
N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionamide
##STR00077##
[0407]
N-[4-chloro-2-(hydroxy-pyridin-3-yl-methyl)-phenyl]-2,2-dimethyl-pr-
opionamide (1.0 g, 3.14 mmol) was dissolved in 5 mL pyridine and
treated with CrO.sub.3 (0.75 g, 7.5 mmol, 2.39 eq). The mixture was
stirred under N.sub.2 at room temperature for five hours, diluted
with 20 mL 1:2 EtOAc/H.sub.2O, and filtered through Celite. The
aqueous phase was separated and discarded, then the organics dried
under vacuum yielding product (680 mg, 70%). 1H NMR (CDCl3) .delta.
11.06 (s, 1H) 8.92 (d, J=2.4 Hz, 1H) 8.84 (d, J=8.0 Hz, 1H) 8.73
(d, J=9.2 Hz, 1H) 8.00 (d, J=8.0 Hz, 1H) 7.56 (dd, J=11.2 Hz, 2.0
Hz, 1H) 7.48 (m, 2H) 1.36 (s, 9H) MS (ES) m/z=317.1 (MH).sup.+
Synthesis of (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone
##STR00078##
[0409]
N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionami-
de (0.65 g) was suspended in 5 mL of 70% H.sub.2SO.sub.4 and heated
at 95.degree. C. in oil bath overnight. After cooling to room
temperature the solution was added drop wise with stirring to 20 mL
of 40% NaOH solution placed in an ice-water bath. The fine yellow
precipitate formed was collected by vacuum filtration, washed well
with water and dried under vacuum to give 370 mg of product. 1H NMR
(CDCl3) .delta. 8.84 (dd, J=2.4 Hz, 0.8 Hz, 1H) 8.77 (dd, J=4.8 Hz,
2.0 Hz, 1H) 7.93 (dt, J=8.4 Hz, 2.0 Hz, 1H) 7.43 (m, 1H) 7.35 (d,
J=2.0 Hz, 1H) 7.25 (d, J=0.8 Hz, 1H) 6.71 (d, J=8.8 Hz, 1H) 6.21
(s, 2H) MS (ES) m/z=233.0 (MH).sup.+
Synthesis of 2-methyl-isonicotinonitrile
##STR00079##
[0411] Dimethyl sulfate (18.3 mL, 192.4 mmol) was added to stirring
2-picoline-N-oxide (20 g) over a 10 minute period. The reaction was
exothermic and the material quickly became homogeneous. The mixture
was heated in a 60.degree. C. oil bath for 2 hours, then the
volatiles were removed under vacuum and the pale yellow oil was
diluted with 25 mL H.sub.2O and added drop wise over 10 minutes to
160 mL of 25% (w/v) KCN/H.sub.2O. After stirring for 3.5 hours the
yellow precipitate formed was collected by vacuum filtration and
purified by column chromatography (EtOAc/Hexane) to yield 13.0 g of
product (60%). 1H NMR (CDCl3) .delta. 8.66 (d, J=4.8 Hz, 1H) 7.37
(s, 1H) 7.31 (d, J=4.4 Hz, 1H) 2.62 (s, 3H) (s, 3H); MS (ES)
m/z=119.0
Synthesis of
(2-amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone
##STR00080##
[0413] The title compound was prepared according to the general
procedure for the Synthesis of (2-Amino-phenyl)-aryl-methanones,
using 4-chloro-phenylamine (1.8 g, 14.2 mmol) and
2-methyl-isonicotinonitrile (2.0 g, 16.9 mmol). 1H NMR (CDCl3)
.delta. 8.64 (d, J=4.8 Hz, 1H) 7.28 (m, 3H) 7.20 (d, J=6.0 Hz, 1H)
6.70 (d, J=12.4 Hz, 1H) 6.28 (s, 2H) 2.66 (s, 3H) MS (ES)
m/z=247.0
Synthesis of (2-amino-5-chloro-phenyl)-pyridin-2-yl-methanone
##STR00081##
[0415] To a solution of 2-bromopyridine (5 ml, 52 mmol) in
Et.sub.2O (60 ml) was added 40 ml of a n-butyllithium (1.6M in
hexane, 64 mmol) drop wise at -40.degree. C. over 30 min under a
nitrogen atmosphere. The resulting yellow solution was stirred for
a further 1 hr at -50.degree. C. to -30.degree. C. In a separate
flask, a solution of 2-amino-5-chlorobenzoic acid (2.05 g, 12 mmol)
in dry THF (90 ml), under nitrogen atmosphere and with ice-cooling,
was added in one portion to the solution prepared as described
above. The reaction mixture was stirred for 2 hrs at 0.degree. C.
and then chlorotrimethylsilane (30 ml) was added at 0.degree. C.
with stirring. The reaction mixture was allowed to warm to room
temperature and 1 N HCl aq (100 ml) was added. The resulting
two-phase system was separated. The aqueous phase was adjusted to
pH12 with 6N NaOH solution and extracted with ethyl acetate
(2.times.150 ml). The combined organic extractions were dried over
Na.sub.2SO.sub.4. After removal of solvent, the residue was
purified by the flash chromatography using ethyl acetate/hexane
(1:4) as eluent. Crystallization of the product from
Et.sub.2O/hexane mixture gave 1.26 g (45%) of desired product as
yellow solid. .sup.1H-NMR (DMSO-d.sub.6, 500 MHz): .delta. 6.90
(1H, d, J=9 Hz), 7.31 (1H, dd, J=9 and 2.5 Hz), 7.40 (2H, br), 7.53
(1H, d, J=2.5 Hz), 7.61 (1H, m), 7.79 (1H, d, J=8 Hz), 8.03 (1H,
m), 8.69 (1H, m). MS: (ESI.sup.+): 233.2 (M+1).
Synthesis of
(2-Amino-5-chloro-phenyl)-(3-methyl-pyridin-4-yl)-methanone
##STR00082##
[0417] To a solution of 3-picoline (50 g, 0.48 mol) in glacial
acetic acid (150 ml) was added hydrogen peroxide (25 ml) at RT. The
mixture was heated to 90.degree. C. for 3 hr. The mixture was
cooled to RT and more hydrogen peroxide (18.5 ml) was added slowly.
The mixture was again heated to 90.degree. C. for 19 hr. The excess
peroxide was carefully decomposed using Pd--C (2.5 g) at 0.degree.
C. Pd--C was removed by filtration, and the filtrate was
concentrated and crude 3-methylpyridine-1-oxide was purified by
fractional distillation in vacuo.
[0418] A solution of 3-methylpyridine-1-oxide (10 g, 0.092 mol) in
methyl iodide (15 ml) was left at rt for 18 hr and the solid was
filtered. The filtrate was diluted with diethyl ether and extracted
with water (40 ml). The solid was re-dissolved in the aqueous
extract, 1,4-dioxane (50 ml) was added, followed by potassium
cyanide (15 g, 0.23 mol) and the mixture was stirred at RT for 3
hr. The product was extracted with chloroform. The chloroform layer
was washed with water, brine and dried over sodium sulfate. The
solvent was removed in vacuo and the crude product was purified by
fractional distillation (61-62.degree. C./0.2 mm) to yield a white
low melting solid.
[0419] BCl.sub.3 (24 ml, 1M in DCM, 0.024 mol) was added slowly to
a solution of 4-chloroaniline (2 g, 0.016 mol) in 30 ml of
trichloroethylene over a period of 15 min. at 0.degree. C. and
stirred at this temperature for an additional 10 min.
4-Cyano-3-methylpyridine (2.2 g, 0.019 mol) and AlCl.sub.3 (3 g,
0.022 mol) were added at 0.degree. C. The solution was allowed to
warm to RT and stirred for 30 min. The solution was then heated at
80-90.degree. C. for 1 hr. and the DCM was distilled off. The
resulting solution was refluxed at 115.degree. C. for 4 hr and
stirred at RT overnight. 3N HCl (20 ml) was added and the mixture
refluxed at 100.degree. C. for 2 hr. The reaction mixture was
cooled to 0.degree. C. and adjusted to pH-12 with 6N NaOH. The
reaction mixture was extracted with DCM, and the DCM layer washed
with water, brine and dried over Na.sub.2SO.sub.4. The solvent was
removed, and the crude was purified by column chromatography over
silica gel to yield a yellow solid.
Synthesis of
(2-Amino-4,5-difluoro-phenyl)-pyridin-4-yl-methanone
[0420] Iron powder (28.1 g, 0.502 mol) was added as small portions
to 1,2-difluoro nitrobenzene (20.0 g, 0.126 mol) in methanol (200
ml) and heated
##STR00083##
to 60.degree. C. Ammonium chloride (48.4 g, 0.91 mol) in water (100
ml) was added drop wise and the reaction mixture refluxed for 5 hr.
The reaction mixture was filtered over Celite and washed with
methanol. Methanol was removed, and the aqueous layer was extracted
with ethylacetate, washed with brine, dried over sodium sulphate
and concentrated to yield 1,2-difluoro-4-aminobenzene.
[0421] BCl.sub.3 (6.2 ml, 1M in DCM) was added drop wise to
1,2-difluoro-4aminobenzene (0.5 g, 0.004 mol) in trichloroethylene
(6.5 ml) at 0.degree. C. and this mixture stirred for 15 min.
4-Cyanopyridine (0.48 g, 0.005 mol) was added and the solution was
warmed to RT and stirred for 30 min. The solution was then heated
at 80-90.degree. C. for 1 h. The resulting solution was refluxed at
160.degree. C. for 4 hr and stirred at RT over night. 3N HCl was
added to the reaction mixture and refluxed at 110.degree. C. for
1.5 h. The reaction mixture was cooled to RT and made basic (pH=12)
with 6N NaOH. The reaction mixture was diluted with water and DCM.
The resulting two layers were separated and the aqueous layer was
extracted with DCM, dried over sodium sulphate and concentrated.
The compound was purified by column chromatography using silica gel
to yield title compound.
Synthesis of
(6-Amino-2,3-difluoro-phenyl)-pyridin-4-yl-methanone
##STR00084##
[0423] To 3,4-Difluoroaniline (2.0 g, 0.0153 mol) and triethylamine
(3.1 g, 0.0307 mol) in dry benzene (100 ml) was added
trimethylacetylchloride (2.3 g, 0.0184 mol) slowly at 0.degree. C.
and the reaction mixture stirred at RT overnight. The reaction
mixture was then quenched with water and extracted with ethyl
acetate. The organic layer was washed with water, brine, dried over
sodium sulfate and concentrated. Compound was recrystallized from
petroleum ether.
[0424] This protected 3,4-difluoroaniline (2.7 g, 0.0126 mol) was
taken in dry THF (25 ml) and under nitrogen t-butyllithium (2.02 g,
0.032 mol) was added drop wise at -78.degree. C. Stirring was
continued at -78.degree. C. for 2 h. 4-Pyridine carboxaldehyde
(3.55 g, 0.033 mol) dissolved in dry THF (10 ml) was added slowly.
The reaction mixture was warmed to room temperature and stirred
over night. The reaction mixture was then quenched with water and
extracted with ether. The organic layer was washed with brine,
dried over sodium sulfate and concentrated. Compound was purified
by column chromatography to yield carbinol.
[0425] To carbinol (2.6 g, 0.0031 mol) in 17.3 ml of pyridine was
added a suspension of chromium trioxide (0.705 g, 0.007 mol) in
pyridine (6.0 ml) under a nitrogen atmosphere. The resulting
mixture was allowed to stir at RT over night. The reaction mixture
was poured into water and extracted with ether. The ether extract
was washed with brine, dried over sodium sulfate and concentrated.
The compound was purified by column chromatography to yield the
protected precursor to the title compound.
[0426] To this pivaloyl protected amino ketone (1.7 g, 0.0053 mol)
was added 70% sulfuric acid (14.6 ml) and the reaction mixture
heated to 95-100.degree. C. overnight. The reaction mixture was
basified by using 10% sodium hydroxide and extracted with
dichloromethane. The organic layer was washed with water, brine,
dried over sodium sulfate and concentrated. The product obtained
was purified by column chromatography to yield title compound.
Synthesis of
(2-Amino-5-chloro-4-methoxy-phenyl)-pyridin-4-yl-methanone
##STR00085##
[0428] 5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30% sulfuric
acid (300 ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g,
0.304 mol) in water (50 ml) was added slowly at 0.degree. C. After
15 mins, this solution was added slowly to dilute sulfuric acid
(50%, 250 ml) at 110.degree. C. Stirring was continued for 15 min.
The reaction mixture was cooled to RT, ice water was added,
extracted with ethylacetate, washed with water, brine and dried
over Na.sub.2SO.sub.4. The phenol product obtained upon
concentration was purified by column chromatography.
[0429] K.sub.2CO.sub.3 (23.84 g, 0.172 mol) was added to
2-chloro-5-nitrophenol (10.0 g, 0.058 mol) in acetonitrile (100 ml)
at RT. After cooling to 0.degree. C., methyl iodide (19.6 g, 0.138
mol) was added slowly and the reaction mixture stirred at RT
overnight. Water (100 ml) was added and the aqueous layer extracted
with ethyl acetate. The organic layer was washed with water, brine
and dried over Na.sub.2SO.sub.4. The product obtained upon
concentration was purified by column chromatography to yield the
anisole.
[0430] 2-Chloro-5-nitro anisole (6.0 g, 0.032 mol) in MeOH (45 ml)
was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc.
HCl (110 ml) at 40.degree. C. and the temperature was slowly raised
to 50.degree. C. Stirring was continued for 2 h. After cooling to
RT, the reaction mixture was basified with 50% NaOH solution,
extracted by ethyl acetate, washed with water, then brine and dried
over Na.sub.2SO.sub.4. 3-Methoxy-4-chloroaniline was obtained upon
concentration and was purified further by column
chromatography.
[0431] To 3-Methoxy-4-chloroaniline (2.0 g, 0.0126 mol) in
trichloroethylene (30 ml) was added BCl.sub.3 (2.18 g, 1 M solution
in DCM, 0.0188 mol) at 0.degree. C. After stirring for 10 min,
4-cyanopyridine (1.6 g, 0.0153 mol) and AlCl.sub.3 (2.35 g, 0.018
mol) were added and the temperature was raised to RT, with further
stirring for 30 min. The temperature was raised further to
85.degree. C. and maintained at the same temperature for 1 h. DCM
was distilled off and the solution was stirred at 115.degree. C.
for 4 h and then at RT over night. 3N HCl was added at RT and the
reaction mixture refluxed for 1.5 h. The reaction mixture was
allowed to cool and made basic using NaOH (6 N), diluted with water
and extracted with DCM, washed with water, brine and dried over
Na.sub.2SO.sub.4. The crude title compound was obtained upon
concentration and was purified by column chromatography.
Synthesis of (2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone
##STR00086##
[0433] To 4-Methyl pyrimidine (5.0 g, 0.053 mol) in pyridine (55
ml) was added selenium dioxide (8.82 g, 0.079 mol) at RT with
stirring. The reaction mixture was stirred at 55.degree. C. for 2 h
and at 80.degree. C. for 3.5 hr. After cooling to RT and stirring
over night, the reaction mixture was filtered and the residue was
washed with pyridine. The combined pyridine solution was
concentrated and the carboxylic acid obtained was washed with water
to remove traces of selenium dioxide. Yield: 5.3 g, 80.5%.
[0434] To Pyrimidine-4-carboxylic acid (5.0 g, 0.04 mol) in
methanol (170 ml) was added conc. HCl (2 ml) at RT. After refluxing
overnight, the reaction mixture was cooled to RT and neutralized
with 10% sodium bicarbonate solution and concentrated. The ester
was extracted with diethyl ether, dried over Na.sub.2SO.sub.4 and
concentrated to get the methyl ester as a yellow solid, yield: 3.3
g, 57.55%.
[0435] Trimethyl acetylchloride (11.30 g, 0.093 mol) was added to a
benzene (500 ml) solution of triethylamine (15.75 g, 0.155 mol) and
4-chloroaniline (10.0 g, 0.078 mol) at 0.degree. C. The reaction
mixture was warmed to RT and stirred for 3 h. The reaction mixture
was then quenched with water, extracted with ethyl acetate, washed
with water, brine solution and dried over Na.sub.2SO.sub.4. The
solid product obtained was crystallized from pet ether. Yield: 14.0
g, 84.43%.
[0436] To N-(4-chlorophenyl)-2,2-dimethyl propanamide (3.5 g,
0.0165 mol) in THF (50 ml) at 0.degree. C. was added n-butyl
lithium in hexane (2.64 g, 1.2 M, 0.041 mol). Stirring was
continued at 0.degree. C. for 2 h, the reaction then cooled to
-70.degree. C., pyrimidine-4-methyl carboxylate (3.18 g, 0.023 mol)
in THF (25 ml) was then added slowly and the solution was warmed to
RT and stirred overnight. Diethyl ether (50 ml) and water (50 ml)
were added and the organic layer was separated. The aqueous layer
was further extracted with ether. The combined ether layers were
washed with water, brine and dried over Na.sub.2SO.sub.4. The
product obtained upon concentration was purified by column
chromatography. Yield: 1.7 g, 32.69%.
[0437] The protected amino ketone (1.7 g, 0.0054 mol) in sulfuric
acid (10 ml, 70%) was heated at 95.degree. C. over night. The
reaction mixture was cooled to RT and basified with 10% NaOH,
extracted with DCM, washed with water, brine and dried over
Na.sub.2SO.sub.4. The product obtained upon concentration was
purified by column chromatography using basic alumina to yield
title compound (0.20 g, 16%).
Synthesis of
(6-Amino-3-chloro-2-methoxy-phenyl)-pyridin-4-yl-methanone
##STR00087##
[0439] 5-Nitro-2-chloro aniline (50.0 g, 0.289 mol) in 30% sulfuric
acid (300 ml) was stirred at RT for 2 h. Sodium nitrite (21.0 g,
0.304 mol) in water (50 ml) was added slowly at 0.degree. C. and
maintained at this temperature for 15 min. This diazotized solution
was added slowly to dilute sulfuric acid (50%, 250 ml) at
110.degree. C. Stirring was continued for 15 min. After cooling to
RT, ice water was added, the mixture extracted with ethylacetate,
washed with water, brine and dried over Na.sub.2SO.sub.4. The
product obtained upon concentration was purified by column
chromatography. Yield 12.0 g, 24.0%.
[0440] To K.sub.2CO.sub.3 (23.84 g, 0.172 mol) and
2-chloro-5-nitrophenol (10.0 g, 0.0576 mol) in acetonitrile (100
ml) was added methyl iodide (19.60 g, 0.138 mol) at 0.degree. C.
The reaction mixture was warmed to RT and stirred overnight. Water
was added and extracted with ethyl acetate. The organic layer was
washed with water, brine and dried over Na.sub.2SO.sub.4. The
product obtained upon concentration was purified by column
chromatography. Yield: 6.0 g, 55.55%.
[0441] 2-Chloro-5-nitro anisole (6.0 g, 0.032 mol) in MeOH (45 ml)
was added slowly to stannous chloride (15.1 g, 0.08 mol) in conc.
HCl (110 ml) at 40.degree. C. and the temperature was slowly raised
to 50.degree. C. Stirring was continued for 2 h, the reaction
cooled to RT, basified with 50% NaOH solution and extracted by
ethyl acetate. The organic layer was washed with water, brine and
dried over Na.sub.2SO.sub.4. The product obtained upon
concentration was purified by column chromatography. Yield: 4.0 g,
79.36%.
[0442] To triethylamine (3.83 g, 0.037 mol) and 3-methoxy-4-chloro
aniline (3.0 g, 0.0190 mol) in benzene (50 ml) was added
trimethylacetylchloride (2.75 g, 0.022 mol) slowly at 0.degree. C.
The temperature was raised to RT and stirred overnight. The
reaction mixture was added to ice and extracted with ethyl acetate.
The organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4 and concentrated. Yield: 3.7 g, 80.43%.
[0443] To N-pivaloyl-3-methoxy-4-chloroaniline (1.50 g, 0.0062 mol)
in THF (30 ml) was added n-butyl lithium (1.0 g, 0.0156 mol) at
0.degree. C. and the reaction stirred for 2 hr. After cooling to
-70.degree. C., methyl isonicotinate (1.3 g, 0.0094 mol) in THF (12
ml) was added slowly. The reaction was warmed to rt and stirred
overnight and then quenched with water and extracted with ether.
The water layer was further extracted and the combined ether layers
were washed with water, brine and dried over Na.sub.2SO.sub.4. The
product obtained upon concentration was purified by column
chromatography. Yield 0.50 g, 23.25%.
[0444] The protected ketone from step 5 (0.500 g, 0.0014 mol) was
suspended in concentrated HCl (5 ml) at RT, then the temperature
was raised to 95.degree. C. and the mixture stirred over night. The
mixture was cooled to RT, basified with 20% NaOH solution and
extracted with DCM. The combined organic layer was washed with
water, brine and dried over Na.sub.2SO.sub.4. The product obtained
upon concentration was purified by column chromatography using
basic alumina to yield title compound (0.140 g, 37.33%).
Synthesis of
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone
##STR00088##
[0446] To a solution of 2-picoline (50 g, 0.48 mol) in glacial
acetic acid (150 ml) was added hydrogen peroxide (25 ml) at RT. The
mixture was heated to 90.degree. C. for 3 hr. The mixture was
cooled to RT and more hydrogen peroxide (18.5 ml) was added slowly.
The mixture was again heated to 90.degree. C. for 19 hr. The excess
peroxide was cautiously decomposed using Pd--C (2.5 g) at 0.degree.
C. Pd--C was filtered, the filtrate was concentrated and the crude
2-methyl pyridine-1-oxide was purified by fractional distillation
under vacuum. Yield: 40 g, 69%.
[0447] A solution of 2-methylpyridine-1-oxide (10 g, 0.092 mol) in
methyl iodide (15 ml) was stirred at RT for 18 hr. The solid was
filtered. The filtrate was diluted with diethyl ether, extracted
with water (40 ml). The solid was re-dissolved in the aqueous
layer, 1,4-dioxane (50 ml) was added, followed by potassium cyanide
(15 g, 0.23 mol). The mixture was stirred at RT for 3 hr. The
product was extracted with chloroform. The chloroform layer was
washed with water, brine and dried over sodium sulfate. The solvent
was removed under vacuo and the crude material was purified by
fractional distillation (61-62.degree. C./0.2 mm) to yield a white
low melting solid (6 g, 35%).
[0448] BCl.sub.3 (24 ml, 1M in DCM, 0.024 mol) was added slowly to
a solution of 4-chloroaniline (2 g, 0.016 mol) in 30 ml of
trichloroethylene over a period of 15 min. at 0.degree. C. and
stirred at this temperature for an additional 10 min.
4-Cyano-2-methylpyridine (2.2 g, 0.019 mol) and AlCl.sub.3 (3 g,
0.022 mol) were added at 0.degree. C. The solution was warmed to RT
and stirred for 30 min. The solution was then heated at
80-90.degree. C. for 1 h and the DCM was distilled off. The
resulting solution was refluxed at 115.degree. C. for 4 hr and
stirred at RT over night. 3N HCl (20 ml) was added to the mixture
and refluxed at 100.degree. C. for 2 hr. The reaction mixture was
cooled to 0.degree. C. and was made basic (pH-12) with 6N NaOH and
the reaction mixture was extracted with DCM. The DCM layer was
washed with water, brine and dried over Na.sub.2SO.sub.4. The
solvent was removed, the crude was purified by column
chromatography (silica gel) to yield title compound as yellow solid
(1.55 g, 40%).
Synthesis of (2-Amino-4-chloro-phenyl)-pyridin-4-yl-methanone
##STR00089##
[0450] To BCl.sub.3 (1M in DCM) (24 mL, 24 mmol), cooled to
0.degree. C., a solution of 3-chloroaniline (2.0 g, 16 mmol) in 30
mL of TCE was added drop wise over a period of 15 min and the
mixture stirred at that temperature for an additional 10 min.
4-cyanopyridine (2.0 g, 19 mmol) and AlCl.sub.3 (3.0 g, 22 mmol)
was added under ice-water cooling. The solution was allowed to warm
to rt and stirred for 30 min. The solution was then heated at
80-90.degree. C. for 1 h and the DCM distilled off. The resulting
solution was refluxed at 160.degree. C. for 4 h and stirred at rt
overnight. 3N HCl (20 ml approx.) was added to the reaction mixture
and then refluxed at 110.degree. C. for 1.5 hr. The reaction
mixture was cooled to rt and the solution was made basic (pH 12)
with 6N NaOH. The reaction mixture was diluted with water and DCM.
The resulting two layers were separated and the aqueous layer was
extracted with DCM (3.times.150 mL), and dried (Na.sub.2SO.sub.4).
After removal of solvent, the solid was washed with Et.sub.2O to
give 650 mg (24%) of desired product.
Synthesis of (2-Amino-3-chloro-phenyl)-pyridin-4-yl-methanone
##STR00090##
[0452] To a solution of BCl.sub.3 (1M in DCM) (24 mL, 24 mmol),
cooled to 0.degree. C., was added a solution of 2-chloroaniline
(2.0 g, 16 mmol) in 30 mL of TCE drop wise over a period of 15 min
and the reaction stirred for an additional 10 min. 4-cyanopyridine
(2.0 g, 19 mmol) and AlCl.sub.3 (3.0 g, 22 mmol) were added under
ice-water cooling. The solution was allowed to warm to rt and
stirred for 30 min. The solution was then heated at 80-90.degree.
C. for 1 h and the DCM distilled off. The resulting solution was
refluxed at 160.degree. C. for 4 h and stirred at rt overnight. 3N
HCl (20 ml approx.) was added to the reaction mixture and refluxed
at 110.degree. C. for 1.5 hr. The reaction mixture was cooled to rt
and the solution was made basic (pH 12) with 6N NaOH. The reaction
mixture was diluted with water and DCM. The resulting layers were
separated and the aqueous layer was extracted with DCM (3.times.150
mL), and the combined organic layers dried (Na.sub.2SO.sub.4).
After removal of solvent, the solid was washed with Et.sub.2O to
give 600 mg (21%) of desired product.
Synthesis of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone
##STR00091##
[0454] To a solution of BCl.sub.3 (1M in DCM) (18 mL, 18 mmol),
cooled to 0.degree. C., was added drop wise over a period of 15 min
a solution of 4-bromoaniline (2 g, 11.6 mmol) in 30 mL of TCE and
the mixture stirred for an additional 10 min.
[0455] 4-cyanopyridine (2.0 g, 19 mmol) and AlCl.sub.3 (3.0 g, 22
mmol) were added under ice-water cooling. The solution was warmed
to rt and stirred for 30 min. The solution was then heated at
80-90.degree. C. for 1 h and the DCM distilled off. The resulting
solution was refluxed at 160.degree. C. for 4 h and stirred at rt
overnight. 3N HCl (20 ml approx.) was added to the reaction mixture
and refluxed at 110.degree. C. for 1.5 hr. The reaction mixture was
allowed to cool down and the solution was made basic (pH 12) with
6N NaOH. The reaction mixture was diluted with water and DCM. The
resulting two layers were separated and the aqueous layer was
extracted with DCM (3.times.150 mL), and the combined organic
layers dried (Na.sub.2SO.sub.4). After removal of solvent, the
solid was washed with Et.sub.2O to give 1.050 g of desired
product.
Synthesis of (2-amino-5-fluoro-phenyl)-pyridin-4-yl-methanone
##STR00092##
[0457] To a solution of BCl.sub.3 (1M in DCM) (27 mL, 27 mmol),
cooled to 0.degree. C., was added drop wise over a period of 15 min
a solution of 4-fluoroaniline (2.0 g, 18 mmol) in 30 mL of TCE and
the mixture stirred at that temperature for an additional 10 min.
4-cyanopyridine (2.6 g, 25 mmol) and AlCl.sub.3 (3.0 g, 22 mmol)
were added under ice-water cooling. The solution was allowed to
warm to rt and then stirred for 30 min. The solution was then
heated at 80-90.degree. C. for 1 h and the DCM distilled off. The
resulting solution was refluxed at 160.degree. C. for 4 h and
stirred at rt overnight. 3N HCl (20 ml approx.) was added to the
reaction mixture and refluxed at 110.degree. C. for 1.5 hr. The
reaction mixture was allowed to cool down and the solution was made
basic (pH 12) with 6N NaOH. The reaction mixture was diluted with
water and DCM. The resulting two layers were separated and the
aqueous layer was extracted with DCM (3.times.150 mL), and the
combined organic layers dried (Na.sub.2SO.sub.4). After removal of
solvent, the solid was washed with Et.sub.2O to give 1.05 g (27%)
of desired product.
Synthesis of
(2-Amino-5-chloro-phenyl)-(1-methyl-1H-imidazol-2-yl)-methanone
##STR00093##
[0459] To a solution of .sup.nBuLi (0.0730 mol) in hexane was added
N-methyl imidazole (0.0608 mol) drop wise at -40.degree. C. over 30
min under a nitrogen atmosphere. The resulting yellow solution was
stirred for a further 3 hr at rt, and then refluxed for 1 h.
2-amino-5-chlorobenzoic acid (1.74 g, 0.01014 mole) in dry ether
(60 ml) was then added to the reaction mixture. The reaction
mixture was stirred overnight at rt. To the reaction mixture was
added saturated NH.sub.4Cl solution and the resulting mixture
extracted with ethyl acetate (2.times.150 ml). The combined organic
layers were dried over Na.sub.2SO.sub.4. After removal of solvent,
the residue was purified by the flash chromatography using ethyl
acetate/hexane (1:4) as eluent. Crystallization of the product from
Et.sub.2O/hexane mixture gave 300 mg (13.7%) of product as yellow
solid.
Synthesis of (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl
methanone
##STR00094##
[0461] Trimethylacetyl chloride (35 g) was added drop wise to a
solution of 4-chloroaniline (31.9 g) in dry pyridine and the
reaction was stirred under nitrogen overnight. About half of the
pyridine was removed by rotary evaporation, then the mixture was
treated with 6M hydrochloric acid and extracted with ethyl acetate.
The extracts were washed with saturated aqueous NaHCO3 and with
water, then were dried (MgSO4), filtered and concentrated by rotary
evaporation. The resulting crystalline product was vacuum filtered
and dried at high vacuum to constant weight, resulting in a good
yield of N-(4-chloro-phenyl)-2,2-dimethyl-propionamide as fine
needles. EDC (10 g) and 2-methyl-nicotinic acid (7.15 g) were
magnetically stirred in acetonitrile-THF with
N,O-dimethylhydroxylamine hydrochloride (9.75 g) and triethylamine
(25 mL). After stirring overnight at ambient temperature, the
resulting white suspension was added to ice water and extracted
with ethyl acetate (3.times.100 mL). The extracts were dried,
filtered, and concentrated to give a light amber oil.
[0462] To a magnetically stirred solution of
N-(4-chloro-phenyl)-2,2-dimethyl-propionamide (3.16 g, 14.9 mmol)
in dry THF was added 2.5M n-butyllithium in hexane at -40.degree.
C. and the mixture was stirred at 0.degree. C. for 2 h and a
suspension of white solid resulted. A solution of the Weinreb amide
(1.80 g, 10.0 mmol) in dry THF was added drop wise and the reaction
was stirred at ambient temp overnight. The mixture was diluted with
water and extracted with ethyl acetate and the organic layer was
dried (MgSO4), filtered and concentrated. Chromatography on silica
gel (20-30% EtOAc/Hexane) provided the desired
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propion-
amide as a waxy bright yellow solid (2.28 g, 6.89 mmol): .sup.1H
NMR (CDCl3) .delta. 11.71 (s, 1H, NH), 8.82 (d, 1H, J=9.2 Hz), 8.67
(dd, 1H, J=4.8 Hz, J=1.8 Hz), 7.55 (m, 2H), 7.28 (d, 1H, J=2.5 Hz),
7.25 (m, 1H), 2.54 (s, 3H), 1.39 (s, 9H).
[0463] The
N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-2,2-dimeth-
yl-propionamide intermediate (2.28 g, 6.89 mmol) was magnetically
stirred with 70% sulfuric acid and heated at 75.degree. C. and
progress of the solvolysis was monitored by LC/MS. The reaction was
allowed to cool to ambient temperature, and was washed with
ether-hexane to remove oily by-products. The acidic aqueous layer
was cooled in an ice bath and aqueous NaOH was added drop wise to
basify the mixture. The product was extracted with ethyl acetate
and the extracts were washed with saturated aqueous NaHCO3
(2.times.100 mL), with saturated aqueous sodium chloride, dried
(MgSO4), filtered and concentrated. The bright yellow product
crystallized on standing: .sup.1H NMR (CDCl3) .delta. 8.54 (dd, 1H,
J=5.2 Hz, J=1.6 Hz), 7.45 (dd, 1H, J=7.6 Hz, J=1.5 Hz), 7.15 (m,
2H), 7.00 (d, 1H, J=2.6 Hz), 6.61 (d, 1H, J=9.1 Hz), 6.39 (br s,
2H), 2.42 (s, 3H).
Synthesis of
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone
##STR00095##
[0465] To N-(4-Chlorophenyl)-2,2-dimethyl propanamide (50 g. 0.236
mol) in THF (800 ml) was added n-butyl lithium (37.76 g, 0.59 mol)
at -5C. After 3 hours, the reaction mixture was cooled to
-70.degree. C. and methyl-6-methyl nicotinate (50 g, 0.330 mol) in
THF (400 ml) was added slowly. After one more hour at -70.degree.
C., the reaction was warmed to room temperature, stirred over
night, then quenched with water and the product extracted with
ether. The organic layer was washed with water, brine, dried over
sodium sulfate and concentrated in vacuo. The crude intermediate
was purified by column chromatography.
[0466] To this crude product (15 g, 0.0453 mol) was added 40% KOH
(75 ml) solution in methanol (150 ml) and the reaction mixture
heated at 65.degree. C. for 24 h. After Concentration and
extraction with ethyl ether, the organic layer was washed with
water, brine, dried over sodium sulphate and concentrated. The
crude product was purified by column chromatography using basic
alumina to yield title compound.
[0467] .sup.1H NMR (CDCl.sub.3): 2.66 (s, 3H), 6.13 (bs, 2H,
NH.sub.2), 6.7 (d, 1H, .sup.3J=9 Hz), 7.28 (m, 2H), 7.39 (s, 1H),
7.85 (d, 1H, .sup.3J=9 Hz), 8.75 (s, 1H). .sup.13C NMR
(CDCl.sub.3): 24.5, 118.5, 120.2, 122.8, 132.1, 132.6, 134.5,
136.7, 149.3, 149.4, 161.7, 195.6. LC-MS m/z=247.2 (M+H).sup.+.
HPLC [c18 BDS 25 min column, flow=0.8 ml/min (70:30; ACN:0.1% TFA),
rt=4.8 min].
Synthesis of
(2-Amino-5-chloro-phenyl)-([1H]-pyrazol-3-yl)-methanone
##STR00096##
[0469] To N-(4-Chlorophenyl)-2,2-dimethyl propanamide (2.6 g,
12.293 mmol) in THF (40 ml) was added n-butyl lithium (1.966 g,
30.732 mmol) at -5.degree. C. and the reaction mixture maintained
at 0.degree. C. for 3 h. After cooling to -70.degree. C.,
ethyl-(1-Boc) pyrazole-5-carboxylate (4.13 g, 17.20 mmol) in THF
(20 ml) was added, the reaction mixture stirred for 1 hour, then
allowed to warm to RT and stirred over night, then quenched with
water and the reaction mixture extracted with ether, washed with
water, brine and dried over sodium sulphate and concentrated in
vacuo. The crude intermediate was purified by column
chromatography.
[0470] 6N HCl (10 ml) and the crude intermediate (1.0 g, 2.466
mmol) were then heated at 90.degree. C. overnight, cooled to room
temperature, basified by adding saturated sodium bicarbonate
solution, extracted with ether and the organic layer was again
washed with brine, dried over sodium sulphate and concentrated in
vacuo. The product was purified by column chromatography using
basic alumina. .sup.1H NMR (CDCl.sub.3): 6.11 (bs, 2H, NH.sub.2),
6.7 (d, 1H, .sup.3J=6.6 Hz), 6.89 (s, 1H), 7.28 (m, 1H), 7.7 (s,
1H), 8.2 (s, 1H), 10.75 (bs, 1H). .sup.13C NMR (CDCl.sub.3):
109.25, 118.4, 118.5, 120.5, 132.4, 134.5, 149.4, 186.6. LC-MS
m/z=222 (M+H).sup.+. HPLC [c18 BDS 25 min column, flow=0.8 ml/min
(70:30; ACN:0.1% TFA), rt=4.11 min].
Synthesis of
(6-Amino-2,3-difluoro-phenyl)-pyridin-3-yl-methanone
##STR00097##
[0472] To 3,4-Difluoro phenyl-2,2-dimethyl propanamide (0.5 g,
0.0023 mol) in dry THF (5 mL) was added n-butyl lithium (0.375 g,
0058 mol) dropwise at -78.degree. C., and the reaction mixture
stirred for 3 hours. 3-Pyridine carboxyaldehyde (0.658 g, 0.0060
mol) in 5 ml dry THF was added drop wise. The reaction mixture was
warmed to room temperature and stirred overnight, quenched with
water, and extracted ethyl acetate. The organic layer was washed
with water, brine and dried over sodium sulfate and concentrated.
Crude intermediate was purified by column chromatography using 30%
ethylacetate in hexane solution. .sup.1H NMR (CDCl.sub.3): 5.28
(bs, 2H, NH.sub.2), 6.49 (m, 1H), 7.17 (dd, 1H), 7.43 (m, 1H), 8.0
(m, 1H), 8.79 (m, 1H), 8.94 (s, 1H). .sup.13C NMR (CDCl3): 109.7,
109.8, 111.8, 122.3, 122.5, 123.2, 135.2, 135.8, 140.4, 140.5,
142.8, 142.9, 145.9, 147.9, 148.1, 149.6, 150.4, 150.6, 152.7,
192.4. LC-MS m/z=235 (M+H).sup.+. HPLC [c18 BDS 25 min column,
flow=0.8 ml/min (70:30; ACN:0.1% TFA), rt=4.07 min].
[0473] To Chromium trioxide (0.493 g, 0.0049 mol) in 6 ml dry
pyridine under a nitrogen atmosphere was added crude intermediate
(0.7 g, 0.0021 mol) in 8 ml pyridine dropwise, the reaction mixture
stirred at RT for overnight, diluted with diethyl ether, filtered
through Celite, the filtrate was washed with water, then brine
again, then dried over sodium sulfate and concentrated in vacuo.
Crude compound was purified by column chromatography using 35%
ethyl acetate in hexane solution, reduced in vacuo, and to this
material was added 5 ml of 70% sulphuric acid, and the resulting
reaction mixture heated to 98.degree. C. overnight, then basified
with 10% sodium bicarbonate solution, and extracted with
dichloromethane. The organic layer was dried over sodium sulfate
and concentrated. Title compound was purified by column
chromatography using 15% ethyl acetate in hexane.
Synthesis of
(6-Amino-3,4-difluoro-phenyl)-pyridin-3-yl-methanone
##STR00098##
[0475] BCl.sub.3 (6.2 ml, 1M in DCM) was added dropwise to
1,2-difluoro-4-aminobenzene (0.5 g, 0.004 mol) in trichloroethylene
(6.5 ml) at 0.degree. C., the reaction mixture stirred for 15 min,
then 3-Cyanopyridine (0.48 g, 0.005 mol) added and the solution
warmed to room temperature and stirred for 30 min. The solution was
then heated at 80-90.degree. C. for 1 h. The resulting solution was
refluxed at 160.degree. C. for 4 hr, then stirred at room
temperature over night, then 3N HCl was added to the reaction
mixture and again refluxed at 110.degree. C. for 1.5 h. The
reaction mixture was cooled to RT and made basic (pH=12) with 6N
NaOH. The reaction mixture was diluted with water and
dichloromethane. The resulting two layers were separated and the
aqueous layer was extracted with dichloromethane, dried over sodium
sulfate and concentrated. The compound was purified by column
chromatography on silica gel. .sup.1H NMR (CDCl.sub.3): 6.29 (bs,
2H, NH.sub.2), 6.56 (m, 1H), 7.25 (m, 1H), 7.46 (m, 1H), 7.93 (m,
1H), 8.80 (m, 1H), 8.85 (s, 1H). .sup.13C NMR (CDCl.sub.3): 104.5,
104.7, 112.7, 121.3, 123.3, 135.1, 136.1, 142.5, 149.3, 149.5,
152.0, 153.8, 153.9, 156.3, 194.7. LC-MS m/e=235 (M+H)+. HPLC [c18
BDS 25 min column, flow=0.8 ml/min (70:30; ACN:0.1% TFA), rt=4.34
min].
Synthesis of (2-Amino-5-chloro-phenyl)-pyrazin-2-yl-methanone
##STR00099##
[0477] To N-(4-Chlorophenyl)-2,2-dimethylpropanamide (10.0 g, 0.047
mol) in dry THF (160 ml) at 0.degree. C. was added n-butyl lithium
(0.0117 mol) and the reaction mixture stirred at 0.degree. C. for 2
h. The solution was cooled to -75.degree. C., methyl pyrazinate
(9.0 g, 0.0657 mol) in THF (90 ml) was added slowly and the
reaction stirred at room temperature overnight, then diluted with
ether and the aqueous layer was extracted with ether. The combined
organic layer was washed with water, brine and concentrated. The
intermediate was purified by column with 5% of ethyl acetate in pet
ether.
[0478] To the Pivaloylamido intermediate (1.2 g, 0.0037 mol) in
methanol (25 ml) was added 2.2 ml of 40% aq. KOH solution. The
reaction was heated at 65.degree. C. for 24 h, then diluted with
water and extracted with ether. The ether layer was washed with
wash, brine and concentrated. The product was purified by column
chromatography (6% ethyl acetate in pet ether).
Synthesis of (2-Amino-5-chloro-phenyl)-pyridazin-4-yl-methanone
##STR00100##
[0480] Citraconic anhydride (53.4 g, 0.476 mol) was added to a
boiling water (130 ml) solution of hydrazine dihydrochloride (50 g,
0.476 mol). The solution was stirred at 90.degree. C. for 5 h. The
reaction mixture was then cooled to 0.degree. C. and the white
solid filtered, washed with cold water and dried in vacuo.
[0481] 4-Methyl-3,6-pyridazinediol (57.0 g, 0.45 mol) in phosphorus
oxychloride (480 ml) was refluxed at 80.degree. C. for 5 h. The
excess of the phosphorus oxychloride was removed under high vacuum
and the red colored residue was poured on to ice. The solid
separated out was filtered, washed with cold water and dried.
Yield: 64.7 g, 87%.
[0482] To 4-Methyl-3,6-dichloropyridazine (64.7 g, 0.397 mol) in
150 ml absolute ethanol was added aqueous ammonia (80 ml). The
solution was purged with nitrogen gas for 10 min, 10% palladium on
carbon (3.24 g) was added and the mixture hydrogenated at room
temperature for 8 h at 3 kg/cm2 pressure. The reaction mixture was
filtered and ethanol was removed in vacuo. The residue was basified
with 20% sodium hydroxide solution and extracted with
dichloromethane (3.times.150 ml). The organic layer was dried with
sodium sulfate and concentrated.
[0483] 4-Methyl pyridazine (31.5 g, 0.335 mol) was dissolved in
pyridine (315 ml) and stirred for 15 mins at RT. Selenium dioxide
(55.75 g, 0.5025 mol) was added and the solution was stirred for 15
min. The dark orange reaction mixture was then heated at 55.degree.
C. for 2 h and at 80.degree. C. for 3.5 h. The resulting dark brown
reaction mixture was cooled to room temperature and stirred
overnight. The reaction mixture was filtered through Celite and
concentrated. The solid obtained was suspended in 250 ml of water
and stirred vigorously for 1 h. The solid was filtered and washed
with water (100 ml) and dried in vacuo.
[0484] A suspension of pyridazine-4-carboxylic acid (10.0 g, 0.04
mol) in 100 ml of DCM and 50 ml of diethyl ether was cooled to
-10.degree. C. Potassium hydroxide (34.0 g) was dissolved in water
(65 ml), cooled to -15.degree. C. and ether (50 ml) was added. To
this biphase solution nitrosomethyl urea (20.0 g) was added portion
wise at -15.degree. C. with occasional manual stirring. After
complete addition (about 30 min) the ether layer became yellow.
This solution was decanted into another conical flask containing
potassium hydroxide pellets in 10 ml diethyl ether and the solution
was stirred manually at -15.degree. C. for 15 min. This solution
was then transferred to the suspension of the
pyridazine-4-carboxylic acid and the reaction mixture was stirred
at -15.degree. C. for 1 h. The reaction mixture was then warmed to
room temperature and concentrated.
[0485] N-4-Chlorophenyl-2,2-dimethylpropanamide (8.0 g, 0.0378 mol)
in dry THF (128 ml) was cooled to 0.degree. C. n-Butyllithium
(6.048 g, 0.0528 mol) was added dropwise at 0.degree. C. and
stirred at 0.degree. C. for 2.5 h. The reaction mixture was then
cooled to -78.degree. C. and a THF (65 ml) solution of
methylpyridazine-4-carboxylate (7.3 g, 0.0528 mol) was added
dropwise. After the addition, the reaction mixture was stirred at
the same temperature for 1 h and warmed to room temperature and
stirred for 16 h. The reaction mixture was diluted with 150 ml
diethyl ether and washed with water. The aqueous washing was
extracted with 4.times.100 ml of diethylether. The combined organic
layer was washed with brine, dried over sodium sulfate and
concentrated. The compound was purified column chromatography using
pet ether-ethylacetate as the eluent.
[0486] The protected amino ketone (1.0 g, 0.0031 mol) in 10 ml of
HBr was heated at 80.degree. C. for 4 h. The reaction mixture was
cooled to 0.degree. C., neutralised using aqueous sodium
bicarbonate, extracted with diethylether (3.times.50 ml), and the
combined organic layer was washed with brine, dried over sodium
sulfate and concentrated. The crude compound was purified by column
chromatography (basic alumina) using chloroform as eluent.
Synthesis of (2-Amino-5-chloro-phenyl)-pyridazin-4-yl-methanone
##STR00101##
[0488] 2-Chloropyrimidine (8.0 g, 0.699 mol) and sodium cyanide
(5.6 g, 0.1139 mol) in dry DMF (80 ml) was stirred at 65.degree. C.
for 24 h. The mixture was quenched with water (400 ml) and stirred
for 0.5 h. The product was extracted with ethyl acetate, the ethyl
acetate layer was dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The crude was purified by column
chromatography over silica gel (pet ether/ethyl acetate) to afford
2-cyano pyrimidine as a white solid.
[0489] Dry hydrogen chloride gas was passed through a solution of
2-cyanopyrimidine (3.5 g, 0.0333 mol) in dry methanol (100 ml) for
1 h, and the well stoppered mixture was allowed to stand for 72 h.
The mixture was concentrated under reduced pressure. The residue
was basified with NaHCO.sub.3 solution (10%) and the product was
extracted with dichloromethane. The dichloromethane layer was dried
over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The
crude ester was purified by crystallization from pet ether/diethyl
ether, to yield a white solid.
[0490] N-(4-Chlorophenyl)-2,2-dimethyl propanamide (2.0 g, 0.0095
mol) in dry THF (40 ml) was cooled to -5.degree. C. n-Butyl lithium
(24 ml, 1.2 M, 0.0284 mol) was added drop wise and stirred at the
same temperature for 2 h. The reaction mixture was cooled to
-70.degree. C. and methylpyridin-2-carboxylate (1.96 g, 0.0142 mol)
dissolved in dry THF (10 ml) and added dropwise. The mixture was
stirred at RT for 18 h. The reaction mixture was quenched with
water and extracted with ethyl acetate. The extract was washed with
brine solution and concentrated. The product was purified by column
using 5-10% of ethyl acetate in pet ether as eluent.
[0491] To the protected amino ketone (0.4 g, 0.0013 mol) in 2 ml of
methanol was added potassium hydroxide (0.48 g, 0.00857 mol) in 1.2
ml of water. The reaction mixture was heated at 70.degree. C. for 6
h. The reaction mixture was diluted with water and extracted with
ethyl acetate. The extract was washed with water, brine and
concentrated. The crude material was purified by column (5% of
ethyl acetate in pet ether).
Synthesis of
(2-Amino-5-chloro-phenyl)-(3-methoxy-pyridin-4-yl)methanone
##STR00102##
[0493] N-Pivaloyl protected 2-chlorophenyl derivative (0.500 g,
0.0014 mol) was dissolved in 11 ml of methanol and 40% KOH solution
was added. The reaction mixture was refluxed under nitrogen
atmosphere for 28 h. The reaction mixture was cooled to room
temperature and concentrated. The residue was extracted with
(3.times.50 ml) diethyl ether. The combined organic layer was
washed with water, dried over sodium sulfate and reduced in vacuo.
The crude product was purified by column chromatography using basic
alumina.
Synthesis of
(2-Amino-5-chloro-phenyl)-([1H]-1-methyl-pyrazol-5-yl)-methanone
##STR00103##
[0495] To N-(4-Chlorophenyl)-2,2-dimethyl propanamide (2.0 g, 9.456
mmol) in THF (32 ml) at -5.degree. C. was added n-butyl lithium
(1.51 g, 23.64 mmol) slowly. The temperature was maintained at
0.degree. C. for 3 h, then cooled to -70.degree. C., then
ethyl-1-methyl-1H-pyrazole-5-carboxylate (2.03 g, 13.23 mmol) in
THF (16 ml) was added and the temperature was maintained at
-70.degree. C. for 1 h. The reaction mixture was warmed to RT and
stirred overnight, water was added and the mixture extracted with
ether, washed with water, brine, dried over sodium sulphate and
concentrated. The crude intermediate was purified by column
chromatography.
[0496] 6N HCl (10 ml) and intermediate (1.2 g, 3.755 mmol) were
heated at 90.degree. C. overnight, cooled to room temperature, the
reaction mixture basified by adding saturated sodium bicarbonate
solution and extracted with ether. The organic layer was washed
with brine, dried over sodium sulfate and concentrated. The product
was purified by column chromatography using basic alumina. .sup.1H
NMR (CDCl.sub.3): 6.11 (bs, 2H, NH.sub.2), 6.7 (d, 1H, .sup.3J=6.6
Hz), 6.89 (s, 1H), 7.28 (m, 1H), 7.7 (s, 1H), 8.2 (s, 1H), 10.75
(bs, 1H). .sup.13C NMR (CDCl.sub.3): 109.25, 118.4, 118.5, 120.5,
132.4, 134.5, 149.4, 186.6. LC-MS m/e 222 (M+H).sup.+. HPLC [c18
BDS 25 min column, flow=0.8 ml/min (70:30; ACN: 0.1% TFA), rt=4.11
min].
Synthesis of
(2-Amino-5-chloro-phenyl)-([1H]-1-methyl-pyrazol-3-yl)-methanone
##STR00104##
[0498] To N-(4-Chlorophenyl)-2,2-dimethyl propanamide (2.0 g, 9.456
mmol) in THF (32 ml) at -5.degree. C. was added n-butyl lithium
(1.51 g, 23.64 mmol) slowly. The temperature was maintained at
0.degree. C. for 3 h, then cooled to -70.degree. C., then
ethyl-1-methyl-1H-pyrazole-5-carboxylate (2.03 g, 13.23 mmol) in
THF (16 ml) was added and the temperature was maintained at
-70.degree. C. for 1 h. The reaction mixture was warmed to RT and
stirred overnight, water was added and the mixture extracted with
ether, washed with water, brine, dried over sodium sulphate and
concentrated. The crude intermediate was purified by column
chromatography.
[0499] 6N HCl (10 ml) and intermediate (1.2 g, 3.755 mmol) were
heated at 90.degree. C. overnight, cooled to room temperature, the
reaction mixture basified by adding saturated sodium bicarbonate
solution and extracted with ether. The organic layer was washed
with brine, dried over sodium sulfate and concentrated. The product
was purified by column chromatography using basic alumina.
Synthesis of
(2-Amino-5-chloro-phenyl)-(3-methoxy-pyridin-4-yl)methanone
##STR00105##
[0501] To a solution of 3-picoline (50 g, 0.48 mol) in glacial
acetic acid (150 ml) was added hydrogen peroxide (25 ml) at room
temperature. The mixture was heated to 90.degree. C. for 3 hr. The
mixture was then cooled to RT and more hydrogen peroxide (18.5 ml)
was added slowly. The mixture was again heated to 90.degree. C. for
19 hr. The excess peroxide was cautiously decomposed by Pd--C (2.5
g) at 0.degree. C., the Pd--C was filtered, the filtrate was
concentrated yielding crude 3-methylpyridine-1-oxide which was
purified by fractional distillation in vacuo.
[0502] A solution of 3-methylpyridine-1-oxide (10 g, 0.092 mol) in
methyl iodide (15 ml) was left standing for 18 hr. The solid was
filtered. The filtrate was diluted with diethyl ether, extracted
with water (40 ml). The solid was dissolved in the aqueous layer in
a 250 ml 3-necked RB flask. 1,4-dioxane (50 ml) was added, followed
by potassium cyanide (15 g, 0.23 mol). The mixture was stirred at
RT for 3 hr. The product was extracted with chloroform, the
chloroform layer was washed with water, brine and dried over sodium
sulfate. The solvent was removed in vacuo and the crude was
purified by fractional distillation (61-62.degree. C./0.2 mm) as
white low melting solid.
[0503] BCl.sub.3 (24 ml, 1M in DCM, 0.024 mol) was added slowly to
a solution of 4-chloroaniline (2 g, 0.016 mol) in 30 ml of
trichloroethylene over a period of 15 min. at 0.degree. C. and
stirred at this temperature for an additional 10 min.
4-Cyano-3-methylpyridine (2.2 g, 0.019 mol) and AlCl.sub.3 (3 g,
0.022 mol) were added 0.degree. C. The solution was allowed to warm
to RT and stirred for 30 min. The solution was then heated at
80-90.degree. C. for 1 hr. and the DCM was distilled off. The
resulting solution was refluxed at 115.degree. C. for 4 hr and
stirred at RT over night. 3N HCl (20 ml) was added to the mixture
and refluxed at 100.degree. C. for 2 hr. The reaction mixture was
cooled to 0.degree. C. and was made basic (pH-12) with 6N NaOH and
the reaction mixture was extracted with DCM. The dichloromethane
layer was washed with water, brine and dried over Na.sub.2SO.sub.4.
The solvent was removed, and the crude material was purified by
column chromatography on silica gel.
Synthesis of
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone
##STR00106##
[0505] 2,6-lutidine (107 g, 1 mol) was dissolved in water (2.5 L)
and heated to 70.degree. C. To and KMnO.sub.4 (335 g, 2.1 mol)
added in 10 portions (each portion was added at 11/2 hours
interval). After complete addition of KMnO.sub.4, the reaction
mixture was heated at 70.degree. C. for another 5 h. The hot
reaction mixture was then filtered through a celite bed and the
residue was washed with hot water repeatedly. The filtrate was
extracted with ethyl acetate and the ethyl acetate layer was
discarded. The aqueous layer was concentrated to 500 ml and
acidified with HCl to pH exactly to 3.3. Benzene was added to the
aqueous layer and water was evaporated. Benzene was added to the
concentrated reaction mixture and refluxed for 10 minutes, filtered
hot and concentrated.
[0506] The intermediate 6-methyl picolinic acid (55 g, 0.0401 mol)
was dissolved in absolute ethanol (800 ml), conc. H.sub.2SO.sub.4
(55 ml) was added and the reaction refluxed overnight. Ethyl
alcohol was distilled out, water (200 ml) added and the pH was
brought to 9 adding solid NaHCO.sub.3. The reaction was extracted
with ethyl acetate, the organic layer washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated to yield the intermediate
ester.
[0507] 4-chloropivanilide (20 g, 0.0945 mol) was dissolved in
t-butyl methyl ether (200 ml) and distilled tetra methyl ethylene
diamine (TMEDA) (14.2 mL, 0.0945 mol), the reaction cooled to
-20.degree. C. and n-butyl lithium (0.22 mol, 2.7 molar solution in
hexane) was added. The temperature was maintained between 0 and
5.degree. C. for 2 h, then cooled to -15.degree. C. and the
intermediate ester (15.6 g, 0.0945 mol) was added. After a further
30 minutes, the reaction mixture was quenched with 3N HCl and
extracted with ethyl acetate. The ethyl acetate layer was separated
and the HCl layer was basified. The aqueous layer was again
extracted with ethyl acetate. Both the organic phases were
combined, washed with brine and dried over Na.sub.2SO.sub.4. The
crude material obtained on concentration of the dried organic phase
was subjected to column chromatography (using 60-120 mesh size
silica gel. Ethyl acetate: pet ether (10:100)) to afford pivaloyl
protected intermediate as a yellow solid (15 g, 47.9%).
[0508] The pivaloyl protected intermediate (15 g, 0.0453 mol) was
dissolved in methanol 150 ml), 40% KOH solution (60 ml) was added
to it and then heated overnight at 65.degree. C. under N.sub.2
atmosphere. The reaction mixture was concentrated and the aqueous
layer was extracted with ethyl acetate. The ethyl acetate layer was
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to
afford the crude compound. The compound was purified by column
chromatography (using 60-120 mesh size silica gel. Ethyl acetate:
pet ether (7:100)) to obtain pure title compound (8.5 g,
80.50%).
Synthesis of
(2-Amino-5-chloro-phenyl)-(1H-[1,2,3]triazol-4-yl)-methanone
##STR00107##
[0510] The title compound was prepared according to the procedure
previously described in the literature (EPO 0 574 781 A2).
Synthesis of
(5-Chloro-2-nitro-phenyl)-(3-methyl-[1,2,3]triazol-4-yl)-methanone
and (5-Chloro-2-nitro-phenyl)-(1-methyl-[1,2,3]triazol-4-yl)
methanone
##STR00108##
[0512] To 250 mg (1 mmol) of
(5-Chloro-2-nitro-phenyl)-(3H-[1,2,3]triazol-4-yl)-methanone (M. C.
Hsu, D. M. Huryn, and S. Y. K. Tam; EP 0 574 781 A2, filed May 6,
1993) and 214 mg (1.5 mmol) of iodomethane in 6 ml of an hydrous
N,N-Dimethylformamide at 0.degree. C. was added 80 mg (2 mmol) of
60% sodium hydride in oil. After 10 minutes, the flask was taken
out of the ice bath, and the mixture was stirred for an additional
hour. The reaction was quenched with water, partitioned between
water and ethyl acetate, and the phases were separated. The ethyl
acetate phase was washed twice with water, once with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to a
solid. The solid was chromatographed, using a 20% ethyl acetate in
hexane to a 40% ethyl acetate in hexane gradient, to give the two
title products as pure isomers.
Synthesis of
(2-Amino-5-chloro-phenyl)-(1-methyl-[1,2,3]triazol-4-yl)
methanone
##STR00109##
[0514] To 51 mg (0.19 mmol) of
(5-Chloro-2-nitro-phenyl)-(1-methyl-[1,2,3]triazol-4-yl)-methanone
in 2 ml of methanol were added 0.05 ml of 12M HCl and 200 mg (0.89
mmol) of stannous (II) chloride monohydrate, and the mixture was
heated at 100.degree. C. for four hours. The mixture was then
cooled to ambient temperature, partitioned between 1M NaOH and
ethyl acetate, and the phases were separated. The ethyl acetate
phase was washed once each with water and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to a solid.
The solid was chromatographed to give the title product as a yellow
solid.
Synthesis of
(2-Amino-5-chloro-phenyl)-(3-methyl-[1,2,3]triazol-4-yl)-methanone
##STR00110##
[0516] To 31 mg (0.12 mmol) of
(5-Chloro-2-nitro-phenyl)-(3-methyl-[1,2,3]triazol-4-yl)-methanone
in 1.5 ml of methanol were added 0.05 ml of 12M HCl and 200 mg
(0.89 mmol) of stannous (II) chloride monohydrate, and the mixture
was heated at 100.degree. C. for four hours. The mixture was then
cooled to ambient temperature, partitioned between 1M NaOH and
ethyl acetate, and the phases were separated. The ethyl acetate
phase was washed once each with water and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to a solid.
The solid was chromatographed to give the title product as a yellow
solid.
Synthesis of (2-Amino-5-chloro-phenyl)-(ozaxol-4-yl)-methanone
##STR00111##
[0518] n-Butyllithium (0.01739 mol, 2.5 molar in hexane) was added
to a solution of oxazole (1 g, 0.015 mol) in dry THF (55 ml) at
-78.degree. C. The reaction mixture was maintained at -78.degree.
C. for 0.5 h and 2-nitro-5-chloro benzaldehyde (2.68 g, 0.01449
mol) in dry THF (10 mL) was added. Then the temperature was brought
to -25.degree. C. and quenched with saturated NH.sub.4Cl solution.
The reaction mixture was diluted with ethyl acetate. The organic
layer was collected, washed with brine solution, dried over
Na.sub.2SO.sub.4 and concentrated. The product crude material
obtained was purified by column chromatography (using 60-120 mesh
size silica gel. Pet ether: Ethyl Acetate (100:18)) to obtain the
intermediate secondary alcohol.
[0519] Pyridiniumchlorochromate (PCC) (3.55 g, 0.0165 mol) was
added to a solution of the alcohol (1.4 g, 0.0055 mol) in dry
dichloromethane (200 ml), silica gel (10 g) was added and the
reaction mixture stirred at room temperature for 48 h. The solid
was filtered off and the filtrate concentrated. The solid residue
obtained was purified by column chromatography (using 60-120 mesh
size silica gel. Pet ether: Ethyl Acetate (100:13) as eluent) to
obtain intermediate nitroketone.
[0520] The nitroketone (800 mg, 0.00344 mol) was dissolved in
ethanol (25 ml), Pd--C (500 mg) was added to it and the reaction
mixture heated to 60.degree. C. and to the hot solution was added
hydrazine hydrate (0.344 g, 0.00688 mol). The reaction mixture was
then heated at 90.degree. C. for 15 min. The Pd--C was filtered off
from the reaction mixture and the filtrate was concentrated. This
residue was dissolved in DCM and the DCM layer washed with water,
brine, dried over Na.sub.2SO.sub.4 and concentrated to obtain pure
title compound.
Synthesis of (2-Amino-5-chloro-phenyl)-(thiazol-5-yl)-methanone
##STR00112##
[0522] n-BuLi (0.0609 mol, 2.5 molar solution in hexane) was taken
in dry ether and cooled to -78.degree. C. and 2-bromo thiazole (10
gm, 0.0609 mol) solution in ether (20 ml) was added during 40 min.
This reaction mixture was stirred at -78.degree. C. for 0.5 h and a
solution of trimethylchlorosilane (6.58 g, 0.0609 mol) in dry ether
was added and stirring continued for another 1 h. After quenching
with saturated NaHCO3 solution, the organic layer was collected and
concentrated. The residue so obtained was purified by distillation
under reduced pressure.
[0523] 2-trimethylsilylthiazole (1 g, 0.00636 mol) was dissolved in
dry THF (25 ml) and cooled to -78.degree. C. n-BuLi (0.0876 mol,
2.5 molar solution in hexane) was added at -78.degree. C. and the
temperature maintained at -78.degree. C. for 0.5 h.
2-nitro-5-chloro benzaldehyde (1.18 g, 0.00636 mol) in THF (10 ml)
was added at -78.degree. C. After addition was completed, the
temperature was raised to -25.degree. C. The reaction mixture was
quenched with saturated NH.sub.4Cl solution at -25.degree. C. and
diluted with ethyl acetate. The organic layer was washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated. The product
was purified by column chromatography (using 60-120 mesh size
silica gel. Pet ether: Ethyl Acetate (100:15) as eluent).
[0524] Pyridiniumchlorochromate (PCC) (1.27 g, 0.0059 mol) was
added to a solution of the intermediate alcohol (800 mg, 0.00295
mol) in dry DCM (1500 ml) followed by silica gel (10 g) and the
reaction mixture stirred for 48 h. The solid was filtered off and
the filtrate concentrated. The solid residue obtained was purified
by column chromatography (using 60-120 mesh size silica gel. Pet
ether: Ethyl Acetate (100:13) as eluent) to obtain nitroketone.
[0525] The nitroketone (790 mg, 0.00295 mol) was dissolved in
ethanol (25 ml), Pd--C (500 mg) was added to it and heated to
60.degree. C. and to this hot solution was added hydrazine hydrate
(0.294 g, 0.00588 mol). The reaction was then heated at 90.degree.
C. for 15 min. The Pd--C was filtered off and the filtrate was
concentrated. This residue was dissolved in DCM and the DCM layer
washed with water, brine, dried over Na.sub.2SO.sub.4 and
concentrated to obtain pure title compound
Synthesis of (2-amino-5-chloro-phenyl)-pyridin-2-yl-methanone
##STR00113##
[0527] To a stirred solution of
N-(4-chlorophenyl)-2,2-dimethylpropanamide (0.5 g, 0.0024 mol) and
TMEDA (0.278 g, 0.024 mol) in tert-butyl methyl ether (10 mL) was
added n-BuLi (0.384 g, 0.006 mol) at a temperature of -20.degree.
C. The mixture was allowed to stir at 0 to 5.degree. C. for 2 h,
then cooled to -20.degree. C. and methyl 2-pyridine carboxylate
(0.46 g, 0.0034 mol) added. The reaction mixture was maintained at
-15.degree. C. for half an hour, the mixture was stirred at room
temperature overnight, then quenched with HCl (5 mL, 1.5 N),
diluted with water, extracted with ethyl acetate (20 mL.times.2),
washed again with water, brine and dried over anhydrous sodium
sulfate. The crude product obtained upon evaporation was purified
by column chromatography using ethyl acetate:pet ether (7:93).
[0528] To a stirred solution of the intermediate pivaloyl protected
ketone (0.33 g, 0.001 mol) in methanol (10 mL) was added potassium
hydroxide solution (2 mL, 40%) and the reaction refluxed at
70.degree. C. for 15 h. The methanol was distilled off under vacuum
and the residue obtained was extracted with ethylacetate (20
mL.times.3), washed with water, brine and dried over anhydrous
sodium sulphate. The product obtained upon concentration was
recrystallized from ether and pet ether to yield title
compound.
Syntheses of Substituted Phenyl Sulfonyl Chlorides, including
heteroaryl, heterocycyl and [heteroaryl]alkyl substituted
systems
Synthesis of N-Methoxy-N-methyl-2-phenyl-isobutyramide
##STR00114##
[0530] To 6.55 g (39.7 mmol) of 2-phenyl-isobutyric acid in 100 ml
of dry methylene chloride at ambient temperature was added 12.5 g
(99 mmol) of oxalyl chloride. The bubbling stopped after 2 hours,
and the solution was concentrated in vacuo to give a clear oil.
[0531] The clear oil from above was dissolved in 30 ml of
dichloromethane, and was added to a rapidly stirring biphasic
mixture of 150 ml of saturated sodium bicarbonate containing 7.9 g
(79 mmol) of methoxymethylamine hydrochloride and 120 ml of
dichloromethane at 0.degree. C. The mixture was allowed to warm to
ambient temperature after 10 minutes, and the reaction was done
after an additional 40 minutes as judged by TLC. The mixture was
extracted once with 400 ml of ether, and the ether phase was washed
once each with 1M HCl and brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo to the title product as a clear
oil.
Synthesis of 3-Methyl-3-phenyl-butan-2-one
##STR00115##
[0533] To 2.1 g (10.1 mmol) of
N-Methoxy-N-methyl-2-phenyl-isobutyramide in 80 ml of dry
tetrahydrofuran at ambient temperature was added 6.7 ml (20.2 mmol)
of 3M methylmagnesium bromide in heptane, and the solution was
warmed to 60.degree. C. After 6 hours, the mixture was allowed to
cool to ambient temperature and was quenched with 1M HCl. The
resulting mixture was partitioned between water and ether, and the
phases were separated. The ether phase was washed once each with 1M
HCl and brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo to an oil. The oil was chromatographed to
give the title compound as a clear oil: .sup.1H NMR CDCl.sub.3
.delta. (ppm): 1.49 (s, 6H), 1.93 (s, 3H), 7.24-7.34 (m, 5H).
Synthesis of 4-(1-Methyl-1-phenyl-ethyl)-oxazole
##STR00116##
[0535] To 1.34 g (8.2 mmol) of 3-Methyl-3-phenyl-butan-2-one in 25
ml of dry chloroform at ambient temperature was added 1.44 g (9.0
mmol) of bromine, and the solution was warmed to 45.degree. C.
After 1 hour, the solution was allowed to cool to ambient
temperature and was concentrated in vacuo to an orange oil.
[0536] 1.72 g (7.1 mmol) of the oil was mixed with 20 ml of
anhydrous formamide, and the mixture was heated at 115.degree. C.
for 2.5 hours. The mixture was allowed to cool to ambient
temperature, partitioned between water and ether, and the phases
were separated. The ether phase was washed once each with water and
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo to an oil. The oil was chromatographed to give the title
compound as a colorless solid: .sup.1H NMR CDCl.sub.3 .delta.
(ppm): 1.68 (s, 6H), 7.16-7.35 (m, 6H), 7.81 (s, 1H).
Synthesis of 4-(1-Methyl-1-oxazol-4-yl-ethyl)-benzenesulfonyl
chloride
##STR00117##
[0538] To 261 mg (1.4 mmol) of 4-(1-Methyl-1-phenyl-ethyl)-oxazole
in 15 ml of chloroform at 0.degree. C. was added 0.49 gm (4.2 mmol)
of chlorosulfonic acid. After 30 minutes, the solution was allowed
to warm to ambient temperature and an additional 0.49 gm (4.2 mmol)
of chlorosulfonic acid was added. After one hour, the mixture was
cooled in an ice/water bath, and crushed ice was added to the
reaction. The mixture was partitioned between 1M pH=7 phosphate
buffer and ether, and the phases were separated. The ether phase
was washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo to give the crude title product as an
oil.
Synthesis of 2-Methyl-2-phenylpropionyl chloride
##STR00118##
[0540] A solution of 2-Methyl-2-phenylpropionic acid (10 mmol, 1.0
eq.) and oxalyl chloride (40 mmol, 4.0 eq.) in dichloromethane (30
mL) was stirred at room temperature for 18 h. The mixture was
concentrated in vacuo to afford the title compound as a yellow
oil.
Synthesis of 5-(1-Methyl-1-phenylethyl)oxazole
##STR00119##
[0542] To a solution of methyl isocyanide (1.3 mmol, 1.3 eq.) in
THF (5 mL) at -78.degree. C. was added dropwise a solution of
n-BuLi in Hexane (2.5 M, 1.3 mmol, 1.3 eq.). The resulting
yellowish solution was stirred at -78.degree. C. for an additional
45 min and 2-Methyl-2-phenylpropionyl chloride (1.0 mmol, 1.0 eq.)
was slowly added. The mixture was stirred at -78.degree. C. for an
additional 1 h and allowed to warm to room temperature followed by
the addition of saturated aqueous NaCl solution (5 mL). The mixture
was extracted by EtOAc (3.times.5 mL) and the combined organic
extracts were washed by saturated aqueous NaCl solution, dried by
Na.sub.2SO.sub.4, filtered and evaporated in vacuo. The residue was
further purified by flash chromatography (silica gel, 10%
EtOAc/Hexanes) to afford 5-(1-Methyl-1-phenylethyl)oxazole as a
colorless oil (101 mg, 54%). .sup.1H NMR: 6 (400 MHz, CDCl.sub.3)
7.74 (s, 1H), 7.30 (m, 2H), 7.23 (m, 3H), 6.85 (s, 1H), 1.69 (s,
6H). MS (M+H.sup.+): 188.1
Synthesis of 4-(1-Methyl-1-oxazol-5-yl-ethyl)benzenesulfonyl
chloride
##STR00120##
[0544] A solution of 5-(1-Methyl-1-phenylethyl)oxazole (3.87 mmol,
1.0 eq.) in CDCl.sub.3 (0.3 mL) was stirred at 0.degree. C. and
chlorosulfonic acid (11.7 mmol, 3.0 eq.)was slowly added in. The
mixture was heated to 60.degree. C. for 3 h and cooled to room
temperature. The solution was further mixed with crushed ice (15 g)
and extracted with EtOAc (3.times.15 mL). The extracts were
combined, washed by saturated aqueous NaCl solution, dried by
MgSO.sub.4, filtered and concentrated in vacuo to afford the title
compound as a pale yellow oil (697 mg, 63%) which was used as it
was. .sup.1H NMR: .delta. (400 MHz, CDCl.sub.3) 7.97 (d, 2H), 7.83
(s, 1H), 7.47 (d, 2H), 6.96 (s, 1H), 1.74 (s, 6H). MS (M+H.sup.+):
286.0
Synthesis of 4-(2-methyl-oxazol-5-yl)-benzenesulfonyl chloride
##STR00121##
[0546] 2-Methyl-5-phenyl-oxazole (1.6 g, 10 mmol), prepared
according to the literature procedure (Varma, R. S.; Kumar, D. J.
Heterocyclic Chem., 1998, 35, 1533), was dissolved in
chlorosulfonic acid (10 mL) and stirred at room temperature for 16
h. The reaction mixture was added to crushed ice (50 g) and the
product was extracted with ether (3.times.50 mL). The combined
organic extract was dried over anhydrous Na2SO4 and ether was
evaporated. The product was purified by flash chromatography
(silica-gel, 5-20% ethylacetate/hexane mobile phase) to yield 0.82
g of the desired title compound as tan solid. MS: m/z 258.0
(M.sup.++1).
Synthesis of 2-Phenethyloxazole
##STR00122##
[0548] A mixture of hydrocinnamoyl chloride (5 mmol, 1.0 eq.),
1,2,3-triazole (7 mmol, 1.4 eq.) and K.sub.2CO.sub.3 (10 mmol, 2.0
eq.) in tetramethylenesulfone (10 mL) was heated to 140.degree. C.
for 15 minutes and was allowed to cool to room temperature. The
mixture was diluted with aqueous saturated NaCl solution (30 mL)
and extracted with EtOAc (3.times.10 mL). The extracts were
combined, dried by Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was further purified by flash column
chromatography (silica gel, 10% EtOAc/hexanes) to afford 1 as a
colorless oil (784 mg, 91%). .sup.1H NMR: .delta. (400 MHz,
CDCl.sub.3) 7.55 (d, 1H), 7.29 (m, 2H), 7.20 (m, 3H), 7.02 (s, 1H),
3.10 (s, 4H). MS (M+H.sup.+): 174.0
Synthesis of 4-(2-Oxazol-2-yl-ethyl)benzenesulfonyl chloride
##STR00123##
[0550] A solution of 2-Phenethyloxazole (1.74 mmol, 1.0 eq.) in
CDCl.sub.3 (0.2 mL) was stirred at 0.degree. C. and chlorosulfonic
acid (6.96 mmol, 4.0 eq.) was slowly added in. The mixture was
heated to 60.degree. C. for 1 h and cooled to room temperature. The
solution was further mixed with crushed ice (5 g) and extracted
with EtOAc (3.times.5 mL). The extracts were combined, washed by
saturated aqueous NaCl solution, dried by MgSO.sub.4, filtered and
concentrated in vacuo. The residue was further purified by flash
column chromatography (silica gel, 10% EtOAc/hexanes) to afford 2
as a white solid (275 mg, 58%). .sup.1H NMR: .delta. (400 MHz,
CDCl.sub.3) 7.95 (d, 2H), 7.58 (s, 1H), 7.44 (d, 2H), 7.04 (s, 1H),
3.25 (t, 2H), 3.16 (t, 2H). MS (M+H.sup.+): 372.0
Synthesis of 4-(4-methyl-oxazol-5-yl)-benzenesulfonyl chloride
##STR00124##
[0552] 4-methyl-5-phenyl-oxazole (1.6 g, 10 mmol), prepared
according to the literature (Heterocycles, 1977, 7, 77-80), was
dissolved in chlorosulfonic acid (10 mL) and stirred at room
temperature for 4 h. The reaction mixture was added to crushed ice
(50 g) and the product was extracted with ether (3.times.50 mL).
The combined organic extract was dried over anhydrous Na.sub.2SO4
and ether was evaporated. The product was purified by flash
chromatography (silica-gel, 5-20% ethylacetate/hexane mobile phase)
to yield 0.91 g of the desired title compound light yellow solid.
MS: m/z 258.0 (M.sup.++1).
Synthesis of 4-ethoxycarbonyl-benzenesulfonyl chloride
##STR00125##
[0554] To 4-Aminobenzoic acid (10.0 g, 0.0729 mol) in 100 ml of
absolute ethanol was added 10.4 ml of concentrated sulphuric acid
dropwise and the mixture refluxed overnight. The reaction mixture
was then neutralized with saturated sodium bicarbonate solution and
concentrated to remove ethanol. The aqueous layer was extracted
with ethyl acetate, the organic layer was washed with brine, dried
over sodium sulfate and concentrated.
[0555] To water (0198.8 ml) at 0.degree. C. was added thionyl
chloride (42.9 g, 0.3605 mol) dropwise. The reaction was stirred at
18.degree. C. for 17 h, then cooled to -2.degree. C. to 0.degree.
C., then copper (I) chloride (0.120 g) was added in small portions
to get a yellowish green solution.
[0556] Ethyl 4-aminobenzoate (14.0 g, 0.0848 mol) was added slowly
to concentrated HCl (109.2 ml) and stirred at RT for 15 min, then
the reaction was cooled to -5.degree. C. to 0.degree. C. Sodium
nitrite (6.2 g, 0.1103 mol) in 26 ml of water was added dropwise
and stirring at the same temperature continued for 15 min.
[0557] The thionyl chloride derived solution was added dropwise to
solution B at -5.degree. C. to 0.degree. C., followed by stirring
at 0.degree. C. for 75 min. The reaction mixture was diluted with
chloroform. The organic layer was separated, dried over sodium
sulphate and concentrated.
Synthesis of 4-(1-Methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl
chloride
##STR00126##
[0559] 2-Methyl-2-phenyl-propionic acid (8.2 g, 50 mmol) dissolved
in 50 mL thionyl chloride was stirred at room temperature for 2 h
and heated at 80 C for an additional 1 h. The excess thionyl
chloride was evaporated under vacuum to yield light brown oil. To
this oil was added 1,2,3-triazole (4.8 g 70 mmol), K2CO3 (13.8 g,
100 mmol) and tetramethylene sulfone (50 mL) and the mixture was
heated at 140 C for about 30 min and was allowed to cool to room
temperature. The reaction mixture was added to water (100 mL) and
extracted with ethylacetate (3.times.50 mL). The combined organic
extract was washed with saturated brine dried over anhydrous sodium
sulfate and the solvent was evaporated. The residue was further
purified by flash column chromatography (silica gel, 0-20%
EtOAc/hexanes) to afford 2-(1-methyl-1-phenyl-ethyl)-oxazole as a
viscous oil (6.7 g). MS: m/z 188 (M.sup.++1). The viscous oil was
cooled on ice bath and treated with chlorosulfonic acid (15 mL).
After stirring for 1 h on ice bath the mixture was allowed to warm
to room temperature and stir overnight.
[0560] Crushed ice (50 g) was added and the mixture stirred till
all the ice melted. The product was extracted with ether
(3.times.50 mL), dried over anhydrous sodium sulfate, concentrated
by rotary evaporation and further purified by flash chromatography
to yield tan solid (7.1 g). MS: m/z 286 (M.sup.++1).
Synthesis of (oxazol-5-yl)-benzenesulfonyl chloride
##STR00127##
[0562] To Benzaldehyde (5.0 g) in methanol (50 ml) was added dry
potassium carbonate (7.2 g) followed by TosMIC (10.0 g). The
reaction mixture was stirred at 65.degree. C. for 2 h. The solvent
was evaporated and the residue was dissolved in ethyl acetate. The
ethyl acetate solution was washed with water, brine and
concentrated, to yield a yellow solid.
[0563] 5-Phenyloxazole (2.0 g, mmol) in chloroform (50 ml) was
cooled to 0.degree. C. using an ice bath. Chlorosulfonic acid 4.8 g
(2.7 ml, 3 eq) of was added slowly with stirring. The reaction
mixture was heated to 70.degree. C. for 16 h. The reaction mixture
was then cooled to RT, quenched with ice and extracted with
chloroform. The organic layer was washed with cold water, brine and
concentrated. The brown solid obtained was purified by column
chromatography using 5% ethyl acetate in pet ether as eluent, to
yield a yellow solid.
Synthesis of 4-(4-Methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl
chloride
##STR00128##
[0564] Synthesis of 3-Methyl-3-phenyl-pentane-1,5-diol
##STR00129##
[0566] The title compound was prepared was the procedure described
in the literature (S. M. McElvain and David H. Clemens; J. Am.
Chem. Soc. 1958, 3915-3923). MS: m/z 195.1 (M.sup.++1).
Synthesis of 4-Methyl-4-phenyl-tetrahydro-pyran
##STR00130##
[0568] 3-Methyl-3-phenyl-pentane-1,5-diol (3.88 g, 20 mmol),
Ag.sub.2O (6.95 g (30 mmol), potassium iodide (0.66 g, 4 mmol) were
suspended in 50 mL DCM and treated with a solution of
p-toluenesulfonyl chloride (4.19 g, 22 mmol) in 30 mL DCM. The
mixture was allowed to stir under nitrogen atmosphere for 16 h. The
crude reaction mixture was applied on a short plug of silica gel
column and the product was collected by washing with DCM. The
solvent was evaporated and the residue was dissolved in dry THF (30
mL) and added drop wise to a suspension of NaH (0.8 g of 60%
suspension in mineral oil, 20 mmol) in THF (30 ml). The reaction
mixture was allowed to stir at room temperature for 24 h and was
then diluted with 60 mL ether and washed with water (60 mL). The
aqueous phase was washed once with ether (30 mL) and the organic
extracts were combined, washed with brine, dried over Na.sub.2SO4
and the solvent was evaporated by rotary evaporation. The product
was purified by flash chromatography on silica gel column using
0-5% hexane/ethylacetate solvent mixture as the mobile phase. MS:
m/z 177.1 (M.sup.++1).
Synthesis of 4-(4-Methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl
chloride
##STR00131##
[0570] To a magnetically stirred mixture of
4-methyl-4-phenyl-tetrahydro-pyran (1.10 g, 6.24 mmol) in dry
methylene chloride (50 mL) cooled in an ice bath was added 2.07 mL
of chlorosulfonic acid (3.64 g, 31.2 mmol) dropwise under dry
nitrogen. The reaction was stirred overnight at room temperature;
the reaction was added to ice and the product was extracted with
methylene chloride (3.times.100 mL). The organic layer was washed
with saturated brine, dried (MgSO.sub.4), filtered and
concentrated. e product was chromatographed on silica gel using
ethyl acetate-hexane mixtures (2-20% hexane). Removal of solvent
provided pure product as a colorless syrup which crystallized on
standing: .sup.1H NMR (CDCl.sub.3) .delta. 7.99 (d, 2H, J=8.8 Hz),
7.56 (d, 2H, J=8.8 Hz), 3.79 (ddd, 1H, J=11.7 Hz, J=8.4 Hz, J=3.3
Hz), 3.70 (ddd, 1H, J=11.7 Hz, J=6.0 Hz, J=3.8 Hz), 2.11 (ddd, 1H,
J=13.8 Hz, J=8.4 Hz, J=3.8 Hz), 1.81 (dm, 1H, J=13.8 Hz), 1.35 (s,
3H). MS: m/z 275 (M.sup.++1).
Synthesis of 3-([1H]-1,2-methyl-tetrazol-3-yl)-benzenesulfonyl
chloride
##STR00132##
[0572] Benzonitrile (10 g, 97 mmol), sodium azide (6.93 g, 106.6
mmol) and NH.sub.4Cl (5.7 g, 106.6 mmol) in dry DMF (100 ml) were
refluxed at 160.degree. C. overnight and the reaction mixture was
then poured into ice cold water, the pH was adjusted to 2 by adding
2N HCl and the solid filtrate collected to yield the
phenyltetrazol.
[0573] 5-phenyl-2-H-tetrazole (4 g, 27.36 mmol) was taken into NaOH
(2.18 g, 54 mmol, dissolved in 10 ml of water), cooled to 0.degree.
C., methyl iodide (8.5 g, 60 mmol, dissolved in 40 ml acetone) was
added and the reaction mixture was refluxed at 55.degree. C. for 2
hours. The solvent was evaporated and the residue was dissolved in
benzene. The benzene layer was washed with water, brine, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
purified by column chromatography using 60-120 mesh size silica gel
(10% ethyl acetate in pet-ether as eluent) to obtain
2-methyl-5-phenyl-2H-tetrazole as white solid (2 g, 46%).
[0574] 2-methyl-5-phenyl-2H-tetrazole (0.5 g, 3.12 mmol) was taken
into chlorosulfonic acid (5 ml) and heated to 80.degree. C.
overnight. The reaction mixture was then cooled to 0.degree. C.,
quenched with ice cold water and extracted with ethyl acetate. The
organic phase was washed with water, brine solution, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
crystallized from dichloromethane to yield title compound.
Synthesis of
N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(2-methyl[1,3]dioxolan-2-yl-
)-benzenesulfonamide
##STR00133##
[0576] A solution consisting of 0.21 g of
4-acetyl-N-[4-chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-benzenesulfo-
namide, 2 mL anhydrous THF, 50 .mu.L AcOH and 400 .mu.L ethylene
glycol was prepared in a vial. The vial was heated by swaying
gently in front of a heat gun, cooled for one minute and 400 .mu.L
46.5% BF.sub.3:Et.sub.2O were immediately added. The vial was
quickly shaken, left standing and an LC-MS sample was taken after 1
minute of reaction. After another minute the reaction mixture was
partitioned between 10 mL DCM and 10 mL H.sub.2O. To the reaction
mixture was then added an additional 20 mL DCM and 20 mL aqueous 1
M NaOH. The pH of the aqueous layer was brought to 3 using HCl and
then quickly brought to pH 8-9 using saturated NaHCO.sub.3. The DCM
layer was collected, the aqueous layer was extracted with DCM
(2.times.20 mL) and all organic layers were combined and
concentrated by rotary evaporation. The product was isolated by
preparative HPLC, and the fractions containing the product were
concentrated to a volume of 15 mL. To this solution was added 3 mL
3 M NaOH and 0.52 g KMnO4. The reaction was stirred at RT,
monitored by LC-MS and additional KMnO4 (0.55 g.times.2) was added
at intervals of ca. 2 hours. After a total r.times.n time of ca. 5
h, the crude mixture was brought to pH 4 using 10% AcOH, extracted
with DCM (125 mL) and washed with saturated aqueous NaHCO.sub.3.
The DCM was removed by rotary evaporation and the product was
obtained by preparative HPLC. MS: m/z 459 (M.sup.++1).
[0577] The procedure described above was used to synthesize
analogous compounds as described for the following two compounds
shown below:
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(2,4-dimethyl-[1,3]dioxolan--
2-yl)-benzenesulfonamide
##STR00134##
[0579] The title compound was prepared using
4-Acetyl-N-[4-chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-benzenesulfo-
namide and propane-1,2-diol following the procedure described in
the preceding example. MS: m/z 473 M.sup.++1).
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-((4R,5S)-2,4,5-trimethyl-[1,-
3]dioxolan-2-yl)-benzenesulfonamide
##STR00135##
[0581] The title compound was prepared using
4-Acetyl-N-[4-chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-benzenesulfo-
namide and (2R,3S)--Butane-2,3-diol following the procedure
described in the preceding two examples. MS: m/z 487
M.sup.++1).
Synthesis of
4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-3-([1H]-112-methyl-tetrazol-3-yl-
)-benzenesulfonamide
##STR00136##
[0583] 3-([1H]-1-methyl-tetrazol-3-yl)-benzenesulfonyl chloride
(0.3 g, 1.28 mmol) and the parent benzophenone (0.5 g, 1.93 mmol)
were dissolved in dry pyridine (10 ml) and heated overnight at
100.degree. C. The reaction mixture was then diluted with
dichloromethane and this layer was washed with water and brine
solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated.
The residue was purified by column chromatography using 60-120 mesh
size silica gel (Pet ether/ethyl acetate as eluent) to afford the
title compound as yellow solid.
Synthesis of
4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
##STR00137##
[0585] 4-Bromo-benzenesulfonyl chloride 27.5 g (107 mmol) was
dissolved in 180 ml of anhydrous pyridine. To this solution was
added (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone 25 g (107
mmol). The reaction mixture was stirred under nitrogen 5 hour at
80.degree. C. and pyridine was then evaporated under vacuum. The
resulting crude material was dissolved in dichloromethane, and
extracted with saturated bicarbonate solution. The combined organic
layer was washed with brine dried over magnesium sulfate, filtered
and concentrated, then ethyl acetate (50 mL) added to the solid,
the solid was filtered, washed again with ethyl acetate, to yield a
pale yellow solid: LC-MSD, m/z for
C.sub.18H.sub.12BrClN.sub.2O.sub.3S [M+H]+: 452.9
[0586] Retention time on reverse phase HPLC gradient 20%-95%: 7
minutes: 4.307
Synthesis of
N-[4-Chloro-2(pyridine-4-carbonyl)-phenyl]-4-morpholin-4-yl-benzenesulfon-
amide
##STR00138##
[0588]
4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonam-
ide 0.1 g (0.22 mmol), was dissolved in 6 ml anhydrous dioxane, and
to this solution was added potassium phosphate tribasic monohydrate
0.3 g (1.32 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
0.02 g (0.032 mmol), followed by morpholine 0.95 g (1.1 mmol). The
mixture was purged under nitrogen, and Pd (dba).sub.3 10 mg (0.01
mmol) was added. The reaction mixture was heated overnight at
90.degree. C., cooled, water (5 mL) added, and extracted with ethyl
acetate 3 times. The combined organic layer was washed with brine,
dried over magnesium sulfate, filtered and concentrated. The crude
reaction mixture was purified using HPLC with a gradient of 20 to
95% acetonitrile over 40 minutes, to yield a yellow solid: LC-MSD,
m/z for C.sub.22H.sub.20ClN.sub.3O.sub.4S [M+H]+: 458
[0589] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.952
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-piperidin-1-yl-benzenesulfo-
namide
##STR00139##
[0591] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g
(3.96 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.12 g
(0.198 mmol), piperidine 0.28 g (3.3 mmol) and Pd (dba).sub.3 60 mg
(0.066 mmol) in 6 ml dioxane. The crude reaction mixture was
purified using HPLC to yield the title compound as a yellow
solid.
[0592] LC-MSD, m/z for C.sub.23H.sub.22ClN.sub.3O.sub.3S [M+H]+:
456
[0593] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
5.037
Synthesis of
N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-4-pyrrolidin-1-yl-benzenesulf-
onamide
##STR00140##
[0595] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g
(3.96 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.12 g
(0.198 mmol), pyrrolidine 0.23 g (3.3 mmol) and Pd (dba).sub.3 60
mg (0.066 mmol) in 6 ml dioxane, yielding title compound after HPLC
purification.: LC-MSD, m/z for C.sub.22H.sub.20ClN.sub.3O.sub.3S
[M+H]+: 442.1
[0596] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.853
Synthesis of
N-[4-Chloro-2(pyridine-4-carbonyl)-phenyl]-4-(1,1-dioxo-thiomorpholin-4-y-
l)-benzenesulfonamide
##STR00141##
[0598] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g
(3.96 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.12 g
(0.198 mmol), thiomorpholine 1,1-dioxide 0.44 g (3.3 mmol) and Pd
(dba).sub.3 60 mg (0.066 mmol) in 6 ml dioxane, followed by work up
and HPLC purification: LC-MSD, m/z for
C.sub.22H.sub.20ClN.sub.3O.sub.3S.sub.2 [M+H]+: 502
[0599] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.743
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(cis-2,6-dimethyl-morpholin-
-4-yl)-benzenesulfonamide
##STR00142##
[0601] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g
(3.96 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.12 g
(0.198 mmol), cis-2,6-dimethylmorpholine 0.37 g (3.3 mmol) and Pd
(dba).sub.3 60 mg (0.066 mmol) in 6 ml dioxane, followed by work up
and HPLC purification: LC-MSD, m/z for
C.sub.24H.sub.24ClN.sub.3O.sub.4S [M+H]+: 486.0
[0602] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.539
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-thiomorpholin-4-yl-benzenes-
ulfonamide
##STR00143##
[0604] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g
(3.96 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.12 g
(0.198 mmol), thiomorpholine 0.34 g (3.3 mmol) and Pd (dba).sub.3
60 mg (0.066 mmol) in 3 ml DMF followed by work up and HPLC
purification: LC-MSD, m/z for
C.sub.22H.sub.20ClN.sub.3O.sub.3S.sub.2 [M+H]+: 474.0
[0605] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.714
Synthesis of
N-[4-Chloro-2(pyridine-4-carbonyl)-phenyl]-4-piperazin-1-yl-benzenesulfon-
amide
##STR00144##
[0607] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
0.1 g (0.22 mmol), potassium phosphate tribasic monohydrate 0.30 g
(1.2 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.02 g
(0.032 mmol), piperazine-1-carboxylic acid tert-butyl ester 0.18 g
(1 mmol) and Pd (II) trifluoroacetate 10 mg (0.01 mmol) in 6 ml
dioxane. The compound was then deprotected to yield free amine
using dichloromethane (2 mL) with trifluoroacetic acid (3 mL) for 1
hour at room temperature. The crude material was concentrated under
vacuo, purified by HPLC, to give yellow solid.
[0608] LC-MSD, m/z for C.sub.22H.sub.21ClN.sub.4O.sub.3S [M+2H]+:
458.0
[0609] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.952
Synthesis of
4-Azetidin-1-yl-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfon-
amide
##STR00145##
[0611] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g
(3.96 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.12 g
(0.198 mmol), azetidine 0.18 g (3.3 mmol) and Pd (dba).sub.3 60 mg
(0.066 mmol) in 3 ml DMF, followed by workup and HPLC
purification.
[0612] LC-MSD, m/z for C.sub.21H.sub.18ClN.sub.3O.sub.3S [M+H]+:
428
[0613] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.77
Synthesis of
4-Bromo-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamide
##STR00146##
[0615] The title compound was prepared according to the general
procedures for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone 5 g (21.5 mmol)
and 4-bromo-benzenesulfonyl chloride 5.78 g (21.5 mmol), in 150 ml
anhydrous pyridine, overnight at 80.degree. C., followed by flash
column chromatography on silica gel to yield a salmon color
solid.
[0616] LC-MSD, m/z for C.sub.18H.sub.12BrClN.sub.2O.sub.3S [M+H]+:
452.9
[0617] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.584
Synthesis of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-(cis-2,6-dimethyl-morpholin-
-4-yl)-benzenesulfonamide
##STR00147##
[0619] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamide
0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g
(3.96 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.12 g
(0.198 mmol), cis-2,6-dimethylmorpholine 0.37 g (3.3 mmol) and Pd
(dba).sub.3 60 mg (0.066 mmol) in 3 ml DMF, followed by work up and
HPLC purification to yield yellow title compound.
[0620] LC-MSD, m/z for C.sub.24H.sub.24ClN.sub.3O.sub.4S [M+H]+:
516.1
[0621] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.242
Synthesis of
4-Bromo-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfo-
namide
##STR00148##
[0623] The title compound was prepared according to the general
procedures for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-ethanone 1.5 g
(6.1 mmol), and 4-bromo-benzenesulfonyl chloride 1.55 g (6.1 mmol),
stirred in 12 ml anhydrous pyridine, for 2 days room temperature,
yielded title compound as a yellow solid.
[0624] LC-MSD, m/z for C.sub.19H.sub.14BrClN.sub.2O.sub.3S [M+H]+:
466.9
[0625] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.77
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-(cis-2,6-dimethyl--
morpholin-4-yl)-benzenesulfonamide
##STR00149##
[0627] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfo-
namide. 0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate
0.91 g (3.96 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
0.12 g (0.198 mmol), cis-2,6-dimethylmorpholine 0.37 g (3.3 mmol)
and Pd (dba).sub.3 60 mg (0.066 mmol) in 3 ml DMF, followed by
workup and HPLC purification to yield yellow title compound.
[0628] LC-MSD, m/z for C.sub.25H.sub.26ClN.sub.3O.sub.4S [M+H]+:
500.1
[0629] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.796
Synthesis of
4-Bromo-N-[4-chloro-2-(2-pyridine-4-carbonyl)-phenyl]-3-fluoro-benzenesul-
fonamide
##STR00150##
[0631] The title compound was prepared according to the general
procedures for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-pyridine-4-yl-methanone 2 g (7.8 mmol),
and 4-bromo-3-fluoro-benzenesulfonyl chloride 2.56 g (9.4 mmol),
with stirring in 14.4 ml anhydrous pyridine, at 80.degree. C.
overnight, to yield yellow title compound.
[0632] LC-MSD, m/z for C.sub.18H.sub.21BrFClN.sub.2O.sub.3S [M+H]+:
470.9 R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.78
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-3-fluoro-4-morpholin-4-yl-ben-
zenesulfonamide
##STR00151##
[0634] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(2-pyridine-4-carbonyl)-phenyl]-3-fluoro-benzenesul-
fonamide. 0.15 g (0.3 mmol), potassium phosphate tribasic
monohydrate 0.41 g (18 mmol),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.03 g (0.045
mmol), morpholine 0.13 g (1.5 mmol) and Pd (dba).sub.3 10 mg (0.011
mmol) in 2 ml DMF, followed by workup and HPLC purification.
[0635] LC-MSD, m/z for C.sub.22H.sub.19ClN.sub.3O.sub.4SF [M+H]+:
476.0
[0636] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.472
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(cis-2,6-dimethyl-morpholin-
-4-)yl-3-fluoro-benzenesulfonamide
##STR00152##
[0638] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(2-pyridine-4-carbonyl)-phenyl]-3-fluoro-benzenesul-
fonamide. 0.15 g (0.3 mmol), potassium phosphate tribasic
monohydrate 0.41 g (1.8 mmol),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.05 g (0.09 mmol),
cis-2,6-dimethyl-morpholin 0.13 g (1.5 mmol) and Pd (dba).sub.3 0.4
mg (0.04 mmol) in 2 ml DMF, followed by workup and purification
using silica gel chromatography (gradient of dichloromethane to 1-1
dichloromethane-ethyl acetate), to yield a light yellow solid.
[0639] LC-MSD, m/z for C.sub.24H.sub.23ClN.sub.3O.sub.4SF [M+H]+:
504.1
[0640] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
5.024
Synthesis of
4-Bromo-N-[4,5-difluoro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamid-
e
##STR00153##
[0642] The title compound was prepared according to the general
procedures for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-4,5-difluoro-phenyl)-pyridin-3-yl-methanone 1 g (4.27
mmol) and 4-bromo-benzenesulfonyl chloride 1.15 g (4.27 mmol) with
stirring in 20 ml pyridine. Purification on silica gel with flash
column chromatography yielded light orange solid
[0643] LC-MSD, m/z for C.sub.18H.sub.11N.sub.2O.sub.2S F.sub.2
[M+H]+:454.9
[0644] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.574
Synthesis of
N-[4,5-Difluoro-2-(pyridine-3-carbonyl)-phenyl]-4-morpholin-4-yl-benzenes-
ulfonamide
##STR00154##
[0646] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4,5-difluoro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamid-
e 0.2 g (0.44 mmol), potassium phosphate tribasic monohydrate 0.607
g (2.64 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
0.082 g (0.06 mmol), morpholine 0.30 g (2.2 mmol) and Pd
(dba).sub.3 0.06 g (0.06 mmol) in 2 ml DMF. HPLC purification gave
yellow title compound.
[0647] LC-MSD, m/z for C.sub.22H.sub.19N.sub.3O.sub.4S F.sub.2
[M+H]+: 502
[0648] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.918
Synthesis of
4-Bromo-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-3-fluoro-ben-
zenesulfonamide
##STR00155##
[0650] The title compound was prepared according to the general
procedures for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone 2.4 g
(8.77 mmol) and 4-bromo-3-fluoro-benzenesulfonyl chloride 2.16 g
(8.77 mmol) stirred in 14 ml pyridine. Purification on silica gel
with flash column chromatography gave a light orange solid.
[0651] LC-MSD, m/z for C.sub.19H.sub.13N.sub.2O.sub.3S FBrCl
[M+H]+: 484.9
[0652] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.875
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-3-fluoro-4-morpholin-
-4-yl-benzenesulfonamide
##STR00156##
[0654] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-3-fluoro-ben-
zenesulfonamide 0.2 g (0.4 mmol), potassium phosphate tribasic
monohydrate 0.570 g (2.4 mmol),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.077 g (0.12
mmol), morpholine 0.17 g (2 mmol) and Pd (dba).sub.3 0.057 g (0.06
mmol) in 2 ml DMF. HPLC purification gave a yellow compound.
[0655] LC-MSD, m/z for C.sub.23H.sub.21ClN.sub.3O.sub.4S F [M+H]+:
490.1
[0656] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.603
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-(cis-2,6-dimethyl--
morpholin-4-yl)-3-fluoro-benzenesulfonamide
##STR00157##
[0658] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-3-fluoro-ben-
zenesulfonamide 0.2 g (0.4 mmol), potassium phosphate tribasic
monohydrate 0.570 g (2.4 mmol),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.077 g (0.12
mmol), cis-2,6-dimethyl-morpholine 0.23 g (2 mmol) and Pd
(dba).sub.3 0.057 g (0.06 mmol) in 2 ml DMF. HPLC purification gave
yellow compound.
[0659] LC-MSD, m/z for C.sub.25H.sub.25ClN.sub.3O.sub.4S F [M+H]+:
518.1
[0660] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
5.084
Synthesis of
4-Bromo-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfo-
namide
##STR00158##
[0662] The title compound was prepared according to the general
procedures for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-(pyridin-3-yl)-methanone 2 g (8.7 mmol)
and 4-bromo-3-fluoro-benzenesulfonyl chloride 2.35 g (8.77 mmol) in
15 ml pyridine. Purification with silica chromatography eluted with
dichlorometane:10-ethyl acetate gave a yellow powder.
[0663] LC-MSD, m/z for C.sub.18H.sub.11ClN.sub.2O.sub.4SBrF [M+H]+:
470
[0664] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.801
Synthesis of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-(cis-2,6-dimethyl-morpholin-
e-4-yl]-3-fluoro-benzenesulfonamide
##STR00159##
[0666] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfo-
namide 0.2 g (0.42 mmol), potassium phosphate tribasic monohydrate
0.58 g (2.56 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
0.079 g (0.12 mmol), cis-2,6-dimethyl-morpholine 0.24 g (2.13 mmol)
and Pd (dba).sub.3 0.057 g (0.06 mmol) in 2 ml DMF. HPLC
purification gave a pale yellow compound.
[0667] LC-MSD, m/z for C.sub.24H.sub.23ClN.sub.3O.sub.4S F [M+H]+:
504.1
[0668] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
5.026
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-morpholin-4-yl-benzen-
esulfonamide
##STR00160##
[0670] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl substituted
phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonam-
ide 0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate
0.911 g (3.96 mmol),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.12 g (0.18 mmol),
morpholine 0.26 g (3 mmol) and Pd (dba).sub.3 0.16 g (0.18 mmol) in
2 ml DMF. HPLC purification gave yellow compound
[0671] LC-MSD, m/z for C.sub.22H.sub.20ClN.sub.3O.sub.5S
[M+H]+:474.0
[0672] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.660
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-(cis-2,6-dimethyl-mor-
pholin-4-yl)-benzenesulfonamide
##STR00161##
[0674] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl substituted
phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonam-
ide 0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate
0.911 g (3.96 mmol),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.12 g (0.18 mmol),
cis-2,6-dimethyl-morpholine 0.37 g (3 mmol) and Pd (dba).sub.3 0.12
g (0.12 mmol) in 2 ml DMF. Purification by HPLC gave yellow
compound.
[0675] LC-MSD, m/z for C.sub.24H.sub.24ClN.sub.3O.sub.5S [M+H]+:
502.1
[0676] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.852
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-(cis-2,6-dimethyl-mor-
pholin-4-yl)-3-fluoro-benzenesulfonamide
##STR00162##
[0678] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-3-fluoro-benzen-
esulfonamide 0.25 g (0.5 mmol), potassium phosphate tribasic
monohydrate 0.68 g (3 mmol),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.09 g (0.14 mmol),
cis-2,6-dimethyl-morpholine 0.3 g (2.5 mmol) and Pd (dba).sub.3
0.135 g (0.14 mmol) in 2 ml DMF. HPLC purification gave a yellow
compound.
[0679] LC-MSD, m/z for C.sub.24H.sub.23ClN.sub.3O.sub.5S F [M+H]+:
520.1
[0680] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.446
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-4-(cis-2,6-dimethyl-mor-
pholin-4-yl)-3-fluoro-benzenesulfonamide
##STR00163##
[0682] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described
[0683] LC-MSD, m/z for C.sub.24H.sub.23ClN.sub.3O.sub.5S F [M+H]+:
502.1, 503.1
[0684] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.230
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-3-carbonyl-6-methyl)-phenyl]-4-(morpholin-4-
-yl)-3-fluoro-benzenesulfonamide
##STR00164##
[0686] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described
[0687] LC-MSD, m/z for C.sub.24H.sub.23ClN.sub.3O.sub.5S F [M+H]+:
488.0, 489.0
[0688] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.801
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-3-carbonyl-6-methyl)-phenyl]-4-(cis-2,6-dim-
ethyl-morpholin-4-yl)-3-fluoro-benzenesulfonamide
##STR00165##
[0690] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described
[0691] LC-MSD, m/z for C.sub.24H.sub.23ClN.sub.3O.sub.5S F [M+H]+:
516.0, 517.0
[0692] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.242
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-morpholin-4-yl-3-fluo-
ro-benzenesulfonamide
##STR00166##
[0694] The title compound was prepared according to the general
procedure for the synthesis of heterocyclyl and heteroaryl
substituted phenylsulfonyl derivatives previously described, using
4-Bromo-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-3-fluoro-benzen-
esulfonamide 0.25 g (0.5 mmol), potassium phosphate tribasic
monohydrate 0.68 g (3 mmol),
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 0.09 g (0.14 mmol),
morpholine 0.21 g (1.5 mmol) and Pd (dba).sub.3 0.135 g (0.14 mmol)
in 2 ml DMF. HPLC purification gave yellow compound.
[0695] LC-MSD, m/z for C.sub.22H.sub.19ClN.sub.3O.sub.5S F [M+H]+:
492.0
[0696] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.966
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-furan-3-yl-benzenesulfonami-
de
##STR00167##
[0698]
4-bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonam-
ide 0.25 g (0.55 mmol) was dissolved in 2.5 ml of anhydrous
dimethylformamide. To this solution was added 0.14 g (1.3 mmol)
sodium carbonate, furan-3-boronic acid 0.77 g (0.68 mmol), and
Pd(PPh.sub.3).sub.4 19 mg (0.014 mmol). The reaction mixture was
heated overnight at 80.degree. C. under a nitrogen atmosphere. The
mixture was quenched with water and extracted 3 times with
dichloromethane. The organic layer was dried over magnesium
sulfate, filtered, and concentrated. Purification by flash column
chromatography with a gradient 100% hexane to ethyl-acetate:hexane
1-1, gave the desired compound as a white powder.
[0699] LC-MSD, m/z for C.sub.22H.sub.15ClN.sub.2O.sub.4S [M+H]+:
439
[0700] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.512
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-thiophen-2-yl-benzenesulfon-
amide
##STR00168##
[0702] To
4-bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfo-
namide 0.12 g (0.26 mmol), sodium carbonate 70 mg (0.65 mmol),
thiophene-2-boronic acid 42 mg (0.32 mmol), and Pd
(PPh.sub.3).sub.4 18 mg (0.004 mmol) was added DMF (1 mL). The
reaction mixture was heated overnight at 80.degree. C. under a
nitrogen atmosphere. The mixture was quenched with water and
extracted 3 times with dichloromethane. The organic layer was dried
over magnesium sulfate, filtered, and concentrated. HPLC
Purification gave off white solid.
[0703] LC-MSD, m/z for C.sub.22H.sub.15ClN.sub.2O.sub.3S.sub.2
[M+H]+:455
[0704] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.827
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(2-fluoro-pyridin-3-yl)-ben-
zenesulfonamide
##STR00169##
[0706] To
4-bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfo-
namide 0.10 g (0.21 mmol), sodium carbonate 70 mg (0.65 mmol),
2-fluoropyridine-3-boronic acid hydrate 76 mg (0.53 mmol), Pd
(PPh.sub.3).sub.4 15.2 mg (0.013 mmol) was added DMF (1 mL). The
reaction mixture was heated overnight at 80.degree. C. under a
nitrogen atmosphere. The mixture was quenched with water and
extracted 3 times with dichloromethane. The organic layer was dried
over magnesium sulfate, filtered, and concentrated. HPLC
purification gave off white solid
[0707] LC-MSD, m/z for C.sub.23H.sub.15ClFN.sub.2O.sub.3S.sub.2
[M+H]+: 452.9
[0708] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.427
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-pyrimidin-5-yl-benzenesulfo-
namide
##STR00170##
[0710] To
4-bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfo-
namide 0.10 g (0.21 mmol), sodium carbonate 127 mg (1.17 mmol),
pyrimidine-5-boronic acid 95 mg (0.76 mmol), Pd (PPh.sub.3).sub.4
22.8 mg (0.019 mmol) was added DMF (1 mL). The reaction mixture was
heated overnight at 80.degree. C. under a nitrogen atmosphere. The
mixture was quenched with water and extracted 3 times with
dichloromethane. The organic layer was dried over magnesium
sulfate, filtered, and concentrated. HPLC purification gave an off
white solid.
[0711] LC-MSD, m/z for C.sub.22H.sub.15ClFN.sub.4O.sub.3S [M+H]+:
451
[0712] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.510
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-quinolin-3-yl-benzenesulfon-
amide
##STR00171##
[0714] To
4-bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfo-
namide 0.10 g (0.21 mmol), sodium carbonate 150 mg (1.4 mmol),
isoquinoline-4-boronic acid 152 mg (0.87 mmol), Pd
(PPh.sub.3).sub.4 30 mg (0.025 mmol) was added DMF (1 mL). The
reaction mixture was heated overnight at 80.degree. C. under a
nitrogen atmosphere. The mixture was quenched with water and
extracted 3 times with dichloromethane. The organic layer was dried
over magnesium sulfate, filtered, and concentrated. HPLC
purification gave off white solid.
[0715] LC-MSD, m/z for C.sub.27H.sub.18ClN.sub.3O.sub.3S [M+H]+:
500.0
[0716] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.398
Synthesis of
2-{4-[4-Chloro-2-(pyridine-4-carbonyl)-phenylsulfamoyl]-phenyl}-pyrrole-1-
-carboxylic acid tert-butyl ester
##STR00172##
[0718] To
4-bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfo-
namide 0.25 g (0.55 mmol), sodium carbonate 146 mg (1.4 mmol),
1-N--BOC-pyrrole-2-boronic acid 145 mg (0.68 mmol), Pd
(PPh.sub.3).sub.4 19 mg (0.016 mmol), was added DMF (2.5 mL). The
reaction mixture was heated overnight at 80.degree. C. under a
nitrogen atmosphere. The mixture was quenched with water and
extracted 3 times with dichloromethane. The organic layer was dried
over magnesium sulfate, filtered, and concentrated. HPLC
purification gave a light yellow solid.
[0719] LC-MSD, m/z for C.sub.27H.sub.24ClN.sub.3O.sub.5S [M+H]+:
538.1
[0720] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
5.431
Synthesis of
2-{4-[4-Chloro-2-(pyridine-4-carbonyl)-phenylsulfamoyl]-phenyl}-indole-1--
carboxylic acid tert-butyl ester
##STR00173##
[0722] To
4-bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfo-
namide 0.25 g (0.55 mmol), sodium carbonate 146 mg (1.4 mmol),
1-N--BOC-indole-2-boronic acid 180 mg (0.68 mmol), Pd
(PPh.sub.3).sub.4 19 mg (0.016 mmol), was added DMF (2.5 mL). The
reaction mixture was heated overnight at 80.degree. C. under a
nitrogen atmosphere. The mixture was quenched with water and
extracted 3 times with dichloromethane. The organic layer was dried
over magnesium sulfate, filtered, and concentrated. HPLC
purification gave an off white solid.
[0723] LC-MSD, m/z for C.sub.31H.sub.26ClN.sub.3O.sub.5S [M+H]+:
588.1
[0724] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
5.925
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(1H-pyrrol-2-yl)-benzenesul-
fonamide
##STR00174##
[0726] To a mixture of dichloromethane (1 ml) and trifluoroacetic
acid (0.3 ml) stirred at room temperature was added
2-{4-[4-Chloro-2-(pyridine-4-carbonyl)-phenylsulfamoyl]-phenyl}-pyrrole-1-
-carboxylic acid tert-butyl ester 70 mg (0.13 mmol). The reaction
mixture was followed using thin layer chromatography (eluted with
ethyl acetate:1-hexane:1), and after completion saturated aqueous
sodium bicarbonate solution was added, the reaction mixture
concentrated and purified using preparative HPLC (20%-70%
acetonitrile gradient), to yield a white powder.
[0727] LC-MSD, m/z for C.sub.22H.sub.15ClN.sub.3O.sub.3S [M+H]+:
438.0
[0728] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
5.226
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(1H-indol-2-yl)-benzenesulf-
onamide
##STR00175##
[0730] To a mixture of dichloromethane (1 ml) and trifluoroacetic
acid (0.3 ml) stirred at room temperature was added
2-{4-[4-Chloro-2-(pyridine-4-carbonyl)-phenylsulfamoyl]-phenyl}-indole-1--
carboxylic acid tert-butyl ester 0.1 g (0.17 mmol). The reaction
mixture was followed using thin layer chromatography, and after
completion saturated aqueous sodium bicarbonate solution was added,
the reaction mixture concentrated and purified using preparative
HPLC to yield to off white solid.
[0731] LC-MSD, m/z for C.sub.26H.sub.18ClN.sub.3O.sub.3S [M+H]+:
488.0
[0732] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
5.013
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(3,5-dimethyl-isoxazol-4-yl-
)-benzenesulfonamide
##STR00176##
[0734] To
4-bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfo-
namide 0.260 mg (0.57 mmol), sodium carbonate 178 mg (1.69 mmol),
3,5-dimethylisoxazol-4-boronic acid 150 mg (1.4 mmol), Pd
(PPh.sub.3).sub.4 23 mg (0.019 mmol), was added DMF (1.5 mL). The
reaction mixture was heated overnight at 80.degree. C. under a
nitrogen atmosphere. The mixture was quenched with water and
extracted 3 times with dichloromethane. The organic layer was dried
over magnesium sulfate, filtered, and concentrated. HPLC
purification (gradient 20 to 70% in 50 minutes), gave a white
powder.
[0735] LC-MSD, m/z for C.sub.23H.sub.18ClN.sub.3O.sub.4S [M+H]+:
468.0
[0736] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.475
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-furan-2-yl-benzenesulfonami-
de
##STR00177##
[0738] To
4-bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfo-
namide 0.25 mg (0.55 mmol), sodium carbonate 0.21 g (2 mmol), furan
2-boronic acid 0.11 g (1 mmol), Pd (PPh.sub.3).sub.4 38 mg (0.032
mmol), was added DMF (2.5 mL). The reaction mixture was heated
overnight at 80.degree. C. under a nitrogen atmosphere. The mixture
was quenched with water and extracted 3 times with dichloromethane.
The organic layer was dried over magnesium sulfate, filtered, and
concentrated. Purification using column chromatography
(hexane:ethyl acetate 2:1_, gave a pale yellow powder.
[0739] LC-MSD, m/z for C.sub.22H.sub.15ClN.sub.2O.sub.4S [M+H]+:
439.0
[0740] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.769
Synthesis of
4-(4-Acetyl-piperazin-1-yl)-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-b-
enzenesulfonamide
##STR00178##
[0742]
N-[4-Chloro-2(pyridine-4-carbonyl)-phenyl]-4-piperazin-1-yl-benzene-
sulfonamide 0.11 g (0.24 mmol) was dissolved in 1 ml
dichloromethane, under nitrogen at 0.degree. C., and to this
solution was added triethylamine 0.05 ml (0.36 mmol) and acetic
anhydride 0.027 ml (0.29 mmol). The reaction mixture was stirred at
0.degree. C. for 30 minutes. Saturated aqueous sodium bicarbonate
(3 mL) was added, followed by extraction, 3 times, with
dichloromethane. The combined organic layers was dried over
magnesium sulfate, filtered and concentrated in vacuo. The title
compound was purified using flash column chromatography on silica,
eluted with ethyl-acetate 100% followed by
dichloromethane-methanol, to yield a pale yellow compound.
[0743] LC-MSD, m/z for C.sub.24H.sub.23ClN.sub.4O.sub.4S [M+H]+:
499.0
[0744] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.785
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-[4-(2,2,2-trifluoro-ethyl)--
piperazin-1-yl]-benzenesulfonamide
##STR00179##
[0746]
N-[4-Chloro-2(pyridine-4-carbonyl)-phenyl]-4-piperazin-1-yl-benzene-
sulfonamide 0.1 g (0.24 mmol) was dissolved in acetone (1.1 ml),
and to this solution was added trifluoro-methanesulfonic acid
2,2,2-trifluoro-ethyl ester
[0747] 70.8 mg (0.28 mmol). The mixture was refluxed for 5 hours.
The reaction was cooled to room temperature, quenched with
saturated aqueous sodium bicarbonate, and extracted with
dichloromethane (3 times). The combined organic layer was dried
over magnesium sulfate, filtered and concentrated in vacuo, to
yield to 24 mg a pale yellow compound.
[0748] LC-MSD, m/z for C.sub.24H.sub.22ClN.sub.4O.sub.3SF.sub.3
[M+H]+: 539.1
[0749] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.976
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-[1,2,3]thiadiazol-4-yl-benz-
enesulfonamide
##STR00180##
[0751] (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone 0.2 g (0.86
mmol) was dissolved in anhydrous pyridine (1 mL)m, and to this
solution was added 4-[1,2,3]-thiadiazole-4-yl-benzenesulfonyl
chloride 0.24 g (0.94 mmol). The mixture was stirred overnight at
80.degree. C. under nitrogen, and the pyridine then removed in
vacuo. Water was added and the reaction mixture extracted with
dichloromethane (3 times). The organic layers were combined, dried
over magnesium sulfate, filtered and concentrated in vacuo. HPLC
purification yielded a white powder.
[0752] LC-MSD, m/z for C.sub.20H.sub.13ClN.sub.4O.sub.3S.sub.2
[M+H]+: 466.9
[0753] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.82
Syntheses of N-Aryl-benzenesulfonamides
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonam-
ide
##STR00181##
[0755] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg
4-oxazol-5-yl-benzenesulfonyl chloride. Purification by
purification by reversed phase HPLC gave pure product. .sup.1H-NMR
(400 MHz, CDCl.sub.3): .delta. 7.21 (dd, H, J=1.5, 4.4 Hz), 7.30
(d, 1H, J=2.5 Hz), 7.42 (s, 1H), 7.54 (dd, 1H, J=2.5, 8.8 Hz), 7.61
(d, 2H, J=8.4 Hz), 7.77 (s, 1H), 7.78 (d, 2H, J=8.4 Hz), 7.95 (s,
1H), 8.69 (d, 2H, J=5.8 Hz), 10.06 (br, 1H). MS: m/z 440.9
(M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonami-
de
##STR00182##
[0757] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 116 mg of
4-tert-Butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.25 (s, 9H), 7.02 (d, 1H, J=8.4 Hz). 7.44 (m,
3H), 7.66 (d, 2H, J=8.4), 7.79 (d, 1H, J=2.4 Hz), 8.11 (d, 2H,
J=6.4), 8.88 d, 2H, J=6.0 Hz), 10.51 (s, 1H). MS: m/z 429.9
(M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
##STR00183##
[0759] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 101 mg of
4-methoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 3.74 (s, 3H), 6.77 (d, 2H, J=8.8 Hz), 7.21 (m,
2H), 7.27 (d, 1H, J=2 Hz), 7.52 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.63
(m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.76 (d, 2H, J=5.6 Hz), 9.88 (s,
1H). MS: m/z 403.9 (M.sup.++1).
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
##STR00184##
[0761] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 101 mg of
4-methoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 3.69 (s, 3H), 6.68 (d, 2H, J=8.8 Hz),
7.36-7.47 (m, 4H), 7.46, 7.55-7.69 (m, 5H), 9.65 (s, 1H). MS: m/z
448.3 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-fluoro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonami-
de
##STR00185##
[0763] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 108 mg of
(2-Amino-5-fluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of
4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.25 (s, 9H), 6.98 (dd, 1H, J=8.8 Hz, 3.2 Hz),
7.30-7.38 (m, 3H), 7.43 (m, 2H), 7.62 (m, 2H), 7.80 (dd, 1H, 9.2
Hz, 4.8 Hz), 8.82 (d, 2H, 4.8 Hz), 9.82 (s, 1H). MS: m/z 413.5
(M.sup.++1).
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-tert-butyl-benzenesulfonamid-
e
##STR00186##
[0765] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 116 mg of
4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.27 (3, 9H), 7.41 (m, 3H), 7.50 (dd, 2H,
J=4.8 Hz, 1.6 Hz), 7.67-72 (m, 4H), 8.85 (d, 2H, J=6 Hz), 10.19 (s,
1H). MS: m/z 473.9 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[5-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonami-
de
##STR00187##
[0767] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-4-chloro-phenyl)-pyridin-4-yl-methanone and 116 mg of
4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.30 (s, 9H), 7.04 (d, 1H, J=8.4 Hz), 7.25 (d,
1H, J=8.4 Hz), 7.45-7.52 (m, 4H), 7.74 (dd, 2H, J=8.8 Hz, 1.6 Hz),
7.52 (dd, 2H, J=4.4 Hz, 1.6 Hz), 7.78 (m, 2H), 7.84 (d, 1.6 Hz),
8.84 (d, 2H, J=5.6 Hz), 10.61 (s, 1H). MS: m/z 429.0
(M.sup.++1).
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulf-
onamide
##STR00188##
[0769] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 130 mg of
4-trifluoromethoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.21 (d, 2H, J=8.8 Hz), 7.35 (m, 2H), 7.45 (s,
1H), 7.70 (m, 2H), 7.83 (m, 2H), 8.82 (dd, 2H, J=4.8 Hz, 1.6 Hz),
10.21 (s, 1H). MS: m/z 502.3 (M.sup.++1).
Synthesis of
4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
##STR00189##
[0771] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg of
4-bromo-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.21 (d, 1H, J=2.4 Hz), 7.49-7.61 (m, 5H),
7.73 (d, 1H, J=8.8 Hz), 8.86 (dd, 2H, J=4.4 Hz, 1.2 Hz), 10.00 (s,
1H). MS: m/z 451.9 (M.sup.++1)
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-3-cyano-benzenesulfonamide
##STR00190##
[0773] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 100 mg of
3-cyano-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.36 (d, 1H, J=2.4 Hz), 7.57-7.62 (m, 4H),
7.68 (d, 1H, J=8.8 Hz), 7.80 (m, 1H), 8.04 (m, 2H), 8.90 (dd, 2H,
J=4.8 Hz, 1.6 Hz), 10.3 (b, 1H). MS: m/z 398.8 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulf-
onamide
##STR00191##
[0775] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 127 mg of
4-methanesulfonyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 3.06 (s, 3H), 7.31 (d, 1H, J=2.0 Hz), 7.45 (m,
2H), 7.58 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.99 (b, 4H), 8.88 (dd, 2H,
J=4.8 Hz, 1.6 Hz), 10.29 (b, 1H). MS: m/z 451.9 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(pyrimidine-4-carbonyl)-phenyl]-benzenesulfona-
mide
##STR00192##
[0777] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone and 116 mg of
4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.23 (s, 9H), 7.40 (d, 2H, J=8.4 Hz), 7.51
(dd, 1H, J=8.8 Hz, 2 Hz), 7.71-7.80 (m, 6H), 9.03 (d, 1H, J=4.8
Hz), 9.33 (d, 1.2 Hz), 10.91 (b, 1H). MS:m/z 434.0 (M.sup.++1).
Synthesis of Biphenyl-4-sulfonic acid
[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-amide
##STR00193##
[0779] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 126 mg of
biphenyl-4-sulfonyl chloride. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta.7.24 (m, 1H), 7.36 (m, 2H), 7.42 (m, 5H), 7.56 (m, 3H),
7.77-7.84 (m, 3H), 8.73 (d, 2H, J=4.4 Hz), 10.01 (s, 1H). MS: m/z
449.0 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(3-methyl-pyridine-4-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00194##
[0781] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 123 mg of
(2-Amino-5-chloro-phenyl)-(3-methyl-pyridin-4-yl)-methanone and 116
mg of 4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta.1.32 (s, 9H), 2.19 (s, 3H), 7.04 (d, 1H, J=1.4
Hz), 7.21 (d, 1H, J=5.2 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.52 (dd, 1H,
J=8.8 Hz, 2.4 Hz), 7.77-7.83 (m, 3H), 8.64 (d, 1H, J=5.2 Hz), 8.71
(s, 1H), 10.75 (s, 1H). MS: m/z 443.0 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulf-
onamide
##STR00195##
[0783] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 122 mg of
4-Trifluoromethyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.31 (d, 1H, J=2.8 Hz), 7.36 (m, 2H),
7.54-7.59 (m, 2H), 7.73 (d, 1H, J=8.0 Hz), 7.77 (d, 1H, J=9.2 Hz),
7.97 (d, 1H, J=8.0 Hz), 8.00 (s, 1H), 8.82 (dd, 2H, J=6.0 Hz, 1.2
Hz), 10.16 (s, 1H). MS: m/z 441.8 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4,5-difluoro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfo-
namide
##STR00196##
[0785] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 117 mg of
(2-Amino-4,5-difluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of
4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.28 (s, 9H), 7.17 (t, 1H, J=8.4 Hz), 7.45 (d,
2H, J=8.4 Hz), 7.54 (d, 2H, J=4.4 Hz), 7.64 (dd, 1H, J=11.6 Hz, 6.8
Hz), 7.72 (d, 2H, J=8.4 Hz), 8.85 (d, 2H, J=5.2 Hz), 10.42 (s, 1H).
MS: m/z 431.1 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-morpholin-4-yl-pyridine-3-carbonyl)-phenyl]-
-benzenesulfonamide
##STR00197##
[0787] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 158 mg of
(2-Amino-5-chloro-phenyl)-(6-morpholin-4-yl-pyridin-3-yl)-methanone
and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR
(400 MHz, CDCl.sub.3): .delta. 1.22 (s, 3H), 3.76 (t, 4H, J=4.6
Hz), 3.857 (t, 4H, J=4.6H), 8.78 (d, 1H, J=9.2 Hz), 7.30 (m, 2H),
7.34 (m, 1H), 7.46 (m, 1H), 7.54-7.56 (m, 3H), 7.99 (d, 1H, J=9.2
Hz), 8.16 (v, 1H), 9.29 (s, 1H). MS: m/z 515.1 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzen-
esulfonamide
##STR00198##
[0789] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 123 mg of
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 122
mg of 4-oxazol-5-yl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 2.63 (s, 3H), 7.33 (m, 2H), 7.37 (s, 1H), 7.56
(m, 3H), 7.67-7.3 (m, 3H), 7.94 (m, 1H), 7.97 (s, 1H), 8.52 (b,
1H), 9.45 (s, 1H). MS: m/z 454.1 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(2-methylsulfanyl-pyridine-4-carbonyl)-phenyl]-
-benzenesulfonamide
##STR00199##
[0791]
4-tert-Butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-b-
enzenesulfonamide (475 mg, 1.0 mmol) was dissolved in 10 mL dry THF
and treated with solid sodium thiomethoxide (355 mg, 5 mmol) and
the mixture heated at 70.degree. C. for 16 h. The solvent was
concentrated to about 2 mL and added to 5 mL cold 1M HCl. The light
yellow solid precipitate was collected by filtration and product
was purified by HPLC. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.
1.26 (s, 9H), 2.61 (s, 3H), 6.86 (d, 1H, J=5.2 Hz), 7.18 (s, 1H),
7.28 (d, 1H, J=2.4 Hz), 7.39 (d, 2H, J=8.8 Hz), 7.51 (dd, 1H, J=8.8
Hz, 2.4 Hz), 7.67 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.56 (d, 1H,
J=5.2 Hz), 10.13 (s, 1H). MS: m/z 476.1 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-oxazol-5-yl-benzen-
esulfonamide
##STR00200##
[0793] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 123 mg of
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 122
mg of 4-oxazol-5-yl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 2.78 (s, 3H), 7.29 (d, 1H, J=2.8 Hz), 7.45 (m,
2H), 7.48 (s, 1H), 7.55 (dd, 1H, J=9.2 Hz, 2.8 Hz)), 7.67 (m, 3H),
7.83 (d, 2H, J=8.4 Hz), 8.03 (s, 1H), 8.81 (d, 1H, J=5.6 Hz), 10.10
(s, 1H). MS: m/z 454.9 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-(2-hydroxy-1,1-dimeth-
yl-ethyl)-benzenesulfonamide
##STR00201##
[0795] To a suspension of NaBH.sub.4 (0.70 g, 18.3 mmol) in dry THF
(20 mL) was added BF.sub.3.Et.sub.2O (0.25 mL, 20.1 mmol) drop wise
at 0.degree. C. over 5 min and the mixture was stirred for 30 min.
A solution of 2-methyl-2-phenyl-propionic acid (1.0 g, 6.1 mmol) in
dry THF (10 mL) was added drop wise at 0.degree. C. over 30 min,
and the mixture was stirred at room temperature for 4 h. Methanol
was slowly added to the reaction mixture until hydrogen evolution
stopped. The mixture was diluted with 10% HCl and extracted twice
with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4 and
then under vacuum to yield colorless oil.
[0796] This material was dissolved in DCM (25 mL), pyridine (1.2
mL, 15.3 mmol) and acetyl chloride (2.2 mL, 30.5 mmol) added, and
the reaction mixture left to stir at room temperature overnight.
The reaction mixture was washed with 10% HCl and the organic layer
was dried over MgSO.sub.4.
[0797] The material was then dissolved in DCM (25 mL) and cooled to
0.degree. C. Chlorosulfonic acid (1.2 mL, 18 mmol) was added drop
wise over 15 minutes and the mixture was stirred at the same
temperature for 3H. The volatiles were evaporated and SOCl.sub.2
(10 mL) was added and the mixture stirred at room temperature for 3
h. The excess SOCl.sub.2 was evaporated and the residue was treated
with ice-water and extracted with ether. The organic layer was
washed with water and brine, dried over MgSO.sub.4 and concentrated
in vacuo to afford the aryl sulfonyl chloride as a yellowish
oil.
[0798] This oil was treated with a solution of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone (1.2 g, 5 mmol) in
10 mL pyridine and heated at 60 C for 4 h. The solvent was
evaporated and the residue suspended in 3M HCl (10 mL) and stirred
at room temperature for 16 h. The reaction mixture was put in an
ice bath and neutralized with concentrated NaOH solution. The white
precipitate formed was collected by filtration, washed with water
and dried in vacuo and purified by flash chromatography to yield
320 mg of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(2-hydroxy-1,1-dimethyl-eth-
yl)-benzenesulfonamide.
[0799] Oxidation of this intermediate with mCPBA according to the
general procedure gave
N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-(2-hydroxy-1,1-dimeth-
yl-ethyl)-benzenesulfonamide. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. 1.24 (s, 6H), 3.58 (s, 2H), 7.29 (d, 1H, J=2.4 Hz), 7.37
(m, 4H), 7.53 (m, 2H), 7.62 (m, 2H), 7.78 (d, 1H, J=8.8 Hz), 8.23
(d, 2H, J=6.8 Hz), 9.51 (s, 1H). MS: m/z 461.1 (M.sup.++1).
Synthesis of
N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-4-ethyl-benzenesulfonamide
##STR00202##
[0801] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 102 mg of
4-ethyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta.0.94 (t, 3H, J=7.6 Hz), 2.38 (q, 2H, J=15.2 Hz,
7.6 Hz), 6.94 (d, 2H, J=6.8 Hz), 7.16 (m, 2H), 7.23 (m, 1H), 7.30
(m, 4H), 8.60 (b, 2H), 9.73 (b, 1H). MS: m/z 401.1 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyrimidine-2-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfon-
amide
##STR00203##
[0803] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyrimidin-2-yl-methanone and 122 mg of
4-oxazol-5-yl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.43 (s, 1H), 7.45 (m, 1H), 7.50 (m, 1H), 7.55
(m, 1H), 7.64 (m, 2H), 7.66 (d, 1H, J=8.8 Hz), 7.86 (m, 2H), 7.97
(s, 1H), 8.86 (d, 2H), 10.63 (s, 1H). MS: m/z 441.9
(M.sup.++1).
Synthesis of
N-[4-chloro-2-(pyrimidine-4-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfon-
amide
##STR00204##
[0805] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone and 122 mg of
4-oxazol-5-yl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.43 (s, 1H), 7.53 (dd, 1H, J=8.8 Hz, 2.4 Hz),
7.62 (m, 2H), 7.75 (m, 2H), 7.80 (m, 3H), 7.98 (s, 1H), 8.99 (d,
1H, J=5.2 Hz), 9.25 (b, 1H), 10.29 (b, 1H). MS: m/z 441.9
(M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonam-
ide
##STR00205##
[0807] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 122 mg of
4-oxazol-5-yl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta.7.23 (m, 2H), 7.42-7.47 (m, 3H), 7.58-7.62 (m,
3H), 7.71 (dt, 1H, J=7.6 Hz, 2.0 Hz), 7.88 (s, 1H), 8.45 (b, 1H),
8.58 (bd, 1H, J=3.6 Hz), 9.67 (s, 1H). MS: m/z 458.1
(M.sup.++1)
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(pyridine-2-carbonyl)-phenyl]-benzenesulfonami-
de
##STR00206##
[0809] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 116 mg of
4-tert-Butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.24 (s, 9H), 7.34-7.38 (m, 2H), 7.47 (dd, 1H,
J=8.8 Hz, 2.4 Hz), 7.60 (m, 1H), 7.65-7.68 (m, 4H), 7.85 (d, 1H,
J=8 Hz), 8.00 (td, 1H, J=7.6 Hz, 2 Hz), 8.71 (bd, 1H, J=4.8 Hz).
MS: m/z 429.9 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(1,1-dimethyl-propyl)-benze-
nesulfonamide
##STR00207##
[0811] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 123 mg of
4-(1,1-dimethyl-propyl)-benzenesulfonyl chloride. .sup.1H-NMR (400
MHz, CDCl.sub.3): .delta. 0.59 (t, 3H, J=7.2 Hz), 1.23 (s, 6H),
1.61 (q, 2H, J=7.2 Hz), 7.28 (d, 1H, J=2.8 Hz), 7.36 (m, 2H), 7.53
(m, 3H), 7.67-7.74 (m, 3H), 8.84 (m, 2H), 10.14 (s, 1H). MS: m/z
443.9 (M.sup.++1).
Synthesis of
4-tert-butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00208##
[0813] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 133 mg of
(2-Amino-5-chloro-phenyl)-(2-chloro-pyridin-4-yl)-methanone and 116
mg of 4-tert-Butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.26 (s, 9H), 7.18 (dd, 5.2 Hz, 1.6 Hz), 7.25
(m, 1H), 7.32 (m, 1H), 7.41 (d, 2H, J=6.4 Hz), 7.54 (dd, 1H, J=9.2
Hz, 2.4 Hz), 7.67 (m, 2H), 7.77 (d, 1H, J=8.8 Hz), 8.55 (d, 1H,
J=5.2 Hz), 10.09 (s, 1H). MS: m/z 463.0 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-2-carbonyl)-phenyl]-4-oxazol-5-yl-benzen-
esulfonamide
##STR00209##
[0815] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 123 mg of
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and 122
mg of 4-oxazol-5-yl-benzenesulfonyl chloride .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 2.67 (s, 3H), 7.46-7.50 (m, 4H), 7.61-7.70 (m,
4H), 7.65 (m, 2H), 7.94-8.00 (m, 1H), 8.15 (s, 1H). MS: m/z 454.0
(M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00210##
[0817] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 123 mg of
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 116
mg of 4-tert-Butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.26 (s, 9H), 2.63 (s, 3H) 7.29 (d, 1H, J=2.8
Hz), 7.45-7.55 (m, 3H), 7.67 (m, 2H), 7.83 (m, 2H), 8.03 (s, 1H),
8.81 (d, 1H, J=5.6 Hz), 10.10 (s, 1H). MS: m/z 443.9
(M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-methylsulfanyl-pyridine-3-carbonyl)-phenyl]-
-benzenesulfonamide
##STR00211##
[0819]
4-tert-Butyl-N-[4-chloro-2-(6-chloro-pyridine-3-carbonyl)-phenyl]-b-
enzenesulfonamide (231 mg, 0.5 mmol) was dissolved in dry THF (5
mL) and treated with sodium thiomethoxide (175 mg, 2.5 mmol) and
the mixture was heated at 70.degree. C. for 4 h. The solvent was
evaporated and the residue suspended in water (5 mL) and the
product was precipitated by the drop wise addition of 3M HCl and
purified by HPLC. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.19
(s, 9H), 2.60 (s, 3H), 7.21-7.28 (m, 3H), 7.31 (m, 1H), 7.50-7.54
(m, 3H), 7.65 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.78 (d, 1H, J=8.8 Hz),
8.19 (m, 1H), 9.62 (s, 1H). MS: m/z 476.0 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-methanesulfonyl-pyridine-3-carbonyl)-phenyl-
]-benzenesulfonamide
##STR00212##
[0821]
4-tert-Butyl-N-[4-chloro-2-(6-methylsulfanyl-pyridine-3-carbonyl)-p-
henyl]-benzenesulfonamide (48 mg, 0.1 mmol) and mCPBA (35 mg, 0.2
mmol) were dissolved in DCM (4 mL) and the mixture stirred at room
temperature overnight. The solvent was evaporated and product was
purified by HPLC. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.25
(s, 9H), 3.30 (s, 3H), 7.27 (m, 1H), 7.38 (m, 2H), 7.56 (dd, 1H,
J=8.8 Hz, 2.8 Hz), 7.66 (m, 2H), 7.80 (d, 1H, J=8.8 Hz), 8.04 (dd,
1H, J=8 Hz, 2 Hz), 8.18 (d, 1H, J=8.0 Hz), 8.61 (m, 1H), 10.00 (s,
1H). MS: m/z 508.0 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[3,4-difluoro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfo-
namide
##STR00213##
[0823] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 117 mg of
(6-Amino-2,3-difluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of
4-tert-Butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.22 (s, 9H), 7.31 (d, 2H, J=8.4 Hz),
7.40-7.47 (m, 3H), 7.55 (d, 2H, J=8.4 Hz), 7.59 (m, 1H), 8.69 (b,
1H), 8.82 (d, 2H, J=6.0 Hz). MS: m/z 431.0 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(pyrazine-2-carbonyl)-phenyl]-benzenesulfonami-
de
##STR00214##
[0825] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 117 mg of
(2-Amino-5-chloro-phenyl)-pyrazin-2-yl-methanone and 116 mg of
4-tert-butyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.24 (s, 9H), 7.38 (dm, 2H, J=6.8 Hz), 7.50
(dd, 1H, J=9.2 Hz, 1.6 Hz), 7.70 (m, 2H), 7.76 (m, 1H), 7.80 (m,
1H), 8.62 (m, 1H), 8.77 (m, 1H), 9.06 (m, 1H), 10.37 (s, 1H). MS:
m/z 430.0 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonami-
de
##STR00215##
[0827] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 117 mg of
4-Isopropoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.01 (d, 6H, J=5.6 Hz), 4.27 (m, 1H), 6.51 (d,
2H, J=8.8 Hz), 6.87 (d, 1H, J=8.8 Hz), 7.15-7.25 (m, 4H), 7.60 (d,
2H, J=6.0 Hz), 8.64 (d, 2H, J=6 Hz), 9.60 (s, 1H). MS: m/z 431.9
(M.sup.++1).
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonamid-
e
##STR00216##
[0829] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 117 mg of
4-Isopropoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.31 (d, 6H, J=6 Hz), 4.49 (q, 1H, J=6.0 Hz),
6.73 (d, 2H, J=6.8 Hz), 7.39 (m, 3H), 7.63-7.70 (m, 4H), 8.82 (d,
2H, J=6.0 Hz), 9.99 (s, 1H). MS:m/z 476.0 (M.sup.++1)
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-ethyl-benzenesulfonamide
##STR00217##
[0831] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 102 mg of
4-ethyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.19 (t, 3H, J=7.6 Hz), 2.62 (q, 2H, J=7.6
Hz), 7.20 (d, 2H, J=8.8 Hz, 7.38 (m, 3H), 7.65-7.72 (m, 4H), 8.81
(d, 2H, 6.4 Hz), 10.06 (s, 1H). MS: m/z 446.0 (M.sup.++1).
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesulf-
onamide
##STR00218##
[0833] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 130 mg of
4-Trifluoromethoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 7.23 (d, 2H, J=8.0 Hz), 7.45 (m, 3H), 7.71 (m,
2H), 7.85 (d, 2H, J=8.8 Hz), 8.85 (d, 2H, J=6.4 Hz), 10.23 (s, 1H).
MS: m/z 502.9 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(2-cyano-pyridine-4-carbonyl)-phenyl]-benzenes-
ulfonamide
##STR00219##
[0835] Dimethyl sulfate (126 mg, 1 mmol) and
4-tert-butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesul-
fonamide (445 mg, 1 mmol) were dissolved in dry THF (5 mL). The
reaction mixture was stirred at room temperature for 1 hour and at
60.degree. C. for two hours. After cooling to room temperature, to
the solution was added 25% (w/v) aqueous KCN solution (5 mL) and
the mixture stirred for 16 h. The solvent was evaporated in vacuo
and the product was purified by HPLC. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 1.27 (s, 9H), 7.22 (d, 1H, J=2.0 Hz),
7.41-7.47 (m, 3H), 7.56 (dd, 1H, J=2.4 Hz), 7.69 (m, 3H), 7.79 (d,
1H, J=9.2 Hz), 8.87 (d, 1H, J=5.2 Hz), 10.06 (s, 1H). MS: m/z 454.0
(M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(2-methanesulfonyl-pyridine-4-carbonyl)-phenyl-
]-benzenesulfonamide
##STR00220##
[0837]
4-tert-Butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-b-
enzenesulfonamide (232 mg, 0.5 mmol) was dissolved in dry THF (5
mL) and treated with sodium thiomethoxide (175 mg, 2.5 mmol) and
the mixture was heated at 70.degree. C. for 16 h. The solvent was
evaporated and the residue suspended in water (5 mL) and the
product was precipitated by the drop wise addition of 3M HCl. The
precipitate was collected by filtration, dissolved in DCM (10 mL)
and treated with mCPBA (172 mg, 1 mmol). After stirring at room
temperature for 16 h, the DCM solution was washed with saturated
NaHCO.sub.3 solution (10 mL). The organic layer was washed with
water, dried and the solvent was evaporated. The product was
purified by HPLC to give white powder after lyophilization.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.28 (s, 9H), 3.30 (s,
3H), 7.24 (d, 1H, J=2.4 Hz), 7.45 (d, 2H, J=8.0 Hz), 7.48 (m, 1H),
7.54 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.74 (d, 2H, J=8.0 Hz), 7.78 (d,
1H, J=8.8 Hz), 8.87 (d, 1H, J=5.2 Hz), 10.23 (s, 1H). MS: m/z 507.0
(M.sup.++1).
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulfo-
namide
##STR00221##
[0839] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-phenyl-methanone and 127 mg of
4-Methanesulfonyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 3.07 (s, 3H), 7.45 (d, 1H, J=2.0 Hz), 7.49 (d,
2H, J=6.0 Hz), 7.15 (m, 3H), 8.00 (s, 4H), 8.89 (d, 2H, J=6.0 Hz),
10.32 (b, 1H). MS: m/z 496.9.0 (M.sup.++1).
Synthesis of 4-Acetyl
--N-[4-bromo-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
##STR00222##
[0841] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 138 mg of
(2-Amino-5-bromo-phenyl)-phenyl-methanone and 109 mg of
4-acetyl-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 2.59 (s, 3H), 7.44 (d, 1H, J=2.0 Hz), 7.56 (d,
2H, J=6.4 Hz, 7.64-7.71 (m, 2H), 7.90 (d, 2H, J=8.8 Hz), 7.97 (d,
2H, J=8.8 Hz), 8.88 (d, 2H, J=6.4 Hz), 10.24 (b, 1H). MS: m/z 459.8
(M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-methyl-pyridine-2-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00223##
[0843] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and
4-tert-Butyl-benzenesulfonyl chloride and purified by HPLC. .sup.1H
NMR: .delta. 1.29 (s, 9H), 2.94 (s, 3H), 7.42-7.46 (m, 3H), 7.51
(d, J=8.8 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H),
7.66 (d, J=6.8 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 8.1 (bs, 1H). MS:
M/z 443.1 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-chloro-pyridine-3-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00224##
[0845] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-chloro-pyridin-3-yl)-methanone and
4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. .sup.1H
NMR: .delta. 1.21 (s, 9H), 7.30 (d, J=2.4 Hz, 1H), 7.33 (d, J=6.6
Hz, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.52 & 7.55 (dd, J=8.8 Hz, 2.8
Hz, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.79 (m, 3H), 8.27 (d, J=2.0 Hz,
1H), 9.73 (s, 1H). MS: M/z 463.0 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesul-
fonamide
##STR00225##
[0847] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and
4-Trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC.
.sup.1H NMR: .delta. 6.93 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.8 Hz,
2H), 7.58-7.61 (m, 3H), 7.67 (d, J=8.8 Hz, 2H), 8.03-8.05 (m, 1H),
8.74 (d, J=1.6 Hz, 1H), 8.79 & 8.80 (dd, J=6.0 Hz, 1.6 Hz, 1H),
9.73 (s, 1H). MS: M/z 456.9 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benzenesulf-
onamide
##STR00226##
[0849] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and
4-Methanesulfonyl-benzenesulfonyl chloride and purified by HPLC.
.sup.1H NMR (CDCl.sub.3): .delta. 3.01 (s, 3 H), 7.36-7.37 (d,
J=2.4 Hz, 1H), 7.43 (m, 1H), 7.54 & 7.57 (dd, J=8.8 Hz, 2.4 Hz,
1H), 7.70-7.73 (m, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.90 (m, 4H), 8.59
(d, J=2.0 Hz, 1H), 8.80 & 8.82 (dd, J=4.8 Hz, 1.6 Hz, 1H), 9.98
(s, 1H). MS: M/z 450.9 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-benzenesul-
fonamide
##STR00227##
[0851] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and
4-Trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC.
.sup.1H NMR (DMSO-d6): .delta. 6.90 (d, J=8.4 Hz, 1H), 7.50 (d,
J=8.8 Hz, 2H), 7.49-7.61 (m, 4H), 7.66 (d, J=8.8 Hz, 2H), 8.81 (d,
J=4.8 Hz, 2H), 10.26 (s, 1H). MS: M/z 456.9 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzenesulfonami-
de
##STR00228##
[0853] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and
4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. .sup.1H
NMR (CDCl.sub.3): .delta. 1.19 (s, 3H), 1.20 (s, 3H), 4.35-4.38 (m,
1H), 6.63 (d, J=9.2 Hz, 2H), 7.24 (m, 2H), 7.35-7.38 (m, 1H), 7.43
(d, J=2.4 Hz, 1H), 7.45-7.49 (m, 2H), 7.62 (d, J=8.8 Hz, 1H),
7.70-7.73 (m, 1H), 8.51 (bs, 1H), 8.68 (bs, 1H), MS: M/z=431.0
(M.sup.++1).
Synthesis of
4-Chloro-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide
##STR00229##
[0855] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and
4-chloro-benzenesulfonyl chloride and purified by HPLC. .sup.1H NMR
(CDCl.sub.3): .delta. 7.20 (dd, 2H, J=4.4 Hz, 2.0), 7.31 (m, 2H),
7.53 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.65 (m, 2H), 7.76 (d, 1H, J=8.8
Hz), 8.79 (dd, 2H, J=4.4 Hz, 1.6 Hz), 10.00 (s, 1H). MS: m/z 407.1
(M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonami-
de
##STR00230##
[0857] To (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone (150 mg,
0.64 mmol) dissolved in 750 uL pyridine was added
4-tert-butylbenzenesulfonyl chloride (225 mg, 0.97 mmol) and the
mixture stirred at 60.degree. C. overnight. The reaction mixture
was diluted with 1.0 mL H.sub.2O and the precipitate formed was
collected by vacuum filtration. The crude product was
recrystallized from EtOAc/hexane yielding 190 mg of pure title
compound. 1H NMR (CDCl3) .delta. 9.87 (s, 1H), 8.79 (d, J=4.8 Hz,
1H), 8.52 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H),
7.52 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.40 (dd, J=7.6 Hz, 4.8 Hz, 1H),
7.33-7.31 (m, 3H), 1.22 (s, 9H). MS: m/z=429.0 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-b-
enzenesulfonamide
##STR00231##
[0859] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and
4-trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC.
1H NMR (CDCl3) .delta. 10.17 (s, 1H) 8.63 (d, J=4 Hz, 1H) 7.78 (m,
3H) 7.51 (s, 1H) 7.30 (s, 1H) 7.17 (s, 1H) 7.09 (s, 1H) 6.97 (d,
J=4 Hz, 2H) 2.64 (s, 3H). MS (ES) m/z=471.0 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide
##STR00232##
[0861] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and
4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR
(CDCl3) .delta. 9.94 (s, 1H) 8.61 (d, J=5 Hz, 1H) 7.78 (d, J=8.8,
1H) 7.61 (d, J=8 Hz, 1H) 7.50 (dd, J=11 Hz, 2 Hz, 2H) 7.27 (d,
J=2.4 Hz, 1H) 7.07 (s, 1H) 6.96 (d, J=4 Hz, 1H) 6.75 (d, J=8.8 Hz,
2H) 4.47 (m, 1H) 2.63 (s, 3H) 1.27 (s, 6H). MS (ES) m/z=445.0
(M.sup.++1).
Synthesis of
4-Acetyl-N-[4-chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-benzenesulf-
onamide
##STR00233##
[0863] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and
4-acetyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR
(CDCl3) .delta. 8.50 (d, J=4.8 Hz, 1H) 7.67-7.25 (m, 5H) 7.20-6.85
(m, 4H) 2.52 (s, 3H) 2.45 (s, 3H). MS: (ES) m/z=429.0
(M.sup.++1).
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-methanesulfonyl-be-
nzenesulfonamide
##STR00234##
[0865] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and
4-methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. 1H
NMR (CDCl3) .delta. 10.38 (s, 1H) 8.64 (s 1H) 7.95 (s, 4H) 7.72 (s,
1H) 7.51 (s, 1H) 7.31 (s, 1H) 7.11 (s, 1H) 6.99 (s, 1H) 3.04 (s,
3H) 2.64 (s, 3H). MS: (ES) m/z=464.9 (M.sup.++1).
Synthesis of
3-{4-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenylsulfamoyl]-phenyl}--
propionic acid methyl ester
##STR00235##
[0867] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and
3-(4-chlorosulfonyl-phenyl)-propionic acid methyl ester and
purified by HPLC. 1H NMR (CDCl3) .delta. 10.13 (s, 1H) 8.62 (d,
J=4.8 Hz, 1H) 7.73 (d, J=8.8 Hz, 1H) 7.65 (d, J=8.8 Hz, 2H) 7.49
(dd, J=8.8 Hz, 2.4 Hz, 1H) 7.28 (d, J=2.4 Hz, 1H) 7.19 (d, J=12 Hz,
2H) 7.13 (s, 1H) 6.95 (d, J=4.8 Hz, 1H) 3.62 (s, 3H) 2.90 (t, J=8
Hz, 2H) 2.63 (s, 3H) 2.56 (t, J=8 Hz, 2H). MS: m/z=473.0
(M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-iodo-benzenesulfonamide
##STR00236##
[0869] To a magnetically stirred mixture of precursor amino-ketone
(2.32 g, 10.0 mmol) in dry pyridine (20 mL) was added a solution of
pipsyl chloride (4.78 g, 15.8 mmol) in toluene (20 mL) under dry
nitrogen. The addition was performed over a 2 h period. The
reaction was stirred overnight at 50.degree. C., then additional
pipsyl chloride (850 mg), as a solution in toluene, was added.
After 6 h, the reaction was concentrated and the residue was taken
up in ethyl acetate. The organic layer was washed with water, then
the mixture was filtered. The layers were separated and the organic
layer was dried (MgSO.sub.4), filtered and concentrated to provide
crystalline material. .sup.1H-NMR (CDCl3) .delta. 9.95 (br s, 1H,
NH), 8.82 (dm, 2H, J=5.2 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.54 (dm, 1H,
J=8.8 Hz, J=2.6 Hz), 7.41 (dm, 2H, J=8.8 Hz), 7.30 (d, 1H, J=2.6
Hz), 7.30 (d, 1H, J=2.6 Hz), 7.19 (dm, 2H, J=5.2 Hz). MS: m/z 499
(M+1).
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(2,4-dimethyl-oxazol-5-yl)--
benzenesulfonamide
##STR00237##
[0871] Trifluoromethanesulfonic acid (4.5 mmol) was added to a
stirred solution of iodobenzene diacetate (0.39 g, 1.2 mmol) in
acetonitrile (10 mL) and stirred at ambient temperature for 20
minutes. To this reaction propiophenone (1.0 mmol) was added and
the reaction was refluxed for 2.5 h. After completion of the
reaction, as judged by TLC, excess acetonitrile was evaporated and
the crude product was extracted into dichloromethane (3.times.40
mL). The combined organic extracts were then washed with saturated
aqueous sodium bicarbonate (2.times.50 mL), dried (MgSO4), filtered
and concentrated to give a dark amber waxy solid. The product was
purified by column chromatography on silica gel using ethyl
acetate-hexane (5:95, 10:90) to furnish a crystalline solid.
[0872] 2,4-dimethyl-5-phenyloxazole (53 mg, 0.31 mmol) was treated
with chlorosulfonic acid (3.0 equivalents) in dry dichloromethane
(8 mL) at 0.degree. C. The solution was allowed to slowly warm to
room temperature and monitored by LC/MS for complete reaction, then
the reaction was washed with cold water. The organic layer was
dried over magnesium sulfate, filtered and concentrated.
[0873] The residue was treated with thionyl chloride (2
equivalents) in dry dichloromethane (5 mL). The desired product was
isolated by concentration of the reaction mixture to give
4-(2,4-dimethyl-oxazol-5-yl)benzenesulfonyl chloride, which was
used immediately in the next step: mass spectrum m/z 272 (M+1);
[0874] To a magnetically stirred solution of the aminoketone (1.62
g, 7.0 mmol) in dry pyridine (30 mL) was added drop wise a solution
of the sulfonyl chloride in 1.0 mL of dichloromethane and the
slightly turbid reaction was stirred at ambient temperature. After
5 h, the reaction was diluted with ethyl acetate (25 mL) and washed
with cold 3M HCl, followed by washing with aqueous NaHCO.sub.3,
then washed with water. The organic layer was dried (MgSO4),
filtered and concentrated to give a pale yellow waxy solid. The
product was purified by preparative hplc and pure material
lyophilized to give the desired product. .sup.1H NMR (CDCl3)
.delta. 8.84 (br s, 2H), 7.69 (dm, 2H, J=8.4 Hz), 7.65 (d, 1H,
J=8.8 Hz), 7.46 (dm, 1H, J=2.2 Hz), 7.43 (dm, 2H, J=8.4 Hz), 7.36
(ddd, 1H, J=8.8 Hz, J=2.6 Hz, J=0.7 Hz), 7.24 (2H, obscured), 7.15
(br s, 1H), 3.19 (s, 3H), 3.13 (s, 3H). MS: m/z 468 (M+1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00238##
[0876] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone (243
mg, 1.0 mmol) and 4-tert-Butyl-benzenesulfonyl chloride (232 mg,
1.0 mmol) and purified by HPLC. .sup.1H NMR (CDCl3) .delta. 10.71
(brs, 1H, NH), 8.63 (dd, 1H, J=5.1 Hz, J=1.6 Hz), 7.83 (d, 1H,
J=8.8 Hz), 7.73 (dm, 2H, J=8.4 Hz), 7.49 (dd, 1H, J=8.8 Hz, J=2.6
Hz), 7.43 (dm, 2H, J=8.5 Hz), 7.27 (dd, 1H, J=9.5 Hz, J=1.8 Hz),
7.18 (dd, 1H, J=7.7 Hz, J=4.8 Hz), 7.13 (d, 1H, J=2.6 Hz), 2.29 (s,
3H), 1.29 (s, 9H). MS: m/z 443 (M+1).
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide
##STR00239##
[0878] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and
4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. .sup.1H
NMR (CDCl3) .delta. 10.63 (brs, 1H, NH), 8.63 (dd, 1H, J=4.8 Hz,
J=1.8 Hz), 7.79 (d, 1H, J=8.8 Hz), 7.71 (d, 1H, J=8.8 Hz), 7.48
(dd, 1H, J=9.0 Hz, J=2.2 Hz), 7.27 (dd, 1H, J=7.7 Hz, J=1.8 Hz),
7.19 (dd, 1H, J=7.7 Hz, J=4.8 Hz), 7.14 (d, 1H, J=2.2 Hz), 4.55
(septet, 1H, J=6 Hz), 2.35 (s, 3H), 1.35 (d, 3H, J=6 Hz). MS: m/z
445 (M+1).
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-b-
enzenesulfonamide
##STR00240##
[0880] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using (2
amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and
4-trifluoromethoxy-benzenesulfonyl chloride and purified by
HPLC.
[0881] .sup.1H NMR (CDCl3) .delta. 10.76 (br s, 1H, NH), 8.65 (dd,
1H, J=4.8 Hz, J=2.0 Hz), 7.88 (dm, 2H, J=8.8 Hz), 7.80 (d, H1,
J=9.2 Hz), 7.52 (dd, 1H, J=9.0 Hz, J=2.2 Hz), 7.1-7.3 (m, 4H), 7.18
(d, 1H, J=2.6 Hz), 2.35 (s, 3H). MS: m/z 471 (M+1).
Synthesis of
4-Acetyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulf-
onamide
##STR00241##
[0883] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using (2
amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and
4-acetyl-benzenesulfonyl chloride and purified by HPLC. .sup.1H NMR
(CDCl3) .delta. 10.79 (br s, 1H, NH), 8.65 (dd, 1H, J=4.8 Hz, J=1.8
Hz), 7.98 (d, 2H, J=8.8 Hz), 7.92 (d, 2H, J=8.8 Hz), 7.79 (d, 1H,
J=9.2 Hz), 7.50 (dd, 1H, J=9.0 Hz, J=2.2 Hz), 7.22 (dd, 1H, J=7.7
Hz, J=1.5 Hz), 7.16 (m, 2H), 2.60 (s, 3H), 2.36 (s, 3H). MS: m/z
429 (M+1).
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-be-
nzenesulfonamide
##STR00242##
[0885] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using (2
amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and
4-methanesulfonyll-benzenesulfonyl chloride and purified by HPLC.
.sup.1H NMR (CDCl3) .delta. 10.86 (br s, 1, NH), 8.65 (dd, 1H,
J=4.8 Hz, J=1.8 Hz), 8.02 (m, 4H), 7.78 (d, 1H, J=8.8 Hz), 7.53
(dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.1-7.3 (m, 3H), 3.07 (s, 3H), 2.41
(s, 3H). MS: m/z 465 (M+1).
Synthesis of
3-{4-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}--
propionic acid methyl ester
##STR00243##
[0887] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using (2
amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and
3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and
purified by HPLC. .sup.1H-NMR (CDCl3) .delta. 10.75 (br s, 1H, NH),
8.64 (dm, 1H, J=4.8 Hz), 7.79 (dd, 1H, J=9.2 Hz, J=1.1 Hz), 7.75
(d, 2H, J=7.3 Hz), 7.49 (dm, 1H, J=9.2 Hz), 7.1-7.3 (m, 5H), 3.65
(s, 3H), 2.97 (t, 2H, J=7.6 Hz), 2.61 (t, 2H, J=7.6 Hz), 2.35 (s,
3H). MS: m/z 473 (M+1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzene-
sulfonamide
##STR00244##
[0889] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. .sup.1H
NMR (CDCl.sub.3) .delta. 9.77 (br s, 1H, NH), 8.40 (dm, 1H, J=1.8
Hz), 7.77 (dm, 1H, J=8.6 Hz), 7.71 (dd, 1H, J=8.1 Hz, J=2.2 Hz),
7.58 (dm, 2H, J=8.6 Hz), 7.50 (dd, 1H, J=9.0 Hz, J=2.4 Hz), 7.32
(d, 1H, J=2.2 Hz), 7.29 (dm, 2H, J=8.6 Hz), 7.23 (d, 1H, J=8.1 Hz),
2.63 (s, 3H), 1.20 (s, 9H). MS: m/z 443 (M+1).
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-b-
enzenesulfonamide
##STR00245##
[0891] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
4-trifluoromethyl-benzenesulfonyl chloride and purified by HPLC.
.sup.1H-NMR (CDCl3) .delta. 9.76 (br s, 1, NH), 8.50 (d, 1H, J=2.2
Hz), 7.76 (d, 1H, J=8.8), 7.73 (d, 2H, J=9.2), 7.66 (dd, 1H, J=8.0,
J=2.2), 7.54 (ddm, 1H, J=8.8 Hz, J=2.6 Hz), 7.37 (d, 1H, J=2.6),
7.24 (d, 1H, J=6 Hz), 7.10 (d, 2H, J=8.8 Hz), 2.35 (s, 3). MS: m/z
471 (M+1).
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide
##STR00246##
[0893] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. .sup.1H
NMR (CDCl.sub.3) .delta. 9.67 (br s, 1H, NH), 8.45 (d, 1H, J=1.8
Hz), 7.75 (d, 1H, J=8.8 Hz), 7.68 (dd, 1H, J=8.0 Hz, J=2.2 Hz),
7.55 (d, 2H, J=9.0 Hz), 7.50 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 7.32 (d,
1H, J=2.6 Hz), 7.24 (d, 1H, J=8.0 Hz), 6.68 (d, 2H, J=9.0 Hz), 4.43
(septet, 1H, J=6 Hz), 2.65 (s, 3H), 1.28 (d, 3H, J=6 Hz). MS: m/z
445 (M+1).
Synthesis of
4-Acetyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulf-
onamide
##STR00247##
[0895] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
4-acetyl-benzenesulfonyl chloride and purified by HPLC. .sup.1H NMR
(CDCl.sub.3) .delta. 9.54 (br s, 1, NH), 8.30 (m, 1), 7.77 (d, 2,
J=8.8 Hz), 7.71 (d, 2, J=8.8 Hz), 7.69 (m, 1), 7.54 (dd, 1, J=8.8
Hz, J=2.2 Hz), 7.33 (d, 1, J=2.2 Hz), 7.26 (m, 1), 7.21 (d, 1,
J=8.0 Hz), 2.63 (s, 3), 2.52 (s, 3). MS: m/z 429 (M+1).
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-be-
nzenesulfonamide
##STR00248##
[0897] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
4-Methanesulfonyl-benzenesulfonyl chloride and purified by HPLC.
.sup.1H NMR (CDCl.sub.3) .delta. 9.77 (br s, 1H, NH), 8.44 (dm, 1H,
J=2.2 Hz), 7.87 (d, 2H, J=8.8 Hz), 7.83 (d, 2H, J=8.8 Hz), 7.76 (d,
1H, J=8.8 Hz), 7.60 (dd, 1H, J=8.0 Hz, J=2.2 Hz), 7.55 (dd, 1H,
J=8.8 Hz, J=2.2 Hz), 7.36 (d, 1H, J=2.2), 7.26 (d, 1H, J=8.0 Hz),
3.00 (s, 3H), 2.66 (s, 3H). MS: m/z 465 (M+1).
Synthesis of
3-{4-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}--
propionic acid methyl ester
##STR00249##
[0899] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and
purified by HPLC. .sup.1H NMR (CDCl3) .delta. 9.66 (br s, 1H, NH),
8.34 (d, 1H, J=2.2 Hz), 7.75 (d, 1H, J=8.8 Hz), 7.72 (d, 1H, J=8.0
Hz, J=2.2 Hz), 7.56 (d, 2H, J=8.4 Hz), 7.51 (dd, 1H, J=8.8 Hz,
J=2.2 Hz), 7.32 (d 1H, J=2.2 Hz), 7.26 (d, 1H, J=7 Hz), 7.09 (d,
2H, J=8.4 Hz), 3.65 (s, 3H), 2.97 (t, 2H, J=7.6 Hz), 2.66 (s, 3H),
2.51 (t, 2H, J=7.6 Hz). MS: m/z 473 (M+1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(1-methyl-[1,2,3]triazole-4-carbonyl)-phenyl]--
benzenesulfonamide
##STR00250##
[0901] Following the general procedure for synthesis of
N-arylbenzenesulfonamides, 28 mg (0.12 mmol) of
(2-Amino-5-chloro-phenyl)-(1-methyl-[1,2,3]triazol-4-yl) methanone
and 56 mg (0.24 mmol) of 4-tert-butylphenylsulfonyl chloride were
combined in 0.5 ml of anhydrous pyridine at 60.degree. C. to give,
after purification, the title product as a pale yellow solid:
.sup.1H NMR CD.sub.3OD .delta. (ppm): 1.21 (s, 9H), 4.25 (s, 3H),
7.38 (d, 2H), 7.53 (d, 2H), 7.54-7.63 (m, 2H), 8.11 (s, 1H), 8.22
(d, 1H); MS: (M+H)/z=433.1.
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(3-methyl-[1,2,3]triazole-4-carbonyl)-phenyl]--
benzenesulfonamide
##STR00251##
[0903] Following the general procedure for synthesis of
N-arylbenzenesulfonamides, 28 mg (0.12 mmol) of
(2-Amino-5-chloro-phenyl)-(3-methyl-[1,2,3]triazol-4-yl) methanone
and 56 mg (0.24 mmol) of 4-tert-butylphenylsulfonyl chloride were
combined in 0.5 ml of anhydrous pyridine at 60.degree. C. to give,
after purification, the title product as a pale yellow solid:
.sup.1H NMR CD.sub.3OD .delta. (ppm): 1.20 (s, 9H), 4.15 (s, 3H),
7.37 (d, 2H), 7.52 (d, 2H), 7.59-7.62 (m, 2H), 8.27 (d, 1H), 8.53
(s, 1H); MS: (M+H)/z=433.0.
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(1-methylenyl-[1H]-3-methyl-
-5-trifluoromethyl-oxazolyl)-benzenesulfonamide
##STR00252##
[0905] Title compound was prepared according to the standard
general procedures. .sup.1H NMR (400 MHz, CDCl.sub.3); 10.277 (s,
1H), 8.79-8.85 (m, 2H), 7.76-7.79 (m, 3H), 7.53-7.55 (m, 1H),
7.36-7.37 (m, 1H), 7.23-7.33 (m, 2H), 7.08-7.1 (d, 2H), 6.38 (s,
1H), 5.26-5.3 (d, 2H), 2.2 (s, 3H). MS (ES) (M+H) expected 534.95
found 534.8.
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(1-methylenyl-[1H]-oxazolyl-
)-benzenesulfonamide
##STR00253##
[0907] Title compound was prepared according to the standard
general procedures. .sup.1H NMR (400 MHz, CDCl.sub.3); 9.07 (s,
1H), 8.79-8.84 (m, 2H), 7.71-7.78 (m, 3H), 7.53-7.55 (m, 1H),
7.36-7.37 (m, 2H), 7.23-7.33 (m, 2H), 7.08-7.1 (d, 2H), 6.38 (s,
1H), 5.26-5.3 (d, 2H). MS (ES) (M+H) expected 452.92 found 452.
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-4-yl-eth-
yl)-benzenesulfonamide
##STR00254##
[0909] Following the general procedure for synthesis of
N-arylbenzenesulfonamides, 73 mg (0.32 mmol) of
(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 36 mg (0.13
mmol) of 4-(1-Methyl-1-oxazol-4-yl-ethyl)-benzenesulfonyl chloride
were combined in 1 ml of anhydrous pyridine at 60.degree. C. to
give, after purification, the title product as a pale yellow solid:
.sup.1H NMR (CDCl.sub.3): .delta. (ppm): 1.61 (s, 6H), 7.26-7.66
(m, 12H), 8.90 (br, 1H), 10.13 (br, 1H) ppm; MS: (M+H)/z=482.0.
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-
-4-yl-ethyl)-benzenesulfonamide
##STR00255##
[0911] Following the general procedure for synthesis of
N-arylbenzenesulfonamides, 63 mg (0.26 mmol) of
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 50
mg (0.17 mmol) of 4-(1-Methyl-1-oxazol-4-yl-ethyl)-benzenesulfonyl
chloride were combined in 0.8 ml of anhydrous pyridine at
60.degree. C. to give, after purification, the title product as a
pale yellow solid: .sup.1H NMR (CDCl.sub.3): .delta. (ppm): 1.54
(s, 6H), 2.63 (s, 3H), 7.22-7.30 (m, 2H), 7.32 (m, 2H), 7.55 (m,
1H), 7.61-7.63 (m, 2H), 7.70-7.80 (m, 3H), 8.49 (d, 1H), 9.95 (s,
1H); MS: (M+H)/z=496.0.
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)phenyl]-4-(2-oxazol-2-ylethyl)benzenes-
ulfonamide
##STR00256##
[0913] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described and purified by HPLC. .sup.1H NMR: .delta.
(400 MHz, CDCl.sub.3) 10.07 (s, 1H), 8.75 (m, 2H), 7.73 (d, 2H),
7.63 (d, 2H), 7.50 (s, 1H), 7.28 (d, 1H), 7.22 (m, 2H), 7.15 (d,
2H), 6.96 (s, 1H), 3.02 (m, 4H). MS (M+H.sup.+): 468.0
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)phenyl]-4-(1-methyl-1-oxazol-5-ylethyl-
)-benzenesulfonamide
##STR00257##
[0915] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described and purified by HPLC. .sup.1H NMR: .delta.
(400 MHz, CDCl.sub.3) 10.16 (s, 1H), 8.77 (d, 2H), 7.73 (d, 2H),
7.67 (d, 2H), 7.51 (dd, 1H), 7.29 (d, 1H), 7.23 (m, 2H), 7.22 (m,
2H), 6.84 (s, 1H), 1.60 (s, 6H). MS (M+H.sup.+): 482.0
Synthesis of
N-[4-Chloro-2-(6-methylpyridine-3-carbonyl)phenyl]-4-(1-methyl-1-oxazol-5-
-ylethyl)-benzenesulfonamide
##STR00258##
[0917] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described and purified by HPLC. .sup.1H NMR: .delta.
(400 MHz, CDCl.sub.3) 9.67 (s, 1H), 8.77 (d, 1H), 8.35 (dd, 1H),
8.03 (s, 1H), 7.67 (m, 3H), 7.51 (s, 2H), 7.45 (s, 1H), 7.29 (d,
2H), 6.94 (s, 1H), 2.87 (s, 3H), 1.66 (s, 6H). MS (M+H.sup.+):
496.0
Synthesis of
N-[4-Bromo-2-(pyridine-4-carbonyl)-phenyl]-4-oxazol-5-yl-benzenesulfonami-
de
##STR00259##
[0919] The title compound was prepared according the general
procedure for the synthesis of N-aryl-benzenesulfonamides using
(2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and
4-oxazol-5-yl-benzenesulfonyl chloride and purified by HPLC. MS:
m/z 485 (M.sup.++1).
Synthesis of
N-[4-bromo-2-(pyridine-4-carbonyl)-phenyl]-4-isopropyl-benzenesulfonamide
##STR00260##
[0921] The title compound was prepared according the general
procedure for the synthesis of N-aryl-benzenesulfonamides using
4-isopropyl-benzenesulfonyl chloride and
(2-amino-5-bromo-phenyl)-pyridin-4-yl-methanone and purified by
HPLC. MS: m/z 460 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzen-
esulfonamide
##STR00261##
[0923] The title compound was prepared according to the general
procedure using
(2-amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and
4-oxazol-5-yl-benzenesulfonyl chloride and purified by HPLC. MS:
m/z 454 (M.sup.++1).
Synthesis of
N-[4-cloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-(2-methyl-oxazol-5--
yl)-benzenesulfonamide
##STR00262##
[0925] The title compound was prepared according to the general
procedure for the preparation of N-aryl-benzenesulfonamides using
4-(2-methyl-oxazol-5-yl)-benzenesulfonyl chloride and
(2-amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
purified by HPLC. MS: m/z 468.0 (M.sup.++1).
Synthesis
N-[4-Chloro-2-(6-methyl-pyridine-2-carbonyl)-phenyl]-4-(2-methyl-
-oxazol-5-yl)-benzenesulfonamide
##STR00263##
[0927] The title compound was prepared according to the general
procedure for the preparation of N-aryl-benzenesulfonamides using
4-(2-methyl-oxazol-5-yl)-benzenesulfonyl chloride and
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and
purified by HPLC. MS: m/z 468.0 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(1-methyl-1H-indazole-3-carbonyl)-phenyl]-benz-
enesulfonamide
##STR00264##
[0929] The title compound was prepared according to the general
procedure for the preparation of N-aryl-benzenesulfonamides using
4-tert-butyl-benzenesulfonyl chloride and
(2-Amino-5-chloro-phenyl)-(1-methyl-1H-indazol-3-yl)-methanone and
purified by HPLC: MS: m/z 483 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-(4-methyl-oxazol-5-
-yl)-benzenesulfonamide
##STR00265##
[0931] The title compound was prepared according to the general
procedure for the preparation of N-aryl-benzenesulfonamides using
by the reaction of 4-(4-methyl-oxazol-5-yl)-benzenesulfonyl
chloride with
(2-amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
purified by HPLC: MS: m/z 468.0 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(4-methyl-pyridine-3-carbonyl)-phenyl]-4-oxazol-5-yl-benzen-
esulfonamide
##STR00266##
[0933] The title compound was prepared using
4-oxazol-5-yl-benzenesulfonyl chloride and
(2-amino-5-chloro-phenyl)-(4-methyl-pyridin-3-yl)-methanone
according to the general procedure for the preparation of the
N-aryl-benzenesulfonamides. MS: m/z 454.0 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(1-methyl-1H-imidazole-2-carbonyl)-phenyl]-ben-
zenesulfonamide
##STR00267##
[0935] The title compound was prepared using
4-t-butyl-benzenesulfonyl chloride and
(2-Amino-5-chloro-phenyl)-(1-methyl-1H-imidazol-2-yl)-methanone
following the general procedure described for the preparation of
N-aryl-benzenesulfonamides. MS: m/z 452.1 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-isopropylsulfanyl-benzenesu-
lfonamide
##STR00268##
[0937] The intermediate 4-isopropylsulfanyl-benzenesulfonyl
chloride, which was prepared from isopropylsulfanyl-benzene
following general chlorosulfonylation procedure, was reacted with
(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone to yield the title
compound. MS: m/z 447.0 (M.sup.++1).
Synthesis of
4-tert-butyl-N-[4-chloro-2-(thiazole-2-carbonyl)-phenyl]benzenesulfonamid-
e
##STR00269##
[0939] The title compound was prepared by the reaction of
4-t-butylbenzenesulfonyl chloride with
(2-Amino-5-chloro-phenyl)-thiazol-2-yl-methanone following the
general procedure. MS: m/z 435.0 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(1H-pyrazole-3-carbonyl)-phenyl]-benzenesulfon-
amide
##STR00270##
[0941] The title compound was prepared by the reaction of
4-t-butylbenzenesulfonyl chloride with
(2-Amino-5-chloro-phenyl)-(1H-pyrazol-3-yl)-methanone following the
general procedure. MS: m/z 418.1 (M.sup.++1). Remove this
example--same as [0676 below]
Synthesis of
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-methoxy-benzenesulfonamide
##STR00271##
[0943] The title compound was prepared according to the general
procedure for the synthesis of N-Aryl-benzenesulfonamides
previously described using 116 mg of
(2-Amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 101 mg of
4-methoxy-benzenesulfonyl chloride. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 3.75 (s, 3H), 6.76 (m, 2H, 7.45 (m, 2H), 7.63
(m, 2H), 7.71 (d, 1H, J=8.8 Hz), 7.78 (m, 1H), 7.88 (m, 2H), 8.64
(m, 1H), 10.24 (s, 1H). MS: m/z 403.9 (M.sup.++1).
Synthesis of
4-tert-Butyl-N-[3,4-difluoro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfo-
namide
##STR00272##
[0945] The title compound was prepared by the reaction of
4-t-butylbenzenesulfonyl chloride with
(6-Amino-2,3-difluoro-phenyl)-pyridin-3-yl-methanone following the
general procedure. MS: m/z 431.1 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(4-methyl-tetrahydro-pyran--
4-yl)-benzenesulfonamide
##STR00273##
[0947] The title compound was prepared by the reacting
4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone according to the
general procedure described for the preparation of
(N-aryl-benzenesulfonamides. .sup.1H NMR (CDCl.sub.3) .delta. 10.21
(s, 1H), 8.77 (d, 2H, J=6.0 Hz), 7.79 (d, 1H, J=8.8 Hz), 7.73 (m,
2H), 7.51-7.54 (m, 1H), 7.31-7.36 (m, 3H), 7.24-7.26 (m, 2H),
3.58-3.80 (m, 4H), 1.95-1.99 (m, 2H), 1.70-1.74 (m, 2H), 1.22 (s,
3H). MS: m/z 471 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-(4-methyl-tetrahydro-pyran--
4-yl)-benzenesulfonamide
##STR00274##
[0949] The title compound was prepared by the reacting
4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with
(2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone according to the
general procedure described for the preparation of
(N-aryl-benzenesulfonamides. MS: m/z 471 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-(4-methyl-tetrahydro-pyran--
4-yl)-benzenesulfonamide
##STR00275##
[0951] The title compound was prepared by the reacting
4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with
(2-amino-5-chloro-phenyl)-pyridin-2-yl-methanone according to the
general procedure described for the preparation of
(N-aryl-benzenesulfonamides. MS: m/z 471 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-2-carbonyl)-phenyl]-4-(4-methyl-tetrahyd-
ro-pyran-4-yl)-benzenesulfonamide
##STR00276##
[0953] The title compound was prepared by the reacting
4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with
(2-amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone
according to the general procedure described for the preparation of
(N-aryl-benzenesulfonamides. MS: m/z 486 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-(4-methyl-tetrahyd-
ro-pyran-4-yl)-benzenesulfonamide
##STR00277##
[0955] The title compound was prepared by the reacting
4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone
according to the general procedure described for the preparation of
(N-aryl-benzenesulfonamides. MS: m/z 486 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-(4-methyl-tetrahyd-
ro-pyran-4-yl)-benzenesulfonamide
##STR00278##
[0957] The title compound was prepared by the reacting
4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with
(2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone
according to the general procedure described for the preparation of
(N-aryl-benzenesulfonamides. MS: m/z 486 (M.sup.++1).
Synthesis of
4-tert-butyl-N-[4-chloro-2-(1H-pyrazole-3-carbonyl)-phenyl]-benzenesulfon-
amide
##STR00279##
[0959] The title compound was prepared by the reacting
4-t-butyl-benzenesulfonyl chloride with
(2-amino-5-chloro-phenyl)-(1H-pyrazol-3-yl)-methanone according to
the general procedure described for the preparation of
(N-aryl-benzenesulfonamides. MS: m/z 418 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-2-yl-eth-
yl)-benzenesulfonamide
##STR00280##
[0961] The title compound was prepared from
(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and
4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following
the general procedure described for the preparation of
N-aryl-benzenesulfonamides. MS: m/z 482 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-
-2-yl-ethyl)-benzenesulfonamide
##STR00281##
[0963] The title compound was prepared from
(2-amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and
4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following
the general procedure described for the preparation of
N-aryl-benzenesulfonamides. MS: m/z 496 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-2-yl-eth-
yl)-benzenesulfonamide
##STR00282##
[0965] The title compound was prepared from
(2-Amino-5-chloro-phenyl)-pyridin-3-yl-methanone and
4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following
the general procedure described for the preparation of
N-aryl-benzenesulfonamides. MS: m/z 482 (M.sup.++1).
Synthesis of
N-[4,5-Difluoro-2-(pyridine-3-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-2-yl-
-ethyl)-benzenesulfonamide
##STR00283##
[0967] The title compound was prepared from
(2-Amino-4,5-difluoro-phenyl)-pyridin-3-yl-methanone and
4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following
the general procedure described for the preparation of
N-aryl-benzenesulfonamides. MS: m/z 484 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-2-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-2-yl-eth-
yl)-benzenesulfonamide
##STR00284##
[0969] The title compound was prepared from
(2-amino-5-chloro-phenyl)-pyridin-2-yl-methanone and
4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following
the general procedure described for the preparation of
N-aryl-benzenesulfonamides. MS: m/z 482 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-2-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-
-2-yl-ethyl)-benzenesulfonamide
##STR00285##
[0971] The title compound was prepared from
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and
4-(1-methyl-1-oxazol-2-yl-ethyl)-benzenesulfonyl chloride following
the general procedure described for the preparation of
N-aryl-benzenesulfonamides. MS: m/z 496 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-4-yl-eth-
yl)-benzenesulfonamide
##STR00286##
[0973] Following the general procedure for synthesis of
N-arylbenzenesulfonamides, 73 mg (0.32 mmol) of
(2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 36 mg (0.13
mmol) of 4-(1-Methyl-1-oxazol-4-yl-ethyl)-benzenesulfonyl chloride
were combined in 1 ml of anhydrous pyridine at 60.degree. C. to
give, after purification, the title product as a pale yellow solid:
.sup.1H NMR (CDCl.sub.3): .delta. (ppm): 1.61 (s, 6H), 7.26-7.66
(m, 12H), 8.90 (br, 1H), 10.13 (br, 1H) ppm; MS: (M+H)/z=482.0.
Synthesis of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-
-4-yl-ethyl)-benzenesulfonamide
##STR00287##
[0975] Following the general procedure for synthesis of
N-arylbenzenesulfonamides, 63 mg (0.26 mmol) of
(2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 50
mg (0.17 mmol) of 4-(1-Methyl-1-oxazol-4-yl-ethyl)-benzenesulfonyl
chloride were combined in 0.8 ml of anhydrous pyridine at
60.degree. C. to give, after purification, the title product as a
pale yellow solid: .sup.1H NMR (CDCl.sub.3): .delta. (ppm): 1.54
(s, 6H), 2.63 (s, 3H), 7.22-7.30 (m, 2H), 7.32 (m, 2H), 7.55 (m,
1H), 7.61-7.63 (m, 2H), 7.70-7.80 (m, 3H), 8.49 (d, 1H), 9.95 (s,
1H); MS: (M+H)/z=496.0.
Synthesis of
N-[4-Chloro-2-(pyridine-4-carbonyl)phenyl]-4-(2-oxazol-2-ylethyl)benzenes-
ulfonamide
##STR00288##
[0977] The title compound was prepared according to the general
procedure for the preparation of N-aryl-benzenesulfonamides:
.sup.1H NMR: .delta. (400 MHz, CDCl.sub.3) 10.07 (s, 1H), 8.75 (m,
2H), 7.73 (d, 2H), 7.63 (d, 2H), 7.50 (s, 1H), 7.28 (d, 1H), 7.22
(m, 2H), 7.15 (d, 2H), 6.96 (s, 1H), 3.02 (m, 4H). MS (M+H.sup.+):
468.0
Synthesis of
4-Acetyl-N-[4-chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-benzenesulfo-
namide
##STR00289##
[0979] (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone (2.2 g, 9.4
mmol) suspended in 20 mL of anhydrous EtOH was treated with
NaBH.sub.4 (3.4 g, 89.4 mmol) in small portions. The reaction
mixture was stirred vigorously and within minutes changed from deep
yellow to an off-white color. After 30 minutes the crude reaction
mixture was concentrated by rotary evaporation and the resulting
residue was partitioned between 75 mL EtOAc and 75 mL 50% aqueous
NaHCO.sub.3. The EtOAc layer was collected and the aqueous layer
was washed with 75 mL EtOAc. The two organic fractions were
combined, dried on MgSO.sub.4 and concentrated by rotary
evaporation. The resulting solid was dried under vacuum to yield
1.7 g of a white powder. The white powder was dissolved in 10 mL
anhydrous pyridine and treated with 1.6 g (7.4 mmol) of
4-acetylbenzenesulfonyl chloride. The sulfonylation reaction
monitored by LC-MS was complete after 1 h. The pyridine was
evaporated under vacuum and the resulting crude residue was
partitioned between 50 mL EtOAc and 50 mL 50% aqueous NaHCO.sub.3.
The bicarbonate layer was extracted with EtOAc (1.times.50 mL). The
two organic fractions were combined, dried on MgSO.sub.4 and
concentrated by rotary evaporation to yield the title compound as a
pale-amber solid. MS: m/z 417 (M.sup.++1).
Syntheses of Sulfonamide Pyridine-N-Oxides
Synthesis of
N-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-trifluoromet-
hoxy-benzenesulfonamide
##STR00290##
[0981] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-b-
enzenesulfonamide according to the general procedure. .sup.1H NMR
(CDCl3) .delta. 9.60 (br s, 1, NH), 8.42 (m, 1H), 7.78 (dm, 2H,
J=8.4 Hz), 7.70 (dm, 1H, J=8.8 Hz), 7.56 (dd, 1H, J=8.0 Hz, J=2.2
Hz), 7.44 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=2.2 Hz), 7.38 (dm, 1H,
J=8.0 Hz), 7.20 (dm, 2H, J=8.4 Hz), 2.65 (s, 3H). MS: m/z 487
(M+1).
Synthesis of
N-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-b-
enzenesulfonamide
##STR00291##
[0983] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide according to the general procedure. .sup.1H-NMR
(CDCl.sub.3) .delta. 9.53 (br s, 1H, NH), 8.25 (dm, 1H, J=1.5 Hz),
7.74 (d, 1H, J=8.8 Hz), 7.59 (dm, 2H, J=8.8 Hz), 7.52 (dd, 1H,
J=8.8 Hz, J=2.6 Hz), 7.24 (d, 1H, J=8.0 Hz), 7.33 (d, 1H, J=2.6
Hz), 7.20 (dd, 1H, J=8.0 Hz, J=1.6 Hz), 6.75 (dm, 2H, J=8.8 Hz),
4.51 (septet, 1H, J=6 Hz), 2.59 (s, 3H), 1.30 (d, 3H, J=6 Hz). MS:
m/z 461 (M+1).
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-benze-
nesulfonamide
##STR00292##
[0985] The title compound was prepared by the mCPBA oxidation of
4-methanesulfonyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulf-
onamide according to the general procedure. .sup.1H NMR (DMSO-d6):
.delta. 3.27 (s, 3H), 6.90 (d, J=8.8 Hz, 1H), 7.47 & 7.49 (dd,
J=8.0 Hz, 1.2 Hz, 1H), 7.51-7.55 (m, 1H), 7.56 & 7.58 (dd,
J=8.0 Hz, 2.4 Hz, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.79 (d, J=7.6 Hz,
2H), 8.05 (d, J=8.8 Hz, 2H), 8.19 (d, J=2.0 Hz, 1H), 8.41 &
8.42 (dd, J=6.8 Hz, 1.2 Hz, 1H), 10.46 (s, 1H). MS: M/z 467.0
(M.sup.++1).
Synthesis of
4-Acetyl-N-[4-chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-benze-
nesulfonamide
##STR00293##
[0987] The title compound was prepared by the mCPBA oxidation of
4-Acetyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulf-
onamide according to the general procedure. .sup.1H-NMR (CDCl3)
.delta. 9.16 (br s, 1H, NH), 8.15 (dm, 1H, J=2.0 Hz), 7.83 (d, 2H,
J=8.1 Hz), 7.71 (d, 2H, J=8.1 Hz), 7.71-7.67 (m, 2H), 7.58 (dd, 1H,
J=8.8 Hz, J=2.2 Hz), 7.52 (d, 1H, J=8.4 Hz), 7.37 (d, 1H, J=2.2
Hz), 2.66 (s, 3H), 2.60 (s, 3H). MS: m/z 445 (M+1).
Synthesis of
N-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-methanesulfo-
nyl-benzenesulfonamide
##STR00294##
[0989] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-be-
nzenesulfonamide according to the general procedure. .sup.1H-NMR
(CDCl3) .delta. 9.39 (br s, 1H, NH), 8.61 (m, 1H), 7.88 (m, 4H),
7.68 (d, 1H, J=8.8 Hz), 7.60 (m, 2H), 7.40 (m, 2H), 3.03 (s, 3H),
2.69 (s, 3H). m/z 481 (M+1)
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesul-
fonamide
##STR00295##
[0991]
4-tert-Butyl-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesul-
fonamide (107 mg, 0.25 mmol) was dissolved in 4 mL DCM and
m-chloroperoxybenzoic (0.26 mmol) was added. The mixture was
stirred at room temperature for 16 h. The solvent was evaporated on
a rotary evaporator and the product was purified by reversed phase
HPLC to yield title compound. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. 1.24 (s, 9H), 7.32-7.4 (m, 5H), 7.52 (dd, 1H, J=8.8, Hz,
2.4 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.74 (d, 1H, J=8.8 Hz), 8.18 (d,
2H, J=7.6 Hz), 9.60 (s, 1H). MS: m/z 445.9 (M.sup.++1).
Synthesis of
3-{4-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenylsulfamoyl]-ph-
enyl}-propionic acid methyl ester
##STR00296##
[0993] The title compound was prepared by the mCPBA oxidation of
3-{4-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}--
propionic acid methyl ester according to the general procedure.
.sup.1H-NMR (CDCl3) .delta. 9.47 (br s, 1H, NH), 8.26 (m, 1H), 7.69
(d, 1H, J=8.8 Hz), 7.59 (dm, 2H, J=8.4 Hz), 7.53 (dd, 1H, J=8.8 Hz,
J=2.6 Hz), 7.48 (m, 2H), 7.35 (d, 1H, J=2.6 Hz), 7.18 (dm, 2H,
J=8.4 Hz), 3.64 (s, 3H), 2.88 (t, 2H, J=7.6 Hz), 2.67 (s, 3H), 2.51
(t, 2H, J=7.6 Hz). MS: m/z 489 (M+1).
Synthesis of
4-Acetyl-N-[4-chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesulfona-
mide
##STR00297##
[0995] The title compound was prepared by the mCPBA oxidation of
4-Acetyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonamide
according to the general procedure.
Synthesis of
N-[4-Chloro-2-(1-oxypyridine-4-carbonyl)phenyl]-4-(1-methyl-1-oxazol-5-yl-
ethyl)-benzenesulfonamide
##STR00298##
[0997] The title compound was prepared by the general oxidation
procedure using mCPBA described for the synthesis of pyridine
N-oxides: .sup.1H NMR: .delta. (400 MHz, CDCl.sub.3) 9.80 (s, 1H),
8.41 (d, 2H), 8.79 (s, 1H), 7.74 (s, 1H), 7.72 (d, 2H), 7.70 (s,
1H), 7.56 (d, 1H), 7.53 (m, 2H), 7.51 (s, 1H), 6.95 (s, 1H), 1.65
(s, 6H). MS (M+H.sup.+): 498.0
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-b-
enzenesulfonamide
##STR00299##
[0999] The title compound was prepared by the mCPBA oxidation of
4-tert-Butyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzene-
sulfonamide according to the general procedure. .sup.1H NMR
(CDCl.sub.3) .delta. 10.71 (brs, 1H, NH), 8.62 (dm, 1H, J=5.9 Hz),
7.81 (d, 1H, J=9.1 Hz), 7.78 (dm, 2H, J=8.4 Hz), 7.54 (dd, 1H,
J=8.8 Hz, J=2.6 Hz), 7.48 (dm, 2H, J=8.4 Hz), 7.44 (m, 2H), 7.18
(d, 1H, J=2.6 Hz), 2.32 (s, 3H), 1.32 (s, 9H). MS: m/z 459
(M+1).
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-(4-methyl-tetrahydro--
pyran-4-yl)-benzenesulfonamide
##STR00300##
[1001] The title compound was prepared by the mCPBA oxidation of
N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(4-methyl-tetrahydro-pyran--
4-yl)-benzenesulfonamide according to the general procedure
described for the synthesis of pyridine N-oxides. MS: m/z 487
(M.sup.++1).
Synthesis
4-tert-Butyl-N-[4-chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)--
phenyl]-benzenesulfonamide
##STR00301##
[1003] The title compound was prepared according to the general
procedure by mCPBA oxidation of
4-tert-butyl-N-[4-chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-benzene-
sulfonamide. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.1.26 (s,
9H), 2.63 (s, 3H) 7.29 (d, 1H, J=2.8 Hz), 7.50-7.57 (m, 3H), 7.67
(m, 2H), 7.87 (m, 2H), 8.24 (s, 1H), 8.89 (d, 1H, J=5.6 Hz), 10.31
(s, 1H). MS:m/z 459.0 (M.sup.++1)
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-benzenesul-
fonamide
##STR00302##
[1005] The title compound was prepared by the mCPBA oxidation of
4-tert-Butyl-N-[4-chloro-2-(pyridine-3-carbonyl)-phenyl]-benzenesulfonami-
de according to the general procedure and purified by HPLC. .sup.1H
NMR (CDCl3) .delta. 9.71 (s, 1H) 8.56 (d, J=7.6 Hz, 1H) 8.43 (s,
1H) 7.71-7.66 (m, 4H) 7.61-7.53 (m, 2H) 7.44-7.38 (m, 3H) 1.28 (s,
9H). MS (ES) m/z=445.0 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)-phenyl]-4-trifluoromet-
hoxy-benzenesulfonamide
##STR00303##
[1007] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-trifluoromethoxy-b-
enzenesulfonamide according to the general procedure and purified
by HPLC. 1H NMR (CDCl3) .delta. 9.66 (s, 1H) 8.26 (d, J=6.8 Hz, 1H)
7.89 (d, 2H, J=8.4 Hz) 7.85 (s, 1H) 7.81 (d, 2H, J=8.4 Hz) 7.73 (d,
1H, J=8.8 Hz) 7.54 (dd, 1H, J=12 Hz, 2 Hz) 7.36 (t, 1H, J=5.6 Hz,
3.2 Hz) 7.24-7.19 (m, 1H) 2.55 (s, 3H). MS (ES) m/z=486.9
(M.sup.++1).
Synthesis of
N-[4-Chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-b-
enzenesulfonamide
##STR00304##
[1009] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(2-methyl-pyridine-4-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide according to the general procedure and purified by
HPLC. 1H NMR (CDCl3) .delta. 9.39 (s, 1H) 8.32 (d, J=6.8 Hz, 1H)
7.75 (d, J=11.2, 1H) 7.57-7.52 (m, 3H) 7.36 (d, J=2.4 Hz, 1H) 7.30
(d, J=2.4 Hz, 1H) 7.21 (dd, J=7.2 Hz, 2.8 Hz, 1H) 6.71 (d, J=7.2
Hz, 2H) 4.46 (p, J=6.0 Hz, 1H) 2.57 (s, 3H) 1.29 (d, J=5.6 Hz, 6H).
MS (ES) m/z=461.0 (M++1).
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-4-(4-methyl-tetrahydro--
pyran-4-yl)-benzenesulfonamide
##STR00305##
[1011] The title compound was prepared by the mCPBA oxidation of
N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(4-methyl-tetrahydro-pyran--
4-yl)-benzenesulfonamide according to the general procedure
described for the synthesis of pyridine N-oxides. MS: m/z 487
(M.sup.++1).
Synthesis of
N-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-(4-methyl-te-
trahydro-pyran-4-yl)-benzenesulfonamide
##STR00306##
[1013] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-(4-methyl-tetrahyd-
ro-pyran-4-yl)-benzenesulfonamide according to the general
procedure described for the synthesis of pyridine N-oxides. MS: m/z
502 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-2--
yl-ethyl)-benzenesulfonamide
##STR00307##
[1015] This compound was prepared by the mCPBA oxidation of
N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-2-yl-eth-
yl)-benzenesulfonamide following the general procedure described
for the synthesis of pyridine N-oxides.
Synthesis of
N-[4-Chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-(1-methyl-1--
oxazol-2-yl-ethyl)-benzenesulfonamide
[1016] The title compound was prepared by mCPBA oxidation of
N-[4-Chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-
-2-yl-ethyl)-benzenesulfonamide according to the general procedure
described for the synthesis of pyridine N-oxides. MS: m/z 512
(M.sup.++1).
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-3-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-2--
yl-ethyl)-benzenesulfonamide
##STR00308##
[1018] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(pyridine-3-carbonyl)-phenyl]-4-(1-methyl-1-oxazol-2-yl-eth-
yl)-benzenesulfonamide following the general procedure described
for the synthesis of pyridine N-oxides. MS: m/z 498
(M.sup.++1).
Synthesis of Pivaloyl protected
(2-Amino-5-chloro-phenyl)-(1-oxy-pyridin-4-yl)-methanol
##STR00309##
[1020] To a solution of pivaloyl protected
(2-Amino-5-chloro-phenyl)-1-oxy-pyridin-4-yl-methanone (1.4 g,
0.0044 mol) in glacial acetic acid (15 ml) was added H.sub.2O.sub.2
(0.376 g, 0.011 mols) and the reaction mixture was heated at
90.degree. C. for 3 h under N.sub.2 atmosphere. After 3 h
H.sub.2O.sub.2 (0.1496 g, 0.0044 mols) was added again with further
reflux at 90.degree. C. overnight, and the reaction mixture
concentrated to get the title compound.
Synthesis of
(2-nitro-5-chloro-phenyl)-(1-oxy-pyridin-4-yl)-methanone
##STR00310##
[1022] The title compound was synthesized using standard
procedures. .sup.1H NMR (300 MHz, CDCl.sub.3); 8.25-8.28 (m, 3H),
7.83-8.86 (m, 1H), 7.61-7.73 (m, 2H), 7.46-5.48 (m, 1H). MS (ES)
M+H) expected=278.65, found 278.8.
Synthesis of
4-Bromo-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzenesulfonam-
ide
##STR00311##
[1024]
4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonam-
ide 1 g (2.19 mmol) was dissolved in 10 ml anhydrous
dichloromethane. To this solution was added meta-chloroperbenzoic
acid (77%) 0.49 g (2.19 mmol), and the mixture was stirred at room
temperature overnight. The resulting white solid was filtered and
washed with dichloromethane.
[1025] LC-MSD, m/z for C.sub.18H.sub.12ClN.sub.2O.sub.4S [M+H]+:
468.9
[1026] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.774
Synthesis of
4-Bromo-N-[4-chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-3-fluo-
ro-benzenesulfonamide
##STR00312##
[1028]
4-Bromo-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-3-fluo-
ro-benzenesulfonamide 1.7 g (3.5 mmol) was dissolved in 10 ml
anhydrous dichloromethane, and to this solution was added
meta-chloroperbenzoic acid (77%) 0.787 g (3.5 mmol), and the
mixture was stirred at room temperature overnight. Purification
using flash column chromatography on silica (elution with, 2.9
Dichloromethane-0.1 methanol), gave an off-white solid.
[1029] LC-MSD, m/z for C.sub.19H.sub.13ClN.sub.2O.sub.4SBrF [M+H]+:
500.9
[1030] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.206
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-furan-3-yl-benzenesul-
fonamide
##STR00313##
[1032]
N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-4-furan-3-yl-benzenesul-
fonamide 0.1 g (0.22 mmol) was dissolved in 10 ml anhydrous
dichloromethane, and to this solution was added
meta-chloroperbenzoic acid (77%) 76 mg (0.3 mmol), and the mixture
was stirred at room temperature overnight. Purification using
preparative HPLC (20-70% acetonitrile in 50 min), gave a white
solid.
[1033] LC-MSD, m/z for C.sub.22H.sub.15ClN.sub.2O.sub.5S [M+H]+:
455.0
[1034] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
3.988
Synthesis of
4-Bromo-N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-3-fluoro-benzen-
esulfonamide
##STR00314##
[1036]
4-Bromo-N-[4-chloro-2-(2-pyridine-4-carbonyl)-phenyl]-3-fluoro-benz-
enesulfonamide 2 g (4.06 mmol) was dissolved in 10 ml anhydrous
dichloromethane, and to this solution was added
meta-chloroperbenzoic acid (77%) 1.62 g (7 mmol). Purification
using flash column chromatography on silica (elution with, 2.9
Dichloromethane-0.1 methanol), gave an off-white solid.
[1037] LC-MSD, m/z for C.sub.18H.sub.11ClN.sub.2O.sub.4SBrF [M+H]+:
486.9
[1038] R. time Reverse phase HPLC gradient 20%-95% in 7 minutes:
4.180
Synthesis of
N-[4-Chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-4-(2-methyl-[1,3]dioxol-
an-2-yl)-benzenesulfonamide
##STR00315##
[1040] The title compound was prepared by mCPBA oxidation of
N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-4-(2-methyl-[1,3]dioxolan-2-y-
l)-benzenesulfonamide prepared in the preceding example as
described in the general procedure for the preparation of pyridine
N-oxides. MS: m/z 475 (M.sup.++1).
Synthesis of
N-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-trifluoromet-
hoxy-benzenesulfonamide
##STR00316##
[1042] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-trifluoromethoxy-b-
enzenesulfonamide according to the general procedure. .sup.1H NMR
(CDCl3) .delta. 10.68 (br s, 1H, NH), 8.54 (dm, 1H, J=6.6 Hz), 7.92
(dm, 2H, J=8.8 Hz), 7.78 (d, 1, J=8.8 Hz), 7.56 (dd, 1, J=8.8 Hz,
J=2.2 Hz), 7.45-7.15 (m, 4), 7.18 (d, 1, J=2.6 Hz), 2.33 (s, 3H).
MS: m/z 487 (M+1).
Synthesis of
N-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-b-
enzenesulfonamide
##STR00317##
[1044] The title compound was prepared by the mCPBA oxidation of
N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-isopropoxy-benzene-
sulfonamide according to the general procedure. .sup.1H NMR (CDCl3)
.delta. 10.56 (brs, 1H, NH), 8.56 (dm, 1H, J=6.6 Hz), 7.79 (d, 1H,
J=8.8 Hz), 7.75 (d, 2H, J=8.8 Hz), 7.53 (dd, 1H, J=8.8 Hz, J=2.6
Hz), 7.39 (t, 1H, J=7.2 Hz), 7.21 (d, 1H, J=8.0 Hz), 7.17 (d, 1H,
J=2.6 Hz), 6.87 (d, 2H, J=8.8 Hz), 4.58 (septet, 1H, J=6 Hz), 2.32
(s, 3H), 1.35 (d, 3H, J=6 Hz). MS: m/z 461 (M+1).
Synthesis of
4-Acetyl-N-[4-chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-benze-
nesulfonamide
##STR00318##
[1046] The title compound was prepared by the mCPBA oxidation of
4-Acetyl-N-[4-chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulf-
onamide according to the general procedure. .sup.1H NMR (CDCl3)
.delta. 10.7 (br s, 1H, NH), 8.54 (d, 1H, J=6.6 Hz), 8.02 (d, 2H,
J=8.4 Hz), 7.95 (d, 2H, J=8.4 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.54
(dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.38 (m, 1H), 7.22 (d, 1H, J=2.6 Hz),
7.16 (dm, 1H, J=7.7 Hz), 2.62 (s, 3H), 2.33 (s, 3H). MS: m/z 445
(M+1).
Synthesis of
N-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-4-methanesulfo-
nyl-benzenesulfonamide
##STR00319##
[1048] The title compound was prepared by the mCPBA oxidation of
N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-4-methanesulfonyl-be-
nzenesulfonamide according to the general procedure. .sup.1H NMR
(CDCl3) .delta. 10.78 (br s, 1H, NH), 8.38 (dm, 1H, J=6.6 Hz), 8.05
(s, 4H), 7.76 (d, 1H, J=8.8 Hz), 7.55 (dd, 1H, J=8.8 Hz, J=2.2 Hz),
7.25 (m, 1H), 7.22 (d, 1H, J=2.2 Hz), 6.76 (dm, 1H, J=7.7 Hz), 3.09
(s, 3H), 2.32 (s, 3H). MS: m/z 481 (M+1).
Synthesis of
3-{4-[4-Chloro-2-(2-methyl-1-oxy-pyridine-3-carbonyl)-phenylsulfamoyl]-ph-
enyl}-propionic acid methyl ester
##STR00320##
[1050] The title compound was prepared by the mCPBA oxidation of
3-{4-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenylsulfamoyl]-phenyl}--
propionic acid methyl ester according to the general procedure.
.sup.1H NMR (CDCl3) .delta. 10.66 (br s, 1H, NH), 8.54 (dm, 1H,
J=6.2 Hz), 7.78 (m, 3H), 7.52 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.39
(t, 1H, J=7.2 Hz), 7.31 (d, 2H, J=8.0 Hz), 7.18 (m, 2H), 3.65 (s,
3H), 2.99 (t, 2H, J=7.6 Hz), 2.64 (t, 2H, J=7.6 Hz), 2.31 (s, 3H).
MS: m/z 489 (M+1).
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(6-methyl-1-oxy-pyridine-3-carbonyl)-phenyl]-b-
enzenesulfonamide
##STR00321##
[1052] The title compound was prepared by the mCPBA oxidation of
4-tert-butyl-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzene-
sulfonamide according to the general procedure. .sup.1H NMR
(CDCl.sub.3) .delta. 9.64 (br s, 1H, NH), 8.47 (m, 1H), 7.68 (d,
1H, J=8.8 Hz), 7.66 (d, 2H, J=8.8 Hz), 7.64 (m, 1H), 7.53 (m, 2H),
7.41 (d, 1H, J=2.2 Hz), 7.40 (d, 2H, J=8.8 Hz), 2.69 (s, 3H), 1.26
(s, 9H). MS: m/z 459 (M+1).
Approaches towards the synthesis of
2-sulphonamide-5-chloro-benzamide derivatives
Example A
##STR00322##
[1054] 3-phenylpropyl amine (0.217 g, 1.61 mmol) and the acid (0.5
g, 1.5 mmol) were taken into dry DCM (30 ml). Triethyl amine (0.2
ml) was added to the mixture and this stirred at rt for 20 min.
TBTU (0.987 g, 3.07 mmol) was then added to the mixture in portions
and the mixture left overnight at rt with stirring. Then 10 ml of
water was added to the mixture with stirring for a further 5 min.
The layers were separated. The aqueous layer was extracted with DCM
and combined with the organic layer obtained before. The combined
organic layer was then dried concentrated and subjected to column
chromatography (3:7: Ethyl acetate: Pet-ether as eluent) on
silica.
Example B
##STR00323##
[1056] N-boc-piperazine (0.226 g, 1.21 mmol) and the acid (0.5 g,
1.4 mmol) were taken into dry DCM (30 ml). Triethyl amine (0.2 ml)
was added to the mixture, which was then stirred at rt for 20 min.
TBTU (1.974 g) was then added to the mixture in portions and the
mixture left overnight at rt with stirring. 10 ml of water was then
added to the mixture, with stirring for a further 5 min. The layers
were separated. The aqueous layer was extracted with DCM and
combined with the organic layer obtained before. The combined
organic layer then dried. concentrated and subjected to column
chromatography (3:7: Ethyl acetate: Pet-ether as eluent) on silica
gel to obtain BOC-protected intermediate.
[1057] The BOC-protected compound from the previous step (300 mg)
was taken in dry ether (10 ml), cooled to 0.degree. C. and a
saturated solution of ether in dry HCl (10 ml) was added slowly and
the reaction kept overnight at room temperature with stirring. Next
day the reaction mixture was washed with water and brine and dried
with Na.sub.2SO.sub.4. Concentration, followed by purification of
the crude product through column chromatography on silica gel
(60-120 mesh, pet-ether/ethyl acetate) afforded product as pale
yellow solid.
Approaches towards the synthesis of
[4-chloro-2-(pyridin-4-ylsulfanyl)-phenyl]-benzenesulfonamide
derivatives and
[4-chloro-2-(heteroaryl-sulfanyl)-phenyl]-benzenesulfonamide
derivatives
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(pyridin-4-ylsulfanyl)-phenyl]-benzenesulfonam-
ide
##STR00324##
[1059] 4-Mercaptopyridine (1.11 g, 10 mmol) and K.sub.2CO.sub.3
(1.38 g, 10 mmol) were suspended in DMF (10 mL) and stirred at room
temperature for 15 min. The mixture was treated with
4-chloro-2-fluoro-1-nitro-benzene (1.75 g, 10 mmol) and heated at
50.degree. C. for 16 h. After cooling to room temperature, water
(50 mL) was added and the mixture extracted 3 times with ethyl
acetate. The organic layer was combined the ethyl acetate and then
reduced in vacuo. The residue was dissolved in DMF (30 mL) and
treated with SnCl.sub.2.2H.sub.2O. The mixture was heated at
50.degree. C. for 16 hr. The DMF was distilled off under vacuum and
the reduction product was purified by flash chromatography on
silica gel column (50-100% EtOAc/hexane) to afford
4-chloro-2-(pyridin-4-ylsulfanyl)-phenylamine as light yellow
solid. The title sulfonamide compound was prepared according to the
general procedure using 118 mg of
4-chloro-2-(pyridin-4-ylsulfanyl)-phenylamine prepared above and
116 mg of 4-tert-Butyl-benzenesulfonyl chloride. .sup.1H-NMR (400
MHz, CDCl.sub.3): .delta. 1.33 (s, 9H), 7.06 (d, 2H, J=6.8 Hz),
7.45 (d, 2H, J=8.4 Hz), 7.51 (m, 2H), 7.66 (d, 2H, 8.4 Hz), 7.71
(d, 1H, J=9.2 Hz), 8.43 (d, 2H, J=6.4 Hz). MS: m/z 433.9
(M.sup.++1).
Approaches towards the synthesis of
[4-chloro-2-(1-oxy-pyridine-4-sulfonyl)-phenyl]-benzenesulfonamide
derivatives and
[4-chloro-2-(heteroaryl-sulfonyl)-phenyl]-benzenesulfonamide
derivatives
Synthesis of
4-tert-Butyl-N-[4-chloro-2-(1-oxy-pyridine-4-sulfonyl)-phenyl]-benzenesul-
fonamide
##STR00325##
[1061]
4-tert-Butyl-N-[4-chloro-2-(pyridin-4-ylsulfanyl)-phenyl]-benzenesu-
lfonamide (59 mg, 0.25 mmol) and mCPBA (129 mg, 0.75 mmol) were
dissolved in DCM (4 mL) and the mixture stirred at room temperature
for 16 h. The solvent was evaporated and product was purified by
HPLC. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.32 (s, 9H), 7.00
(d, 1H, J=8.4 Hz), 7.409 (b, 2H), 7.53 (dd, 1H, J=8.8 Hz, 2.0 Hz),
7.57 (d, 2H, J=8.4 Hz), 7.90 (d, 2H, J=8.4 Hz), 8.37 (b, 3H). MS:
m/z 481.0 (M.sup.++1).
Measuring Efficacy of CCR9 Modulators
In Vitro Assays
[1062] A variety of assays can be used to evaluate the compounds
provided herein, including signaling assays, migration assays, and
other assays of cellular response. CCR9 receptor signaling assays
can be used to measure the ability of a compound, such as a
potential CCR9 antagonist, to block CCR9 ligand--(e.g.
TECK)-induced signaling. A migration assay can be used to measure
the ability of a compound of interest, such as a possible CCR9
antagonist, to block CCR9-mediated cell migration in vitro. The
latter is believed to resemble chemokine-induced cell migration in
vivo.
[1063] In a suitable assay, a CCR9 protein (whether isolated or
recombinant) is used which has at least one property, activity, or
functional characteristic of a mammalian CCR9 protein. The property
can be a binding property (to, for example, a ligand or inhibitor),
a signaling activity (e.g., activation of a mammalian G protein,
induction of rapid and transient increase in the concentration of
cytosolic free calcium [Ca.sup.++]), cellular response function
(e.g., stimulation of chemotaxis or inflammatory mediator release
by leukocytes), and the like.
[1064] The assay can be a cell based assay that utilizes cells
stably or transiently transfected with a vector or expression
cassette having a nucleic acid sequence which encodes the CCR9
receptor. The cells are maintained under conditions appropriate for
expression of the receptor and are contacted with a putative agent
under conditions appropriate for binding to occur. Binding can be
detected using standard techniques. For example, the extent of
binding can be determined relative to a suitable control (for
example, relative to background in the absence of a putative agent,
or relative to a known ligand). Optionally, a cellular fraction,
such as a membrane fraction, containing the receptor can be used in
lieu of whole cells.
[1065] Detection of binding or complex formation can be detected
directly or indirectly. For example, the putative agent can be
labeled with a suitable label (e.g., fluorescent label,
chemiluminescent label, isotope label, enzyme label, and the like)
and binding can be determined by detection of the label. Specific
and/or competitive binding can be assessed by competition or
displacement studies, using unlabeled agent or a ligand (e.g.,
TECK) as a competitor.
[1066] Binding inhibition assays can be used to evaluate the
present compounds. In these assays, the compounds are evaluated as
inhibitors of ligand binding using, for example, TECK. In this
embodiment, the CCR9 receptor is contacted with a ligand such as
TECK and a measure of ligand binding is made. The receptor is then
contacted with a test agent in the presence of a ligand (e.g.,
TECK) and a second measurement of binding is made. A reduction in
the extent of ligand binding is indicative of inhibition of binding
by the test agent. The binding inhibition assays can be carried out
using whole cells which express CCR9, or a membrane fraction from
cells which express CCR9.
[1067] The binding of a G protein coupled receptor by, for example,
an agonist, can result in a signaling event by the receptor.
Accordingly, signaling assays can also be used to evaluate the
compounds of the present invention and induction of signaling
function by an agent can be monitored using any suitable method.
For example, G protein activity, such as hydrolysis of GTP to GDP,
or later signaling events triggered by receptor binding can be
assayed by known methods (see, for example, PCT/US97/15915; Neote,
et al., Cell, 72:415-425 (1993); Van Riper, et al., J. Exp. Med.,
177:851-856 (1993) and Dahinden, et al., J. Exp. Med., 179:751-756
(1994)).
[1068] Chemotaxis assays can also be used to assess receptor
function and evaluate the compounds provided herein. These assays
are based on the functional migration of cells in vitro or in vivo
induced by an agent, and can be used to assess the binding and/or
effect on chemotaxis of ligands, inhibitors, or agonists. A variety
of chemotaxis assays are known in the art, and any suitable assay
can be used to evaluate the compounds of the present invention.
Examples of suitable assays include those described in
PCT/US97/15915; Springer, et al., WO 94/20142; Berman et al.,
Immunol. Invest., 17:625-677 (1988); and Kavanaugh et al., J.
Immunol., 146:4149-4156 (1991)).
[1069] Calcium signaling assays measure calcium concentration over
time, preferably before and after receptor binding. These assays
can be used to quantify the generation of a receptor signaling
mediator, Ca.sup.++, following receptor binding (or absence
thereof). These assays are useful in determining the ability of a
compound, such as those of the present invention, to generate the
receptor signaling mediator by binding to a receptor of interest.
Also, these assays are useful in determining the ability of a
compound, such as those of the present invention, to inhibit
generation of the receptor signaling mediator by interfering with
binding between a receptor of interest and a ligand.
[1070] In calcium signaling assays used to determine the ability of
a compound to interfere with binding between CCR9 and a known CCR9
ligand, CCR9-expressing cells (such as a T cell line MOLT-4 cells)
are first incubated with a compound of interest, such as a
potential CCR9 antagonist, at increasing concentrations. The cell
number can be from 105 to 5.times.10.sup.5 cells per well in a
96-well microtiter plate. The concentration of the compound being
tested may range from 0 to 100 uM. After a period of incubation
(which can range from 5 to 60 minutes), the treated cells are
placed in a Fluorometric Imaging Plate Reader (FLIPR.RTM.)
(available from Molecular Devices Corp., Sunnyvale, Calif.)
according to the manufacturer's instruction. The FLIPR system is
well known to those skilled in the art as a standard method of
performing assays. The cells are then stimulated with an
appropriate amount of the CCR9 ligand TECK (e.g. 5-100 nM final
concentration) and the signal of intracellular calcium increase
(also called calcium flux) is recorded. The efficacy of a compound
as an inhibitor of binding between CCR9 and the ligand can be
calculated as an IC50 (the concentration needed to cause 50%
inhibition in signaling) or IC90 (at 90% inhibition).
[1071] In vitro cell migration assays can be performed (but are not
limited to this format) using the 96-well microchamber (called
ChemoTX.TM.). The ChemoTX system is well known to those skilled in
the art as a type of chemotactic/cell migration instrument. In this
assay, CCR9-expressing cells (such as MOLT-4) are first incubated
with a compound of interest, such as a possible CCR9 antagonist, at
increasing concentrations. Typically, fifty thousand cells per well
are used, but the amount can range from 10.sup.3-10.sup.6 cells per
well. CCR9 ligand TECK, typically at 50 nM (but can range from
5-100 nM), is placed at the lower chamber and the migration
apparatus is assembled. Twenty microliters of test compound-treated
cells are then placed onto the membrane. Migration is allowed to
take place at 37 C for a period of time, typically 2.5 hours. At
the end of the incubation, the number of cells that migrated across
the membrane into the lower chamber is then quantified. The
efficacy of a compound as an inhibitor of CCR9-mediated cell
migration is calculated as an IC50 (the concentration needed to
reduce cell migration by 50%) or IC90 (for 90% inhibition).
In Vivo Efficacy Models for Human IBD
[1072] T cell infiltration into the small intestine and colon have
been linked to the pathogenesis of human inflammatory bowel
diseases which include Coeliac disease, Crohn's disease and
ulcerative colitis. Blocking trafficking of relevant T cell
populations to the intestine is believed to be an effective
approach to treat human IBD. CCR9 is expressed on gut-homing T
cells in peripheral blood, elevated in patients with small bowel
inflammation such as Crohn's disease and Coeliac disease. CCR9
ligand TECK is expressed in the small intestine. It is thus
believed that this ligand-receptor pair plays a role in IBD
development by mediating migration of T cells to the intestine.
Several animal models exist and can be used for evaluating
compounds of interest, such as potential CCR9 antagonists, for an
ability to affect such T cell migration and/or condition or
disease, which might allow efficacy predictions of antagonists in
humans.
Animal Models with Pathology Similar to Human Ulcerative
Colitis
[1073] A murine model described by Panwala and coworkers (Panwala,
et al., J Immunol., 161(10):5733-44 (1998)) involves genetic
deletion of the murine multi-drug resistant gene (MDR). MDR
knockout mice (MDR-/-) are susceptible to developing a severe,
spontaneous intestinal inflammation when maintained under specific
pathogen-free facility conditions. The intestinal inflammation seen
in MDR-/- mice has a pathology similar to that of human
inflammatory bowel disease (IBD) and is defined by Th1 type T cells
infiltration into the lamina propria of the large intestine.
[1074] Another murine model was described by Davidson et al., J Exp
Med., 184(1):241-51 (1986). In this model, the murine IL-10 gene
was deleted and mice rendered deficient in the production of
interleukin 10 (IL-10-/-). These mice develop a chronic
inflammatory bowel disease (IBD) that predominates in the colon and
shares histopathological features with human IBD.
[1075] Another murine model for IBD has been described by Powrie et
al., Int Immunol., 5(11):1461-71 (1993), in which a subset of CD4+
T cells (called CD45RB(high)) from immunocompetent mice are
purified and adoptively transferred into immunodeficient mice (such
as C.B-17 scid mice). The animal restored with the CD45RBhighCD4+ T
cell population developed a lethal wasting disease with severe
mononuclear cell infiltrates in the colon, pathologically similar
with human IBD.
Murine Models with Pathology Similar to Human Crohn's Disease
[1076] The TNF ARE(-/-) model. The role of TNF in Crohn's disease
in human has been demonstrated more recently by success of
treatment using anti-TNF alpha antibody by Targan et al., N Engl J.
Med., 337(15):1029-35 (1997). Mice with aberrant production of
TNF-alpha due to genetic alteration in the TNF gene (ARE-/-)
develop Crohn's-like inflammatory bowel diseases (see Kontoyiannis
et al., Immunity, 10(3):387-98 (1999)).
[1077] The SAMP/yit model. This is model described by Kosiewicz et
al., J Clin Invest., 107(6):695-702 (2001). The mouse strain,
SAMP/Yit, spontaneously develops a chronic inflammation localized
to the terminal ileum. The resulting ileitis is characterized by
massive infiltration of activated T lymphocytes into the lamina
propria, and bears a remarkable resemblance to human Crohn's
disease.
Biological Activity
[1078] The compound in [00755] illustrates the activity associated
with representative compounds of the invention.
Materials and Methods (In Vitro Assays)
Reagents and Cells
[1079] MOLT-4 cells were obtained from the American Type Culture
Collection (Manassas, Va.) and cultured in RPMI tissue culture
medium supplemented with 10% fetal calf serum (FCS) in a humidified
5% CO.sub.2 incubator at 37.degree. C. Recombinant human chemokine
protein TECK was obtained from R&D Systems (Minneapolis,
Minn.). ChemoTX.RTM. chemotaxis microchambers were purchased from
Neuro Probe (Gaithersburg, Md.). CyQUANT.RTM. cell proliferation
kits were purchased from Molecular Probes (Eugene, Oreg.). Calcium
indicator dye Fluo-4 AM was purchased from Molecular Devices
(Mountain View, Calif.).
Conventional Migration Assay
[1080] Conventional migration assay was used to determine the
efficacy of potential receptor antagonists in blocking migration
mediated through CCR9. This assay was routinely performed using the
ChemoTX.RTM. microchamber system with a 5-.mu.m pore-sized
polycarbonate membrane. To begin such an assay, MOLT-4 cells were
harvested by centrifugation of cell suspension at 1000 PRM on a
GS-6R Beckman centrifuge. The cell pellet was resuspended in
chemotaxis buffer (H BSS with 0.1% BSA) at 5.times.10.sup.6
cells/mL. Test compounds at desired concentrations were prepared
from 10 mM stock solutions by serial dilutions in chemotaxis
buffer. An equal volume of cells and compounds were mixed and
incubated at room temperature for 15 minutes. Afterwards, 20 .mu.L
of the mixture was transferred onto the porous membrane of a
migration microchamber, with 29 .mu.L of 50 nM chemokine TECK
protein placed at the lower chamber. Following a 150-minute
incubation at 37.degree. C., during which cells migrated against
the chemokine gradient, the assay was terminated by removing the
cell drops from atop the filter. To quantify cells migrated across
the membrane, 5 .mu.L of 7.times. CyQUANT.RTM. solution was added
to each well in the lower chamber, and the fluorescence signal
measured on a Spectrafluor Plus fluorescence plate reader (TECAN,
Durham, N.C.). The degree of inhibition was determined by comparing
migration signals between compound-treated and untreated cells.
IC50 calculation was further performed by non-linear squares
regression analysis using Graphpad Prism (Graphpad Software, San
Diego, Calif.).
RAM Assay
[1081] The primary screen to identify CCR9 antagonists was carried
out using RAM assay (WO 02101350), which detects potential hits by
their ability to activate cell migration under inhibitory TECK
concentration. To begin such an assay, MOLT-4 cells were harvested
by centrifugation of cell suspension at 1000 RPM on a GS-6R Beckman
centrifuge. The cell pellet was resuspended in chemotaxis buffer
(HBSS/0.1% BSA) at 5.times.10.sup.6 cells/mL. Twenty-five
microliters of cells was mixed with an equal volume of a test
compound diluted to 20 .mu.M in the same buffer. Twenty microliters
of the mixture was transferred onto the filter in the upper
chemotaxis chamber, with 29 .mu.L of 500 nM chemokine protein TECK
placed in the lower chamber. Following a 150-minute incubation at
37.degree. C., the assay was terminated by removing the cell drops
from atop the filter. To quantify cells migrated across the
membrane, 5 .mu.L of 7.times. CyQUANT.RTM. solution was added to
each well in the lower chamber, and the fluorescence signal
measured on a Spectrafluor Plus fluorescence plate reader (TECAN,
Durham, N.C.).
[1082] For selection of potential hits, the level of migration
activation was calculated as a RAM index--the ratio between the
signal of a particular well and the median signal of the whole
plate. Compounds with a RAM index of greater than 1.8 were regarded
as RAM positive, and were selected for IC.sub.50 determinations in
conventional functional assays.
Calcium Flux Assay
[1083] Calcium flux assay measures an increase in intracellular
calcium following ligand-induced receptor activation. In the screen
of CCR9 antagonists, it was used as a secondary assay carried out
on a FLIPR.RTM. machine (Molecular Devices, Mountain View, Calif.).
To begin an assay, MOLT-4 cells were harvested by centrifugation of
cell suspension, and resuspended to 1.5.times.10.sup.6 cells/mL in
HBSS (with 1% fetal calf serum). Cells were then labeled with a
calcium indicator dye Fluo-4 AM for 45 minutes at 37.degree. C.
with gentle shaking. Following incubation, cells were pelletted,
washed once with HBSS and resuspended in the same buffer at a
density of 1.6.times.10.sup.6 cells/mL. One hundred microliters of
labeled cells were mixed with 10 .mu.L of test compound at the
appropriate concentrations on an assay plate. Chemokine protein
TECK was added at a final concentration of 25 nM to activate the
receptor. The degree of inhibition was determined by comparing
calcium signals between compound-treated and untreated cells. IC50
calculations were further performed by non-linear squares
regression analysis using Graphpad Prism (Graphpad Software, San
Diego, Calif.).
Discovery of CCR9 Antagonists
[1084] The discovery of CCR9 antagonists was carried out in two
steps: First, RAM assay was used to screen a compound library in a
high-throughput manner. The assay detected compounds by their
ability to cause a positive migration signal under RAM condition.
Secondly, RAM positive compounds were tested to determine their
IC.sub.50s using the conventional migration and calcium flux
assays.
[1085] For instance, in a screen of approximately 100,000
compounds, 2000 individual wells representing approximately 2% of
total compounds showed a RAM index greater than 1.8. These
compounds were cheery-picked and retested in duplicate wells by RAM
assay. A total of 270 compounds, or 0.27% of the library, were
confirmed RAM positives.
[1086] Since a RAM positive signal indicates only the presence of a
receptor antagonist and not how strongly it blocks receptor
functions, the RAM positive compounds were further tested for
potency in calcium flux assay using MOLT-4 cells. IC.sub.50
determinations on this subset discovered several compounds with
IC.sub.50's less than 1 .mu.M and that did not inhibit other
chemokine receptors examined at significant levels.
In Vivo Efficacy Studies
[1087] The MDR1a-knockout mice, which lack the P-glycoprotein gene,
spontaneously develop colitis under specific pathogen-free
condition. The pathology in these animals has been characterized as
Th1-type T cell-mediated inflammation similar to ulcerative colitis
in humans. Disease normally begins to develop at around 8-10 weeks
after birth. However the ages at which disease emerges and the
ultimate penetrance level often vary considerably among different
animal facilities.
[1088] In a study using the MDR1a-knockout mice, the CCR9
antagonist shown below:
##STR00326##
was evaluated by prophylactic administration for its ability to
delay disease onset. Female mice (n=34) were dosed with 50 mg/kg
twice a day by subcutaneous injections for 14 consecutive weeks
starting at age 10 weeks. The study showed that the compound
prevented IBD-associated growth retardation. Moreover, the number
of mice developing diarrhea was also lower among compound-treated
mice (17%), compared to mice receiving vehicle alone (24%)(FIG.
1).
[1089] In the tables below, structures and activity are provided
for representative compounds described herein. Activity is provided
as follows for either or both of the chemotaxis assay and/or
calcium mobilization assays, described above: +, IC.sub.50>1000
nM; and ++, IC.sub.50<1000 nM.
TABLE-US-00001 TABLE 1 Compounds with activity in either or both of
the chemotaxis assay and calcium mobilization assays, with
IC.sub.50 < 1000 nM (++) ##STR00327## ##STR00328## ##STR00329##
##STR00330## ##STR00331## ##STR00332## ##STR00333## ##STR00334##
##STR00335## ##STR00336## ##STR00337## ##STR00338## ##STR00339##
##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344##
##STR00345## ##STR00346## ##STR00347## ##STR00348## ##STR00349##
##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354##
##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359##
##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364##
##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369##
##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374##
##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379##
##STR00380## ##STR00381## ##STR00382## ##STR00383## ##STR00384##
##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389##
##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394##
##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399##
##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404##
##STR00405## ##STR00406## ##STR00407## ##STR00408## ##STR00409##
##STR00410## ##STR00411## ##STR00412## ##STR00413## ##STR00414##
##STR00415## ##STR00416## ##STR00417## ##STR00418## ##STR00419##
##STR00420## ##STR00421## ##STR00422## ##STR00423## ##STR00424##
##STR00425## ##STR00426## ##STR00427## ##STR00428## ##STR00429##
##STR00430## ##STR00431## ##STR00432## ##STR00433## ##STR00434##
##STR00435## ##STR00436## ##STR00437## ##STR00438## ##STR00439##
##STR00440## ##STR00441## ##STR00442## ##STR00443## ##STR00444##
##STR00445## ##STR00446## ##STR00447## ##STR00448##
##STR00449##
##STR00450## ##STR00451## ##STR00452## ##STR00453## ##STR00454##
##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459##
##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464##
##STR00465## ##STR00466## ##STR00467## ##STR00468## ##STR00469##
##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474##
##STR00475## ##STR00476## ##STR00477## ##STR00478## ##STR00479##
##STR00480## ##STR00481## ##STR00482## ##STR00483## ##STR00484##
##STR00485## ##STR00486## ##STR00487## ##STR00488## ##STR00489##
##STR00490## ##STR00491## ##STR00492## ##STR00493## ##STR00494##
##STR00495## ##STR00496## ##STR00497## ##STR00498## ##STR00499##
##STR00500## ##STR00501## ##STR00502## ##STR00503## ##STR00504##
##STR00505## ##STR00506## ##STR00507## ##STR00508## ##STR00509##
##STR00510##
TABLE-US-00002 TABLE 2 Compounds with activity in either or both of
the chemotaxis assay and calcium mobilization assays, with
IC.sub.50 > 1000 nM (+): ##STR00511## ##STR00512## ##STR00513##
##STR00514## ##STR00515## ##STR00516## ##STR00517## ##STR00518##
##STR00519## ##STR00520## ##STR00521## ##STR00522## ##STR00523##
##STR00524## ##STR00525## ##STR00526## ##STR00527## ##STR00528##
##STR00529## ##STR00530## ##STR00531## ##STR00532## ##STR00533##
##STR00534## ##STR00535## ##STR00536## ##STR00537## ##STR00538##
##STR00539## ##STR00540## ##STR00541## ##STR00542## ##STR00543##
##STR00544## ##STR00545## ##STR00546## ##STR00547## ##STR00548##
##STR00549## ##STR00550## ##STR00551## ##STR00552## ##STR00553##
##STR00554## ##STR00555## ##STR00556## ##STR00557##
##STR00558##
[1090] 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 for all purposes.
* * * * *