U.S. patent application number 11/897620 was filed with the patent office on 2008-03-13 for anilinopyrazole derivatives useful for the treatment of diabetes.
This patent application is currently assigned to Bayer Pharmaceuticals Corporation. Invention is credited to Ann-Marie Bullion, William Bullock, Louis-David Cantin, Libing Chen, Chih-Yuan Chuang, Sidney Liang, Steven Magnuson, Dyuti Majumdar, Herbert Ogutu, Alan Olague, Ning Qi, Joachim Rudolph, Philip L. Wickens.
Application Number | 20080064734 11/897620 |
Document ID | / |
Family ID | 32474531 |
Filed Date | 2008-03-13 |
United States Patent
Application |
20080064734 |
Kind Code |
A1 |
Rudolph; Joachim ; et
al. |
March 13, 2008 |
Anilinopyrazole derivatives useful for the treatment of
diabetes
Abstract
The present invention relates to anilinopyrazole compounds,
pharmaceutical compositions, and methods for treating diabetes and
related disorders.
Inventors: |
Rudolph; Joachim; (Guilford,
CT) ; Cantin; Louis-David; (Hamden, CT) ;
Magnuson; Steven; (Wallingford, CT) ; Bullock;
William; (Easton, CT) ; Bullion; Ann-Marie;
(Milford, CT) ; Chen; Libing; (Milford, CT)
; Chuang; Chih-Yuan; (New Haven, CT) ; Liang;
Sidney; (Bethany, CT) ; Majumdar; Dyuti;
(Milford, CT) ; Ogutu; Herbert; (Hamden, CT)
; Olague; Alan; (Shelton, CT) ; Qi; Ning;
(Hamden, CT) ; Wickens; Philip L.; (Wallingford,
CT) |
Correspondence
Address: |
JEFFREY M. GREENMAN
BAYER PHARMACEUTICALS CORPORATION
400 MORGAN LANE
WEST HAVEN
CT
06516
US
|
Assignee: |
Bayer Pharmaceuticals
Corporation
West Haven
CT
05616
|
Family ID: |
32474531 |
Appl. No.: |
11/897620 |
Filed: |
August 31, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10719485 |
Nov 21, 2003 |
7265144 |
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11897620 |
Aug 31, 2007 |
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60498214 |
Aug 27, 2003 |
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60429917 |
Nov 27, 2002 |
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Current U.S.
Class: |
514/406 ;
548/371.4 |
Current CPC
Class: |
A61P 3/00 20180101; C07D
403/12 20130101; A61P 5/50 20180101; A61P 7/12 20180101; A61P 3/10
20180101; C07D 471/04 20130101; C07D 401/04 20130101; C07D 413/12
20130101; A61P 5/48 20180101; A61P 3/04 20180101; A61P 3/06
20180101; C07D 231/38 20130101 |
Class at
Publication: |
514/406 ;
548/371.4 |
International
Class: |
A61K 31/415 20060101
A61K031/415; A61P 3/04 20060101 A61P003/04; C07D 231/10 20060101
C07D231/10 |
Claims
1. A compound of Formula (I) ##STR515## wherein R is H or
(C.sub.1-C.sub.6)alkyl; R.sup.1 is H, (C.sub.1-C.sub.6)alkyl
optionally substituted with one substituent selected from the group
consisting of (C.sub.1-C.sub.4)alkoxy, phenyl optionally
substituted with halo, and [tri(C.sub.1-C.sub.4)alkyl]silyl,
(C.sub.3-C.sub.6)alkenyl, (C.sub.3-C.sub.6)alkynyl,
(C.sub.3-C.sub.6)cycloalkyl optionally substituted with up to two
substituents selected from the group consisting of
(C.sub.1-C.sub.3)alkyl, CF.sub.3, and halo,
(C.sub.1-C.sub.3)haloalkyl, or phenyl optionally substituted with
up to four substituents selected from the group consisting of halo,
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
NR.sup.8R.sup.8, cyano, and (C.sub.1-C.sub.6)alkylthio; R.sup.2 is
H, halo, (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.3-C.sub.6)cycloalkyl optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.3)alkyl and halo,
(C.sub.1-C.sub.3)haloalkyl, pyridyl optionally substituted with up
to two substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkythio, halo, and
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, pyrimidyl, phenyl optionally substituted
with up to four substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy, hydroxy,
NR.sup.8R.sup.8, cyano, (C.sub.1-C.sub.6)alkylthio, halo,
CO.sub.2R.sup.8, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.4)acyl, and benzoyl, or tetrahydronaphthyl, indanyl,
benzodioxolyl, or benzodioxanyl, each of which may be optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkythio,
halo, and (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, or when R.sup.1 and R.sup.2 are
(C.sub.1-C.sub.6)alkyl, they may, together with C atoms to which
they are attached, form a 5- or 6-membered carbocyclic ring, or
R.sup.1 and R.sup.2 may, together with the C atoms to which they
are attached form a 6-membered heterocyclic ring containing a N
atom and optionally substituted on N with (C.sub.1-C.sub.3)alkyl;
R.sup.3 is (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
benzyl optionally substituted on the aryl ring with up to four
substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, halo, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.3)haloalkoxy,
NR.sup.8R.sup.8, cyano, (C.sub.1-C.sub.6)alkylthio, and
SO.sub.2(C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.3)haloalkyl, or
phenyl optionally substituted with up to four substituents selected
from the group consisting of (C.sub.1-C.sub.6)alkyl optionally
substituted with one (C.sub.1-C.sub.4)alkoxy, halo,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkoxy NR.sup.8R.sup.8, cyano,
(C.sub.1-C.sub.6)alkylthio, and SO.sub.2(C.sub.1-C.sub.3)alkyl;
R.sup.4 is (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, halo, NR.sup.8R.sup.8, pyrimidyl,
pyridyl, imidazolyl, or phenyl optionally substituted with up to
four substituents selected from the group consisting of halo,
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
NR.sup.8R.sup.8, cyano, and (C.sub.1-C.sub.6)alkylthio; n=0, 1, 2,
or 3; X is CO.sub.2R.sup.8, CONR.sup.5R.sup.6, SO.sub.2NHR.sup.7,
or oxadiazolyl optionally substituted with (C.sub.1-C.sub.6)alkyl;
R.sup.5 is H, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkyl
substituted with OR.sup.6, benzyl optionally substituted on the
aryl ring with up to four substituents selected from the group
consisting of halo, (C.sub.1-C.sub.6)alkyl optionally substituted
with one (C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
NR.sup.8R.sup.8, cyano, and (C.sub.1-C.sub.6)alkylthio, phenyl
optionally substituted with up to four substituents selected from
the group consisting of (C.sub.1-C.sub.6)alkyl optionally
substituted with one (C.sub.1-C.sub.4)alkoxy, halo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, NR.sup.8R.sup.8, cyano, and
(C.sub.1-C.sub.6)alkylthio, pyridyl optionally substituted with up
to two substituents selected from the group consisting of halo,
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkoxy, NR.sup.8R.sup.8, cyano, and
(C.sub.1-C.sub.6)alkylthio, ##STR516## SO.sub.2-phenyl said phenyl
optionally substituted with up to four substituents selected from
the group consisting of halo (C.sub.1-C.sub.6)alkyl optionally
substituted with one (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, NR.sup.8R.sup.8, cyano, and
(C.sub.1-C.sub.6)alkylthio; R.sup.6 is H or (C.sub.1-C.sub.6)alkyl;
or R.sup.5 and R.sup.6 together with N atom to which they are
attached, may form a piperidine, morpholine, thiomorpholine, or
piperazine ring said piperazine optionally substituted on N with
(C.sub.1-C.sub.3)alkyl; R.sup.7 is H or methyl; R.sup.8 is H,
(C.sub.1-C.sub.6)alkyl, benzyl optionally substituted on the aryl
ring with up to four substituents selected from the group
consisting of halo, (C.sub.1-C.sub.6)alkyl optionally substituted
with one (C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.3)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy, cyano, and
(C.sub.1-C.sub.6)alkylthio, or phenyl optionally substituted with
up to four substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, halo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy, cyano, and
(C.sub.1-C.sub.6)alkylthio; and pharmaceutically acceptable salts
thereof; provided that when R and R.sup.2 are H and X is CO.sub.2H,
then R.sub.1 is not H, methyl, or ethyl, and further provided that
the Formula (I) compound is not ##STR517##
2. The compound of claim 1, wherein R.sup.1 is phenyl optionally
substituted with up to four substituents selected from the group
consisting of halo, (C.sub.1-C.sub.6)alkyl optionally substituted
with one (C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
NR.sup.8R.sup.8, cyano, and (C.sub.1-C.sub.6)alkylthio; and R,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, X,
and n are as defined in claim 1.
3. The compound of claim 1, wherein R.sup.2 is pyridyl optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkythio,
halo, and (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, or phenyl optionally substituted with up
to four substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy, hydroxy,
NR.sup.8R.sup.8, cyano, (C.sub.1-C.sub.6)alkylthio, halo,
CO.sub.2R.sup.8 , (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.4)acyl, and benzoyl; and R, R.sup.1, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, X, and n are as
defined in claim 1.
4. The compound of claim 1, wherein X is CO.sub.2R.sup.8; and R,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.8, and n are as defined
in claim 1.
5. The compound of claim 1, wherein R.sup.1 is phenyl optionally
substituted with up to four substituents selected from the group
consisting of halo, (C.sub.1-C.sub.6)alkyl optionally substituted
with one (C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
NR.sup.8R.sup.8, cyano, and (C.sub.1-C.sub.6)alkylthio; R.sup.2 is
H, halo, (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.3-C.sub.6)cycloalkyl optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.3)alkyl and halo, or
(C.sub.1-C.sub.3)haloalkyl; and R, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, X, and n are as defined in claim 1.
6. The compound of claim 1, wherein R.sup.1 is H,
(C.sub.1-C.sub.6)alkyl optionally substituted with one substituent
selected from the group consisting of (C.sub.1-C.sub.4)alkoxy,
phenyl optionally substituted with halo, and
[tri(C.sub.1-C.sub.4)alkyl]silyl, (C.sub.3-C.sub.6)alkenyl,
(C.sub.3-C.sub.6)alkynyl, (C.sub.3-C.sub.6)cycloalkyl optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.3)alkyl, CF.sub.3, and halo, or
(C.sub.1-C.sub.3)haloalkyl; R.sup.2 is H, halo,
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.3-C.sub.6)cycloalkyl optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.3)alkyl and halo, or
(C.sub.1-C.sub.3)haloalkyl; and R, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, X, and n are as defined in claim 1.
7. The compound of claim 1, wherein R.sup.1 is H,
(C.sub.1-C.sub.6)alkyl optionally substituted with one substituent
selected from the group consisting of (C.sub.1-C.sub.4)alkoxy,
phenyl optionally substituted with halo, and
[tri(C.sub.1-C.sub.4)alkyl]silyl, (C.sub.3-C.sub.6)alkenyl,
(C.sub.3-C.sub.6)alkynyl, (C.sub.3-C.sub.6)cycloalkyl optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.3)alkyl, CF.sub.3, and halo, or
(C.sub.1-C.sub.3)haloalkyl; R.sup.2 is pyridyl optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkythio,
halo, and (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, or phenyl optionally substituted with up
to four substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy, hydroxy,
NR.sup.8R.sup.8, cyano, (C.sub.1-C.sub.6)alkylthio, halo,
CO.sub.2R.sup.8, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.4)acyl, and benzoyl; and R, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, X, and n are as defined in
claim 1.
8. The compound of claim 1, wherein R.sup.1 is phenyl optionally
substituted with up to four substituents selected from the group
consisting of halo, (C.sub.1-C.sub.6)alkyl optionally substituted
with one (C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
NR.sup.8R.sup.8, cyano, and (C.sub.1-C.sub.6)alkylthio; R.sup.2is
H, halo, (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.3-C.sub.6)cycloalkyl optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.3)alkyl and halo, or
(C.sub.1-C.sub.3)haloalkyl; X is CO.sub.2R.sup.8; and R, R.sup.3,
R.sup.4, R.sup.8, and n are as defined in claim 1.
9. The compound of claim 1, wherein R.sup.1 is H,
(C.sub.1-C.sub.6)alkyl optionally substituted with one substituent
selected from the group consisting of (C.sub.1-C.sub.4)alkoxy,
phenyl optionally substituted with halo, and
[tri(C.sub.1-C.sub.4)alkyl]silyl, (C.sub.3-C.sub.6)alkenyl,
(C.sub.3-C.sub.6)alkynyl, (C.sub.3-C.sub.6)cycloalkyl optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.3)alkyl, CF.sub.3, and halo, or
(C.sub.1-C.sub.3)haloalkyl; R.sup.2is H, halo,
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.3-C.sub.6)cycloalkyl optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.3)alkyl and halo, or
(C.sub.1-C.sub.3)haloalkyl; X is CO.sub.2R.sup.8; and R, R.sup.3,
R.sup.4, R.sup.8, and n are as defined in claim 1.
10. The compound of claim 1, wherein R.sup.1 is H,
(C.sub.1-C.sub.6)alkyl optionally substituted with one substituent
selected from the group consisting of (C.sub.1-C.sub.4)alkoxy,
phenyl optionally substituted with halo, and
[tri(C.sub.1-C.sub.4)alkyl]silyl, (C.sub.3-C.sub.6)alkenyl,
(C.sub.3-C.sub.6)alkynyl, (C.sub.3-C.sub.6)cycloalkyl optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.3)alkyl, CF.sub.3, and halo, or
(C.sub.1-C.sub.3)haloalkyl; R.sup.2 is pyridyl optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkythio,
halo, and (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, or phenyl optionally substituted with up
to four substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy, hydroxy,
NR.sup.8R.sup.8, cyano, (C.sub.1-C.sub.6)alkylthio, halo,
CO.sub.2R.sup.8, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.4)acyl, and benzoyl; X is CO.sub.2R.sup.8; and R,
R.sup.3, R.sup.4, R.sup.8, and n are as defined in claim 1.
11. The compound of claim 1, wherein R is H; R.sup.1 is H,
(C.sub.1-C.sub.6)alkyl optionally substituted with one substituent
selected from the group consisting of (C.sub.1-C.sub.4)alkoxy,
phenyl optionally substituted with halo, and
[tri(C.sub.1-C.sub.4)alkyl]silyl, (C.sub.3-C.sub.6)cycloalkyl
optionally substituted with up to two substituents selected from
the group consisting of (C.sub.1-C.sub.3)alkyl, CF.sub.3, and halo,
(C.sub.1-C.sub.3)haloalkyl, or phenyl optionally substituted with
up to four substituents selected from the group consisting of halo,
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
NR.sup.8R.sup.8, cyano, and (C.sub.1-C.sub.6)alkylthio; R.sup.2is
H, (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, pyridyl optionally substituted with up to
two substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkythio, halo, and
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, or phenyl optionally substituted with up
to four substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy, hydroxy,
NR.sup.8R.sup.8, cyano, (C.sub.1-C.sub.6)alkylthio, halo,
CO.sub.2R.sup.8, (C.sub.1-C.sub.3)haloalkoxy,
(C.sub.1-C.sub.4)acyl, and benzoyl; R.sup.3 is
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, or phenyl
optionally substituted with up to four substituents selected from
the group consisting of (C.sub.1-C.sub.6)alkyl optionally
substituted with one (C.sub.1-C.sub.4)alkoxy, halo,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkoxy NR.sup.8R.sup.8, cyano,
(C.sub.1-C.sub.6)alkylthio, and SO.sub.2(C.sub.1-C.sub.3)alkyl;
R.sup.4 is (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy, halo, phenyl
optionally substituted with up to four substituents selected from
the group consisting of halo, (C.sub.1-C.sub.6)alkyl optionally
substituted with one (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, NR.sup.8R.sup.8, cyano, and
(C.sub.1-C.sub.6)alkylthio; n=0, 1, 2, or 3; X is CO.sub.2R.sup.8;
and R.sup.8 is H, (C.sub.1-C.sub.6)alkyl, benzyl optionally
substituted on the aryl ring with up to four substituents selected
from the group consisting of halo, (C.sub.1-C.sub.6)alkyl
optionally substituted with one (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.3)alkoxy, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, cyano, and (C.sub.1-C.sub.6)alkylthio,
or phenyl optionally substituted with up to four substituents
selected from the group consisting of (C.sub.1-C.sub.6)alkyl
optionally substituted with one (C.sub.1-C.sub.4)alkoxy, halo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, cyano, and
(C.sub.1-C.sub.6)alkylthio.
12. The compound of claim 1, wherein R is H; R.sup.1 is H,
(C.sub.1-C.sub.6)alkyl optionally substituted with one substituent
selected from the group consisting of (C.sub.1-C.sub.4)alkoxy,
phenyl optionally substituted with halo, and
[tri(C.sub.1-C.sub.4)alkyl]silyl, or phenyl optionally substituted
with up to four substituents selected from the group consisting of
halo, (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
NR.sup.8R.sup.8, cyano, and (C.sub.1-C.sub.6)alkylthio; R.sup.2 is
H, halo, or (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy; R.sup.3 is (C.sub.1-C.sub.6)alkyl, or
phenyl optionally substituted with up to four substituents selected
from the group consisting of (C.sub.1-C.sub.6)alkyl optionally
substituted with one (C.sub.1-C.sub.4)alkoxy, halo,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkoxy NR.sup.8R.sup.8, cyano,
(C.sub.1-C.sub.6)alkylthio, and SO.sub.2(C.sub.1-C.sub.3)alkyl;
R.sup.4 is (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylthio, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, halo; n=0, 1, 2, or 3; X is
CONR.sup.5R.sup.6; R.sup.5 is H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkyl substituted with OR.sup.6, benzyl optionally
substituted on the aryl ring with up to four substituents selected
from the group consisting of halo, (C.sub.1-C.sub.6)alkyl
optionally substituted with one (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.3)haloalkyl,
(C.sub.1-C.sub.3)haloalkoxy, NR.sup.8R.sup.8, cyano, and
(C.sub.1-C.sub.6)alkylthio, phenyl optionally substituted with up
to four substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, halo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
NR.sup.8R.sup.8, cyano, and (C.sub.1-C.sub.6)alkylthio, pyridyl
optionally substituted with up to two substituents selected from
the group consisting of halo, (C.sub.1-C.sub.6)alkyl optionally
substituted with one (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.3)haloalkoxy,
NR.sup.8R.sup.8, cyano, and (C.sub.1-C.sub.6)alkylthio, ##STR518##
SO.sub.2-phenyl said phenyl optionally substituted with up to four
substituents selected from the group consisting of halo
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy,
NR.sup.8R.sup.8, cyano, and (C.sub.1-C.sub.6)alkylthio; R.sup.6 is
H or (C.sub.1-C.sub.6)alkyl; or R.sup.5 and R.sup.6 together with N
atom to which they are attached, may form a piperidine, morpholine,
thiomorpholine, or piperazine ring said piperazine optionally
substituted on N with (C.sub.1-C.sub.3)alkyl; and R.sup.8 is H,
(C.sub.1-C.sub.6)alkyl, benzyl optionally substituted on the aryl
ring with up to four substituents selected from the group
consisting of halo, (C.sub.1-C.sub.6)alkyl optionally substituted
with one (C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.3)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy, cyano, and
(C.sub.1-C.sub.6)alkylthio, or phenyl optionally substituted with
up to four substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, halo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)haloalkoxy, cyano, and
(C.sub.1-C.sub.6)alkylthio.
13. The compound of claim 1 selected from the group consisting of
2-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoic
acid;
2-{[3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzamide;
2-{[3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid;
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-metho-
xybenzoic acid;
2-{[3-tert-butyl-1-(2-methoxyphenyl)-1H-pyrazol-5-yl]amino}-5-methoxybenz-
oic acid; 2-[(1,3-diphenyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoic
acid;
2-fluoro-6-{[3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-
benzoic acid;
2-fluoro-6-{[1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-yl]amino}-
benzoic acid;
2-{[3-tert-butyl-1-(5-fluoro-2-methylphenyl)-1H-pyrazol-5-yl]amino}-6-flu-
orobenzoic acid;
2-({3-tert-butyl-1-[2-(methylthio)phenyl]-1H-pyrazol-5-yl}amino)-5-methox-
ybenzoic acid;
2-{[3-tert-butyl-1-(2-ethoxyphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid;
2-{[3-tert-butyl-1-(2-ethoxyphenyl)-1H-pyrazol-5-yl]amino}-5-methoxybenzo-
ic acid;
2-{[3-(3-methoxyphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino-
}benzoic acid;
5-methoxy-2-{[3-(3-methoxyphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amin-
o}benzoic acid;
2-{[3-(3-methoxyphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-methy-
lbenzoic acid;
2-{[3-tert-butyl-1-(2-methoxyphenyl)-4-methyl-1H-pyrazol-5-yl]amino}-5-me-
thoxybenzoic acid;
2-[(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoic
acid;
2-{[3-tert-butyl-1-(5-fluoro-2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoi-
c acid;
2-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}ben-
zoic acid;
2-{[3-tert-butyl-1-(2-methoxy-5-methylphenyl)-1H-pyrazol-5-yl]amino}benzo-
ic acid;
2-{[3-tert-butyl-1-(2,3-dimethylphenyl)-1H-pyrazol-5-yl]amino}-5-
-methoxybenzoic acid;
2-{[3-tert-butyl-1-(2-methoxy-6-methylphenyl)-1H-pyrazol-5-yl]amino}-5-me-
thoxybenzoic acid;
2-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}-5-methoxyb-
enzoic acid;
2-{[1-(2,6-dimethylphenyl)-3-(1-methylcyclopropyl)-1H-pyrazol-5-yl]amino}-
benzoic acid; 5)
2-{[1-(2,6-dimethylphenyl)-3-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl]amin-
o}-5-methoxybenzoic acid;
5-methoxy-2-{[3-methyl-1-(2-methylphenyl)-4-phenyl-1H-pyrazol-5-yl]amino}-
benzoic acid;
5-methoxy-2-{[4-(6-methoxypyridin-3-yl)-3-methyl-1-(2-methylphenyl)-1H-py-
razol-5-yl]amino}benzoic acid;
5-methoxy-2-{[1-(2-methylphenyl)-4-pyridin-4-yl-3-(trifluoromethyl)-1H-py-
razol-5-yl]amino}benzoic acid;
5-methoxy-2-{[4-(4-methoxyphenyl)-1-(2-methylphenyl)-3-(trifluoromethyl)--
1H-pyrazol-5-yl]amino}benzoic acid;
2-{[3-ethyl-4-(6-methoxypyridin-3-yl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]-
amino}-5-methoxybenzoic acid;
2-{[4-(2-fluorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-
-5-methoxybenzoic acid;
5-methoxy-2-{[1-(2-methoxyphenyl)-3-methyl-4-phenyl-1H-pyrazol-5-yl]amino-
}benzoic acid; and
2-{[4-(2,4-dimethoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]a-
mino}-5-methoxybenzoic acid.
14. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt, in combination with a pharmaceutically acceptable
carrier.
15. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt thereof, in combination with a pharmaceutically
acceptable carrier and one or more pharmaceutical agents.
16. The pharmaceutical composition of claim 15, wherein said
pharmaceutical agent is selected from the group consisting of PPAR
agonists, sulfonylurea drugs, non-sulfonylurea secretagogues,
.alpha.-glucosidase inhibitors, insulin sensitizers, insulin
secretagogues, hepatic glucose output lowering compounds, insulin,
anti-obesity agents, HMG CoA reductase inhibitors, nicotinic acid,
bile acid sequestrants, fibric acid derivatives, and
anti-hypertensive agents.
17. A composition comprising an effective amount of a compound of
claim 1, or a salt thereof, in combination with an inert
carrier.
18. A method of treating diabetes comprising the step of
administering to a subject in need thereof a therapeutically
effective amount of a compound of claim 1.
19. The method of claim 18, wherein said diabetes is selected from
the group consisting of type 1 diabetes, type 2 diabetes,
maturity-onset diabetes of the young, latent autoimmune diabetes
adult, and gestational diabetes.
20. A method of treating Syndrome X comprising the step of
administering to a subject in need thereof a therapeutically
effective amount of a compound of claim 1.
21. A method of treating diabetes-related disorders comprising the
step of administering to a subject in need thereof a
therapeutically effective amount of a compound of claim 1.
22. The method of claim 21, wherein said diabetes-related disorder
is selected from the group consisting of hyperglycemia,
hyperinsulinemia, impaired glucose tolerance, impaired fasting
glucose, dyslipidemia, hypertriglyceridemia, and insulin
resistance.
23. A method of treating obesity comprising the step of
administering to a subject in need thereof a therapeutically
effective amount of a compound of claim 1.
24. A method of treating cardiovascular diseases comprising the
step of administering to a subject in need thereof a
therapeutically effective amount of a compound of claim 1.
25. A method of treating diabetes comprising the step of
administering to a subject in need thereof a therapeutically
effective amount of a compound of claim 1 in combination with one
or more pharmaceutical agents.
26. The method of claim 25, wherein said pharmaceutical agent is
selected from the group consisting of PPAR agonists, sulfonylurea
drugs, non-sulfonylurea secretagogues, .alpha.-glucosidase
inhibitors, insulin sensitizers, insulin secretagogues, hepatic
glucose output lowering compounds, insulin, and anti-obesity
agents.
27. The method of claim 25, wherein said diabetes is selected from
the group consisting of type 1 diabetes, type 2 diabetes,
maturity-onset diabetes of the young, latent autoimmune diabetes
adult, and gestational diabetes.
28. A method of treating Syndrome X comprising the step of
administering to a subject in need thereof a therapeutically
effective amount of a compound of claim 1 in combination with one
or more pharmaceutical agents.
29. The method of claim 28, wherein said pharmaceutical agent is
selected from the group consisting of PPAR agonists, sulfonylurea
drugs, non-sulfonylurea secretagogues, .alpha.-glucosidase
inhibitors, insulin sensitizers, insulin secretagogues, hepatic
glucose output lowering compounds, insulin, and anti-obesity
agents.
30. A method of treating diabetes-related disorders comprising the
step of administering to a subject in need thereof a
therapeutically effective amount of a compound of claim 1 in
combination with one or more pharmaceutical agents.
31. The method of claim 30, wherein said diabetes-related disorder
is selected from the group consisting of hyperglycemia,
hyperinsulinemia, impaired glucose tolerance, impaired fasting
glucose, dyslipidemia, hypertriglyceridemia, and insulin
resistance.
32. The method of claim 30, wherein said pharmaceutical agent is
selected from the group consisting of PPAR agonists, sulfonylurea
drugs, non-sulfonylurea secretagogues, .alpha.-glucosidase
inhibitors, insulin sensitizers, insulin secretagogues, hepatic
glucose output lowering compounds, insulin, and anti-obesity
agents.
33. A method of treating diabetes, Syndrome X, or diabetes-related
disorders comprising the step of administering to a subject in need
thereof a therapeutically effective amount of a compound of claim 1
in combination with one or more agents selected from the group
consisting of HMG CoA reductase inhibitors, nicotinic acid, bile
acid sequestrants, fibric acid derivatives, and anti-hypertensive
agents.
34. The method of claim 33, wherein said diabetes-related disorder
is selected from the group consisting of hyperglycemia,
hyperinsulinemia, impaired glucose tolerance, impaired fasting
glucose, dyslipidemia, hypertriglyceridemia, and insulin
resistance.
35. The method of any one of claims 25 to 34, wherein the compound
of claim 1 and one or more pharmaceutical agents are administered
as a single pharmaceutical dosage formulation.
36. A method of treating or preventing secondary causes of diabetes
comprising the step of administering to a subject in need thereof a
therapeutically effective amount of a compound of claim 1.
37. The method of claim 36, wherein said secondary cause is
selected from the group consisting of glucocorticoid excess, growth
hormone excess, pheochromocytoma, and drug-induced diabetes.
38. A method of treating or preventing secondary causes of diabetes
comprising the step of administering a subject in need thereof a
therapeutically effective amount of a compound of claim 1 in
combination with one or more pharmaceutical agents.
39. The method of claim 38, wherein said pharmaceutical agent is
selected from the group consisting of PPAR agonists, sulfonylurea
drugs, non-sulfonylurea secretagogues, .alpha.-glucosidase
inhibitors, insulin sensitizers, insulin secretagogues, hepatic
glucose output lowering compounds, insulin, and anti-obesity
agents.
40. A method of stimulating insulin secretion in a subject in need
thereof by administering to said subject a compound of claim 1.
41. Compounds according to claim 1 for the treatment and/or
prophylaxis of diabetes and diabetes-related disorders.
42. Medicament containing at least one compound according to claim
1 in combination with at least one pharmaceutically acceptable,
pharmaceutically safe carrier or excipient.
43. Use of compounds according to claim 1 for manufacturing a
medicament for the treatment and/or prophylaxis of diabetes and
diabetes-related disorders.
44. Medicaments according to claim 42 for the treatment and/or
prophylaxis of diabetes.
45. A method of identifying a biological target comprising
contacting a compound of claim 1 with a biological sample; forming
a complex with the compound and the biological target; isolating
the compound-target complex; and identifying the target.
46. The method of claim 45, wherein the biological sample is
pancreatic .beta.-cells.
47. The method of claim 45, wherein the compound is labeled with a
photoactive group and/or radioisotope.
48. The method of claim 45, wherein the compound is coupled to a
polymer.
Description
[0001] This application claims benefit of U.S. Provisional
Application Ser. No. 60/429,917, filed Nov. 27, 2002, and U.S.
Provisional Application Ser. No. 60/498,214, filed on Aug. 27,
2003, the contents of which are incorporated herein by reference in
their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to anilinopyrazole compounds,
pharmaceutical compositions, and methods for treating diabetes and
related disorders.
BACKGROUND OF THE INVENTION
[0003] Diabetes is characterized by impaired glucose metabolism
manifesting itself among other things by an elevated blood glucose
level in the diabetic patient. Underlying defects lead to a
classification of diabetes into two major groups. Type 1 diabetes,
or insulin dependent diabetes mellitus (IDDM), arises when patients
lack insulin-producing beta-cells in their pancreatic glands. Type
2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM),
occurs in patients with impaired beta-cell function and alterations
in insulin action.
[0004] The current treatment for type 1 diabetic patients is
injection of insulin, while the majority of type 2 diabetic
patients are treated with agents that stimulate beta-cell function
or with agents that enhance the tissue sensitivity of the patients
towards insulin. The drugs presently used to treat type 2 diabetes
include alpha-glucosidase inhibitors, insulin sensitizers, insulin
secretagogues, and metformin.
[0005] Over time, almost one-half of type 2 diabetic subjects lose
their response to these agents. Insulin treatment is instituted
after diet, exercise, and oral medications have failed to
adequately control blood glucose. The drawbacks of insulin
treatment are the need for drug injection, the potential for
hypoglycemia, and weight gain.
[0006] Because of the problems with current treatments, new
therapies to treat type 2 diabetes are needed. In particular, new
treatments to retain normal (glucose-dependent) insulin secretion
are needed. Such new drugs should have the following
characteristics: dependency on glucose for promoting insulin
secretion (i.e., compounds that stimulate insulin secretion only in
the presence of elevated blood glucose); low primary and secondary
failure rates; and preservation of islet cell function.
[0007] INS-1 cells are a model for islet beta-cell insulin
secretion. When maintained in the presence of beta-mercaptoethanol,
these cells retain many of the characteristics of islet beta-cells
in situ. The cells secrete insulin in response to physiologically
relevant glucose concentrations with an EC.sub.50 of 6 mM glucose
(Hohmeier, et al., Diabetes 49:424, 2002). These cells also secrete
insulin in response to multiple known secretagogues, including
agents that elevate intracellular cyclic AMP, nutrients other than
glucose, and potassium chloride. This characteristic of INS-1 cells
further demonstrates that the cells retain many of the signaling
pathways that are involved in the insulin secretory response, and
as such are suitable for identifying compounds that affect these
pathways. INS-1 cells are therefore useful tools for identifying
compounds that stimulate insulin secretion in the presence of
glucose and thus useful in the treatment of diabetes and related
disorders.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The invention provides anilinopyrazole derivatives of
Formula (I) ##STR1## wherein [0009] R is H or
(C.sub.1-C.sub.6)alkyl; [0010] R.sup.1 is H, [0011]
(C.sub.1-C.sub.6)alkyl optionally substituted with one substituent
selected from the group consisting of (C.sub.1-C.sub.4)alkoxy,
phenyl optionally substituted with halo, and
[tri(C.sub.1-C.sub.4)alkyl]silyl, [0012] (C.sub.3-C.sub.6)alkenyl,
[0013] (C.sub.3-C.sub.6)alkynyl, [0014] (C.sub.3-C.sub.6)cycloalkyl
optionally substituted with up to two substituents selected from
the group consisting of (C.sub.1-C.sub.3)alkyl, CF.sub.3, and halo,
[0015] (C.sub.1-C.sub.3)haloalkyl, or [0016] phenyl optionally
substituted with up to four substituents selected from the group
consisting of [0017] halo, [0018] (C.sub.1-C.sub.6)alkyl optionally
substituted with one (C.sub.1-C.sub.4)alkoxy, [0019]
(C.sub.1-C.sub.6)alkoxy, [0020] (C.sub.1-C.sub.3)haloalkyl, [0021]
(C.sub.1-C.sub.3)haloalkoxy, [0022] NR.sup.8R.sup.8, [0023] cyano,
and [0024] (C.sub.1-C.sub.6)alkylthio; [0025] R.sup.2 is H, [0026]
halo, [0027] (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, [0028] (C.sub.3-C.sub.6)cycloalkyl
optionally substituted with up to two substituents selected from
the group consisting of (C.sub.1-C.sub.3)alkyl and halo, [0029]
(C.sub.1-C.sub.3)haloalkyl, [0030] pyridyl optionally substituted
with up to two substituents selected from the group consisting of
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkythio, halo, and
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, [0031] pyrimidyl, [0032] phenyl optionally
substituted with up to four substituents selected from the group
consisting of [0033] (C.sub.1-C.sub.6)alkyl optionally substituted
with one (C.sub.1-C.sub.4)alkoxy, [0034] (C.sub.1-C.sub.6)alkoxy,
[0035] hydroxy, [0036] NR.sup.8R.sup.8, [0037] cyano, [0038]
(C.sub.1-C.sub.6)alkylthio, [0039] halo, [0040] CO.sub.2R.sup.8,
[0041] (C.sub.1-C.sub.3)haloalkoxy, [0042] (C.sub.1-C.sub.4)acyl,
and [0043] benzoyl, [0044] or [0045] tetrahydronaphthyl, indanyl,
benzodioxolyl, or benzodioxanyl, each of which may be optionally
substituted with up to two substituents selected from the group
consisting of (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkythio,
halo, and (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, [0046] or [0047] when R.sup.1 and R.sup.2
are (C.sub.1-C.sub.6)alkyl, they may, together with C atoms to
which they are attached, form a 5- or 6-membered carbocyclic ring,
[0048] or [0049] R.sup.1 and R.sup.2 may, together with the C atoms
to which they are attached form a 6-membered heterocyclic ring
containing a N atom and optionally substituted on N with
(C.sub.1-C.sub.3)alkyl; [0050] R.sup.3 is (C.sub.1-C.sub.6)alkyl,
[0051] (C.sub.3-C.sub.6)cycloalkyl, [0052] benzyl optionally
substituted on the aryl ring with up to four substituents selected
from the group consisting of [0053] (C.sub.1-C.sub.6)alkyl
optionally substituted with one (C.sub.1-C.sub.4)alkoxy, [0054]
halo, [0055] (C.sub.1-C.sub.3)haloalkyl, [0056]
(C.sub.1-C.sub.6)alkoxy, [0057] (C.sub.1-C.sub.3)haloalkoxy, [0058]
NR.sup.8R.sup.8, [0059] cyano, [0060] (C.sub.1-C.sub.6)alkylthio,
and [0061] SO.sub.2(C.sub.1-C.sub.3)alkyl, [0062]
(C.sub.2-C.sub.3)haloalkyl, or [0063] phenyl optionally substituted
with up to four substituents selected from the group consisting of
[0064] (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, [0065] halo, [0066]
(C.sub.1-C.sub.3)haloalkyl, [0067] (C.sub.1-C.sub.6)alkoxy, [0068]
(C.sub.1-C.sub.3)haloalkoxy [0069] NR.sup.8R.sup.8, [0070] cyano,
[0071] (C.sub.1-C.sub.6)alkylthio, and [0072]
SO.sub.2(C.sub.1-C.sub.3)alkyl; [0073] R.sup.4 is
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, [0074] (C.sub.1-C.sub.6)alkoxy, [0075]
(C.sub.1-C.sub.6)alkylthio, [0076] (C.sub.1-C.sub.3)haloalkyl,
[0077] (C.sub.1-C.sub.3)haloalkoxy, [0078] halo, [0079]
NR.sup.8R.sup.8, [0080] pyrimidyl, [0081] pyridyl, [0082]
imidazolyl, or [0083] phenyl optionally substituted with up to four
substituents selected from the group consisting of [0084] halo,
[0085] (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, [0086] (C.sub.1-C.sub.6)alkoxy, [0087]
(C.sub.1-C.sub.3)haloalkyl, [0088] (C.sub.1-C.sub.3)haloalkoxy,
[0089] NR.sup.8R.sup.8, [0090] cyano, and [0091]
(C.sub.1-C.sub.6)alkylthio; [0092] n=0, 1, 2, or 3; [0093] X is
CO.sub.2R.sup.8, CONR.sup.5R.sup.6, SO.sub.2NHR.sup.7, or
oxadiazolyl optionally substituted with (C.sub.1-C.sub.6)alkyl;
[0094] R.sup.5is H, [0095] (C.sub.1-C.sub.6)alkyl, [0096]
(C.sub.2-C.sub.6)alkyl substituted with OR.sup.6, [0097] benzyl
optionally substituted on the aryl ring with up to four
substituents selected from the group consisting of [0098] halo,
[0099] (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, [0100] (C.sub.1-C.sub.6)alkoxy, [0101]
(C.sub.1-C.sub.3)haloalkyl, [0102] (C.sub.1-C.sub.3)haloalkoxy,
[0103] NR.sup.8R.sup.8, [0104] cyano, and [0105]
(C.sub.1-C.sub.6)alkylthio, [0106] phenyl optionally substituted
with up to four substituents selected from the group consisting of
[0107] (C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, [0108] halo, [0109]
(C.sub.1-C.sub.6)alkoxy, [0110] (C.sub.1-C.sub.3)haloalkyl, [0111]
(C.sub.1-C.sub.3)haloalkoxy, [0112] NR.sup.8R.sup.8, [0113] cyano,
and [0114] (C.sub.1-C.sub.6)alkylthio, [0115] pyridyl optionally
substituted with up to two substituents selected from the group
consisting of [0116] halo, [0117] (C.sub.1-C.sub.6)alkyl optionally
substituted with one (C.sub.1-C.sub.4)alkoxy, [0118]
(C.sub.1-C.sub.6)alkoxy, [0119] (C.sub.1-C.sub.3)haloalkoxy, [0120]
NR.sup.8R.sup.8, [0121] cyano, and [0122]
(C.sub.1-C.sub.6)alkylthio, ##STR2## [0123] SO.sub.2-phenyl said
phenyl optionally substituted with up to four substituents selected
from the group consisting of [0124] halo [0125]
(C.sub.1-C.sub.6)alkyl optionally substituted with one
(C.sub.1-C.sub.4)alkoxy, [0126] (C.sub.1-C.sub.6)alkoxy, [0127]
(C.sub.1-C.sub.3)haloalkyl, [0128] (C.sub.1-C.sub.3)haloalkoxy,
[0129] NR.sup.8R.sup.8, [0130] cyano, and [0131]
(C.sub.1-C.sub.6)alkylthio; [0132] R.sup.6 is H or
(C.sub.1-C.sub.6)alkyl; [0133] or [0134] R.sup.5 and R.sup.6
together with N atom to which they are attached, may form a
piperidine, morpholine, thiomorpholine, or piperazine ring said
piperazine optionally substituted on N with (C.sub.1-C.sub.3)alkyl;
[0135] R.sup.7 is H or methyl; [0136] R.sup.8 is H, [0137]
(C.sub.1-C.sub.6)alkyl, [0138] benzyl optionally substituted on the
aryl ring with up to four substituents selected from the group
consisting of [0139] halo, [0140] (C.sub.1-C.sub.6)alkyl optionally
substituted with one (C.sub.1-C.sub.4)alkoxy, [0141]
(C.sub.1-C.sub.3)alkoxy, [0142] (C.sub.1-C.sub.3)haloalkyl, [0143]
(C.sub.1-C.sub.3)haloalkoxy, [0144] cyano, and [0145]
(C.sub.1-C.sub.6)alkylthio, [0146] or [0147] phenyl optionally
substituted with up to four substituents selected from the group
consisting of [0148] (C.sub.1-C.sub.6)alkyl optionally substituted
with one (C.sub.1-C.sub.4)alkoxy, [0149] halo, [0150]
(C.sub.1-C.sub.6)alkoxy, [0151] (C.sub.1-C.sub.3)haloalkyl, [0152]
(C.sub.1-C.sub.3)haloalkoxy, [0153] cyano, and [0154]
(C.sub.1-C.sub.6)alkylthio; [0155] and the pharmaceutically
acceptable salts thereof; [0156] provided that when R and R.sup.2
are H and X is CO.sub.2H, then R.sub.1 is not H, methyl, or ethyl,
and further provided that the Formula (I) compound is not
##STR3##
[0157] The terms identified above have the following meaning
throughout:
[0158] The term "halo" means F, Br, Cl, and I.
[0159] The terms "(C.sub.1-C.sub.3)alkyl,"
"(C.sub.1-C.sub.6)alkyl," and "(C.sub.2-C.sub.6)alkyl" mean a
linear or branched saturated hydrocarbon radical having from about
1 to about 3 C atoms, about 1 to about 6 C atoms, about 2 to about
6 C atoms, respectively. Such groups include, but are not limited
to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl,
hexyl, and the like.
[0160] The term "(C.sub.3-C.sub.6)alkenyl" means a linear or
branched unsaturated hydrocarbon radical containing a double bond
and from about 3 to about 6 carbon atoms. The double bond may be
between any two available carbon atoms in the chain. Such groups
include, allyl, isopropenyl, 2-butenyl, 2-ethyl-2-butenyl,
1-hexenyl, and the like.
[0161] The term "(C.sub.3-C.sub.6)alkynyl" means a linear or
branched unsaturated hydrocarbon radical containing a triple bond
and from about 3 to about 6 carbon atoms. The triple bond may be
between any two available carbon atoms in the chain. Such groups
include, propargyl, 2-butynyl, 1-methyl-2-butynyl, 3-hexynyl, and
the like.
[0162] The term "(C.sub.3-C.sub.6)cycloalkyl" includes cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl.
[0163] The terms "(C.sub.1-C.sub.3)alkoxy,"
"(C.sub.1-C.sub.4)alkoxy," and "(C.sub.1-C.sub.6)alkoxy" mean a
linear or branched saturated hydrocarbon radical having from about
1 to about 3 C atoms, about 1 to about 4 C atoms, or about 1 to
about 6 C atoms, respectively, said radical being attached to an O
atom. The O atom is the atom through which the alkoxy substituent
is attached to the rest of the molecule. Such groups include, but
are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy,
pentyloxy, hexyloxy, and the like.
[0164] The terms "(C.sub.1-C.sub.3)haloalkoxy" and
"(C.sub.2-C.sub.3)haloalkoxy" mean a (C.sub.1-C.sub.3)alkoxy group
or a (C.sub.2-C.sub.3)alkoxy group, respectively, substituted on C
with a halogen atom. Such groups include trifluoromethoxy,
difluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,
2-chloroethoxy, 3-chloropropoxy, 1-fluoro-2,2,-dichloroethoxy, and
the like.
[0165] The terms "(C.sub.1-C.sub.3)haloalkyl" and
"(C.sub.2-C.sub.3)haloalkyl" mean a (C.sub.1-C.sub.3)alkyl group or
(C.sub.2-C.sub.3)alkyl group substituted on C with a halogen atom.
Such groups include trifluoromethyl, difluoroethyl,
1-fluoro-2,2-dichloroethyl, 3-chloropropyl, 4-bromohexyl, and the
like.
[0166] The term "[tri(C.sub.1-C.sub.4)alkylsilyl]" means a Si
radical bearing three (C.sub.1-C.sub.4)alkyl substituents, each
substituent being independently selected. The Si atom is the atom
through which the radical is attached to the rest of the molecule.
Such groups include, but are not limited to, trimethylsilyl,
tert-butyl-dimethylsilyl, and the like.
[0167] The formula C(O) means a radical in which the C atom bears a
doubly bonded oxygen, (an oxo substituent) and in which there
remains two additional binding sites, that is, represents a radical
of the formula: ##STR4##
[0168] The term "(C.sub.1-C.sub.4)acyl" means a
(C.sub.1-C.sub.4)alkyl radical substituted on the C of a C(O)
group. The C of the C(O) is the group is also the atom through
which the substituent is attached to the rest of the molecule. Such
groups include, but are not limited to, acetyl(CH.sub.3C(O)--),
n-propanoyl(CH.sub.3CH.sub.2C(O)--),
isobutanoyl[(CH.sub.3).sub.2CHC(O)--], and the like.
[0169] The formula "NR.sup.8R.sup.8" means that each of the two
possible R.sup.8 groups attached to the N atom are selected
independently from the other so that they may be the same or they
may be different.
[0170] The terms "(C.sub.1-C.sub.3)alkylthio" and
"(C.sub.1-C.sub.6)alkylthio" mean a linear or branched saturated
hydrocarbon radical having from about 1 to about 3 C atoms, or
about 1 to about 6 C atoms, respectively, said radical being
attached to an S atom. The S atom is the atom through which the
alkylthio substituent is attached to the rest of the molecule. Such
groups include, but are not limited to, methylthio, ethylthio,
n-propylthio, isopropylthio, and the like.
[0171] The term "SO.sub.2(C.sub.1-C.sub.3)alkyl" means a linear or
branched saturated hydrocarbon radical having from about 1 to about
3 C atoms, said radical being attached to the S atom of the
SO.sub.2 group. The S atom of the SO.sub.2 group is the atom
through which the SO.sub.2(C.sub.1-C.sub.3)alkyl substituent is
attached to the rest of the molecule. Such groups include
methylsulfonyl, ethylsulfonyl, n-propylsulfonyl and
isopropylsulfonyl, and the like.
[0172] The term "6-membered carbocyclic ring" means a partially
unsaturated ring containing C atoms fused to the pyrazole ring to
form a tetrahydroindazole ring system. The ring may be optionally
substituted with (C.sub.1-C.sub.6)alkyl groups at any available
position, up to a total of about 6 C atoms.
[0173] The term "6-membered heterocyclic ring containing an N atom
and substituted on N with (C.sub.1-C.sub.3)alkyl" means a
heterocyclic ring fused to the pyrazole ring to form either a
tetrahydropyrazolo[4,3-c]pyridine or
tetrahydropyrazolo[3,4-c]pyridine bicyclic ring system. The N atom
of the tetrahydropyridine heterocycle is located at either the 5 or
6-position of the bicyclic system, as illustrated below. The N atom
may be optionally substituted (indicated as R.sup.opt sub in the
illustration below), with (C.sub.1-C.sub.3)alkyl. ##STR5##
[0174] The terms "tetrahydronaphthyl," "indanyl," "benzodioxolyl,"
or "benzodioxanyl" mean bicyclic ring radicals of the formulae
##STR6## respectively. The radical is attached to the rest of the
molecule at any available carbon of the phenyl ring. Where the
radical is optionally substituted, the substituent may be attached
at any available carbon atom.
[0175] The term "optionally substituted" means that the moiety so
modified may have from none to up to at least the highest number of
substituents indicated. Each substituent may replace any H atom on
the moiety so modified as long as the replacement is chemically
possible and chemically stable. When there are two or more
substituents on any moiety, each substituent is chosen
independently of any other substituent and can, accordingly, be the
same or different.
[0176] Alternative Forms of Novel Compounds
[0177] Also included in the compounds of the present invention are
(a) the stereoisomers thereof, (b) the pharmaceutically-acceptable
salts thereof, (c) the tautomers thereof, (d) the protected acids
and the conjugate acids thereof, and (e) the prodrugs thereof.
[0178] The stereoisomers of these compounds may include, but are
not limited to, enantiomers, diastereomers, racemic mixtures, and
combinations thereof. Such stereoisomers may be prepared and
separated using conventional techniques, either by reacting
enantiomeric starting materials, or by separating isomers of
compounds of the present invention. Isomers may include geometric
isomers. Examples of geometric isomers include, but are not limited
to, cis isomers or trans isomers across a double bond. Other
isomers are contemplated among the compounds of the present
invention. The isomers may be used either in pure form or in
admixture with other isomers of the inhibitors described above.
[0179] Pharmaceutically-acceptable salts of the compounds of the
present invention include salts commonly used to form alkali metal
salts or form addition salts of free acids or free bases. The
nature of the salt is not critical, provided that it is
pharmaceutically-acceptable. Suitable pharmaceutically-acceptable
acid addition salts may be prepared from an inorganic acid or from
an organic acid. Examples of such inorganic acids are hydrochloric,
hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric
acid. Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, heterocyclic, carboxylic, and sulfonic
classes of organic acids. Examples of organic and sulfonic classes
of organic acids includes, but are not limited to, formic, acetic,
propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,
citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic,
glutamic, benzoic, anthranilic, mesylic, salicylic,
4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,
cyclohexylaminosulfonic, stearic, algenic, N-hydroxybutyric,
salicylic, galactaric, and galacturonic acid, and combinations
thereof.
[0180] Tautomers of the compounds of the invention are encompassed
by the present invention. Thus, for example, a carbonyl includes
its hydroxy tautomer.
[0181] The protected acids include, but are not limited to, esters,
hydroxyamino derivatives, amides and sulfonamides.
[0182] The present invention includes the prodrugs and salts of the
prodrugs. Formation of prodrugs is well known in the art in order
to enhance the properties of the parent compound; such properties
include solubility, absorption, biostability, and release time
(see, e.g., "Pharmaceutical Dosage Form and Drug Delivery Systems"
(Sixth Edition), edited by Ansel et al., publ. by Williams &
Wilkins, pgs. 27-29, (1995), which is hereby incorporated by
reference). Commonly used prodrugs are designed to take advantage
of the major drug biotransformation reactions, and are also to be
considered within the scope of the invention. Major drug
biotransformation reactions include N-dealkylation, O-dealkylation,
aliphatic hydroxylation, aromatic hydroxylation, N-oxidation,
S-oxidation, deamination, hydrolysis reactions, glucuronidation,
sulfation, and acetylation (see, e.g., Goodman and Gilman's The
Pharmacological Basis of Therapeutics (Ninth Edition), editor
Molinoff et al., publ. by McGraw-Hill, pages 11-13, (1996), which
is hereby incorporated by reference).
[0183] A comprehensive list of the abbreviations utilized by
organic chemists of ordinary skill in the art appears in the first
issue of each volume of the Journal of Organic Chemistry; this list
is typically presented in a table entitled Standard List of
Abbreviations. The abbreviations contained in said list, and all
abbreviations utilized by organic chemists of ordinary skill in the
art are hereby incorporated by reference.
[0184] For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 67th Ed.,
1986-87.
[0185] General Preparative Methods
[0186] In general, the compounds used in this invention may be
prepared by standard techniques known in the art, by known
processes analogous thereto, and/or by the processes described
herein, using starting materials which are either commercially
available or producible according to routine, conventional chemical
methods. The following preparative methods are presented to aid the
reader in the synthesis of the compounds of the present
invention.
[0187] Reaction Scheme A illustrates the general method for the
preparation of the Formula (Ia) [Formula (I) where R is H]
compounds. An aminopyrazole of Formula (III) is coupled with either
a 2-bromo or 2-iodobenzoic acid, benzoic ester, benzoic acid amide,
or benzenesulfonamide of Formula (IV), using Ullmann-type
conditions (copper (II) acetate in DMF, heated in a sealed tube for
16 h) or a 2-bromobenzoic ester, benzoic acid amide, or
benzenesulfonamide of Formula (IV) using Buchwald-type conditions
(cesium carbonate, BINAP and Pd.sub.2(dba).sub.3 in anhydrous
toluene, heated to 110.degree. C. for 16 h under argon).
##STR7##
[0188] Reaction Scheme B illustrates a general method for
conversion of compounds of Formula (Ib) into other Formula (Ia)
compounds having at least one R.sup.4 substituent, by reaction of
the halogen-containing (Ib) under Suzuki coupling conditions [e.g.,
a palladium catalyst such as Pd(dppf)Cl.sub.2, and a boronic acid
(V)]. ##STR8##
[0189] Reaction Scheme C outlines a general method for the
preparation of other Formula (Ia) compounds from compounds of
Formula (Id) [Formula (I) where R.sup.2 is bromo or iodo]. In this
scheme, a bromine or iodine is introduced to the compound of
Formula (Ic) [Formula (I) where R.sup.2 is H] and the resulting
Formula (Id) compound is allowed to undergo a Suzuki reaction with
a boronic acid R.sup.2B(OH).sub.2. ##STR9##
[0190] By combining the methods of Reaction Schemes A, B, and C,
Formula (Ia) compounds may be prepared containing a variety of
R.sup.2 and R.sup.4 substituents as shown in Reaction Scheme D1.
For example, coupling a dibromobenzoic acid, dibromobenzoic ester,
or dibromobenzenesulfonamide of Formula (IVa) with a pyrazole of
Formula (IIIa) provides an intermediate of Formula (Ie). Suzuki
reaction of (Ie) with a boronic acid derivative gives (If) which
can be brominated or iodinated to give (Id). Finally, (Id) can be
converted to the Formula (Ia) compounds via another Suzuki
reaction. ##STR10## Other compounds of Formula (I) where R.sup.2 is
iodo (Formula Ig) or fluoro (Formula Ih) may be prepared from
Formula (If) compounds as shown in Reaction Scheme D2, by
iodination with NIS or fluorination with Selectfluor.RTM.,
respectively. ##STR11##
[0191] Compounds of Formula (I) in which R.sup.4 is an amino group
NR.sup.5R.sup.6 or imidazole can be prepared by a special sequence
outlined in Reaction Scheme E. ##STR12##
[0192] In this sequence, a 4-fluoro group on the phenyl ring can be
displaced by an R.sup.4 group, where R.sup.4.dbd.NR.sup.5R.sup.6 or
an imidazolyl, in an aromatic nucleophilic substitution reaction.
The reaction is conducted in the presence of a base such as
LiNMe.sub.2 or K.sub.2CO.sub.3,
[0193] Compounds of Formula (I) where X is C(O)NR.sup.5R.sup.6 or
oxadiazolyl can be prepared by the route described in Reaction
Scheme F. ##STR13##
[0194] An ester compound of Formula (Im) is hydrolyzed to the acid
compound of Formula (In) usually in mild aqueous base. Formula (In)
can then be converted to amides of Formula (Io) by reaction with an
amine R.sup.5R.sup.6NH and a coupling agent, or with an optionally
substituted phenyl sulfonamide ArSO.sub.2NH.sub.2 and a coupling
agent, to give the acyl sulfonamide of Formula (Ip). The Formula
(In) compound may also be converted to the Formula (Iq) compound by
reaction with an N-hydroxy-acetamidine facilitated by base such as
triethylamine and coupling agents such as HOAT and EDCl. The
oxadiazole ring in Formula (Iq) is formed when the Formula (VI)
compound is subjected to cyclodehydration conditions such as the
addition of (methoxycarbonylsulfamoyl)-triethylammonium hydroxide
(Burgess reagent).
[0195] Reaction Scheme G outlines the general method for
preparation of Formula (I) compounds in which
X.dbd.SO.sub.2NHR.sup.7 and R.sup.7 is H. ##STR14##
[0196] The N,N-dibenzylsulfonamide compound of Formula (Ir) is
prepared as described in Reaction Scheme A and can be de-benzylated
with sulfuric acid to give the compound of Formula (Is).
##STR15##
[0197] The compounds of Formula (I) where R is
(C.sub.1-C.sub.6)alkyl are prepared by N-alkylation of the
corresponding Formula (I) compounds where R is H, using standard
conditions such as those shown in Reaction Scheme H. Such
conditions include an alkylating agent such as iodomethane, and a
base such as sodium hydride, and the reaction is carried out in
inert solvent such as DMF.
[0198] Synthesis of Intermediates
[0199] Intermediates are either commercially available, or are
prepared by standard methods known in the art and/or by analogy to
one of the procedures shown below.
[0200] 5-Aminopyrazoles
[0201] 5-Aminopyrazole starting materials of Formula (III) are
either commercially available or can be prepared as shown in
Reaction Schemes I, J, or K. ##STR16##
[0202] In Reaction Scheme I, condensation of an optionally
substituted acetonitrile with an appropriately substituted ester
(VII), and base, gives the cyanoketone (VIII). Esters of Formula
(VII) where R.sup.1 is an optionally substituted phenyl, can be
prepared, if necessary, from the corresponding bromo compound of
Formula R.sup.1--Br, for example, by reaction with BuLi and
CO.sub.2 to form an acid of Formula R.sup.1--COOH, which can be
esterified to (VII). The compound of formula (VIII) is then allowed
to react with a substituted hydrazine of Formula (II) to give the
desired aminopyrazole (III). If the cyanoketone (VIII) is
commercially available, the first step is omitted. ##STR17##
[0203] In Reaction Scheme J, acetonitrile is allowed to condense to
the enaminonitrile (IX), then react with the hydrazine (II) to form
(IIIa) [(III) where R.sup.2.dbd.H]. ##STR18## [0204] *Suitable
boronic acid esters include [0205] R.sup.2B(OR').sub.2 where R' is
a lower alkyl group, or two R' groups may form a ring such as
##STR19## [0206] and trimeric boronic acid esters such as
##STR20##
[0207] Reaction Scheme K illustrates how the aminopyrazole of
Formula (IIIa) may be converted to other aminopyrazoles of Formula
(III) by bromination and Suzuki or Stille coupling reactions to
introduce an R.sup.2 group other than H. The product of the Stille
reaction (IIIc) can also be reduced, for example by hydrogenation,
to give the saturated compound of Formula (IIId).
[0208] Examples of preparations of aminopyrazoles are shown in the
descriptions of Intermediates B-M, below.
[0209] Hydrazines
[0210] Hydrazine starting materials of Formula (II) are either
commercially available or, in the case of phenyl hydrazines
(R.sup.3=optionally substituted phenyl), can be prepared as shown
in Reaction Scheme L. ##STR21##
[0211] A substituted aniline is converted into a diazonium salt
intermediate which is subsequently reduced using tin(II)chloride as
the reductant.
[0212] An example of a preparation of an arylhydrazine is shown in
the description of Intermediate A, below.
[0213] 2-Bromobenzoic acid Derivatives
[0214] The 2-bromobenzoic acid derivatives used in the coupling
reactions with 5-aminopyrazoles were either commercially available
or prepared by straightforward means well known in the art. An
example of one such preparation is shown in the description of
Intermediate N below.
[0215] Specific Examples of the Invention
[0216] The following specific examples are presented to illustrate
the invention described herein, but should not be construed as
limiting the scope of the invention in any way.
[0217] Abbreviations and Acronyms
[0218] When the following abbreviations are used throughout the
disclosure, they have the following meaning: [0219] abs absolute
[0220] Ac acetyl [0221] AcOH acetic acid [0222] amu atomic mass
unit [0223] aq aqueous [0224] BINAP
2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl [0225] Bn benzyl [0226]
Boc t-butoxycarbonyl [0227] BTMAlCl.sub.2 benzyltrimethylammonium
dichloriodate [0228] Bu butyl [0229] CDCl.sub.3 deuterochloroform
[0230] CDI carbonyl diimidazole [0231] Celite.RTM. brand of
diatomaceous earth filtering agent, registered trademark of Celite
Corporation [0232] Cl-MS chemical ionization mass spectroscopy
[0233] conc concentrated [0234] d doublet [0235] DCM
dichloromethane [0236] dd doublet of doublet [0237] ddd doublet of
doublet of doublet [0238] DMAP 4-(N,N-dimethyl)amino pyridine
[0239] DMF N,N-dimethyl formamide [0240] DMSO dimethylsulfoxide
[0241] DMSO-d.sub.6 dimethylsulfoxide-d.sub.6 [0242] DOWEX.RTM. 66
Dowex hydroxide, weakly basic anion, macroporous, 25-50 mesh [0243]
dppf 1,1'-bis(diphenylphosphino)ferrocene [0244] EDCl
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [0245]
El electron impact ionization [0246] El-MS electron impact-mass
spectrometry [0247] equiv equivalent [0248] ES-MS electrospray mass
spectrometry [0249] Et ethyl [0250] Et.sub.2O diethyl ether [0251]
Et.sub.3N triethylamine [0252] EtOAc ethyl acetate [0253] EtOH
ethanol [0254] g gram [0255] GC-MS gas chromatography-mass
spectrometry [0256] h hour(s) [0257] Hex hexanes [0258] .sup.1H NMR
proton nuclear magnetic resonance [0259] HOAT
1-hydroxy-7-aza-benzotriazole [0260] HOBT 1-hydroxybenzotriazole
[0261] HPLC high-performance liquid chromatography [0262] HPLC
ES-MS high-performance liquid chromatography-electrospray mass
spectroscopy [0263] KOtBu potassium tert-butoxide [0264] L liter
[0265] LC-MS liquid chromatography/mass spectroscopy [0266] LDA
lithium diisopropylamide [0267] m multiplet [0268] M molar [0269]
mL milliliter [0270] m/z mass over charge [0271] Me methyl [0272]
MeCN acetonitrile [0273] MeOH methanol [0274] mg milligram [0275]
MHz megahertz [0276] min minute(s) [0277] mmol millimole [0278] mol
mole [0279] mp melting point [0280] MS mass spectrometry [0281] N
normal [0282] NaOAc sodium acetate [0283] NBS N-bromosuccinimide
[0284] NIS N-iodosuccinimide [0285] NMM 4-methylmorpholine [0286]
NMR nuclear magnetic resonance [0287] Pd.sub.2(dba).sub.3
tris(dibenzylideneacetone)dipalladium(0) [0288] Pd(OAc).sub.2
palladium acetate [0289] Pd(PPh.sub.3).sub.4
tetrakis(triphenylphosphine)palladium(0) [0290] Pd/C palladium on
carbon [0291] Pd(dppf)Cl.sub.2
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [0292]
Ph phenyl [0293] ppm parts per million [0294] Pr propyl [0295] psi
pounds per square inch [0296] q quartet [0297] qt quintet [0298]
R.sub.f TLC retention factor [0299] rt room temperature [0300] RT
retention time (HPLC) [0301] s singlet [0302] TBAF
tetrabutylammonium fluoride [0303] TBDMS tert-butyldimethylsilyl
[0304] TBDMSCl tert-butyldimethylsilyl chloride [0305] TBS
tert-butyldimethylsilyl [0306] TFA trifluoroacetic acid [0307] THF
tetrahydrofuran [0308] TLC thin layer chromatography [0309] TMS
tetramethylsilane [0310] v/v volume per unit volume [0311] vol
volume [0312] w/w weight per unit weight
[0313] General Experimental Methods
[0314] Air and moisture sensitive liquids and solutions were
transferred via syringe or cannula, and introduced into reaction
vessels through rubber septa. Commercial grade reagents and
solvents were used without further purification. The term
"concentration under reduced pressure" refers to use of a Buchi
rotary evaporator at approximately 15 mm of Hg. All temperatures
are reported uncorrected in degrees Celsius (.degree. C). Thin
layer chromatography (TLC) was performed on EM Science pre-coated
glass-backed silica gel 60 A F-254 250 .mu.m plates. Column
chromatography (flash chromatography) was performed on a Biotage
system using 32-63 micron, 60 A, silica gel pre-packed cartridges.
Purification using preparative reversed-phase HPLC chromatography
were accomplished using a Gilson 215 system, typically using a YMC
Pro-C18 AS-342 (150.times.20 mm I.D.) column. Typically, the mobile
phase used was a mixture of H.sub.2O (A) and MeCN (B). The water
could be mixed or not with 0.1% TFA. A typical gradient was:
TABLE-US-00001 Time Flow [min] A: % B: % [mL/min] 0.50 90.0 10.0
1.0 11.00 0.0 100.0 1.0 14.00 0.0 100.0 1.0 15.02 100.0 0.0 1.0
[0315] Electron impact mass spectra (El-MS) were obtained with a
Hewlett Packard 5989A mass spectrometer equipped with a Hewlett
Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25
.mu.M coating; 30 m.times.0.25 mm). The ion source was maintained
at 250.degree. C. and spectra were scanned from 50-800 amu at 2 sec
per scan.
[0316] High pressure liquid chromatography-electrospray mass
spectra (LC-MS) were obtained using either a: [0317] (A)
Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a
variable wavelength detector set at 254 nm, a YMC pro C-18 column
(2.times.23 mm, 120 A), and a Finnigan LCQ ion trap mass
spectrometer with electrospray ionization. Spectra were scanned
from 120-1200 amu using a variable ion time according to the number
of ions in the source. The eluents were A: 2% acetonitrile in water
with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA.
Gradient elution from 10% to 95% B over 3.5 minutes at a flow rate
of 1.0 mL/min was used with an initial hold of 0.5 minutes and a
final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.
[0318] or [0319] (B) Gilson HPLC system equipped with two Gilson
306 pumps, a Gilson 215 Autosampler, a Gilson diode array detector,
a YMC Pro C-18 column (2.times.23 mm, 120 A), and a Micromass LCZ
single quadrupole mass spectrometer with z-spray electrospray
ionization. Spectra were scanned from 120-800 amu over 1.5 seconds.
ELSD (Evaporative Light Scattering Detector) data was also acquired
as an analog channel. The eluents were A: 2% acetonitrile in water
with 0.02% TFA, and B: 2% water in acetonitrile with 0.018% TFA.
Gradient elution from 10% to 90% B over 3.5 minutes at a flow rate
of 1.5 mL/min was used with an initial hold of 0.5 minutes and a
final hold at 90% B of 0.5 minutes. Total run time was 4.8 minutes.
An extra switching valve was used for column switching and
regeneration.
[0320] Routine one-dimensional NMR spectroscopy was performed on
300/400 MHz Varian Mercury-plus spectrometers. The samples were
dissolved in deuterated solvents obtained from Cambridge Isotope
Labs, and transferred to 5 mm ID Wilmad NMR tubes. The spectra were
acquired at 293 K. The chemical shifts were recorded on the ppm
scale and were referenced to the appropriate solvent signals, such
as 2.49 ppm for DMSO-d.sub.6, 1.93 ppm for CD.sub.3CN, 3.30 ppm for
CD.sub.3OD, 5.32 ppm for CD.sub.2Cl.sub.2 and 7.26 ppm for
CDCl.sub.3 for .sup.1H spectra, and 39.5 ppm for DMSO-d.sub.6, 1.3
ppm for CD.sub.3CN, 49.0 ppm for CD.sub.3OD, 53.8 ppm for
CD.sub.2Cl.sub.2 and 77.0 ppm for CDCl.sub.3 for .sup.13C
spectra.
Synthesis of Intermediates
Hydrazines
Intermediate A
Preparation of (2,6-dimethylphenyl)hydrazine hydrochloride
[0321] ##STR22##
[0322] To a cold (0.degree. C.) solution of 2,6-dimethylaniline
(5.0 g, 41.3 mmol) in 50% aqueous HCl (45 mL), was added slowly
under stirring a cold (0.degree. C.) solution of NaNO.sub.2 (2.85
g, 41.3 mmol) in water (22.5 mL). The temperature was closely
monitored during the addition and was not allowed to exceed
5.degree. C. Upon completion of the addition, the bright orange
solution containing the diazonium salt intermediate was stirred at
the same temperature for 20 min. A mixture of SnCl.sub.2 (11.0 g,
57.8 mmol) in conc HCl (30 mL) was added to the reaction mixture at
0.degree. C. over a period of .about.5 min. The reaction mixture
was then warmed to rt and stirred for 6 h. The precipitate was
collected by filtration and washed with a small volume of cold
water. Drying in vacuo afforded the title compound as a white
amorphous solid (7.00 g, 98%). The product was used in the next
step without further purification. ES-MS m/z 137.0 (MH.sup.+); HPLC
RT (min) 1.09.
[0323] 5-Aminopyrazoles
Intermediate B
Preparation of
3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0324] ##STR23##
Step 1: Preparation of 3-cyclopentyl-3-oxopropanenitrile
[0325] ##STR24##
[0326] To a suspension of NaH (2.75 g, 68.7 mmol) in THF (15 mL) at
70.degree. C. was added dropwise a solution of methyl
cyclopentanecarboxylate (8.00 g, 62.4 mmol) and anhydrous
acetonitrile (3.91 mL, 74.9 mmol) in THF (5 mL). The mixture was
stirred for 16 h at 70.degree. C.-72.degree. C., cooled to rt, and
diluted with ethyl acetate and aqueous HCl. The organic layer was
washed with water and brine and dried (MgSO.sub.4). Removal of the
solvent provided 3-cyclopentyl-3-oxopropanenitrile, which was used
without further purification.
Step 2: Preparation of
3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0327] ##STR25##
[0328] A solution of (2-methylphenyl)hydrazine hydrochloride (2.00
g, 14.6 mmol) and crude 3-cyclopentyl-3-oxopropanenitrile from the
previous step (2.32 g, .about.14.6 mmol) in toluene (6 mL) was
heated to reflux for 16 h. Removal of the solvent under reduced
pressure provided a residue which was purified by silica gel
chromatography using hexane/EtOAc (3:1, v/v) as the eluent.
Concentration under reduced pressure provided
3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-amine as a light
orange solid (2.19 g, 62%). ES-MS m/z 241.9 (MH.sup.+); HPLC RT
(min) 1.69. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.58-1.82 (m,
6H), 2.00-2.16 (m, 2H), 2.17-2.21 (s, 3H), 2.93-3.11 (m, 1H),
3.42-3.58 (s, 2H), 5.41-5.46 (s, 1H), 7.20-7.28 (m, 2H) 7.29-7.37
(m, 2H).
Intermediate C
Preparation of
3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0329] ##STR26##
[0330] 4,4-Dimethyl-3-oxopentanenitrile (36.7 g, 0.29 mol),
(2-methylphenyl)hydrazine hydrochloride (47.7 g, 0.29 mol), and
glacial acetic acid (7.03 g, 6.7 mL, 0.12 mol) were dissolved in
abs ethanol (585 mL) and heated under reflux for 18 h. After
removal of the solvent under reduced pressure, EtOAc and water (500
mL each) were added, then sodium bicarbonate (42 g, 0.50 mol) was
carefully added. After addition of hexane (500 mL), the organic
phase was separated, washed with brine (500 mL), and dried over
Na.sub.2SO.sub.4. The mixture was then filtered through a pad of
silica gel (500 g) on a sintered glass funnel. The pad was eluted
with hexanes/EtOAc (1:1, v/v), and the filtrate was concentrated
under reduced pressure. The resulting solid was triturated with
hexanes/EtOAc (9:1, v/v), filtered, washed and dried in vacuo to
afford a colorless solid (61.5 g, 93%). .sup.1H NMR (400 MHz,
CD.sub.2Cl.sub.2) .delta. 1.29 (s, 9H), 2.12 (s, 3H), 3.56 (br,
2H), 5.48 (s, 1H), 7.28 (m, 2H), 7.31 (m, 2H).
Intermediate D
Preparation of
3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0331] ##STR27##
Step 1: Preparation of 3-amino-3-(4-fluorophenyl)acrylonitrile
[0332] ##STR28##
[0333] To a solution of 4-fluorobenzonitrile (5.00 g, 41.3 mmol)
and acetonitrile (4.35 mL, 82.5 mmol) in toluene (100 mL) was added
potassium tert-butoxide (13.9 g, 124 mmol). The mixture was stirred
for 24 h, and then quenched by slow addition of aqueous sodium
bicarbonate. The resulting suspension was extracted with
dichloromethane (3.times.50 mL). The organic solution was washed
with water, dried (Na.sub.2SO.sub.4), and concentrated under
reduced pressure. The residue was triturated with EtOH/Et.sub.2O to
afford 3-amino-3-(4-fluorophenyl)acrylonitrile (6.20 g, 93%) as a
white solid. .sup.1H NMR (300 MHz, acetone-d.sub.6) .delta. 4.23
(s, 1H), 6.20 (s, 2 H), 7.22 (ddd, 2 H), 7.71 (m, 2 H).
Step 2: Preparation of
3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0334] ##STR29##
[0335] To a solution of 3-amino-3-(4-fluorophenyl)acrylonitrile
(600 mg, 3.70 mmol) in 1 N HCl (6 mL) was added
(2-methylphenyl)hydrazine hydrochloride (558 mg, 3.51 mmol). The
reaction was refluxed for 16 h, and then cooled to rt. The
resulting mixture was basified to pH 12 by slow addition of 1 N
aqueous sodium hydroxide. The precipitate was collected by
filtration, and then recrystallized from EtOH/Et.sub.2O to afford
the intermediate (800 mg, 81%) as a light orange solid. .sup.1H NMR
(400 MHz, CD.sub.2Cl.sub.2) .delta. 2.20 (s, 3H), 2.14 (br s, 2H),
5.91 (s, 1H), 7.06 (t, 2H), 7.36 (d, 4H), 7.75 (m, 2H). This
material was us without further purification.
Intermediate E
Preparation of
3-(4-fluoro-2-methylphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0336] ##STR30##
Step 1: Preparation of 4-fluoro-2-methylbenzoic acid
[0337] ##STR31##
[0338] To a cooled (-78.degree. C.) solution of
2-bromo-5-fluorotoluene (10.0 g, 52.9 mmol) in diethyl ether (100
mL) was added dropwise n-butyllithium (1.6 M in hexane, 21.2 mL,
52.9 mmol). The mixture was stirred for 5 min, and slowly warmed to
0.degree. C. Dry ice (100 g, 2.27 mol) was slowly added to the
mixture while stirring, and it was allowed to warm to rt over 16 h.
The mixture was adjusted to pH=2, and extracted with ethyl acetate
(3.times.20 mL). The organic phase was concentrated and the
resulting yellow residue suspended in water (100 mL). The
suspension was adjusted to pH=12 with 2 N NaOH, and washed with
diethyl ether. The aqueous phase was then acidified to pH=2 with 2
N HCl, and extracted with diethyl ether (3.times.50 mL). The
organic extract was washed with water, dried (MgSO.sub.4), and
concentrated under reduced pressure to afford the product (5.0 mg,
61%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
2.53 (s, 3H), 7.06-7.17 (m, 2H), 7.87 (dd, 1H), 12.85 (s, 1H).
Step 2: Preparation of methyl 4-fluoro-2-methylbenzoate
[0339] ##STR32##
[0340] To a solution of 4-fluoro-2-methylbenzoic acid (4.0 g, 26.0
mmol) in THF (30 mL) in a pressure vessel was added cesium
carbonate (8.45 mg, 26.0 mmol) and iodomethane (2.0 M in tert-butyl
methyl ether, 13.0 mL, 26.0 mmol). The vessel was sealed and the
reaction was stirred at 70.degree. C. for 16 h. After cooling to
rt, the reaction was quenched with saturated sodium bicarbonate (10
mL) and water (50 mL). The aqueous layer was extracted with
dichloromethane (3.times.50 mL), and then the organic phase was
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to
give the crude product. This material was triturated with acetone
and hexanes to afford pure product (3.8 g, 87%) as a white solid.
.sup.1H NMR (400 MHz, acetone-d.sub.6) .delta. 2.60 (s, 3H), 3.86
(s, 3H), 7.05-7.12 (m, 2H), 7.96 (s,1H); ES-MS m/z 168.2
(MH.sup.+); HPLC RT (min) 3.20.
Step 3: Preparation of
3-(4-fluoro-2-methylphenyl)-3-oxopropanenitrile
[0341] ##STR33##
[0342] To a suspension of hexane-washed sodium hydride (60% oil
dispersion, 995 mg, 24.9 mmol) was added dropwise a THF solution
(20 mL) of methyl 4-fluoro-2-methylbenzoate (3.8 g, 22.6 mmol) and
anhydrous acetonitrile (2.4 mL, 45.2 mmol). The mixture was stirred
at 70.degree. C. for 16 h, and then cooled to rt. The resulting
mixture was diluted with ethyl acetate (20 mL) and 1 N HCl (10 mL)
and the layers were partitioned. The organic phase was washed with
water (3.times.20 mL) and brine (20 mL), dried (Na.sub.2SO.sub.4),
and concentrated under reduced pressure to afford 4.0 g of yellow
oil, which was taken to the next step without further purification.
ES-MS m/z 178.2 (MH.sup.+); HPLC RT (min) 2.22.
Step 4: Preparation of
3-(4-fluoro-2-methylphenyl)-1-(2-methylphenyl)-1H-pyrazol amine
[0343] ##STR34##
[0344] To a solution of
3-(4-fluoro-2-methylphenyl)-3-oxopropanenitrile (2.0 g, 11.3 mmol)
in toluene (10 mL) was added (2-methylphenyl)hydrazine
hydrochloride (2.15 g, 13.5 mmol). The reaction was stirred at
110.degree. C. for 16 h, and then cooled to rt. It was concentrated
under reduced pressure, and the residue was purified by silica gel
flash chromatography (2:1-1:1=hexanes:ethyl acetate) to afford the
product as a yellow oil (500 mg, 16%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 2.12 (s, 3H), 2.44 (s, 3H), 5.74 (s, 1H),
7.02-7.14 (m, 2H), 7.34-7.43 (m, 4H), 7.52 (dd, 1H); ES-MS m/z
282.4 (MH.sup.+); HPLC RT (min) 3.36.
Intermediate F
Preparation of 3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0345] ##STR35##
[0346] 3-Aminocrotonitrile (2.00 g, 24.4 mmol) was added to a
stirred solution of (2-methylphenyl)hydrazine hydrochloride (3.67
g, 23.1 mmol) in 1 M hydrochloric acid (20 mL). The reaction was
heated (100.degree. C.) for 18 h and then cooled to rt. The
solution was adjusted to pH>12 using 1 M aqueous sodium
hydroxide. The mixture was extracted with dichloromethane
(3.times.20 mL), and then the combined organic extracts were washed
with brine, dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography of the residue over
silica gel using 25-50% ethyl acetate/hexane afforded
3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (3.97 g, 87%) as an
orange oil. .sup.1H NMR (300 MHz, acetone-d.sub.6) .delta. 7.29 (m,
4 H), 5.32 (s, 1 H), 2.12 (s, 3 H), 2.08 (s, 3 H); ES-MS m/z 188.2
(MH.sup.+), HPLC RT (min) 0.79.
Intermediate G
Preparation of
2-(2-methylphenyl)-4,5,6,7-tetrahydro-2H-indazol-3-amine
[0347] ##STR36##
[0348] To a solution of (2-methylphenyl)hydrazine hydrochloride
(464 mg, 2.92 mmol) in ethanol (2 mL) was added
2-oxocyclohexanecarbonitrile (300 mg, 2.44 mmol), and the mixture
was heated to 60.degree. C. and stirred for 16 h. The flask was
then cooled to rt and the solvent was evaporated to give a solid.
The crude residue of
2-(2-methylphenyl)-4,5,6,7-tetrahydro-2H-indazol-3-amine
hydrochloride (449 mg, 70%) was used in the next step with no
further purification. ES-MS m/z 228.2 (MH.sup.+); HPLC RT (min)
1.22.
Intermediate H
Preparation of
4-(4-fluorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0349] ##STR37##
Step 1: Preparation of
4-bromo-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0350] ##STR38##
[0351] To a solution of
3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate F,
7.78 g, 41.7 mmol) in acetic acid (90 mL) was added a solution of
bromine (6.64 g, 41.6 mmol) in acetic acid (10 mL). The reaction
mixture was stirred for 30 min. Water was added to the reaction
mixture, and the mixture was basified using a cold KOH solution (1
N). The white solid,
4-bromo-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine, was
collected and used in the next step without purification.
Step 2: Preparation of
4-(4-fluorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0352] ##STR39##
[0353] 4-Bromo-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (2 g,
7.52 mmol), 4-fluorophenylboronic acid (2.10 g, 11.3 mmol), and
Pd(PPh.sub.3).sub.4 (434 mg, 0.38 mmol) were dissolved in DMF (20
mL), and Na.sub.2CO.sub.3 (saturated aq solution, 18 mL) was added.
The mixture was degassed for 10 min and then heated at 110.degree.
C. for 2 h. The reaction mixture was diluted, and the solid was
filtered off. The solvent was concentrated under reduced pressure,
and the residue purified by silica gel flash chromatography using
10 to 40% ethyl acetate in hexanes to give 1.2 g (90% pure, 51%) of
the title compound. .sup.1H NMR (300 MHz, CD.sub.2Cl.sub.2) .delta.
7.25-7.34 (m, 6H), 7.08 (t, 2H), 3.62 (s, 2H), 2.20 (s, 3H), 2.14
(s, 3H).
Intermediate I
Preparation of
tert-butyl(4-bromo-3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbamate
[0354] ##STR40##
Step 1: Preparation of
4-bromo-3-tert-butyl-1-methyl-1H-pyrazol-5-amine
[0355] ##STR41##
[0356] To a solution of 3-tert-butyl-1-methyl-1H-pyrazol-5-amine
(10 g, 65.3 mmol) in acetic acid (90 mL) was added bromine (10.4 g,
65.26 mmol) in acetic acid (10 mL). The solution was stirred at rt
for 30 min, and then water (100 mL) was added. The reaction mixture
was basified to pH 9 using KOH (1.0 M ice cold solution). The
resulting brown solid was filtered, collected, and purified by
silica gel flash chromatography using 10 to 30% ethyl acetate in
hexanes to afford 13.2 g (87%) of the title compound (white
solid).
Step 2: Preparation of
tert-butyl(4-bromo-3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbamate
[0357] ##STR42##
[0358] The product from Step 1 (2 g, 8.62 mmol), di-tert-butyl
dicarbonate (2.82 g, 12.92 mmol), and DMAP (105 mg, 0.86 mmol) were
dissolved in DCM (40 mL) and stirred for 16 h. Potassium carbonate
(10% aqueous solution, 100 mL) was added into the reaction mixture,
and stirring was continued for another 4 h. The organic layer was
separated and concentrated under reduced pressure. The residue was
purified by silica gel flash chromatography with 5 to 20% ethyl
acetate in hexanes to give 2.3 g (80%) of the title compound.
.sup.1H NMR (300 MHz, CD.sub.2Cl.sub.2) .delta. 3.55 (s, 3 H), 1.37
(s, 9 H), 1.31 (s, 9 H).
Intermediate J
Preparation of
4bromo-3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0359] ##STR43##
[0360] To a solution of
3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (1.00 g, 4.36
mmol) in acetic acid (10 mL) was added bromine (662 mg, 0.21 mL,
4.14 mmol) dropwise. The reaction mixture was stirred for 5 min,
and then diluted with water (50 mL), causing a solid to
precipitate. The solid was collected by filtration, then dissolved
in EtOAc (50 mL). The EtOAc solution was then washed with saturated
NaHCO.sub.3 and brine, dried (Na.sub.2SO.sub.4), and concentrated
under reduced pressure to afford the product (935 mg, 70%) as a
white solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.32 (s,
9H), 2.04 (s, 3H) 5.02 (s, 2H), 7.20-7.38 (m, 4H). ES-MS m/z 308.6
(MH.sup.+); HPLC RT (min) 3.15.
Intermediate K
Preparation of
3-tert-butyl-4-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0361] ##STR44##
[0362] To a solution of
4-bromo-3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine
(Intermediate J, 800 mg, 2.60 mmol) in DMF (5 mL) was added
trimethylboroxine (0.73 mL, 5.19 mmol),
[1,1'-bis(diphenylphosphino)-butane]palladium (II) dichloride (157
mg, 0.26 mmol), and potassium carbonate (1.08 g, 7.79 mmol). The
reaction mixture was stirred for 18 h at 155.degree. C. After
cooling, the reaction mixture was diluted with water (100 mL) and
extracted with EtOAc (3.times.25 mL). The combined organic layers
were washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel flash chromatography using hexane/EtOAc (1:9, v/v) to
afford the product (243 mg, 38%) as a white solid: .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 1.24 (s, 9H), 1.97 (s, 3H), 2.03 (s,
3H), 4.48 (s, 2H) 7.14-7.32 (m, 4H). ES-MS m/z 244.2 (MH.sup.+);
HPLC RT (min) 1.17.
Intermediate L
Preparation of
3-tert-butyl-1-methyl-4-pyridin-3-yl-1H-pyrazol-5-amine
[0363] ##STR45##
[0364]
tert-Butyl(4-bromo-3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbamate
(Intermediate I, 1.7 g, 5.12 mmol), pyridine-3-boronic acid (1.26
g, 10.23 mmol), and Pd(PPh.sub.3).sub.4 (295 mg, 0.26 mmol) were
dissolved in ethanol (25 mL), and Na.sub.2CO.sub.3 (2 M aqueous
solution, 25 mL) was added. The mixture was degassed for 10 min.
The reaction mixture was then heated to 80.degree. C. for 16 h. The
mixture was diluted with ethyl acetate, the solid was filtered off,
and the filtrate was treated with TFA (5 mL). The mixture was
stirred for 30 min before being concentrated under reduced
pressure. The crude was dissolved in methanol and filtered though a
C.sub.8-silica plug. HPLC purification with gradient elution from 5
to 60% acetonitrile in water afforded 300 mg (25%) of the title
compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.73 (d, 1 H),
8.64 (s, 1 H), 8.14 (d, 1 H), 7.81 (dd, 1 H), 3.73 (s, 3 H), 1.20
(s, 9 H). ES-MS m/z 231.2 (MH.sup.+); HPLC RT (min) 0.23.
Intermediate M
Preparation of
4-ethyl-3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0365] ##STR46##
Step 1: Preparation of
3-(4-fluorophenyl)-1-(2-methylphenyl)-4-vinyl-1H-pyrazol-5-amine
[0366] ##STR47##
[0367] To a solution of
4-bromo-3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-amine
(200 mg, 0.58 mmol) in toluene (10 mL) was added tributylvinyl tin
(0.33 mL, 366 mg, 1.16 mmol) and
tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.06 mmol). The
reaction mixture was heated to reflux and stirred for 16 h. After
cooling to rt, the mixture was concentrated under reduced pressure.
The residue was dissolved in EtOAc (100 mL), washed with brine (50
mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated under
reduced pressure. Silica gel flash chromatography of the residue
using 10% EtOAc/Hex afforded
3-(4-fluorophenyl)-1-(2-methylphenyl)-4-vinyl-1H-pyrazol-5-amine
(87 mg, 51%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.12 (s,
3H), 4.96 (dd, 1H) 5.21 (dd, 1H), 5.26 (s, 2H), 6.55 (dd, 1H),
7.18-7.56 (m, 8H). ES-MS m/z 294.2 (MH+); HPLC RT (min) 3.54.
Step 2: Preparation of
4-ethyl-3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-amine
[0368] ##STR48##
[0369] To a mixture of wet palladium on carbon (10 wt %, 10 mg) in
EtOH (5 mL) was added
3-(4-fluorophenyl)-1-(2-methylphenyl)-4-vinyl-1H-pyrazol-5-amine
(87 mg, 0.30 mmol) in EtOH (5 mL). The reaction was mixed on a Parr
shaker under H.sub.2 atmosphere (55 psi) for 16 h. The palladium
catalyst was filtered through Celite.RTM. and rinsed with EtOH
(3.times.20 mL). The solution was concentrated under reduced
pressure to afford the title compound (68 mg, 77%) containing trace
impurities. This material was used in subsequent reactions without
further purification: ES-MS m/z 296.2 (MH.sup.+); HPLC RT (min)
2.65.
[0370] 2-Bromobenzoic acid Derivatives
Intermediate N
Preparation of methyl 2-bromo-5-(difluoromethoxy)benzoate
[0371] ##STR49##
Step 1: Preparation of methyl 2-bromo-5-hydroxybenzoate
[0372] ##STR50##
[0373] To a cold solution (ice water bath) of the
methyl-2-bromo-5-methoxybenzoate (2.00 g, 8.16 mmol) in
dichloromethane (15 mL) was added AlCl.sub.3 (5.44 g, 40.8 mmol)
under argon, and the reaction temperature was maintained below
10.degree. C. using an ice-water bath. The light brown suspension
was stirred for 10 min, then EtSH (3.02 mL, 40.8 mmol) was added
dropwise at such a rate that the reaction temperature was
maintained below 5.degree. C. After 2.5 h of stirring below
10.degree. C., the reaction mixture was slowly poured into ice
water with agitation. The organic layer was separated, and the
aqueous layer was extracted with DCM. The combined organic layers
were washed with water, dried over MgSO.sub.4, filtered and
concentrated under reduced pressure to afford a light yellow oil
which was used in the next step without further purification.
Step 2: Preparation of methyl
2-bromo-5-(difluoromethoxy)benzoate
[0374] ##STR51##
[0375] To a solution of methyl 2-bromo-5-hydroxybenzoate (5.63
mmol, 1.30 g) in DMF (8 mL) was added cesium carbonate (11.3 mmol,
3.67 g) and methyl chlorodifluoroacetate (6.75 mmol, 0.71 mL), and
the reaction mixture stirred at 90.degree. C. for 16 h. After
cooling to rt and dilution with ethyl acetate, the mixture was
filtered and concentrated under reduced pressure. The residue was
purified by silica gel chromatography using hexane/EtOAc (9:1, v/v)
as the eluent. The product was obtained as a light yellow oil (560
mg, 35%). GC-MS m/z: 280 (MH.sup.+).
[0376] Secondary and Tertiary Amides
[0377] The amine precursors used for all amide forming reactions
were commercially available except the amine used for Example 315.
Its synthesis is described in the following section.
Intermediate O
Preparation of
(2-{4-methoxy-3-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}ethyl)amine
dihydrochloride
[0378] ##STR52##
Step 1: Preparation of
2,2,2-trifluoro-N-[2-(4-methoxyphenyl)ethyl]acetamide
[0379] ##STR53##
[0380] To a solution of 4-methoxyphenethylamine (2.5 g, 16.5 mmol)
in CH.sub.2Cl.sub.2 (45 mL) at 0.degree. C. was added a solution of
trifluoroacetic anhydride in CH.sub.2Cl.sub.2 (5 mL). The reaction
mixture was stirred at 0.degree. C. for 30 min and then at rt for 1
h. Then a saturated aqueous solution of NH.sub.4Cl was added, the
phases separated and the aqueous phase extracted with
CH.sub.2Cl.sub.2. The combined organic phases were dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The resulting solid was recrystallized from
Et.sub.2O/hexanes to give the product as a beige solid (2.36 g,
58%). .sup.1H NMR (400 MHz, CDCl.sub.3), .delta. 2.82 (t, 2H), 3.62
(q, 2H), 3.81 (s, 3H), 6.19-6.30 (broad, 1H), 6.87 (d, 2H), 7.10
(d, 2H); GC-MS m/z 247 (M.sup.+),1 RT (min) 12.22.
Step 2: Preparation of
2,2,2-trifluoro-N-(2-{4-methoxy-3-[(4-methylpiperazin-1-yl)
sulfonyl]phenyl}ethyl)acetamide
[0381] ##STR54##
[0382] To a flask charged with
2,2,2-trifluoro-N-[2-(4-methoxyphenyl)ethyl]acetamide (1.00 g, 4.05
mmol) was added chlorosulfonic acid (4 mL) at 0.degree. C. under
N.sub.2. After 30 min, the reaction temperature was raised to rt,
and stirring was continued for an additional 90 min. The reaction
mixture was the added dropwise to a mixture of CH.sub.2Cl.sub.2 and
ice-water being cooled by an ice bath [violent reaction upon
contact with water]. The phases were separated, and the aqueous
layer was extracted with CH.sub.2Cl.sub.2. The combined organic
phases were dried (Na.sub.2SO.sub.4), filtered and concentrated
under reduced pressure.
[0383] The resulting sulfonyl chloride was dissolved in
CH.sub.2Cl.sub.2 (30 mL) to which were added Et.sub.3N (1.29 mL,
8.10 mmol) and 1-methylpiperazine (0.674 mL, 6.08 mmol) at
0.degree. C. under N.sub.2. The solution was warmed to rt and
stirred for 14 h. Then the reaction mixture was concentrated and
purified by silica gel flash chromatography using EtOAc/MeOH (4:1,
v/v) to give the title compound as a yellow oil (1.26 g, 75%).
.sup.1H NMR (400 MHz, CDCl.sub.3). .delta. 2.13 (s, 3H), 2.48
(broad t, 4H), 2.87 (t, 2H), 3.27 (broad t, 4H), 3.56 (q, 2H), 3.88
(s, 3H), 6.70-6.77 (broad s, 1H), 6.94 (d, 1H), 7.33 (dd, 1H), 7.69
(dd, 1H); ES-MS m/z 410.3 ((MH).sup.+), 432.1 ((M+Na).sup.+) 840.7
((2M+Na).sup.+) HPLC RT (min) 1.19.
Step 3: Preparation of
(2-{4-methoxy-3-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}ethyl)amine
dihydrochloride
[0384] ##STR55##
[0385] To a solution of
2,2,2-trifluoro-N-(2-{4-methoxy-3-[(4-methylpiperazin-1-yl)sulfonyl]-phen-
yl}ethyl) acetamide (from Step 2), (1.25 g, 3.05 mmol) in MeOH (30
mL) and H.sub.2O (8 mL) was added K.sub.2CO.sub.3 (2.11 g, 15.3
mmol), and the solution was stirred at 60.degree. C. for 2 h. After
cooling to rt, the MeOH was evaporated under reduced pressure. The
remaining aqueous mixture was extracted with CH.sub.2Cl.sub.2
(6.times.50 mL), and the combined organic phases were dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The residue was then dissolved in MeOH, and 4 equivalents
of 1 N HCl in MeOH were added causing the formation of a white
precipitate. The solvent was removed under reduced pressure, and
the resulting solid was recrystallized from MeOH/Et.sub.2O to give
the title compound [assumed to be the bis-HCl salt] as a white
solid (457 mg, 48%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 2.29
(s, 3H), 2.48 (broad t, 4H), 2.78 (dd, 2H), 2.87-2.92 (m, 2H), 3.23
(broad t, 4H), 3.91 (s, 3H) 7.16 (d, 1H), 7.47 (dd, 1H), 7.68 (d,
1H); ES-MS m/z (MH.sup.+) 314.2, HPLC RT (min) 0.70.
EXAMPLE 1
Preparation of
2-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoic
acid
[0386] ##STR56##
[0387] A mixture of 2-bromo-5-methoxy benzoic acid (2.26 g, 9.79
mmol), potassium carbonate (1.49 g, 10.8 mmol),
5-amino-3-tert-butyl-1-methylpyrazole (1.50 g, 9.79 mmol), and
copper (II) acetate (35 mg, 0.20 mmol) in DMF (20 mL) was heated
(150.degree. C.) in a sealed tube for 16 h. After cooling, the
reaction mixture was diluted with water (10 mL) and acidified to
pH=4 with acetic acid. This mixture was extracted with
dichloromethane (3.times.20 mL), and then the combined organic
extracts were washed with water (2.times.30 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. HPLC purification of the residue (YMC propack C18 column,
150.times.20 mm ID, 30%-80% acetonitrile in water gradient)
afforded the title compound (973 mg, 31%) as a pale yellow solid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.22 (br s, 1 H), 9.24
(br s, 1 H), 7.38 (d, 1 H), 7.10 (dd, 1 H), 6.80 (d, 1 H), 5.95 (s,
1 H), 3.70 (s, 3 H), 3.55 (s, 3 H), 1.21 (s, 9 H); ES-MS m/z 304.2
(MH.sup.+), HPLC RT (min) 2.58.
EXAMPLE 2
Preparation of
2-{[3-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)amino]}-4,5-dimethoxybenz-
oic acid trifluoroacetate
[0388] ##STR57##
[0389] A mixture of 2-bromo-4,5-dimethoxy benzoic acid (105 mg,
0.40 mmol), potassium carbonate (61 mg, 0.44 mmol),
5-amino-3-(4-chlorophenyl)-1-methylpyrazole (84 mg, 0.40 mmol), and
copper (II) acetate (2 mg, 0.01 mmol) in DMF (2 mL) was heated
(150.degree. C.) in a sealed tube for 16 h. After cooling, the
reaction mixture was diluted with water (2 mL) and then acidified
to pH=4 with acetic acid. The mixture was extracted with
dichloromethane (3.times.5 mL), and then the combined organic
extracts were washed with water (2.times.5 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. HPLC-MS purification of the residue (HPLC: YMC propack
C18 column, 100.times.20 mm ID, 10%-95% acetonitrile/TFA (0.1%) in
waterfTFA (0.1%) gradient; MS: 120-1000 amu on Micromass LCZ single
quadrupole with electrospray ionization) afforded the title
compound (28 mg, 14%) as a white solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.78 (s, 1 H), 7.82 (ddd, 2 H), 7.42 (ddd, 2
H), 7.36 (s, 1 H), 6.74 (s, 1 H), 6.56 (s, 1 H), 3.74 (s, 3 H),
3.71 (s, 6 H); ES-MS m/z 388.2 (MH.sup.+), HPLC RT (min) 2.58.
EXAMPLE 3
Preparation of
2-{[3-(4fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid
[0390] ##STR58##
[0391] To a solution of
3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-amine
(Intermediate D, 100 mg, 0.37 mmol) in DMF (3 mL), was added
2-iodobenzoic acid (93 mg, 0.37 mmol), potassium carbonate (62 mg,
0.45 mmol), and copper (II) acetate (3 mg, 0.01 mmol). The mixture
was stirred at 150.degree. C. for 18 h and then cooled to rt. The
solution was adjusted to pH 4 using glacial acetic acid. The
mixture was extracted with dichloromethane (3.times.5 mL), and then
the combined organic extracts were washed with brine, dried
(MgSO.sub.4), filtered, and concentrated under reduced pressure.
The residue was purified by HPLC (45-90% acetonitrile in water) to
afford the title compound (17 mg, 12%) as a light yellow solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.08 (s, 3H), 6.85
(ddd, 1H), 6.93 (s, 1H), 7.24 (ddd, 2H), 7.42 (m, 6H), 7.84 (dd,
1H), 7.92 (ddd, 2H), 10.02 (s, 1H), 13.23 (s, 1H); ES-MS m/z 388.2
(MH.sup.+); HPLC RT (min) 3.47.
EXAMPLE 4
Preparation of
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-methoxybenzo-
ic acid
[0392] ##STR59##
[0393] To a solution of
3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate C,
1.00 g, 4.36 mmol) in DMF (20 mL), was added
2-bromo-5-methoxybenzoic acid (1.01 g, 4.36 mmol), potassium
carbonate (723 mg, 5.23 mmol), and copper (II) acetate (32 mg, 0.17
mmol). The mixture was stirred at 150.degree. C. for 18 h and then
cooled to rt. The solution was adjusted to pH 4 using glacial
acetic acid. The mixture was extracted with dichloromethane
(3.times.5 mL), and then the combined organic extracts were washed
with brine, dried (MgSO.sub.4), filtered, and concentrated under
reduced pressure. The residue was purified by HPLC (45-90%
acetonitrile in water) to afford the product (500 mg, 33%) as a
light yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
1.29 (s, 9H), 1.98 (s, 3H), 3.69 (s, 3H), 6.19 (s, 1H), 7.14 (dd,
1H), 7.26-7.37 (m, 6H), 9.49 (s, 1H), 13.25 (s, 1H); ES-MS m/z
380.3 (MH.sup.+); HPLC RT (min) 3.18.
[0394] The following analogs were synthesized using the methods
described in Examples 1-4. Examples 7 and 28 were obtained as
trifluoroacetic acid salts, as described for Example 2.
[0395] In Table 1a, the locant of the R.sup.4 group(s) is defined
as shown. TABLE-US-00002 TABLE 1a ##STR60## Ex. LC-MS LC-MS No.
R.sup.1 R.sup.2 R.sup.3 R.sup.4 RT (min) [M + H].sup.+ Note* 5 H H
Et -- 2.38 232.1 c 6 H H Ph 5-SMe 3.02 326.1 c 7 Me H Me 4-F 2.31
250.1 c 8 Me H Me 3-CF.sub.3 1.94 300.1 c 9 Me H Bn 4-F 2.85 326.2
c 10 Me H Ph 5-OMe 2.79 324.1 c 11 t-Bu H Me -- 2.81 274.1 c 12
t-Bu H Me 5-SMe 2.90 320.2 c 13 t-Bu H Et 4,5-di-OMe 2.54 366.2 I
14 t-Bu H ##STR61## -- 3.3 350.2 I 15 t-Bu H ##STR62## 4,5-di-OMe
3.06 410.2 I 16 t-Bu H ##STR63## 5-OMe 3.31 394.3 I 17 t-Bu H
##STR64## 4,5-di-OMe 3.77 424.2 I 18 t-Bu H ##STR65## -- 3.99 364.2
I 19 t-Bu H ##STR66## 5-OMe 3.90 394.2 I 20 t-Bu H ##STR67## 6-F
3.84 368.2 I 21 t-Bu H ##STR68## 4-F 4.14 382.2 I 22 t-Bu H
##STR69## 5-F 4.02 382.2 I 23 t-Bu H ##STR70## 6-F 3.97 382.2 I 24
t-Bu H ##STR71## 4-Me 4.07 378.2 I 25 t-Bu H ##STR72## 5-Me 4.06
378.2 I 26 t-Bu H ##STR73## 4,5-di-OMe 3.60 430.2 I 27 t-Bu H
##STR74## 5-OMe 3.65 396.2 I 28 Ph H Me 4,5-di-OMe 2.71 354.2 c 29
Ph H Ph 5-OMe 4.06 386.2 c 30 Ph H ##STR75## -- 3.57 370.1 J 31 Ph
H ##STR76## 4,5-di-OMe 3.36 430.1 J 32 Ph H ##STR77## 5-OMe 3.39
400.2 J 33 Ph H ##STR78## 4-F 3.75 402.1 J 34 Ph H ##STR79## 6-F
3.60 402.2 J 35 Ph H ##STR80## 4-Me 3.76 398.2 J 36 Ph H ##STR81##
5-Me 3.79 398.2 J 37 Ph H ##STR82## -- 3.63 384.2 J 38 Ph H
##STR83## 5-OMe 3.57 414.1 J 39 Ph H ##STR84## 4,5-di-OMe 3.39
444.2 J 40 Ph H ##STR85## 4-F 3.56 388.1 J 41 Ph H ##STR86## 6-F
3.43 388.2 J 42 Ph H ##STR87## 4-Cl 4.20 404.1 J 43 Ph H ##STR88##
5-Me 4.07 384.2 J 44 Ph H ##STR89## 5-OMe 3.56 414.3 J 45 Ph H
##STR90## 4,5-di-OMe 3.36 444.3 J 46 ##STR91## H Ph 5-MeO 3.52
404.2 J 47 ##STR92## H ##STR93## 5-OMe 3.44 418.2 J 48 ##STR94## H
##STR95## -- 3.93 400.2 J 49 ##STR96## H ##STR97## -- 3.55 384.2 J
50 ##STR98## H ##STR99## 5-OMe 3.52 414.3 J 51 ##STR100## H
##STR101## 4,5-di-OMe 3.33 444.2 J 52 ##STR102## H ##STR103## --
3.30 400.2 J 53 ##STR104## H ##STR105## 5-OMe 3.27 430.2 J 54
##STR106## H ##STR107## 4,5-di-OMe 3.47 464.2 J 55 ##STR108## H
##STR109## 5-OMe 3.66 414.2 J 56 ##STR110## H ##STR111## 4-F 3.63
406.2 J 57 ##STR112## H ##STR113## 6-F 3.95 406.1 J 58 ##STR114## H
##STR115## 4-Me 4.10 402.2 J 59 ##STR116## H ##STR117## 5-Me 4.12
402.2 J 60 ##STR118## H ##STR119## -- 3.68 384.2 J 61 ##STR120## H
##STR121## 4-F 3.73 402.1 J 62 ##STR122## H ##STR123## 6-F 3.59
402.1 J 63 ##STR124## H ##STR125## 4-Cl 3.93 418.1 J 64 ##STR126##
H ##STR127## 4-Me 3.73 398.2 J 65 ##STR128## H ##STR129## 5-Me 3.77
398.2 J 66 ##STR130## H ##STR131## -- 4.12 402.2 J 67 ##STR132## H
##STR133## 4-F 4.21 420.2 J 68 ##STR134## H ##STR135## 6-F 4.08
420.1 J 69 ##STR136## H ##STR137## 4-Me 4.23 416.2 J 70 ##STR138##
H ##STR139## 5-Me 4.25 416.2 J 71 ##STR140## H ##STR141## 5-OMe
4.09 432.2 J 72 ##STR142## H ##STR143## 4,5-di-OMe 3.93 462.2 J 73
##STR144## H ##STR145## -- 4.07 384.2 J 74 ##STR146## H ##STR147##
5-OMe 4.05 414.2 J 75 Me ##STR148## ##STR149## 6-F 3.26 420.2 K 76
t-Bu H ##STR150## 6-F 3.94 386.2 I 77 t-Bu H ##STR151## 4-F 4.1
386.2 I 78 t-Bu H ##STR152## 4-F 3.58 384.2 I 79 t-Bu H ##STR153##
5-Me 3.51 380.2 I 80 t-Bu H ##STR154## 5-OMe 3.36 412.2 I 81 t-Bu H
##STR155## -- 3.86 380.3 I 82 t-Bu H ##STR156## 5-OMe 3.73 410.3 I
83 t-Bu H ##STR157## 5-Me 3.92 394.2 I 84 t-Bu H ##STR158## 5-OMe
3.82 400.2 I 85 t-Bu H ##STR159## 4-F 3.99 388.1 I 86 ##STR160## H
##STR161## -- 4.12 402.2 I 87 ##STR162## H ##STR163## 5-OMe 4.08
432.2 I 88 Ph H ##STR164## -- 4 388.2 J 89 ##STR165## H ##STR166##
-- 3.79 402.2 J 90 ##STR167## H ##STR168## 4-F 4 422.2 J 91
##STR169## H ##STR170## 5-OMe 3.76 432.2 J 92 ##STR171## H
##STR172## 4,5-Di-OMe 3.69 464.2 J 93 ##STR173## H ##STR174## 5-OMe
3.71 436.2 J 94 ##STR175## H ##STR176## 5-Me 4.03 418.2 J 95
##STR177## H ##STR178## 5-Me 3.88 420.2 J 96 ##STR179## H
##STR180## 5-OMe 3.87 434.2 J 97 ##STR181## H ##STR182## 4-F 3.66
418.2 J 98 ##STR183## H ##STR184## 4,5-Di-OMe 3.7 460.2 J 99
##STR185## H ##STR186## -- 3.89 400.2 J 100 ##STR187## H ##STR188##
5-OMe 3.86 430.2 J 101 ##STR189## H ##STR190## 5-Me 4.03 414.2 J
102 Me ##STR191## ##STR192## 5-Cl 2.89 419.2 K 103 t-Bu Me
##STR193## -- 4.07 364.2 K 104 t-Bu Me ##STR194## 5-OMe 4.01 394.2
K 105 ##STR195## Me ##STR196## 5-OMe 3.8 424.2 K 106 t-Bu Me
##STR197## -- 3.58 380.2 K 107 t-Bu Me ##STR198## 5-OMe 3.52 410.2
K *Note: Origin of the aminopyrazole used for the coupling
reaction: c = commercial; H, I, J, K = using the methods outlined
in Reaction Schemes I, J, or K as described above.
[0396] TABLE-US-00003 TABLE 1b Ex. No. IUPAC Name 5
2-[(1-ethyl-1H-pyrazol-5-yl)amino]benzoic acid 6
2-[(1-phenyl-1H-pyrazol-5-yl)amino-5-(methylthio)]benzoic acid 7
2-[(1,3-dimethyl-1H-pyrazol-5-yl)amino]-4-fluorobenzoic acid
trifluoroacetate 8
2-[(1,3-dimethyl-1H-pyrazol-5-yl)amino]-3-(trifluoromethyl)benzoic
acid 9 2-[(1-benzyl-3-methyl-1H-pyrazol-5-yl)amino]-4-fluorobenzoic
acid 10
5-methoxy-2-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]benzoic acid
11 2-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]benzoic acid 12
2-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-5-(methylthio)benzoic
acid 13
2-[(3-tert-butyl-1-ethyl-1H-pyrazol-5-yl)amino]-4,5-dimethoxybenzoic
acid 14
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid 15
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4,5-
dimethoxybenzoic acid 16
2-{[3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 17
2-{[3-tert-butyl-1-(2-ethylphenyl)-1H-pyrazol-5-yl]amino}-4,5-
dimethoxybenzoic acid 18
2-{[3-tert-butyl-1-(2-ethylphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid 19
2-{[3-tert-butyl-1-(2-ethylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 20
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-6-fluorobenz-
oic acid 21
2-{[3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-yl]amino}-4-
fluorobenzoic acid 22
2-{[3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-yl]amino}-5-
fluorobenzoic acid 23
2-{[3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-yl]amino}-6-
fluorobenzoic acid 24
2-{[3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-yl]amino}-4-
methylbenzoic acid 25
2-{[3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-yl]amino}-5-
methylbenzoic acid 26
2-{[3-tert-butyl-1-(4-chlorophenyl)-1H-pyrazol-5-yl]amino}-4,5-
dimethoxybenzoic acid 27
2-{[3-tert-butyl-1-(2-methoxyphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 28
4,5-dimethoxy-2-[(1-methyl-3-phenyl-1H-pyrazol-5-yl)amino]benzoic
acid trifluoroacetate 29
2-[(1,3-diphenyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoic acid 30
2-{[1-(2-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}benzoic acid
31 4,5-dimethoxy-2-{[1-(2-methylphenyl)-3-phenyl-1H-pyrazol-5-
yl]amino}benzoic acid 32
5-methoxy-2-{[1-(2-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}benzoic
acid 33
2-{[1-(2,5-dimethylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}-4-
fluorobenzoic acid 34
2-{[1-(2,5-dimethylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}-6-
fluorobenzoic acid 35
2-{[1-(2,5-dimethylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}-4-
methylbenzoic acid 36
2-{[1-(2,5-dimethylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}-5-
methylbenzoic acid 37
2-{[1-(2,5-dimethylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}benzoic
acid 38
2-{[1-(2,5-dimethylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 39
2-{[1-(2,5-dimethylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}-4,5-
dimethoxybenzoic acid 40
4-fluoro-2-{[1-(2-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}benzoic
acid 41
2-fluoro-6-{[1-(2-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}benzoic
acid 42
4-chloro-2-{[1-(2-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}benzoic
acid 43
5-methyl-2-{[1-(2-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}benzoic
acid 44
2-{[1-(2-ethylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}-5-methoxybenzoic
acid 45 2-{[1-(2-ethylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}-4,5-
dimethoxybenzoic acid 46
2-{[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-5-yl]amino}-5-methoxybenzoic
acid 47
2-{[3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 48
2-{[3-(4-methoxyphenyl)-1-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 49
2-{[1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid 50
5-methoxy-2-{[1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 51
4,5-dimethoxy-2-{[1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 52
2-{[3-(4-methoxyphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 53
5-methoxy-2-{[3-(4-methoxyphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 54
2-{[3-(4-chlorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4,5-
dimethoxybenzoic acid 55
2-{[1,3-bis(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-methoxybenzoic
acid 56
4-fluoro-2-{[3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 57
2-fluoro-6-{[3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 58
2-{[3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-
methylbenzoic acid 59
2-{[3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
methylbenzoic acid 60
2-{[1,3-bis(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoic acid 61
4-fluoro-2-{[1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 62
2-fluoro-6-{[1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 63
4-chloro-2-{[1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 64
4-methyl-2-{[1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 65
5-methyl-2-{[1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 66
2-{[1-(2,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}-4-
fluorobenzoic acid 67
2-{[1-(2,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}-4-
fluorobenzoic acid 68
2-{[1-(2,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}-6-
fluorobenzoic acid 69
2-{[1-(2,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}-4-
methylbenzoic acid 70
2-{[1-(2,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}-5-
methylbenzoic acid 71
2-{[1-(2,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 72
2-{[1-(2,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}-4,-
5- dimethoxybenzoic acid 73
2-{[1-(2-methylphenyl)-3-(3-methylphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid 74
5-methoxy-2-{[1-(2-methylphenyl)-3-(3-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 75
2-fluoro-6-{[4-(4-fluorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol--
5- yl]amino}benzoic acid 76
2-{[3-tert-butyl-1-(5-fluoro-2-methylphenyl)-1H-pyrazol-5-yl]amino}-6-
fluorobenzoic acid 77
2-{[3-tert-butyl-1-(5-fluoro-2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-
fluorobenzoic acid 78
2-{[3-tert-butyl-1-(2-methoxyphenyl)-1H-pyrazol-5-yl]amino}-4-
fluorobenzoic acid 79
2-{[3-tert-butyl-1-(2-methoxyphenyl)-1H-pyrazol-5-yl]amino}-5-
methylbenzoic acid 80
2-({3-tert-butyl-1-[2-(methylthio)phenyl]-1H-pyrazol-5-yl}amino)-5-
methoxybenzoic acid 81
2-{[3-tert-butyl-1-(2-ethoxyphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid 82
2-{[3-tert-butyl-1-(2-ethoxyphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 83
2-{[3-tert-butyl-1-(2-ethoxyphenyl)-1H-pyrazol-5-yl]amino}-5-
methylbenzoic acid 84
2-{[3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 85
2-{[3-tert-butyl-1-(2-chlorophenyl)-1H-pyrazol-5-yl]amino}-4-fluorobenz-
oic acid 86
2-{[3-(4-fluoro-2-methylphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 87
2-{[3-(4-fluoro-2-methylphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoic acid 88
2-{[1-(5-fluoro-2-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]amino}benzoic
acid 89
2-{[1-(2-ethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}benzoic
acid 90
4-fluoro-2-{[3-(4-fluorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 91
2-{[1-(2-ethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 92
2-{[3-(4-fluorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-5-yl]amino}-4,5-
dimethoxybenzoic acid 93
2-{[1-(5-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amin-
o}- 5-methoxybenzoic acid 94
2-{[3-(4-fluorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-5-yl]amino}-5-
methylbenzoic acid 95
2-{[1-(5-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-yl]amin-
o}- 5-methylbenzoic acid 96
2-{[3-(4-fluorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 97
4-fluoro-2-{[3-(3-methoxyphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 98
4,5-dimethoxy-2-{[3-(3-methoxyphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 99
2-{[3-(3-methoxyphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 100
5-methoxy-2-{[3-(3-methoxyphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 101
2-{[3-(3-methoxyphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
methylbenzoic acid 102
5-chloro-2-{[3-methyl-1-(2-methylphenyl)-4-pyridin-3-yl-1H-pyrazol-5-
yl]amino}benzoic acid trifluoroacetate 103
2-{[3-tert-butyl-4-methyl-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzoic acid 104
2-{[3-tert-butyl-4-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 105
2-{[3-(4-fluorophenyl)-4-methyl-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoic acid 106
2-{[3-tert-butyl-1-(2-methoxyphenyl)-4-methyl-1H-pyrazol-5-
yl]amino}benzoic acid 107
2-{[3-tert-butyl-1-(2-methoxyphenyl)-4-methyl-1H-pyrazol-5-yl]amino}-5-
- methoxybenzoic acid
EXAMPLE 108
Preparation of methyl
2-{[3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoate
[0397] ##STR199##
[0398] A mixture of
3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate
B, 400 mg, 1.66 mmol), methyl 2-bromobenzoate (297 mg, 1.38 mmol),
cesium carbonate (630 mg, 1.93 mmol), BINAP (87 mg, 0.14 mmol), and
Pd.sub.2(dba).sub.3 (72 mg, 0.07 mmol) in anhydrous toluene (4 mL)
was heated to 110.degree. C. for 16 h under an argon atmosphere.
The reaction mixture was cooled to rt, diluted with ethyl acetate,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel chromatography using EtOAc/Hex (1:8, v/v) as
the eluent. The product was obtained as a light yellow oil (303 mg,
58%). ES-MS m/z 376.3 (MH.sup.+); HPLC RT (min) 3.94.
EXAMPLE 109
Preparation of
2-{[3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid
[0399] ##STR200##
[0400] To a solution of methyl
2-{[3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoate
(0.59 mmol, 220 mg) in MeOH (1.8 mL) was added THF (5.4 mL) and 1N
aqueous NaOH (1.8 mL). The reaction was stirred at rt for 21 h. The
organic solvents were removed under reduced pressure, the residue
was diluted with water, and the aqueous solution extracted with
diethylether (2.times.5 mL). The aqueous layer was acidified to
pH=1 to 2 with 1N aqueous HCl. The mixture was extracted with ethyl
acetate (3.times.5 mL). After removal of the solvent under reduced
pressure, the product was obtained as a white solid (169 mg, 79%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.58-1.62 (m, 2H),
1.65-1.78 (m, 4H), 1.90-2.01 (m, 2H), 2.06 (s, 3H), 2.99-3.10 (m,
1H), 6.23 (s, 1H), 6.80 (t, 1H), 7.20-7.30 (m, 3H), 7.30-7.40 (m,
2H), 7.42-7.51 (m,1H), 7.81 (d, 1H), 9.84 (s, 1H), 13.14 (s, 1H).
ES-MS m/z 362.3 (MH.sup.+), HPLC RT (min) 3.39.
[0401] The following analogs were synthesized using the method
described above for Example 109.
[0402] In Table 2a, the locant of the R.sup.4 group(s) is defined
as shown. TABLE-US-00004 TABLE 2a ##STR201## Ex. LC-MS LC-MS No.
R.sup.1 R.sup.2 R.sup.3 R.sup.4 RT (min) [M + H].sup.+ Note* 110
t-Bu H Me 5-Me 3.31 288.1 c 111 t-Bu H Ph 5-OMe 3.30 366.2 I 112
t-Bu H ##STR202## 5-F 3.90 368.2 I 113 t-Bu H ##STR203## 5-Me 3.47
364.2 I 114 t-Bu H ##STR204## 4-Me 3.47 364.2 I 115 t-Bu H
##STR205## 5-OMe 3.44 434.2 I 116 t-Bu H ##STR206## 5-OCHF.sub.2
3.51 416.2 I 117 t-Bu H ##STR207## 5-OMe 3.54 394.2 I 118 t-Bu H
##STR208## -- 3.66 364.2 I 119 t-Bu H ##STR209## 5-OMe 3.45 398.2 I
120 t-Bu H ##STR210## -- 3.52 368.2 I 121 t-Bu H ##STR211## -- 3.46
364.3 I 122 t-Bu H ##STR212## -- 3.43 364.3 I 123 ##STR213## H
##STR214## 5-OMe 3.27 391.9 I 124 ##STR215## H ##STR216## 5-OMe
3.40 406.3 I 125 ##STR217## Ph 5-OMe 3.06 364.2 I 126 Me ##STR218##
Ph 5-OMe 3.66 400.2 c 127 ##STR219## H ##STR220## 5-OMe 3.43 392.2
I 128 ##STR221## H ##STR222## -- 3.53 362.2 I 129 ##STR223## H
##STR224## -- 3.32 350.2 I 130 ##STR225## H ##STR226## 5-OMe 3.22
380.3 I 131 ##STR227## H ##STR228## -- 3.59 376.3 I 132 ##STR229##
H ##STR230## 5-OMe 3.47 406.3 I 133 CF.sub.3 Ph Me 5-OMe 3.21 392.2
I 134 CF.sub.3 Ph ##STR231## 5-OMe 3.7 468.2 I 135 CF.sub.3 Ph
##STR232## 5-OMe 3.82 482.2 I 136 t-Bu H ##STR233## -- 3.44 380.3 I
137 t-Bu H ##STR234## 5-OMe 3.33 394.3 I 138 t-Bu H ##STR235## --
3.79 384.2 I 139 t-Bu H ##STR236## -- 3.41 380.2 I 140 t-Bu H
##STR237## 5-OMe 3.32 410.3 I 141 t-Bu H ##STR238## 5-OMe 3.27
410.2 I 142 t-Bu H ##STR239## 5-OMe 3.62 414.4 I 143 t-Bu H
##STR240## 5-OMe 3.3 394.4 I 144 Me Ph ##STR241## 5-OMe 3.53 448.1
I 145 Me Ph ##STR242## 5-OMe 3.29 468.2 I 146 Me Ph ##STR243## 5-Me
3.29 414.2 I 147 Me Ph ##STR244## 5-OMe 3.38 428.3 I 148 Me Ph
##STR245## 5-OMe 3.31 432.2 I 149 Me Ph ##STR246## 5-OMe 3.29 434.1
I 150 ##STR247## H ##STR248## -- 3.4 364.3 I 151 ##STR249## H
##STR250## 5-OMe 3.23 392.3 I 152 ##STR251## H ##STR252## 5-OMe
3.28 394.3 I 153 ##STR253## H ##STR254## -- 3.33 362.3 I 154
##STR255## H ##STR256## 5-OMe 3.37 434.2 I *Note: Origin of the
aminopyrazole used for the coupling reaction: c = commercial; I =
using the method of Reaction Scheme I as previously described
[0403] TABLE-US-00005 TABLE 2b Ex. No. IUPAC Name 110
2-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-5-methylbenzoic
acid 111
2-[(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoic
acid 112
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-fluoroben-
zoic acid 113
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-methylben-
zoic acid 114
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-methylben-
zoic acid 115
2-({3-tert-butyl-1-[2-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}amino)--
5- methoxybenzoic acid 116
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
(difluoromethoxy)benzoic acid 117
2-{[3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 118
2-{[3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid 119
2-{[3-tert-butyl-1-(5-fluoro-2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 120
2-{[3-tert-butyl-1-(5-fluoro-2-methylphenyl)-1H-pyrazol-5-yl]amino}ben-
zoic acid 121
2-{[3-tert-butyl-1-(2,3-dimethylphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid 122
2-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid 123
2-{[3-cyclopentyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 124
2-{[3-cyclopentyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 125
5-methoxy-2-[(2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)amino]benzoi-
c acid 126
5-methoxy-2-[(3-methyl-1,4-diphenyl-1H-pyrazol-5-yl)amino]benzoic
acid 127
2-{[1-(2,5-dimethylphenyl)-3-(1-methylcyclopropyl)-1H-pyrazol-5-yl]ami-
no}-5- methoxybenzoic acid 128
2-{[1-(2,5-dimethylphenyl)-3-(1-methylcyclopropyl)-1H-pyrazol-5-
yl]amino}benzoic acid 129
2-{[1-(2,6-dimethylphenyl)-3-isopropyl-1H-pyrazol-5-yl]amino}benzoic
acid 130
2-{[3-isobutyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-methoxybenz-
oic acid 131
2-{[3-cyclohexyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoic
acid 132
2-{[3-cyclohexyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 133
5-methoxy-2-{[1-methyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-
yl]amino}benzoic acid 134
5-methoxy-2-{[1-(2-methylphenyl)-4-phenyl-3-(trifluoromethyl)-1H-pyraz-
ol-5- yl]amino}benzoic acid 135
2-{[1-(2,5-dimethylphenyl)-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoic acid 136
2-{[3-tert-butyl-1-(2-methoxy-5-methylphenyl)-1H-pyrazol-5-yl]amino}be-
nzoic acid 137
2-{[3-tert-butyl-1-(2,3-dimethylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 138
2-{[3-tert-butyl-1-(5-chloro-2-methylphenyl)-1H-pyrazol-5-yl]amino}ben-
zoic acid 139
2-{[3-tert-butyl-1-(2-methoxy-6-methylphenyl)-1H-pyrazol-5-yl]amino}be-
nzoic acid 140
2-{[3-tert-butyl-1-(5-methoxy-2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
- methoxybenzoic acid 141
2-{[3-tert-butyl-1-(2-methoxy-6-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
- methoxybenzoic acid 142
2-{[3-tert-butyl-1-(5-chloro-2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 143
2-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 144
2-{[1-(4-chloro-2-methylphenyl)-3-methyl-4-phenyl-1H-pyrazol-5-yl]amin-
o}-5- methoxybenzoic acid 145
5-methoxy-2-({3-methyl-4-phenyl-1-[2-(trifluoromethyl)phenyl]-1H-pyraz-
ol-5- yl}amino)benzoic acid 146
2-{[1-(2-methoxyphenyl)-3-methyl-4-phenyl-1H-pyrazol-5-yl]amino}-5-
methylbenzoic acid 147
2-{[1-(2,5-dimethylphenyl)-3-methyl-4-phenyl-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 148
2-{[1-(5-fluoro-2-methylphenyl)-3-methyl-4-phenyl-1H-pyrazol-5-yl]amin-
o}-5- methoxybenzoic acid 149
2-{[1-(2-chlorophenyl)-3-methyl-4-phenyl-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 150
2-{[1-(2,6-dimethylphenyl)-3-isobutyl-1H-pyrazol-5-yl]amino}benzoic
acid 151
2-{[1-(2,6-dimethylphenyl)-3-(1-methylcyclopropyl)-1H-pyrazol-5-yl]ami-
no}-5- methoxybenzoic acid 152
2-{[1-(2,6-dimethylphenyl)-3-isobutyl-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 153
2-{[1-(2,6-dimethylphenyl)-3-(1-methylcyclopropyl)-1H-pyrazol-5-
yl]amino}benzoic acid 154
2-{[1-(2,6-dimethylphenyl)-3-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl]a-
mino}-5- methoxybenzoic acid
EXAMPLE 155
Preparation of methyl
2-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoate
[0404] ##STR257##
[0405] To a 100 mL oven dried flask, was added
5-amino-3-tert-butyl-1-methylpyrazole (2.00 g, 13.1 mmol), methyl
2-bromo-5-methoxybenzoate (2.67 g, 10.9 mmol), cesium carbonate
(4.96 g, 15.2 mmol), Pd.sub.2(dba).sub.3 (337 mg, 0.33 mmol), BINAP
(338 mg, 0.54 mmol), and toluene (35 mL). The reaction mixture was
degassed, placed under an N.sub.2 atmosphere, and then stirred at
110.degree. C. for 16 h. The reaction mixture was cooled to rt, and
ethyl acetate (30 mL) was added. The mixture was filtered, the
filter cake washed with EtOAc (10 mL), and the filtrate
concentrated under reduced pressure. The residue was purified by
silica gel flash chromatography (eluent: 10 to 30% EtOAc in hexane)
to give the title compound as a light yellow oil (1.34 g, 38%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.28 (s, 9H), 3.63 (s,
3H), 3.78 (s, 3H), 3.94 (s, 3H), 5.97 (s, 1H), 6.82 (d, 1H), 7.10
(dd, 1H), 7.47 (d, 1H).
EXAMPLE 156
Preparation of methyl
2-[(4-bromo-3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoat-
e
[0406] ##STR258##
[0407] To a solution of
2-(5-tert-butyl-2-methyl-2H-pyrazol-3-ylamino)-5-methoxy-benzoic
acid methyl ester (Example 155, 1.34 g, 4.22 mmol) in acetic acid
(27 mL), was added dropwise a solution of Br.sub.2 (6.74 g, 4.22
mmol) in acetic acid (5 mL). The reaction was stirred for 5 min,
and then water (100 mL) was added. The aqueous phase was extracted
with EtOAc, and the combined organic layers were washed with water,
and then with NaHCO.sub.3 (10% aqueous solution) 10 times. The
organic layer was then dried (Na.sub.2SO.sub.4), filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel flash chromatography (eluent: 5 to 10% EtOAc in hexane)
to give the title compound as a light yellow solid. (1.49 g, 89%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.40 (s, 9H), 3.66 (s,
3H), 3.78 (s, 3H), 4.05 (s, 3H), 6.32 (d, 1H), 7.06 (dd, 1H), 7.48
(d, 1H).
EXAMPLE 157
Preparation of
2-{[3-tert-butyl-4-(4-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl]amino}-5-me-
thoxybenzoic acid
[0408] ##STR259##
[0409] To a solution
2-(4-bromo-5-tert-butyl-2-methyl-2H-pyrazol-3-ylamino)-5-methoxy-benzoic
acid methyl ester (Example 96, 100 mg, 0.25 mmol),
4-methoxyphenylboronic acid (153.4 mg, 1.01 mmol),
PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (18.46 mg, 0.03 mmol) in a
mixture of toluene (6.1 mL) and dioxane (1.22 mL) was added a 2M
aqueous solution of sodium carbonate (1.22 mL, 2.44 mmol). A flow
of Ar was passed through the reaction mixture for 15 min, and then
the reaction was stirred at 75.degree. C. for 18 h. The reaction
mixture was then cooled to rt, and filtered through a plug of
silica gel. The filtrate was concentrated under reduced pressure,
and then the residue was dissolved in a mixture of THF (4 mL), MeOH
(2 mL) and water (4 mL). Lithium hydroxide (60 mg, 2.52 mmol) was
added, and the mixture was stirred at rt for 18 h. The reaction
mixture was then concentrated and the residue purified by
preparative HPLC to give the title compound (27.9 mg, 27%) as a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.21 (s,
9H), 3.61 (s, 3H), 3.74 (s, 6H), 6.41 (d, 1H), 6.70 (d, 2H), 7.04
(dd, 1H), 7.09 (d, 2H), 7.39 (d, 1H). ES-MS m/z 410.2 (MH.sup.+);
HPLC RT (min) 3.66.
[0410] The following analogs, listed in Table 3a, were synthesized
using the methods described above. Examples 162, 163, 173, 174,
182, 183, 186, and 187 were obtained as trifluoroacetic acid
salts.
[0411] In Table 3a, the locant of the R.sup.4 group(s) is defined
as shown. TABLE-US-00006 TABLE 3a ##STR260## LC-MS Ex. RT LC-MS No.
R.sup.1 R.sup.2 R.sup.3 R.sup.4 (min) [M + H].sup.+ Note* 158 H Ph
Ph 5-OMe 3.65 386.2 c 159 H ##STR261## Ph 5-OMe 3.62 416.2 c 160 H
##STR262## Ph 5-OMe 3.77 422.1 c 161 H ##STR263## Ph 5-OMe 3.51
428.2 c 162 H ##STR264## Ph 5-OMe 2.62 388.2 c 163 H ##STR265## Ph
5-OMe 2.63 388.2 c 164 Me Ph ##STR266## 5-OMe 3.71 414.2 J 165 Me
##STR267## ##STR268## 5-OMe 3.75 432.2 J 166 Me ##STR269##
##STR270## 5-OMe 3.84 428.2 J 167 Me ##STR271## ##STR272## 5-OMe
3.67 444.2 J 168 Me ##STR273## ##STR274## 5-OMe 3.92 448.2 J 169 Me
##STR275## ##STR276## 5-OMe 3.30 450.2 J 170 Me ##STR277##
##STR278## 5-OMe 3.22 462.2 J 171 Me ##STR279## ##STR280## 5-OMe
3.07 456.2 J 172 Me ##STR281## ##STR282## 5-OMe 3.57 498.2 J 173 Me
##STR283## ##STR284## 5-OMe 2.65 415.2 J 174 Me ##STR285##
##STR286## 5-OMe 2.71 415.2 J 175 Me ##STR287## ##STR288## 5-OMe
2.96 445.1 J 176 Me ##STR289## ##STR290## 5-F 2.75 403.2 J 177 Me
##STR291## ##STR292## 5-OMe 3.52 448.2 J 178 Me ##STR293##
##STR294## 5-OMe 3.31 447.9 J 179 Me ##STR295## ##STR296## 5-OMe
3.44 446.2 J 180 Me ##STR297## ##STR298## 5-OMe 3.50 446.2 J 181 Me
##STR299## ##STR300## 5-OMe 3.45 458.2 J 182 t-Bu ##STR301## Me
5-OMe 3.92 414.2 c 183 t-Bu Ph Me 5-OMe 3.73 380.2 c 184 t-Bu
##STR302## Me 5-OMe 3.79 394.2 c 185 t-Bu ##STR303## Me 5-OMe 2.97
411.2 c 186 t-Bu ##STR304## Me 5-OMe 2.65 381.2 c 187 t-Bu
##STR305## Me 5-OMe 2.68 381.2 c 188 t-Bu ##STR306## Me 5-OMe 3.7
410.2 c 189 t-Bu ##STR307## Me 5-Me 3.92 382.2 c 190 t-Bu Ph Me
5-Me 3.89 364.2 c 191 t-Bu ##STR308## Me 5-OMe 3.84 394.2 c 192
t-Bu ##STR309## Me 5-Me 3.93 382.2 c 193 t-Bu ##STR310## Me 5-OMe
3.76 398.2 c 194 t-Bu ##STR311## Me 5-Me 2.76 365.2 c 195 CF.sub.3
##STR312## ##STR313## 5-OMe 3.77 486.2 I 196 Et ##STR314##
##STR315## 5-OMe 3.68 460.2 I 197 CF.sub.3 ##STR316## ##STR317##
5-OMe 2.68 469.2 I 198 CF.sub.3 ##STR318## ##STR319## 5-OMe 3.7
498.2 I 199 Et ##STR320## ##STR321## 5-OMe 3.56 446.2 I 200 Et Ph
##STR322## 5-OMe 3.52 428.2 I 201 Et Ph ##STR323## 5-OMe 3.64 442.2
I 202 Et ##STR324## ##STR325## 5-OMe 3.27 459.2 I 203 Et ##STR326##
##STR327## 5-OMe 2.38 429.2 I 204 Et ##STR328## ##STR329## 5-OMe
3.48 458.2 I 205 Et ##STR330## ##STR331## 5-OMe 2.5 443.2 I 206 Et
##STR332## ##STR333## 5-OMe 3.59 472.2 I 207 Me ##STR334##
##STR335## 5-OMe 3.59 518.2 J 208 Me ##STR336## ##STR337## 5-Me
3.43 416.2 J 209 Me ##STR338## ##STR339## 5-Me 3.62 456.2 J 210 Me
##STR340## ##STR341## 5-Me 3.53 412.3 J 211 Me ##STR342##
##STR343## 5-Me 3.67 456.2 J 212 Me ##STR344## ##STR345## 5-Me 3.81
470.3 J 213 Me ##STR346## ##STR347## 5-Me 3.37 446.2 J 214 Me
##STR348## ##STR349## 5-OMe 3.33 428.2 J 215 Me ##STR350##
##STR351## 5-Me 3.4 428.2 J 216 Me ##STR352## ##STR353## 5-OMe 3.27
432.2 J 217 Me ##STR354## ##STR355## 5-OMe 3.37 472.3 J 218 Me
##STR356## ##STR357## 5-Me 3.34 428.2 J 219 Me ##STR358##
##STR359## 5-OMe 3.22 432.2 J 220 Me ##STR360## ##STR361## 5-Me
3.52 442.2 J 221 Me ##STR362## ##STR363## 5-OMe 3.26 444.2 J 222 Me
##STR364## ##STR365## 5-OMe 3.2 444.2 J 223 Me ##STR366##
##STR367## 5-Me 2.28 399.3 J 224 Me ##STR368## ##STR369## 5-OMe
3.25 458.3 J 225 Me ##STR370## ##STR371## 5-OMe 4.02 482.2 J 226 Me
##STR372## ##STR373## 5-OMe 3.87 442.3 J 227 Me ##STR374##
##STR375## 5-OMe 3.81 478.2 J 228 Me ##STR376## ##STR377## 5-OMe
3.89 472.3 J 229 Me Ph ##STR378## 5-OMe 3.1 430.2 J 230 Me
##STR379## ##STR380## 5-OMe 3.91 494.2 J 231 Me ##STR381##
##STR382## 5-OMe 3.67 462.2 J 232 Me ##STR383## ##STR384## 5-OMe
3.59 474.2 J 233 Me ##STR385## ##STR386## 5-OMe 3.74 460.2 J *Note:
Origin of the aminopyrazole used for the coupling reaction: c =
commercial; I and J = using the methods of Reaction Schemes I and J
as previously described
[0412] TABLE-US-00007 TABLE 3b Ex. No. IUPAC Name 158
2-[(1,4-diphenyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoic acid 159
5-methoxy-2-{[4-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-5-yl]amino}benzo-
ic acid 160
2-{[4-(2,4-difluorophenyl)-1-phenyl-1H-pyrazol-5-yl]amino}-5-methoxybe-
nzoic acid 161
2-{[4-(4-acetylphenyl)-1-phenyl-1H-pyrazol-5-yl]amino}-5-methoxybenzoi-
c acid 162
5-methoxy-2-[(1-phenyl-4-pyridin-4-yl-1H-pyrazol-5-yl)amino]benzoic
acid trifluoroacetate 163
5-methoxy-2-[(1-phenyl-4-pyridin-3-yl-1H-pyrazol-5-yl)amino]benzoic
acid trifluoroacetate 164
5-methoxy-2-{[3-methyl-1-(2-methylphenyl)-4-phenyl-1H-pyrazol-5-
yl]amino}benzoic acid 165
2-{[4-(4-fluorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methoxybenzoic acid 166
5-methoxy-2-{[3-methyl-1-(2-methylphenyl)-4-(4-methylphenyl)-1H-pyrazo-
l-5- yl]amino}benzoic acid 167
5-methoxy-2-{[4-(4-methoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyraz-
ol- 5-yl]amino}benzoic acid 168
2-{[4-(4-chlorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methoxybenzoic acid 169
2-{[4-(2,4-difluorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoic acid 170
2-{[4-(3-fluoro-4-methoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazo-
l-5- yl]amino}-5-methoxybenzoic acid 171
2-{[4-(4-acetylphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methoxybenzoic acid 172
5-methoxy-2-({3-methyl-1-(2-methylphenyl)-4-[4-(trifluoromethoxy)pheny-
l]-1H- pyrazol-5-yl}amino)benzoic acid 173
5-methoxy-2-{[3-methyl-1-(2-methylphenyl)-4-pyridin-4-yl-1H-pyrazol-5-
yl]amino}benzoic acid trifluoroacetate 174
5-methoxy-2-{[3-methyl-1-(2-methylphenyl)-4-pyridin-3-yl-1H-pyrazol-5-
yl]amino}benzoic acid trifluoroacetate 175
5-methoxy-2-{[4-(6-methoxypyridin-3-yl)-3-methyl-1-(2-methylphenyl)-1H-
- pyrazol-5-yl]amino}benzoic acid 176
5-fluoro-2-{[3-methyl-1-(2-methylphenyl)-4-pyridin-3-yl-1H-pyrazol-5-
yl]amino}benzoic acid 177
2-{[4-(3-chlorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methoxybenzoic acid 178
2-{[4-(2-chlorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methoxybenzoic acid 179
2-{[4-(4-fluoro-2-methylphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-
-5- yl]amino}-5-methoxybenzoic acid 180
2-{[4-(4-fluoro-3-methylphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-
-5- yl]amino}-5-methoxybenzoic acid 181
2-{[4-(4-ethoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methoxybenzoic acid 182
2-{[3-tert-butyl-4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid trifluoroacetate 183
2-[(3-tert-butyl-1-methyl-4-phenyl-1H-pyrazol-5-yl)amino]-5-methoxyben-
zoic acid trifluoroacetate 184
2-{[3-tert-butyl-1-methyl-4-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 185
2-{[3-tert-butyl-4-(6-methoxypyridin-3-yl)-1-methyl-1H-pyrazol-5-yl]am-
ino}-5- methoxybenzoic acid 186
2-[(3-tert-butyl-1-methyl-4-pyridin-4-yl-1H-pyrazol-5-yl)amino]-5-
methoxybenzoic acid trifluoroacetate 187
2-[(3-tert-butyl-1-methyl-4-pyridin-3-yl-1H-pyrazol-5-yl)amino]-5-
methoxybenzoic acid trifluoroacetate 188
2-{[3-tert-butyl-4-(3-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl]amino}-5-
- methoxybenzoic acid 189
2-{[3-tert-butyl-4-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]amino}-5-
methylbenzoic acid 190
2-[(3-tert-butyl-1-methyl-4-phenyl-1H-pyrazol-5-yl)amino]-5-methylbenz-
oic acid 191
2-{[3-tert-butyl-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 192
2-{[3-tert-butyl-4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]amino}-5-
methylbenzoic acid 193
2-{[3-tert-butyl-4-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 194
2-[(3-tert-butyl-1-methyl-4-pyridin-4-yl-1H-pyrazol-5-yl)amino]-5-
methylbenzoic acid 195
2-{[4-(4-fluorophenyl)-1-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyraz-
ol-5- yl]amino}-5-methoxybenzoic acid 196
2-{[1-(2,5-dimethylphenyl)-3-ethyl-4-(4-fluorophenyl)-1H-pyrazol-5-yl]-
amino}- 5-methoxybenzoic acid 197
5-methoxy-2-{[1-(2-methylphenyl)-4-pyridin-4-yl-3-(trifluoromethyl)-1H-
- pyrazol-5-yl]amino}benzoic acid 198
5-methoxy-2-{[4-(4-methoxyphenyl)-1-(2-methylphenyl)-3-(trifluoromethy-
l)-1H- pyrazol-5-yl]amino}benzoic acid 199
2-{[3-ethyl-4-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]amin-
o}-5- methoxybenzoic acid 200
2-{[3-ethyl-1-(2-methylphenyl)-4-phenyl-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 201
2-{[1-(2,5-dimethylphenyl)-3-ethyl-4-phenyl-1H-pyrazol-5-yl]amino}-5-
methoxybenzoic acid 202
2-{[3-ethyl-4-(6-methoxypyridin-3-yl)-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoic acid 203
2-{[3-ethyl-1-(2-methylphenyl)-4-pyridin-4-yl-1H-pyrazol-5-yl]amino}-5-
- methoxybenzoic acid 204
2-{[3-ethyl-4-(4-methoxyphenyl)-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methoxybenzoic acid 205
2-{[1-(2,5-dimethylphenyl)-3-ethyl-4-pyridin-4-yl-1H-pyrazol-5-yl]amin-
o}-5- methoxybenzoic acid 206
2-{[1-(2,5-dimethylphenyl)-3-ethyl-4-(4-methoxyphenyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoic acid 207
2-{[4-(4-benzoylphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]am-
ino}- 5-methoxybenzoic acid 208
2-{[4-(4-fluorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methylbenzoic acid 209
2-{[4-(2-isopropoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}-5-methylbenzoic acid 210
5-methyl-2-{[3-methyl-1-(2-methylphenyl)-4-(4-methylphenyl)-1H-pyrazol-
-5- yl]amino}benzoic acid 211
5-methyl-2-{[3-methyl-1-(2-methylphenyl)-4-(2-propoxyphenyl)-1H-pyrazo-
l-5- yl]amino}benzoic acid 212
2-{[4-(2-butoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methylbenzoic acid 213
2-{[4-(3-fluoro-4-methoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazo-
l-5- yl]amino}-5-methylbenzoic acid 214
5-methoxy-2-{[3-methyl-1-(2-methylphenyl)-4-(3-methylphenyl)-1H-pyrazo-
l-5- yl]amino}benzoic acid 215
2-{[4-(2-methoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]am-
ino}- 5-methylbenzoic acid 216
2-{[4-(3-fluorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methoxybenzoic acid 217
2-{[4-(2-isopropoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoic acid 218
2-{[4-(4-methoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]am-
ino}- 5-methylbenzoic acid 219
2-{[4-(2-fluorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methoxybenzoic acid 220
2-{[4-(2-ethoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methylbenzoic acid 221
5-methoxy-2-{[4-(2-methoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyraz-
ol- 5-yl]amino}benzoic acid 222
5-methoxy-2-{[4-(3-methoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyraz-
ol- 5-yl]amino}benzoic acid 223
5-methyl-2-{[3-methyl-1-(2-methylphenyl)-4-pyridin-3-yl-1H-pyrazol-5-
yl]amino}benzoic acid 224
2-{[4-(2-ethoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]ami-
no}-5- methoxybenzoic acid 225
2-{[4-(2,4-dichlorophenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoic acid 226
2-{[4-(2-ethylphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amin-
o}-5- methoxybenzoic acid 227
2-{[4-(5-chloro-2-methoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazo-
l-5- yl]amino}-5-methoxybenzoic acid 228
5-methoxy-2-{[3-methyl-1-(2-methylphenyl)-4-(2-propoxyphenyl)-1H-pyraz-
ol- 5-yl]amino}benzoic acid 229
5-methoxy-2-{[1-(2-methoxyphenyl)-3-methyl-4-phenyl-1H-pyrazol-5-
yl]amino}benzoic acid 230
2-{[4-(2,2-difluoro-1,3-benzodioxol-4-yl)-3-methyl-1-(2-methylphenyl)--
1H- pyrazol-5-yl]amino}-5-methoxybenzoic acid 231
2-{[4-(5-fluoro-2-methoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazo-
l-5- yl]amino}-5-methoxybenzoic acid 232
2-{[4-(2,4-dimethoxyphenyl)-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoic acid 233
5-methoxy-2-({3-methyl-1-(2-methylphenyl)-4-[2-(methylthio)phenyl]-1H-
pyrazol-5-yl}amino)benzoic acid
EXAMPLE 234
Preparation of methyl
5-bromo-2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoat-
e
[0413] ##STR387##
[0414] To a dried 25 mL flask was introduced
3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate C,
220 mg, 0.96 mmol), methyl 2,5-dibromobenzoate (235 mg, 0.80 mmol),
Pd.sub.2(dba).sub.3 (36.6 mg, 0.04 mmol), BINAP (49.8 mg, 0.08
mmol), and Cs.sub.2CO.sub.3 (365 mg, 1.12 mmol). The flask was
degassed followed by addition of toluene (1 mL), and the mixture
was then heated to 110.degree. C. for 20 h. The mixture was cooled
to rt, and diluted with ethyl acetate. The solid was filtered off,
and the solvent was removed under reduced pressure. The residue was
redissolved in methanol/THF (4:1, v/v) and filtered though a
C.sub.8-silica plug. HPLC purification using a gradient elution
from 10% to 90% acetonitrile in water afforded 110 mg (31%) of the
title compound. .sup.1H NMR (300 MHz, CD.sub.2Cl.sub.2) .delta.
9.21 (s, 1 H), 7.41 (d, 1 H), 7.20-7.30 (m, 5 H), 7.10 (d, 1 H),
6.09 (s, 1 H), 3.72 (s, 3 H), 2.04 (s, 3 H), 1.30 (s, 9 H). ES-MS
m/z 444.1 (MH.sup.+); HPLC RT (min) 4.30.
EXAMPLE 235
Preparation of methyl
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-ethylbenzoat-
e
[0415] ##STR388##
[0416] To a mixture of methyl
5-bromo-2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoat-
e (Example 234, 1.15 g, 4.13 mmol), ethylboronic acid (1.16 g, 15.7
mmol), and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (114 mg, 0.16 mmol)
was added toluene (20 mL) and dioxane (5 mL). The resulting
solution was degassed under nitrogen for 30 min, followed by
addition of sodium bicarbonate (2 M aq solution, 15 mL). The
mixture was then heated to 85.degree. C. for 16 h. The reaction
mixture was allowed to cool to rt. The solvent was removed under
reduced pressure, and the residue was purified by silica gel flash
chromatography using 0 to 10% ethyl acetate in hexanes to afford
606 mg (61%) of the title compound. .sup.1H NMR (300 MHz,
CD.sub.2Cl.sub.2) .delta. 9.17 (s, 1 H), 7.68 (s, 1 H), 7.22-7.33
(m, 6 H), 6.08 (s, 1 H), 3.70 (s, 3 H), 2.51 (q, 2 H), 2.05 (s, 3
H), 1.30 (s, 9 H), 1.14 (t, 3 H). ES-MS m/z 392.2 (MH.sup.+); HPLC
RT (min) 4.62.
EXAMPLE 236
Preparation of
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-ethylbenzoic
acid
[0417] ##STR389##
[0418] To a solution of methyl
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino]-5-ethylbenzoat-
e (Example 235, 115 mg, 0.29 mmol) in a mixture of methanol (1 mL)
and THF (1 mL) was added lithium hydroxide monohydrate (123 mg,
2.94 mmol) in water (2 mL), and the mixture was heated to
40.degree. C. for 1 h. The reaction mixture was then cooled to rt,
and the pH of the solution was adjusted to 5 using 0.5 N aq HCl.
The solvent was removed under reduced pressure, and the residue was
subjected to HPLC purification using gradient elution from 10% to
90% acetonitrile in water to afford 109.6 mg (99%) of the title
compound. .sup.1H NMR (300 MH.sub.zCD.sub.2Cl.sub.2) .delta. 9.28
(s, 1 H), 7.76 (s, 1 H), 7.26-7.37 (m, 6 H), 6.15 (s, 1 H), 2.60
(q, 2 H), 2.08 (s, 3 H), 1.37 (s, 9 H), 1.23 (t, 3 H). ES-MS m/z
378.3 (MH.sup.+); HPLC RT (min) 3.64.
[0419] The following analogs were synthesized using the method
described above for Example 236. TABLE-US-00008 TABLE 4a ##STR390##
Ex. LC-MS LC-MS No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 RT (min) [M +
H].sup.+ Note* 237 Ph H ##STR391## Et 3.77 397.8 J 238 ##STR392## H
##STR393## Et 4.28 416.2 J 239 ##STR394## H ##STR395## Et 3.92
411.8 J 240 Ph H ##STR396## Et 3.9 411.8 J 241 ##STR397## H
##STR398## Et 3.96 429.8 J *Note: Origin of the aminopyrazole used
for the coupling reaction: c = commercial; J = using the method of
Reaction Scheme J as previously described.
[0420] TABLE-US-00009 TABLE 4b Ex. No. IUPAC Name 237
5-ethyl-2-{[1-(2-methylphenyl)-3-phenyl-1H-
pyrazol-5-yl]amino}benzoic acid 238
5-ethyl-2-{[3-(4-fluorophenyl)-1-(2-methylphenyl)-
1H-pyrazol-5-yl]amino}benzoic acid 239
5-ethyl-2-{[1-(2-methylphenyl)-3-(4-methylphenyl)-
1H-pyrazol-5-yl]amino}benzoic acid 240
2-{[1-(2,5-dimethylphenyl)-3-phenyl-1H-pyrazol-5-
yl]amino}-5-ethylbenzoic acid 241
2-{[1-(2,5-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-
5-yl]amino}-5-ethylbenzoic acid
EXAMPLE 242
Preparation of methyl
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-chlorobenzoa-
te
[0421] ##STR399##
[0422] This compound was prepared using the procedure described in
Example 234 and Intermediate C and methyl 2-bromo-4-chlorobenzoate
as starting materials. .sup.1H NMR (300 MHz, CD.sub.2Cl.sub.2)
.delta. 9.33 (s, 1 H), 7.84 (d, 1 H), 7.20-7.30 (m, 4 H), 7.15 (s,
1 H), 6.68 (d, 1 H), 6.13 (s, 1 H), 3.72 (s, 3 H), 2.06 (s, 3 H),
1.31 (s, 9 H). ES-MS m/z 398.3 (MH).sup.+; HPLC RT (min) 4.27.
EXAMPLE 243
Preparation of methyl
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-ethylbenzoat-
e
[0423] ##STR400##
[0424] To a mixture of methyl
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-chlorobenzoa-
te (Example 242, 50 mg, 0.13 mmol), ethylboronic acid (18.56 mg,
0.26 mmol), Pd.sub.2(dba).sub.3 (5.8 mg, 0.006 mmol),
tris(tert-butyl)phosphine (2.54 mg, 0.013 mmol), and potassium
fluoride (14.6 mg, 0.25 mmol) was added dioxane (1 mL). The
resulting solution was degassed under argon for 30 min and then
heated to 110.degree. C. for 16 h. The reaction mixture was then
cooled to rt. The residue was diluted with ethyl acetate and
filtered through a silica gel plug. The solvent was removed under
reduced pressure, and the crude product was purified by HPLC
purification using gradient elution from 30 to 100% acetonitrile in
water to afford 39.8 mg (81%) of the title compound. .sup.1H NMR
(300 MHz, CD.sub.2Cl.sub.2) .delta. 9.23 (s, 1 H), 7.74 (d, 1 H),
7.23-7.29 (m, 4 H), 7.03 (s, 1 H), 6.57 (d, 1 H), 6.09 (s, 1 H),
3.69 (s, 3 H), 2.55 (q, 2 H), 2.06 (s, 3 H), 1.30 (s, 9 H), 1.15
(t, 3 H). ES-MS m/z 392.2 (MH.sup.+); HPLC RT (min) 4.65.
EXAMPLE 244
Preparation of
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-ethylbenzoic
acid
[0425] ##STR401##
[0426] This compound was prepared from Example 243 using the
hydrolysis procedure described in Example 236. .sup.1H NMR (300
MH.sub.z, CD.sub.2Cl.sub.2) .delta. 9.45 (s, 1 H), 7.81 (d, 1 H),
7.20-7.35 (m, 4 H), 7.09 (s, 1 H), 6.68 (d, 1 H), 6.13 (s, 1 H),
2.61 (q, 2 H), 2.03 (s, 3 H), 1.33 (s, 9 H), 1.19 (t, 3 H). ES-MS
m/z 378.2 (MH.sup.+); HPLC RT (min) 4.12.
EXAMPLE 245
Preparation of
2-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-4-pyrimidin-5-ylbenzoic
acid
[0427] ##STR402##
[0428] Using the method described for Example 244, the title
compound was similarly prepared; ES-MS m/z 352.2 (MH.sup.+); HPLC
RT (min) 2.94.
EXAMPLE 246
Preparation of methyl
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-fluorobenzoa-
te
[0429] ##STR403##
[0430] To a dried 25 mL flask was introduced
3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate C,
110 mg, 0.48 mmol), methyl 2-bromo-4-fluorobenzoate (93.1 mg, 0.40
mmol), Pd.sub.2(dba).sub.3 (18.3 mg, 0.02 mmol), BINAP (24.9 mg,
0.04 mmol), and Cs.sub.2CO.sub.3 (182 mg, 0.56 mmol). The flask was
degassed followed by the addition of toluene (1 mL), and the
mixture was heated to 110.degree. C. for 20 h. The mixture was then
cooled to rt, and diluted with ethyl acetate. The solid was
filtered off, and the solvent was removed under reduced pressure.
The residue was redissolved in methanol/THF (4:1, v/v) and filtered
through a C.sub.8-silica plug. HPLC purification using gradient
elution from 30% to 90% acetonitrile in water afforded 136.2 mg
(89%) of the title compound. .sup.1H NMR (300 MHz,
CD.sub.2Cl.sub.2) .delta. 9.42 (s, 1 H), 7.85 (dd, 1 H), 7.21-7.30
(m, 4 H), 6.86 (dd, 1 H), 6.44 (dt, 1 H), 6.11 (s, 1 H), 3.70 (s, 3
H), 2.04 (s, 3 H), 1.30 (s, 9 H). ES-MS m/z 381.9 (MH.sup.+); HPLC
RT (min) 4.50.
EXAMPLE 247
Preparation of
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-(1H-imidazol-
-1-yl)benzoic acid
[0431] ##STR404##
[0432] To a mixture of methyl
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-fluorobenzoa-
te (Example 246, 50 mg, 0.13 mmol), imidazole (17.8 mg, 0.26 mmol),
and potassium carbonate (90.6 mg, 0.66 mmol) was added DMF (1 mL).
The mixture was then heated to 110.degree. C. for 16 h. The
reaction mixture was allowed to cool to rt. The solvent was removed
under reduced pressure, and the crude was purified by HPLC
purification using gradient elution from 10 to 80% acetonitrile in
water to afford 13.8 mg (25%) of the title compound. .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 9.48 (t, 1 H), 8.15 (d, 1 H), 8.07
(t, 1 H), 7.76 (t, 1 H), 7.52 (d, 1 H), 7.28-7.42 (m, 4 H), 7.10
(dd, 1 H), 6.48 (s, 1 H), 2.06 (s, 3H), 1.35 (s, 9 H). ES-MS m/z
416.2 (MH.sup.+); HPLC RT (min) 2.21.
EXAMPLE 248
Preparation of
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-fluorobenzoi-
c acid
[0433] ##STR405##
[0434] This compound was prepared from Example 246 using the
hydrolysis procedure described in Example 236. .sup.1H NMR (300
MHz, CD.sub.2Cl.sub.2) .delta. 9.49 (s, 1 H), 7.89 (dd, 1 H),
7.19-7.32 (m, 4 H), 6.91 (dd, 1 H), 6.47 (dt, 1 H), 6.13 (s, 1 H),
2.01 (s, 3 H), 1.31 (s, 9 H). ES-MS m/z 368.1 (MH.sup.+); HPLC RT
(min) 4.01.
EXAMPLE 249
Preparation of
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-(dimethylami-
no)benzoic acid
[0435] ##STR406##
[0436] To a solution of
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-fluorobenzoi-
c acid (Example 248, 35 mg, 0.09 mmol) in THF (1 mL) at -40.degree.
C. was added LiNMe.sub.2 (0.19 mL, 1 M in hexanes) under nitrogen.
The mixture was then stirred at this temperature for 30 min, and
then gradually warmed to rt over a 4 h period. The pH of the
solution was adjusted to pH 5, and the mixture was extracted with
ethyl acetate. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure. The
crude was purified by HPLC using gradient elution from 10 to 80%
acetonitrile in water to afford 5.7 mg (15%) of the title compound.
.sup.1H NMR (300 MHz, CD.sub.2Cl.sub.2) .delta. 9.55 (s, 1 H), 7.73
(d, 1 H), 7.22-7.35 (m, 4 H), 6.44 (d, 1 H), 6.18 (dd, 1 H), 6.15
(s, 1 H), 3.00 (s, 6 H), 2.04 (s, 3 H), 1.32 (s, 9 H). ES-MS m/z
393.2 (MH.sup.+); HPLC RT (min) 2.84.
[0437] The examples shown in Table 5a were prepared by
Buchwald-type coupling which was followed by a Suzuki reaction,
bromination (R.sup.2), a second Suzuki reaction, and hydrolysis.
All reaction steps have been described in previous examples.
TABLE-US-00010 TABLE 5a ##STR407## LC-MS LC-MS Ex. No. R.sup.2 RT
(min) [M + H].sup.+ 250 ##STR408## 3.99 408.3 251 ##STR409## 3.96
408.2 252 Ph 4.02 378.2 253 ##STR410## 3.40 380.2 254 ##STR411##
4.02 392.3 255 ##STR412## 2.70 379.2
[0438] TABLE-US-00011 TABLE 5b Ex. No. IUPAC Name 250
2-{[3-tert-butyl-4-(3-methoxyphenyl)-1-methyl-1H-pyrazol-5-
yl]amino}-5-ethylbenzoic acid 251
2-{[3-tert-butyl-4-(4-methoxyphenyl)-1-methyl-1H-pyrazol-5-
yl]amino}-5-ethylbenzoic acid 252
2-[(3-tert-butyl-1-methyl-4-phenyl-1H-pyrazol-5-yl)amino]-5-
ethylbenzoic acid 253
2-[(3-tert-butyl-1-methyl-4-pyrimidin-5-yl-1H-pyrazol-5-
yl)amino]-5-ethylbenzoic acid 254
2-{[3-tert-butyl-1-methyl-4-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}-5-ethylbenzoic acid 255
2-[(3-tert-butyl-1-methyl-4-pyridin-4-yl-1H-pyrazol-5-yl)amino]-
5-ethylbenzoic acid trifluoroacetate
[0439] The following examples represent carboxylic acid esters that
were made using an Ullmann-type coupling reaction, followed by an
esterification step.
EXAMPLE 256
Preparation of isopropyl
5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzoate
[0440] ##STR413##
Step 1: Preparation of
5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzoic acid
[0441] ##STR414##
[0442] A mixture of 2-bromo-5-methoxy benzoic acid (1.31 g, 5.7
mmol), potassium carbonate (859 mg, 6.2 mmol),
5-amino-1-phenyl-pyrazole (900 mg, 5.7 mmol), and copper (II)
acetate (21 mg, 0.11 mmol) in DMF (12 mL) was heated (150.degree.
C.) in a sealed tube for 16 h. After cooling, the reaction mixture
was diluted with water (5 mL), and then acidified to pH 4 with
acetic acid. The mixture was extracted with dichloromethane
(3.times.10 mL), and then the combined organic extracts were washed
with water (2.times.10 mL), dried over Na.sub.2SO.sub.4, filtered,
and concentrated under reduced pressure. HPLC purification of the
residue (YMC propack C18 column, 150.times.20 mm ID, 30%-80%
acetonitrile in water gradient) afforded
5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzoic acid (450 mg,
26%) as a pale yellow solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.33 (br s, 1 H), 9.62 (br s, 1 H), 7.64 (d, 1 H),
7.34-7.58 (m, 6 H), 7.00-7.11 (m, 2 H), 6.30 (d, 1 H), 3.69 (s, 3
H); ES-MS m/z 310.1 (MH.sup.+); HPLC RT (min) 2.74.
Step 2: Preparation of isopropyl
5-methoxy-2-[(1-Phenyl-1H-pyrazol-5-yl)amino]benzoate
[0443] ##STR415##
[0444] Cesium carbonate (105 mg, 0.19 mmol) and 2-iodopropane (18
mg, 0.11 mmol) were added to a solution of the intermediate
5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzoic acid (30 mg,
0.10 mmol) in DMF (4 mL). The mixture was stirred at rt for 16 h.
The reaction was quenched with water (5 mL) and then extracted with
dichloromethane (3.times.5 mL). The combined organic layers were
washed with water (5 mL), dried over Na.sub.2SO.sub.4, filtered,
and concentrated under reduced pressure. HPLC purification of the
residue (YMC propack C18 column, 150.times.20 mm ID, 30%-80%
acetonitrile in water gradient) afforded the desired product as a
white solid (20 mg, 59%). .sup.1H NMR (300 MHz, DMSO-d.sub.6),
.delta. 9.07 (s, 1 H), 7.65 (d, 1 H), 6.96-7.56 (m, 9 H), 6.29 (dd,
1 H), 5.06 (q, 1 H), 3.69 (s, 3H), 1.24 (d, 6 H); ES-MS m/z 352.1
(MH.sup.+); HPLC RT (min) 3.53.
[0445] The following analogs were made using the method described
above. The aminopyrazole used in the coupling reactions was
commercially available. TABLE-US-00012 TABLE 6a ##STR416## LC-MS
LC-MS Ex. No. R.sup.8 RT (min) [M + H].sup.+ 257 Bn 3.68 400.1 258
Me 3.15 324.1 259 Et 3.31 338.3 260 i-Bu 3.75 366.2 261 4-MeOBn
3.68 430.1
[0446] TABLE-US-00013 TABLE 6b Ex. No. IUPAC Name 257 Benzyl
5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzoate 258 Methyl
5-methoxy-2-[(1-phenyl-1H-pyrazol-5- yl)amino]benzoate 259 Ethyl
5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzoate 260 Isobutyl
5-methoxy-2-[(1-phenyl-1H-pyrazol-5- yl)amino]benzoate 261
4-Methoxybenzyl 5-methoxy-2-[(1-phenyl-1H-pyrazol-5-
yl)amino]benzoate
[0447] The following compounds were synthesized by using the
procedure described in Example 108.
[0448] In Table 7a, the locant of the R.sup.4 group(s) is defined
as shown. TABLE-US-00014 TABLE 7a ##STR417## Ex. LC-MS LC-MS No.
R.sup.1 R.sup.2 R.sup.3 R.sup.4 RT (min) [M + H].sup.+ Note* 262 H
H ##STR418## 5-OMe 3.57 354.1 c 263 H H ##STR419## -- 3.11 324.2 c
264 Me H Ph 5-OMe 3.12 338.1 c 265 t-Bu H CH.sub.2CF.sub.3 5-OMe
3.85 386.1 I 266 t-Bu H Me 5-Me 3.27 302.2 c 267 t-Bu H Me 3-Me
2.66 302.2 c 268 cyclopropyl H Ph 5-OMe 3.39 364.2 c 269 Me Me Ph
5-OMe 3.32 352.2 I 270 ##STR420## Ph 5-OMe 2.07 393.2 I 271
##STR421## Ph -- 2.05 363.2 I 272 ##STR422## H ##STR423## 5-OMe
3.95 420.4 I 273 ##STR424## H ##STR425## 5-OMe 3.77 394.2 I 274
t-Bu H ##STR426## 5-OMe 3.78 424.3 I 275 t-Bu H ##STR427## 5-OMe
4.24 408.3 I *Note: Origin of the aminopyrazole used for the
coupling reaction: c = commercial; I = using the methods of
Reaction Scheme I as previously described.
[0449] TABLE-US-00015 TABLE 7b Ex. No. IUPAC Name 262 Methyl
5-methoxy-2-{[1-(4-methoxyphenyl)-1H-pyrazol-5- yl]amino}benzoate
263 Methyl 2-{[1-(4-methoxyphenyl)-1H-pyrazol-5- yl]amino}benzoate
264 Methyl 5-methoxy-2-[(3-methyl-1-phenyl-1H-pyrazol-5-
yl)amino]benzoate 265 Methyl
2-{[3-tert-butyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoate 266 Methyl
2-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-5- methylbenzoate
267 Methyl 2-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-3-
methylbenzoate 268 Methyl
2-[(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)amino]-5-
methoxybenzoate 269 Methyl
2-[(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)amino]-5- methoxybenzoate
270 Methyl 5-methoxy-2-[(5-methyl-2-phenyl-4,5,6,7-tetrahydro-2H-
pyrazolo[4,3-c]pyridin-3-yl)amino]benzoate 271 Methyl
2-[(5-methyl-2-phenyl-4,5,6,7-tetrahydro-2H-
pyrazolo[4,3-c]pyridin-3-yl)amino]benzoate 272 Methyl
2-{[3-cyclohexyl-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoate 273 Methyl
2-{[3-isobutyl-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoate 274 Methyl
2-{[3-tert-butyl-1-(5-methoxy-2-methylphenyl)-
1H-pyrazol-5-yl]amino}-5-methoxybenzoate 275 Methyl
2-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzoate
[0450] The following analogs were synthesized from a Cl precursor
synthesized in a similar fashion as Example 242 using a similar
procedure as described in Example 243. The boronic acids used were
commercially available. TABLE-US-00016 TABLE 8a ##STR428## LC-MS
LC-MS Ex. No. R.sup.4 RT (min) [M + H].sup.+ 276 ##STR429## 3.78
382.2 277 ##STR430## 3.77 382.1 278 ##STR431## 2.83 386.2
[0451] TABLE-US-00017 TABLE 8b Ex. No. IUPAC Name 276 Methyl
3-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-3'-
fluorobiphenyl-4-carboxylate 277 Methyl
3-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-4'-
fluorobiphenyl-4-carboxylate 278 Methyl
2-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-4-
pyrimidin-5-ylbenzoate
[0452] The following examples represent carboxylic acid amides that
were made using an Ullmann-type coupling reaction.
EXAMPLE 279
Preparation of
2-{[3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzamide
[0453] ##STR432##
[0454] A mixture of 3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine
(Intermediate F, 1.00 g, 5.3 mmol), 2-bromobenzamide (1.07 g, 5.3
mmol), potassium carbonate (0.89 g, 6.4 mmol), and copper (II)
acetate (39 mg, 0.2 mmol) in DMF (20 mL) was heated (150.degree.
C.) in a sealed tube for 18 h. After cooling, the solution was
adjusted to pH=4 using glacial acetic acid. The reaction mixture
was extracted with dichloromethane (3.times.20 mL), and then the
combined organic extracts were washed with brine, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography of the residue over silica gel using 33-50%
ethyl acetate/hexane afforded a yellow solid that was washed with
diethyl ether to give
2-{[3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzamide
(350 mg, 21%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 10.48 (s, 1 H), 8.01 (s, 1 H), 7.67 (dd, 1 H), 7.32 (m, 7
H), 6.77 (ddd, 1 H), 6.08 (s, 1 H), 2.19 (s, 3 H), 2.00 (s, 3 H);
ES-MS m/z 307.1 (MH.sup.+); HPLC RT (min) 2.41.
[0455] The following analogs were made using the method described
above for Example 279.
[0456] In Table 9a, the locant of the R.sup.4 group(s) is defined
as shown. TABLE-US-00018 TABLE 9a ##STR433## LC-MS LC-MS Ex. No.
R.sup.3 R.sup.4 RT (min) [M + H].sup.+ Note* 280 ##STR434## -- 2.54
307.1 c 281 ##STR435## 5-OMe 2.54 337.1 c 282 ##STR436## -- 2.8
327.1 c 283 ##STR437## -- 2.41 323.1 J *Note: Origin of the
aminopyrazole used for the coupling reaction: c = commercial; J =
using the method of Reaction Scheme J as previously described.
[0457] TABLE-US-00019 TABLE 9b Ex. No. IUPAC Name 280
2-{[3-methyl-1-(4-methylphenyl)-1H-pyrazol-5- yl]amino}benzamide
281 5-methoxy-2-{[3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}benzamide 282
2-{[1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5- yl]amino}benzamide
283 2-{[1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-5-
yl]amino}benzamide
[0458] The following examples represent carboxylic acid 1.sup.0
amides that were made from their corresponding carboxylic acids
derived from Ullmann-type coupling.
EXAMPLE 284
Preparation of
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-methoxybenza-
mide
[0459] ##STR438##
[0460] To a solution of
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-methoxybenzo-
ic acid (Example 4) (130 mg, 0.34 mmol) in DMF (5 mL) were added
ammonium chloride (22 mg, 0.41 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79 mg,
0.41 mmol), HOBT hydrate (56 mg, 0.41 mmol), and triethylamine
(0.17 mL, 1.20 mmol). The reaction mixture was stirred for 16 h and
then concentrated under reduced pressure. The residue was purified
by HPLC (45-90% acetonitrile in water) to afford the product (63
mg, 49%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.26 (s, 9H), 1.97 (s, 3H), 3.71 (s, 3H), 6.03 (s,1H), 7.04
(dd, 1H), 7.24-7.37 (m, 6H), 7.44 (s, 1H), 8.05 (s, 1H), 10.01 (s,
1H); ES-MS m/z 379.3 (MH.sup.+); HPLC RT (min) 2.83.
[0461] The following analogs appearing in Tables 10a, 10b, 11a, and
11b were synthesized using the sequence described above for Example
284.
[0462] In Table 10a, the locant of the R.sup.4 group(s) is defined
as shown. TABLE-US-00020 TABLE 10a ##STR439## LC-MS LC-MS Ex. No.
R.sup.1 R.sup.3 R.sup.4 RT (min) [M + H].sup.+ Note* 285 Me
##STR440## 5-OMe 2.39 401.1 J 286 Me ##STR441## 5-OMe 2.31 337.2 J
287 t-Bu i-Pr 4,5-di-OMe 2.63 361.2 I 288 t-Bu ##STR442##
4,5-di-OMe 2.78 409.2 I 289 t-Bu ##STR443## -- 3.17 349.2 I 290
t-Bu ##STR444## 5-OMe 3.08 379.3 I 291 t-Bu ##STR445## -- 2.92
349.2 I 292 tBu ##STR446## -- 3.22 363.2 I 293 tBu ##STR447## --
3.38 349.2 I 294 t-Bu ##STR448## 4,5-di-OMe 3.12 423.2 I 295 t-Bu
##STR449## 5-OMe 3.10 393.2 I 296 t-Bu ##STR450## 4,5-di-OMe 3.06
423.2 I 297 Ph Ph 5-OMe 3.2 385.2 c 298 Ph ##STR451## -- 3.18 369.2
J 299 ##STR452## ##STR453## -- 3.56 401.2 J 300 t-Bu ##STR454## --
3.12 363.2 I *Note: Origin of the aminopyrazole used for the
coupling reaction: c = commercial; I, J = using the methods of
Reaction Schemes I or J as previously described
[0463] TABLE-US-00021 TABLE 10b Ex. No. IUPAC Name 285
5-methoxy-2-({3-methyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-
5-yl}amino)benzamide 286
5-methoxy-2-{[3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzamide 287
2-[(3-tert-butyl-1-isopropyl-1H-pyrazol-5-yl)amino]-4,5-
dimethoxybenzamide 288
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4,5-
dimethoxybenzamide 289
2-{[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}benzamide 290
2-{[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzamide 291
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzamide 292
2-{[3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-
yl]amino}benzamide 293
2-{[3-tert-butyl-1-(3-methylphenyl)-1H-pyrazol-5-
yl]amino}benzamide 294
2-{[3-tert-butyl-1-(2-ethylphenyl)-1H-pyrazol-5-yl]amino}-4,5-
dimethoxybenzamide 295
2-{[3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl]amino}-5-
methoxybenzamide 296
2-{[3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-yl]amino}-
4,5-dimethoxybenzamide 297
2-[(1,3-diphenyl-1H-pyrazol-5-yl)amino]-5-methoxybenzamide 298
2-{[1-(2-methylphenyl)-3-phenyl-1H-pyrazol-5- yl]amino}benzamide
299 2-{[1-(2,4-dimethylphenyl)-3-(4-fluorophenyl)-1H-pyrazol-5-
yl]amino}benzamide 300
2-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-
yl]amino}benzamide
[0464] The following examples represent primary amides that are
derived from a sequence consisting of Buchwald-type coupling,
hydrolysis, and amide formation.
[0465] In Table 11a, the locant of the R.sup.4 group(s) is defined
as shown. TABLE-US-00022 TABLE 11a ##STR455## LC- LC- MS MS Ex. RT
[M + No. R.sup.1 R.sup.3 R.sup.4 (min) H].sup.+ Note* 301 H
##STR456## 5-OMe 2.58 339.1 c 302 t-Bu Bn -- 3.02 349.2 I 303 t-Bu
##STR457## 5-OMe 3.02 393.2 I 304 t-Bu Ph -- 3.23 335.1 I 305 t-Bu
Ph 5-OMe 2.98 365.2 I 306 t-Bu ##STR458## -- 3.35 383.2 I 307
CF.sub.3 ##STR459## -- 3.14 361.1 I *Note: Origin of the
aminopyrazole used for the coupling reaction: c = commercial; I =
using the method of Reaction Scheme I as previously described.
[0466] TABLE-US-00023 TABLE 11b Ex. No. IUPAC Name 301
5-methoxy-2-{[1-(4-methoxyphenyl)-1H-pyrazol-5- yl]amino}benzamide
302 2-[(1-benzyl-3-tert-butyl-1H-pyrazol-5-yl)amino]benzamide 303
2-{[3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-
yl]amino}-5-methoxybenzamide 304
2-[(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)amino]benzamide 305
2-[(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)amino]-5-
methoxybenzamide 306
2-{[3-tert-butyl-1-(4-chloro-2-methylphenyl)-1H-pyrazol-5-
yl]amino}benzamide 307
2-{[1-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-
yl]amino}benzamide
[0467] The following examples represent secondary and tertiary
amides derived from a sequence consisting of Ullmann-type coupling
and subsequent amide formation.
EXAMPLE 308
Preparation of
N-benzyl-5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzamide
[0468] ##STR460##
[0469] A mixture of
5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzoic acid (made by
Ullmann reaction as described in Example 1, 42.0 mg, 0.14 mmol),
benzylamine hydrochloride (23.4 mg, 0.16 mmol), EDCl (31.2 mg, 0.16
mmol), HOBT (22.0 mg, 0.16 mmol), and triethylamine (0.066 mL, 0.48
mmol) in DMF (3 mL) was stirred at rt for 16 h. The reaction was
quenched with water (20 mL) and extracted with ethyl acetate (10
mL). The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. Flash chromatography of the residue over silica gel,
using 20% ethyl acetate/hexane, gave the title compound (16.1 mg,
30%) as a white solid. .sup.1H NMR (300 Hz, DMSO-d.sub.6) .delta.
9.72 (s, 1 H), 9.14 (t, 1 H), 7.57 (d, 1 H), 7.38-7.51 (m, 4 H),
7.16-7.36 (m, 7 H), 6.96-7.06 (m, 2 H), 6.15 (s, 1 H), 4.37 (d, 2
H), 3.70 (s, 3 H); ES-MS m/z 399.1 (MH.sup.+), HPLC RT (min)
3.72.
[0470] The following compounds appearing in Tables 12a, 12b, 13a,
and 13b were prepared using the method described above for Example
308.
[0471] In Table 12a, the locant of the R.sup.4 group(s) is defined
as shown. TABLE-US-00024 TABLE 12a ##STR461## Ex. LC-MS LC-MS No.
R.sup.1 R.sup.3 R.sup.4 R.sup.5 R.sup.6 RT (min) [M + H].sup.+
Note* 309 H Ph 5-OMe Et Et 3.24 365.1 c 310 H Ph 5-SMe Me H 2.82
339.1 c 311 H Ph 5-SMe Et H 3.02 353.1 c 312 H Ph 5-SMe i-Pr H 3.19
367.1 c 313 H Ph 5-SMe Et Et 3.00 381.1 c 314 H Ph 5-SMe ##STR462##
3.54 393.1 c 315 H Ph 5-SMe ##STR463## H 2.89 621.2 c 316 Me
##STR464## -- i-Pr H 3.01 349.3 c 317 Me ##STR465## -- Ph H 3.32
383.2 c 318 Me ##STR466## 5-OMe Me H 2.64 351.1 c 319 Me ##STR467##
5-OMe Et H 2.80 365.1 c 320 Me ##STR468## 5-OMe i-Pr H 2.95 379.1 c
321 Me ##STR469## 5-OMe Ph H 3.26 413.1 c 322 Me ##STR470## --
##STR471## H 3.31 397.1 c 323 Me ##STR472## -- ##STR473## H 3.38
401.2 c 324 Me ##STR474## -- ##STR475## H 2.68 384.1 c 325 Me
##STR476## -- ##STR477## H 2.78 384.1 c *Origin of the
aminopyrazole used for the coupling reaction: c = commercial
[0472] TABLE-US-00025 TABLE 12b Ex. No. IUPAC Name 309
N,N-diethyl-5-methoxy-2-[(1-phenyl-1H-pyrazol-5- yl)amino]benzamide
310 N-methyl-5-(methylthio)-2-[(1-phenyl-1H-pyrazol-5-
yl)amino]benzamide 311
N-ethyl-5-(methylthio)-2-[(1-phenyl-1H-pyrazol-5-
yl)amino]benzamide 312
N-isopropyl-5-(methylthio)-2-[(1-phenyl-1H-pyrazol-5-
yl)amino]benzamide 313
N,N-diethyl-5-(methylthio)-2-[(1-phenyl-1H-pyrazol-5-
yl)amino]benzamide 314
N-[4-(methylthio)-2-(piperidin-1-ylcarbonyl)phenyl]-1-phenyl-
1H-pyrazol-5-amine 315 N-(2-{3-methoxy-4-[(4-methylpiperazin-1-
yl)sulfonyl]phenyl}ethyl)-5-(methylthio)-2-[(1-phenyl-1H-
pyrazol-5-yl)amino]benzamide 316
N-isopropyl-2-{[3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}benzamide 317
2-{[3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]amino}-N-
phenylbenzamide 318
5-methoxy-N-methyl-2-{[3-methyl-1-(4-methylphenyl)-1H-
pyrazol-5-yl]amino}benzamide 319
N-ethyl-5-methoxy-2-{[3-methyl-1-(4-methylphenyl)-
1H-pyrazol-5-yl]amino}benzamide 320
N-isopropyl-5-methoxy-2-{[3-methyl-1-(4-methylphenyl)-
1H-pyrazol-5-yl]amino}benzamide 321
5-methoxy-2-{[3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}-N-phenylbenzamide 322
2-{[3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]amino}-N-(2-
methylphenyl)benzamide 323
N-(2-fluorophenyl)-2-{[3-methyl-1-(4-methylphenyl)-1H-
pyrazol-5-yl]amino}benzamide 324
2-{[3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]amino}-N-
pyridin-4-ylbenzamide 325
2-{[3-methyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]amino}-N-
pyridin-3-ylbenzamide
[0473] The following examples represent secondary and tertiary
amides derived from a sequence consisting of Buchwald-type
coupling, hydrolysis and subsequent amide formation. TABLE-US-00026
TABLE 13a ##STR478## Ex. LC-MS LC-MS No. R.sup.1 R.sup.3 R.sup.5
R.sup.6 RT (min) [M + H].sup.+ 326 Me Ph i-Pr H 2.80 365.1 327 Ph
Ph (CH.sub.2).sub.2OH H 3.56 429.2
[0474] TABLE-US-00027 TABLE 13b Ex. No. IUPAC Name 326
N-isopropyl-5-methoxy-2-[(3-methyl-1-phenyl-1H-pyrazol-5-
yl)amino]benzamide 327
2-[(1,3-diphenyl-1H-pyrazol-5-yl)amino]-N-(2-hydroxyethyl)-
5-methoxybenzamide
[0475] The following examples represent N-acylsulfonamides derived
from the coupling of a carboxylic acid precursor with a
sulfonamide.
EXAMPLE 328
Preparation of
2-[(1,3-diphenyl-1H-pyrazol-5-yl)amino]-5-methoxy-N-[(2-methylphenyl)sulf-
onyl]benzamide
[0476] ##STR479##
[0477] To a solution of
2-[(1,3-diphenyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoic acid
(Example 29) (100 mg, 0.26 mmol) in dichloromethane (3 mL) were
added o-toluenesulfonamide (53.3 mg, 0.31 mmol), EDCl (99.47 mg,
0.52 mmol), DMAP (63.40 mg, 0.52 mmol), and triethylamine (0.127
mL, 0.91 mmol). The reaction mixture was stirred for 2 h, and then
diluted with dichloromethane (10 mL) and water (20 mL). The organic
phase was separated and then washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The residue was purified by silica gel flash
chromatography using 90% EtOAc/hexane, to afford the product (13.9
mg, 10.0%) as a white solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.56 (s, 3H), 3.74 (s, 3H) 6.67 (s, 1H), 7.03 (dd, 2H),
7.26-7.60 (m, 14H), 7.84 (dd, 2H), 7.94 (d, 1H). ES-MS m/z 539.1
(MH.sup.+); HPLC RT (min) 3.71.
[0478] The following compounds were synthesized using the same
method as Example 328. TABLE-US-00028 TABLE 14a ##STR480## LC-MS
LC-MS Ex. No. R RT (min) [M + H].sup.+ 329 ##STR481## 3.70 543.2
330 ##STR482## 3.61 543.2
[0479] TABLE-US-00029 TABLE 14b Ex. No. IUPAC Name 329
2-[(1,3-diphenyl-1H-pyrazol-5-yl)amino]-N-[(3-
fluorophenyl)sulfonyl]-5-methoxybenzamide 330
2-[(1,3-diphenyl-1H-pyrazol-5-yl)amino]-N-[(2-
fluorophenyl)sulfonyl]-5-methoxybenzamide
[0480] The following examples represent oxadiazoles derived from a
transformation of the carboxylic acid group into an oxadiazole
moiety.
EXAMPLE 331
Preparation of
N-[4-methoxy-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-3-methyl-1-phenyl-1-
H-pyrazol-5-amine
[0481] ##STR483##
Step 1: Preparation of N-hydroxy-acetamidine
[0482] ##STR484##
[0483] To a solution of hydroxylamine (2.21 g, 67 mmol) in water (5
mL) was added acetonitrile (3.5 mL, 2.75 g, 67 mmol). Ethanol was
added dropwise until a clear solution resulted. The mixture was
cooled to 0.degree. C., and sodium ethoxide (21.7 g of a 21%
solution in ethanol, 67 mmol) was added. After completion of the
addition, the reaction mixture was warmed to 35.degree. C. and
stirred at that temperature for 3 days. The reaction mixture was
then cooled to rt, and the solid residue (NaCl) was removed by
filtration and washed with acetonitrile. The filtrate and the
washings were combined, the solvents partially evaporated in vacuo,
and conc HCl was added until the pH was .about.1.0. The solvents
were then evaporated until a yellow residue appeared. This residue
was dissolved in hot EtOH and reprecipitated by adding
diethylether. Needle-like crystals appeared from the solution which
were filtered off. The filtrate was saved and kept in the freezer
for several days to get a second crop. The product was obtained as
colorless crystals (1.12 g, 15%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6). .delta. 2.09 (s, 3H), 8.45 (br, s, 1H), 10.64-10.90
(br,1H), 12.2-12.5 (br, 1H).
Step 2: Preparation of
N-[(1Z)-N-hydroxyethanimidoyl]-5-methoxy-2-[(3-methyl-1-phenyl-1H-pyrazol-
-5-yl)amino]benzamide
[0484] ##STR485##
[0485] To a mixture of
2-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]benzoic acid (400 mg,
1.04 mmol) (prepared by the sequence of Buchwald-type coupling and
hydrolysis, similar to Examples 108 and 109), HOAT (186 mg, 1.39
mmol), and EDCl (263 mg, 1.39 mmol) in DMF (7 mL) at -20.degree. C.
was added triethylamine (0.45 mL, 3.25 mmol). After stirring at
that temperature for 15 min, N-hydroxy-acetamidine (305 mg, 2.78
mmol) was added, and the temperature was slowly raised to rt.
Stirring was continued for 16 h, the solvent was evaporated in
vacuo and the residue was partitioned between water and EtOAc. The
layers were separated, and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed successively with 5%
citric acid, saturated aqueous Na.sub.2CO.sub.3 solution and brine,
dried (MgSO.sub.4), filtered, and concentrated to give 147 mg of a
crude solid. This solid was used in the next step with no further
purification. ES-MS m/z 380.1 (MH.sup.+); HPLC RT (min) 2.53.
Step 3: Preparation of
N-[4-methoxy-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-3-methyl-1-phenyl-1-
H-pyrazol-5-amine
[0486] ##STR486##
[0487] To a solution of the crude
N-[(1Z)-N-hydroxyethanimidoyl]-2-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)amin-
o]benzamide (257 mg, 0.41 mmol) in THF (3 mL) was added
(methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess
reagent) (145 mg, 0.61 mmol). The flask was flushed with argon and
refluxed for 3 h under argon. The reaction mixture was the cooled
to rt, filtered through a small plug of silica gel, and the plug
was eluted with EtOAc. The filtrate was concentrated under reduced
pressure, and the residue purified by preparative TLC on silica gel
using EtOAc/Hex (1:2, v/v) to give the title product as a solid
(5.5 mg, 4% overall). .sup.1H NMR (400 MHz, CD.sub.3CN). .delta.
2.30 (s, 3H), 2.32 (s, 3H), 3.82 (s, 3H), 6.16 (s, 1H), 7.09 (dd,
1H), 7.21 (d, 1H), 7.38-7.42 (m, 1H), 7.42-7.50 (m, 3H), 7.50-7.58
(m, 2H), 9.46 (br, s, 1H). ES-MS m/z 362.2 (MH.sup.+); HPLC RT
(min) 3.28.
EXAMPLE 332
Preparation of
N-[4-methoxy-2-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1-phenyl-1H-pyrazol-
-5-amine
[0488] ##STR487##
[0489] Using the method described for Example 331, the title
compound was similarly prepared; ES-MS m/z 348.3 (MH.sup.+); HPLC
RT (min) 3.25.
[0490] The following examples represent sulfonamides made by
coupling of a suitable dibenzylsulfonamide precursor with a
5-aminopyrazole which is followed by deprotection of the two benzyl
groups.
EXAMPLE 333
Preparation of
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzenesulfonam-
ide
[0491] ##STR488##
Step 1: Preparation of N,N-dibenzyl-2-bromobenzenesulfonamide
[0492] ##STR489##
[0493] 2-Bromobenzenesulfonyl chloride (1.0 g, 3.91 mmol) and
triethylamine (455 mg, 0.63 mL, 4.5 mmol) were dissolved in THF (15
mL), and the mixture was cooled to 10.degree. C. Dibenzylamine (849
mg, 0.83 mL, 4.3 mmol) was then added dropwise. The cooling bath
was removed, and the reaction mixture was stirred for 10 h at rt
and then an additional 6 h at 60.degree. C. After cooling to rt,
the solvent was removed under reduced pressure, and ethyl acetate
was added. The organic layer was successively washed with 1 N HCl,
water, semi-saturated aq Na.sub.2CO.sub.3 solution, water, and
brine. After drying with Na.sub.2SO.sub.4 and filtration, the
solvent was removed under reduced pressure to afford the title
compound as off-white crystals (1.44 g, 88%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 4.42 (s, 4H), 7.08 (m, 4H), 7.27 (m, 6H), 7.41
(m, 2H), 7.78 (d, 1H), 8.19 (d, 1H).
Step 2: Preparation of
N,N-dibenzyl-2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}be-
nzenesulfonamide
[0494] ##STR490##
[0495] N,N-Dibenzyl-2-bromobenzenesulfonamide (from Step 1, 333 mg,
0.80 mmol), 3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine
(Intermediate C), cesium carbonate (365 mg, 1.12 mmol),
Pd.sub.2dba.sub.3 (41.4 mg, 0.04 mmol), and BINAP (49.8 mg, 0.08
mmol) were dissolved in toluene (7 mL) under nitrogen, and the
flask was heated at 110.degree. C. for 20 h. The reaction mixture
was cooled to rt, and the solid residue removed by filtration. The
solvent was removed under reduced pressure and the residue purified
via silica gel flash chromatography using EtOAc/hexane (1:12, v/v)
to afford the title compound as a viscous oil (348 mg, 77%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.40 (s, 9H), 2.03 (s,
3H), 3.99 (s, 4H), 6.10 (s, 1H), 6.88 (m, 4 H), 7.07 (m, 1H),
7.10-7.27 (m, 10H), 7.38 (d, 1H), 7.47 (t, 1H), 7.71 (s, 1H), 7.77
(d, 1H). ES-MS m/z 565.4 (MH).sup.+; HPLC RT (min) 4.37.
Step 3. Preparation of
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzenesulfonam-
ide
[0496] ##STR491##
[0497]
N,N-Dibenzyl-2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]a-
mino}benzene-sulfonamide (from Step 2, 240 mg, 0.42 mmol) was added
to conc H.sub.2SO.sub.4 (3 mL), and the mixture was vigorously
stirred for 20 min. The mixture was poured onto ice, and conc NaOH
solution was added until a pH of .about.7.5 was reached. The
aqueous layer was extracted 2.times. with EtOAc, and the combined
organic layers were dried with Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure. Purification by silica gel
flash chromatography using EtOAc/hexane (1:3, v/v) afforded the
title compound as a white solid (104 mg, 64%). .sup.1H NMR (400
MHz, CD.sub.2Cl.sub.2) .delta. 1.39 (s, 9H), 2.09 (s, 3H), 4.50
(br, 2H), 6.20 (s, 1H), 7.94 (t, 1H), 7.23 (m, 4H), 7.34 (m, 2H),
7.45 (t, 1H), 7.73 (d, 1H). ES-MS m/z 385.2 (MH.sup.+); HPLC RT
(min) 3.11.
EXAMPLE 334
Preparation of
2-{[1-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]amino}benzenes-
ulfonamide
[0498] ##STR492##
[0499] Using the method described for Example 333, the title
compound was similarly prepared; ES-MS m/z 397.1 (MH.sup.+); HPLC
RT (min) 3.18.
EXAMPLE 335
Preparation of
2-{[4-iodo-1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-yl]amino}-5-
-methylbenzoic acid
[0500] ##STR493##
[0501] To a solution of
5-methyl-2-{[1-(2-methylphenyl)-3-(4-methylphenyl)-1H-pyrazol-5-yl]amino}-
benzoic acid (Example 65), (49.5 mg, 0.13 mmol) in AcOH/DCM (1:1,
v/v) (2 mL) was added a solution of NIS (28 mg, 0.13 mmol) in DCM
(1 mL). The reaction was stirred at rt for 3 h. Water (1 mL) was
added to the reaction mixture. The water layer was extracted with
DCM (2 mL), and the combined organic layers were washed with sodium
sulfite and brine, and concentrated under reduced pressure. The
crude product was subjected to HPLC purification with a gradient
elution from 30% to 95% acetonitrile in water to afford 9.1 mg
(14%) of the title compound. .sup.1H NMR (300 MHz,
CD.sub.2Cl.sub.2) .delta. 8.88 (s, 1 H), 7.85 (d, 2 H), 7.74 (s, 1
H), 7.18-7.32 (m, 7 H), 6.58 (d, 1 H), 2.41 (s 3 H), 2 25 (s, 3 H),
2 21 (s, 3 H). ES-MS m/z 524.1 (MH.sup.+); HPLC RT (min) 4.35.
EXAMPLE 336
Preparation of
2-{[3-tert-butyl-4-fluoro-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-met-
hoxybenzoic acid
[0502] ##STR494##
[0503] To a solution of
2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-methoxybenzoic
acid (Example 4), (49 mg, 0.13 mmol) in CH.sub.3CN ( 1 mL) was
added [(1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate)] (SELECTFLUOR.RTM.) (46 mg, 0.13 mmol), and
the mixture was stirred at rt for 16 h. The solid was filtered off
and the filtrate was subjected to HPLC purification with a gradient
elution from 10% to 90% acetonitrile in water to afford 4 mg (8%)
of the desired product. .sup.1H NMR (300 MHz, CD.sub.2Cl.sub.2)
.delta. 8.62 (s, 1 H), 7.40 (d, 1 H), 7.16-7.35 (m, 4 H), 7.05 (dd,
1 H), 7.76 (dd, 1 H), 3.75 (s, 3 H), 2.12 (s, 3 H), 1.40 (s, 9 H).
ES-MS m/z 398.2 (MH.sup.+); HPLC RT (min) 4.06.
EXAMPLE 337
Preparation of methyl
5-methoxy-2-{methyl[3-methyl-1-(2-methylphenyl)-4-phenyl-1H-pyrazol-5-yl]-
amino}benzoate
[0504] ##STR495##
Step 1: Preparation of methyl
5-methoxy-2-{methyl[3-methyl-1-(2-methylphenyl)-4-phenyl-1H-pyrazol-5-yl]-
amino}benzoate
[0505] ##STR496##
[0506] To a suspension of NaH (60% dispersion in mineral oil; 0.28
g, 7 mmol) in DMF (10 mL) at rt was added a solution of methyl
5-methoxy-2-{[3-methyl-1-(2-methylphenyl)-4-phenyl-1H-pyrazol-5-yl]amino}-
benzoate (1.495 g, 3.5 mmol) in DMF (15 mL) dropwise. The mixture
was stirred for 0.5 h, and then iodomethane (0.88 mL, 14 mmol) was
added. The reaction mixture was stirred at rt for 1 h. Water (100
mL) was cautiously added, and the mixture was extracted with ethyl
acetate (25 mL.times.3). The combined organic phases were washed
with a saturated solution of sodium bicarbonate (50 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The residue was purified by silica gel flash
chromatography (EtOAc/hexanes 1:12) to afford the title compound
(1.18 g, 68%) as a pale yellow solid. .sup.1H NMR (400 MHz,
acetone-d.sub.6) .delta. 2.1 (s, 3H), 2.3 (s, 3H), 2.9 (s, 3H),
3.65 (s, 3H), 3.7 (s, 3H), 6.87-6.92 (m, 2H), 6.94-6.98 (m, 1H),
7.03-7.09 (m, 1H), 7.15-7.27 (m, 4H), 7.30-7.36 (m, 2H), 7.39-7.43
(m, 2H). ES-MS m/z 442.3 (MH.sup.+); HPLC RT (min) 3.96.
Step 2: Preparation of
5-methoxy-2-{methyl[3-methyl-1-(2-methylphenyl)-4-phenyl-1H-pyrazol-5-yl]-
amino}benzoic acid
[0507] ##STR497##
[0508] To a solution of the compound of step 1 (60 mg, 0.129 mmol)
in a mixture of THF (4 mL), water (4 mL), and MeOH (2 mL), was
added LiOH (32 mg, 1.32 mmol). The reaction mixture was vigorously
stirred for 24 h, after which it was concentrated under reduced
pressure, and diluted with water (10 mL). The solution was then
acidified to pH .about.1 using 1 N HCl, and then extracted with
CH.sub.2Cl.sub.2 (3.times.20 mL). The combined organic layers were
dried (Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. The residue was then purified by preparative HPLC to
afford the title compound (32 mg, 58%) as a white solid. .sup.1H
NMR (400 MHz, acetone-d.sub.6) .delta. 2.12 (s, 3H), 2.23 (s, 3H),
2.9 (s, 3H), 3.74 (s, 3H), 6.87-6.90 (m, 2H), 6.92-6.98 (m, 1H),
7.03-7.11 (m, 1H), 7.16-7.27 (m, 4H), 7.30-7.36 (m, 2H), 7.40-7.45
(m, 2H); ES-MS m/z 428.3 (MH.sup.+); HPLC RT (min) 3.54.
EXAMPLE 338
Preparation of
2-[[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl](methyl)amino]-5--
methoxybenzoic acid
[0509] ##STR498##
[0510] This compound was prepared using the procedure as described
in Example 337. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 1.40 (s,
9H), 1.95 (s, 6H), 3.26 (s, 3H), 3.74 (s, 3H), 6.81 (dd, 1H), 6.93
(m, 4H), 7.13 (m, 1H), 7.26 (d, 1H). ES-MS m/z 408.3 (MH.sup.+);
HPLC RT (min) 2.65.
[0511] Using the procedures as described in Examples 108 and 109,
the following compounds can be made. The aminopyrazoles used in the
coupling reactions can be made as described for Intermediate B
starting from commercially available carboxylic acid methyl or
ethyl esters. TABLE-US-00030 TABLE 15 ##STR499## Ex. No. R.sup.1
R.sup.2 R.sup.3 R.sup.4 IUPAC name 339 ##STR500## H ##STR501##
5-OMe 2-({1-(2,6-dimethylphenyl)-3-[1-
(trifluoromethyl)cyclopropyl]-1H-
pyrazol-5-yl}amino)-5-methoxybenzoic acid 340 ##STR502## H
##STR503## 5-OMe 5-methoxy-2-({1-(2-methylphenyl)-3-
[(trimethylsilyl)methyl]-1H-pyrazol-5- yl}amino)benzoic acid 341
##STR504## H ##STR505## 5-OMe 2-{[3-benzyl-1-(2-methylphenyl)-1H-
pyrazol-5-yl]amino}-5-methoxybenzoic acid 342 ##STR506## H
##STR507## 5-OMe 2-{[3-(4-fluorobenzyl)-1-(2-
methylphenyl)-1H-pyrazol-5-yl]amino}- 5-methoxybenzoic acid 343
##STR508## H ##STR509## 5-OMe 2-{[3-[(2E)-but-2-en-1-yl]-1-(2-
methylphenyl)-1H-pyrazol-5-yl]amino}- 5-methoxybenzoic acid 344
##STR510## H ##STR511## 5-OMe 5-methoxy-2-({1-(2-methylphenyl)-3-
[(1E)-prop-1-en-1-yl]-1H-pyrazol-5- yl}amino)benzoic acid 345
##STR512## H ##STR513## 5-OMe 5-methoxy-2-{[1-(2-methylphenyl)-3-
prop-1-yn-1-yl-1H-pyrazol-5- yl]amino}benzoic acid
[0512] The compounds of the present invention may be employed in
the treatment of diabetes, including both type 1 and type 2
diabetes (non-insulin dependent diabetes mellitus). Such treatment
may also delay the onset of diabetes and diabetic complications.
The compounds may be used to prevent subjects with impaired glucose
tolerance from proceeding to develop type 2 diabetes. Other
diseases and conditions that may be treated or prevented using
compounds of the invention in methods of the invention include:
Maturity-Onset Diabetes of the Young (MODY) (Herman, et al.,
Diabetes 43:40, 1994); Latent Autoimmune Diabetes Adult (LADA)
(Zimmet, et al., Diabetes Med. 11:299, 1994); impaired glucose
tolerance (IGT) (Expert Committee on Classification of Diabetes
Mellitus, Diabetes Care 22 (Supp. 1):S5, 1999); impaired fasting
glucose (IFG) (Charles, et al., Diabetes 40:796, 1991); gestational
diabetes (Metzger, Diabetes, 40:197, 1991); and metabolic syndrome
X.
[0513] The compounds of the present invention may also be effective
in such disorders as obesity, and in the treatment of
atherosclerotic disease, hyperlipidemia, hypercholesteremia, low
HDL levels, hypertension, cardiovascular disease (including
atherosclerosis, coronary heart disease, coronary artery disease,
and hypertension), cerebrovascular disease and peripheral vessel
disease.
[0514] The compounds of the present invention may also be useful
for treating physiological disorders related to, for example, cell
differentiation to produce lipid accumulating cells, regulation of
insulin sensitivity and blood glucose levels, which are involved
in, for example, abnormal pancreatic beta-cell function, insulin
secreting tumors and/or autoimmune hypoglycemia due to
autoantibodies to insulin, autoantibodies to the insulin receptor,
or autoantibodies that are stimulatory to beta-cells), macrophage
differentiation which leads to the formation of atherosclerotic
plaques, inflammatory response, carcinogenesis, hyperplasia,
adipocyte gene expression, adipocyte differentiation, reduction in
the pancreatic beta-cell mass, insulin secretion, tissue
sensitivity to insulin, liposarcoma cell growth, polycystic ovarian
disease, chronic anovulation, hyperandrogenism, progesterone
production, steroidogenesis, redox potential and oxidative stress
in cells, nitric oxide synthase (NOS) production, increased gamma
glutamyl transpeptidase, catalase, plasma triglycerides, HDL, and
LDL cholesterol levels, and the like.
[0515] Compounds of the invention may also be used in methods of
the invention to treat secondary causes of diabetes (Expert
Committee on Classification of Diabetes Mellitus, Diabetes Care 22
(Supp. 1 ):S5, 1999). Such secondary causes include glucocorticoid
excess, growth hormone excess, pheochromocytoma, and drug-induced
diabetes. Drugs that may induce diabetes include, but are not
limited to, pyriminil, nicotinic acid, glucocorticoids, phenytoin,
thyroid hormone, .beta.-adrenergic agents, .alpha.-interferon and
drugs used to treat HIV infection.
[0516] The compounds of the present invention may be used alone or
in combination with additional therapies and/or compounds known to
those skilled in the art in the treatment of diabetes and related
disorders. Alternatively, the methods and compounds described
herein may be used, partially or completely, in combination
therapy.
[0517] The compounds of the invention may also be administered in
combination with other known therapies for the treatment of
diabetes, including PPAR agonists, sulfonylurea drugs,
non-sulfonylurea secretagogues, .alpha.-glucosidase inhibitors,
insulin sensitizers, insulin secretagogues, hepatic glucose output
lowering compounds, insulin and anti-obesity drugs. Such therapies
may be administered prior to, concurrently with or following
administration of the compounds of the invention. Insulin includes
both long and short acting forms and formulations of insulin. PPAR
agonist may include agonists of any of the PPAR subunits or
combinations thereof. For example, PPAR agonist may include
agonists of PPAR-.alpha., PPAR-.gamma., PPAR-.delta. or any
combination of two or three of the subunits of PPAR. PPAR agonists
include, for example, rosiglitazone and pioglitazone. Sulfonylurea
drugs include, for example, glyburide, glimepiride, chlorpropamide,
and glipizide. .alpha.-glucosidase inhibitors that may be useful in
treating diabetes when administered with a compound of the
invention include acarbose, miglitol and voglibose. Insulin
sensitizers that may be useful in treating diabetes include
thiazolidinediones and non-thiazolidinediones. Hepatic glucose
output lowering compounds that may be useful in treating diabetes
when administered with a compound of the invention include
metformin, such as Glucophage and Glucophage XR. Insulin
secretagogues that may be useful in treating diabetes when
administered with a compound of the invention include sulfonylurea
and non-sulfonylurea drugs: GLP-1, GIP, secretin, nateglinide,
meglitinide, repaglinide, glibenclamide, glimepiride,
chlorpropamide, glipizide. GLP-1 includes derivatives of GLP-1 with
longer half-lives than native GLP-1, such as, for example,
fatty-acid derivatized GLP-1 and exendin. In one embodiment of the
invention, compounds of the invention are used in combination with
insulin secretagogues to increase the sensitivity of pancreatic
beta-cells to the insulin secretagogue.
[0518] Compounds of the invention may also be used in methods of
the invention in combination with anti-obesity drugs. Anti-obesity
drugs include .beta.-3 agonists, CB-1 antagonists, appetite
suppressants, such as, for example, sibutramine (Meridia), and
lipase inhibitors, such as, for example, orlistat (Xenical).
[0519] Compounds of the invention may also be used in methods of
the invention in combination with drugs commonly used to treat
lipid disorders in diabetic patients. Such drugs include, but are
not limited to, HMG-CoA reductase inhibitors, nicotinic acid, bile
acid sequestrants, and fibric acid derivatives. Compounds of the
invention may also be used in combination with anti-hypertensive
drugs, such as, for example, .beta.-blockers and ACE
inhibitors.
[0520] Such co-therapies may be administered in any combination of
two or more drugs (e.g., a compound of the invention in combination
with an insulin sensitizer and an anti-obesity drug). Such
co-therapies may be administered in the form of pharmaceutical
compositions, as described above.
[0521] As used herein, various terms are defined below.
[0522] When introducing elements of the present invention or the
preferred embodiment(s) thereof, the articles "a," "an," "the," and
"said" are intended to mean that there are one or more of the
elements. The terms "comprising," "including," and "having" are
intended to be inclusive and mean that there may be additional
elements other than the listed elements.
[0523] The term "subject" as used herein includes mammals (e.g.,
humans and animals).
[0524] The term "treatment" includes any process, action,
application, therapy, or the like, wherein a subject, including a
human being, is provided medical aid with the object of improving
the subject's condition, directly or indirectly, or slowing the
progression of a condition or disorder in the subject.
[0525] The term "combination therapy" or "co-therapy" means the
administration of two or more therapeutic agents to treat a
diabetic condition and/or disorder. Such administration encompasses
co-administration of two or more therapeutic agents in a
substantially simultaneous manner, such as in a single capsule
having a fixed ratio of active ingredients or in multiple, separate
capsules for each inhibitor agent. In addition, such administration
encompasses use of each type of therapeutic agent in a sequential
manner.
[0526] The phrase "therapeutically effective" means the amount of
each agent administered that will achieve the goal of improvement
in a diabetic condition or disorder severity, while avoiding or
minimizing adverse side effects associated with the given
therapeutic treatment.
[0527] The term "pharmaceutically acceptable" means that the
subject item is appropriate for use in a pharmaceutical
product.
[0528] Based on well known assays used to determine the efficacy
for treatment of conditions identified above in mammals, and by
comparison of these results with the results of known medicaments
that are used to treat these conditions, the effective dosage of
the compounds of this invention can readily be determined for
treatment of each desired indication. The amount of the active
ingredient (e.g., compounds) to be administered in the treatment of
one of these conditions can vary widely according to such
considerations as the particular compound and dosage unit employed,
the mode of administration, the period of treatment, the age and
sex of the patient treated, and the nature and extent of the
condition treated.
[0529] The total amount of the active ingredient to be administered
may generally range from about 0.0001 mg/kg to about 200 mg/kg, and
preferably from about 0.01 mg/kg to about 200 mg/kg body weight per
day. A unit dosage may contain from about 0.05 mg to about 1500 mg
of active ingredient, and may be administered one or more times per
day. The daily dosage for administration by injection, including
intravenous, intramuscular, subcutaneous, and parenteral
injections, and use of infusion techniques may be from about 0.01
to about 200 mg/kg. The daily rectal dosage regimen may be from
0.01 to 200 mg/kg of total body weight. The transdermal
concentration may be that required to maintain a daily dose of from
0.01 to 200 mg/kg.
[0530] Of course, the specific initial and continuing dosage
regimen for each patient will vary according to the nature and
severity of the condition as determined by the attending
diagnostician, the activity of the specific compound employed, the
age of the patient, the diet of the patient, time of
administration, route of administration, rate of excretion of the
drug, drug combinations, and the like. The desired mode of
treatment and number of doses of a compound of the present
invention may be ascertained by those skilled in the art using
conventional treatment tests.
[0531] The compounds of this invention may be utilized to achieve
the desired pharmacological effect by administration to a patient
in need thereof in an appropriately formulated pharmaceutical
composition. A patient, for the purpose of this invention, is a
mammal, including a human, in need of treatment for a particular
condition or disease. Therefore, the present invention includes
pharmaceutical compositions which are comprised of a
pharmaceutically acceptable carrier and a therapeutically effective
amount of a compound. A pharmaceutically acceptable carrier is any
carrier which is relatively non-toxic and innocuous to a patient at
concentrations consistent with effective activity of the active
ingredient so that any side effects ascribable to the carrier do
not vitiate the beneficial effects of the active ingredient. A
therapeutically effective amount of a compound is that amount which
produces a result or exerts an influence on the particular
condition being treated. The compounds described herein may be
administered with a pharmaceutically-acceptable carrier using any
effective conventional dosage unit forms, including, for example,
immediate and timed release preparations, orally, parenterally,
topically, or the like.
[0532] For oral administration, the compounds may be formulated
into solid or liquid preparations such as, for example, capsules,
pills, tablets, troches, lozenges, melts, powders, solutions,
suspensions, or emulsions, and may be prepared according to methods
known to the art for the manufacture of pharmaceutical
compositions. The solid unit dosage forms may be a capsule which
can be of the ordinary hard- or soft-shelled gelatin type
containing, for example, surfactants, lubricants, and inert fillers
such as lactose, sucrose, calcium phosphate, and corn starch.
[0533] In another embodiment, the compounds of this invention may
be tableted with conventional tablet bases such as lactose,
sucrose, and cornstarch in combination with binders such as acacia,
cornstarch, or gelatin; disintegrating agents intended to assist
the break-up and dissolution of the tablet following administration
such as potato starch, alginic acid, corn starch, and guar gum;
lubricants intended to improve the flow of tablet granulation and
to prevent the adhesion of tablet material to the surfaces of the
tablet dies and punches, for example, talc, stearic acid, or
magnesium, calcium or zinc stearate; dyes; coloring agents; and
flavoring agents intended to enhance the aesthetic qualities of the
tablets and make them more acceptable to the patient. Suitable
excipients for use in oral liquid dosage forms include diluents
such as water and alcohols, for example, ethanol, benzyl alcohol,
and polyethylene alcohols, either with or without the addition of a
pharmaceutically acceptable surfactant, suspending agent, or
emulsifying agent. Various other materials may be present as
coatings or to otherwise modify the physical form of the dosage
unit. For instance tablets, pills or capsules may be coated with
shellac, sugar or both.
[0534] Dispersible powders and granules are suitable for the
preparation of an aqueous suspension. They provide the active
ingredient in admixture with a dispersing or wetting agent, a
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, those sweetening, flavoring and coloring agents described
above, may also be present.
[0535] The pharmaceutical compositions of this invention may also
be in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil such as liquid paraffin or a mixture of vegetable
oils. Suitable emulsifying agents may be (1) naturally occurring
gums such as gum acacia and gum tragacanth, (2) naturally occurring
phosphatides such as soy bean and lecithin, (3) esters or partial
esters derived from fatty acids and hexitol anhydrides, for
example, sorbitan monooleate, and (4) condensation products of said
partial esters with ethylene oxide, for example, polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening and
flavoring agents.
[0536] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil such as, 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 such as, for example, beeswax, hard paraffin, or cetyl
alcohol. The 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.
[0537] Syrups and elixirs may be formulated with sweetening agents
such as, for example, glycerol, propylene glycol, sorbitol, or
sucrose. Such formulations may also contain a demulcent, and
preservative, flavoring and coloring agents.
[0538] The compounds of this invention may also be administered
parenterally, that is, subcutaneously, intravenously,
intramuscularly, or interperitoneally, as injectable dosages of the
compound in a physiologically acceptable diluent with a
pharmaceutical carrier which may be a sterile liquid or mixture of
liquids such as water, saline, aqueous dextrose and related sugar
solutions; an alcohol such as ethanol, isopropanol, or hexadecyl
alcohol; glycols such as propylene glycol or polyethylene glycol;
glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol,
ethers such as poly(ethyleneglycol) 400; an oil; a fatty acid; a
fatty acid ester or glyceride; or an acetylated fatty acid
glyceride with or without the addition of a pharmaceutically
acceptable surfactant such as a soap or a detergent, suspending
agent such as pectin, carbomers, methycellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose, or
emulsifying agent and other pharmaceutical adjuvants.
[0539] Illustrative of oils which can be used in the parenteral
formulations of this invention are those of petroleum, animal,
vegetable, or synthetic origin, for example, peanut oil, soybean
oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum,
and mineral oil. Suitable fatty acids include oleic acid, stearic
acid, and isostearic acid. Suitable fatty acid esters are, for
example, ethyl oleate and isopropyl myristate. Suitable soaps
include fatty alkali metal, ammonium, and triethanolamine salts and
suitable detergents include cationic detergents, for example,
dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and
alkylamine acetates; anionic detergents, for example, alkyl, aryl,
and olefin sulfonates, alkyl, olefin, ether, and monoglyceride
sulfates, and sulfosuccinates; nonionic detergents, for example,
fatty amine oxides, fatty acid alkanolamides, and
polyoxyethylenepolypropylene copolymers; and amphoteric detergents,
for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline
quarternary ammonium salts, as well as mixtures.
[0540] The parenteral compositions of this invention may typically
contain from about 0.5% to about 25% by weight of the active
ingredient in solution. Preservatives and buffers may also be used
advantageously. In order to minimize or eliminate irritation at the
site of injection, such compositions may contain a non-ionic
surfactant having a hydrophile-lipophile balance (HLB) of from
about 12 to about 17. The quantity of surfactant in such
formulation ranges from about 5% to about 15% by weight. The
surfactant can be a single component having the above HLB or can be
a mixture of two or more components having the desired HLB.
[0541] Illustrative of surfactants used in parenteral formulations
are the class of polyethylene sorbitan fatty acid esters, for
example, sorbitan monooleate and the high molecular weight adducts
of ethylene oxide with a hydrophobic base, formed by the
condensation of propylene oxide with propylene glycol.
[0542] The pharmaceutical compositions may be in the form of
sterile injectable aqueous suspensions. Such suspensions may be
formulated according to known methods using suitable dispersing or
wetting agents and suspending agents such as, for example, sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents which may be a naturally occurring phosphatide such
as lecithin, a condensation product of an alkylene oxide with a
fatty acid, for example, polyoxyethylene stearate, a condensation
product of ethylene oxide with a long chain aliphatic alcohol, for
example, heptadecaethyleneoxycetanol, a condensation product of
ethylene oxide with a partial ester derived form a fatty acid and a
hexitol such as polyoxyethylene sorbitol monooleate, or a
condensation product of an ethylene oxide with a partial ester
derived from a fatty acid and a hexitol anhydride, for example
polyoxyethylene sorbitan monooleate.
[0543] The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent. Diluents and solvents that may be
employed are, for example, water, Ringer's solution, and isotonic
sodium chloride solution. In addition, sterile fixed oils are
conventionally employed as solvents or suspending media. For this
purpose, any bland, fixed oil may be employed including synthetic
mono or diglycerides. In addition, fatty acids such as oleic acid
may be used in the preparation of injectables.
[0544] A composition of the invention may also be administered in
the form of suppositories for rectal administration of the drug.
These compositions may be prepared by mixing the drug (e.g.,
compound) with a suitable non-irritation 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
material are, for example, cocoa butter and polyethylene
glycol.
[0545] Another formulation employed in the methods of the present
invention employs transdermal delivery devices ("patches"). Such
transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds of the present invention in
controlled amounts. The construction and use of transdermal patches
for the delivery of pharmaceutical agents is well known in the art
(see, e.g., U.S. Pat. No. 5,023,252, incorporated herein by
reference). Such patches may be constructed for continuous,
pulsatile, or on demand delivery of pharmaceutical agents.
[0546] It may be desirable or necessary to introduce the
pharmaceutical composition to the patient via a mechanical delivery
device. The construction and use of mechanical delivery devices for
the delivery of pharmaceutical agents is well known in the art. For
example, direct techniques for administering a drug directly to the
brain usually involve placement of a drug delivery catheter into
the patient's ventricular system to bypass the blood-brain barrier.
One such implantable delivery system, used for the transport of
agents to specific anatomical regions of the body, is described in
U.S. Pat. No. 5,011,472, incorporated herein by reference.
[0547] The compositions of the invention may also contain other
conventional pharmaceutically acceptable compounding ingredients,
generally referred to as carriers or diluents, as necessary or
desired. Any of the compositions of this invention may be preserved
by the addition of an antioxidant such as ascorbic acid or by other
suitable preservatives. Conventional procedures for preparing such
compositions in appropriate dosage forms can be utilized.
[0548] Commonly used pharmaceutical ingredients which may be used
as appropriate to formulate the composition for its intended route
of administration include: acidifying agents, for example, but are
not limited to, acetic acid, citric acid, fumaric acid,
hydrochloric acid, nitric acid; and alkalinizing agents such as,
but are not limited to, ammonia solution, ammonium carbonate,
diethanolamine, monoethanolamine, potassium hydroxide, sodium
borate, sodium carbonate, sodium hydroxide, triethanolamine,
trolamine.
[0549] Other pharmaceutical ingredients include, for example, but
are not limited to, adsorbents (e.g., powdered cellulose and
activated charcoal); aerosol propellants (e.g., carbon dioxide,
CCl.sub.2F.sub.2, F.sub.2ClC--CClF.sub.2 and CClF.sub.3); air
displacement agents (e.g., nitrogen and argon); antifungal
preservatives (e.g., benzoic acid, butylparaben, ethylparaben,
methylparaben, propylparaben, sodium benzoate); antimicrobial
preservatives (e.g., benzalkonium chloride, benzethonium chloride,
benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol,
phenylethyl alcohol, phenylmercuric nitrate and thimerosal);
antioxidants (e.g., ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid,
monothioglycerol, propyl gallate, sodium ascorbate, sodium
bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);
binding materials (e.g., block polymers, natural and synthetic
rubber, polyacrylates, polyurethanes, silicones and
styrene-butadiene copolymers); buffering agents (e.g., potassium
metaphosphate, potassium phosphate monobasic, sodium acetate,
sodium citrate anhydrous and sodium citrate dihydrate); carrying
agents (e.g., acacia syrup, aromatic syrup, aromatic elixir, cherry
syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil,
peanut oil, sesame oil, bacteriostatic sodium chloride injection
and bacteriostatic water for injection); chelating agents (e.g.,
edetate disodium and edetic acid); colorants (e.g., FD&C Red
No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue
No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No.
8, caramel and ferric oxide red); clarifying agents (e.g.,
bentonite); emulsifying agents (but are not limited to, acacia,
cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin,
sorbitan monooleate, polyethylene 50 stearate); encapsulating
agents (e.g., gelatin and cellulose acetate phthalate); flavorants
(e.g., anise oil, cinnamon oil, cocoa, menthol, orange oil,
peppermint oil and vanillin); humectants (e.g., glycerin, propylene
glycol and sorbitol); levigating agents (e.g., mineral oil and
glycerin); oils (e.g., arachis oil, mineral oil, olive oil, peanut
oil, sesame oil and vegetable oil); ointment bases (e.g., lanolin,
hydrophilic ointment, polyethylene glycol ointment, petrolatum,
hydrophilic petrolatum, white ointment, yellow ointment, and rose
water ointment); penetration enhancers (transdermal delivery)
(e.g., monohydroxy or polyhydroxy alcohols, saturated or
unsaturated fatty alcohols, saturated or unsaturated fatty esters,
saturated or unsaturated dicarboxylic acids, essential oils,
phosphatidyl derivatives, cephalin, terpenes, amides, ethers,
ketones and ureas); plasticizers (e.g., diethyl phthalate and
glycerin); solvents (e.g., alcohol, corn oil, cottonseed oil,
glycerin, isopropyl alcohol, mineral oil, oleic acid, peanut oil,
purified water, water for injection, sterile water for injection
and sterile water for irrigation); stiffening agents (e.g., cetyl
alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl
alcohol, white wax and yellow wax); suppository bases (e.g., cocoa
butter and polyethylene glycols (mixtures)); surfactants (e.g.,
benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80,
sodium lauryl sulfate and sorbitan monopalmitate); suspending
agents (e.g., agar, bentonite, carbomers, carboxymethylcellulose
sodium, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth
and veegum); sweetening e.g., aspartame, dextrose, glycerin,
mannitol, propylene glycol, saccharin sodium, sorbitol and
sucrose); tablet anti-adherents (e.g., magnesium stearate and
talc); tablet binders (e.g., acacia, alginic acid,
carboxymethylcellulose sodium, compressible sugar, ethylcellulose,
gelatin, liquid glucose, methylcellulose, povidone and
pregelatinized starch); tablet and capsule diluents (e.g., dibasic
calcium phosphate, kaolin, lactose, mannitol, microcrystalline
cellulose, powdered cellulose, precipitated calcium carbonate,
sodium carbonate, sodium phosphate, sorbitol and starch); tablet
coating agents (e.g., liquid glucose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose, ethylcellulose, cellulose acetate phthalate and
shellac); tablet direct compression excipients (e.g., dibasic
calcium phosphate); tablet disintegrants (e.g., alginic acid,
carboxymethylcellulose calcium, microcrystalline cellulose,
polacrillin potassium, sodium alginate, sodium starch glycollate
and starch); tablet glidants (e.g., colloidal silica, corn starch
and talc); tablet lubricants (e.g., calcium stearate, magnesium
stearate, mineral oil, stearic acid and zinc stearate);
tablet/capsule opaquants (e.g., titanium dioxide); tablet polishing
agents (e.g., carnuba wax and white wax); thickening agents (e.g.,
beeswax, cetyl alcohol and paraffin); tonicity agents (e.g.,
dextrose and sodium chloride); viscosity increasing agents (e.g.,
alginic acid, bentonite, carbomers, carboxymethylcellulose sodium,
methylcellulose, povidone, sodium alginate and tragacanth); and
wetting agents (e.g., heptadecaethylene oxycetanol, lecithins,
polyethylene sorbitol monooleate, polyoxyethylene sorbitol
monooleate, and polyoxyethylene stearate).
[0550] The compounds described herein may be administered as the
sole pharmaceutical agent or in combination with one or more other
pharmaceutical agents where the combination causes no unacceptable
adverse effects. For example, the compounds of this invention can
be combined with known anti-obesity, or with known antidiabetic or
other indication agents, and the like, as well as with admixtures
and combinations thereof.
[0551] The compounds described herein may also be utilized, in free
base form or in compositions, in research and diagnostics, or as
analytical reference standards, and the like. Therefore, the
present invention includes compositions which are comprised of an
inert carrier and an effective amount of a compound identified by
the methods described herein, or a salt or ester thereof. An inert
carrier is any material which does not interact with the compound
to be carried and which lends support, means of conveyance, bulk,
traceable material, and the like to the compound to be carried. An
effective amount of compound is that amount which produces a result
or exerts an influence on the particular procedure being
performed.
[0552] Formulations suitable for subcutaneous, intravenous,
intramuscular, and the like; suitable pharmaceutical carriers; and
techniques for formulation and administration may be prepared by
any of the methods well known in the art (see, e.g., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.,
20.sup.th edition, 2000).
[0553] The following examples are presented to illustrate the
invention described herein, but should not be construed as limiting
the scope of the invention in any way.
[0554] Capsule Formulation TABLE-US-00031 A capsule formula is
prepared from: Compound of this invention 10 mg Starch 109 mg
Magnesium stearate 1 mg
[0555] The components are blended, passed through an appropriate
mesh sieve, and filled into hard gelatin capsules.
[0556] Tablet Formulation TABLE-US-00032 A tablet is prepared from:
Compound of this invention 25 mg Cellulose, microcrystalline 200 mg
Colloidal silicon dioxide 10 mg Stearic acid 5.0 mg
[0557] The ingredients are mixed and compressed to form tablets.
Appropriate aqueous and non-aqueous coatings may be applied to
increase palatability, improve elegance and stability or delay
absorption.
[0558] Sterile IV Solution
[0559] A mg/mL solution of the desired compound of this invention
is made using sterile, injectable water, and the pH is adjusted if
necessary. The solution is diluted for administration with sterile
5% dextrose and is administered as an IV infusion.
[0560] Intramuscular Suspension
[0561] The following intramuscular suspension is prepared:
TABLE-US-00033 Compound of this invention 50 .mu.g/mL Sodium
carboxymethylcellulose 5 mg/mL TWEEN 80 4 mg/mL Sodium chloride 9
mg/mL Benzyl alcohol 9 mg/mL
[0562] The suspension is administered intramuscularly.
[0563] Hard Shell Capsules
[0564] A large number of unit capsules are prepared by filling
standard two-piece hard galantine capsules each with powdered
active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg
of magnesium stearate.
[0565] Soft Gelatin Capsules
[0566] A mixture of active ingredient in a digestible oil such as
soybean oil, cottonseed oil, or olive oil is prepared and injected
by means of a positive displacement pump into molten gelatin to
form soft gelatin capsules containing the active ingredient. The
capsules are washed and dried. The active ingredient can be
dissolved in a mixture of polyethylene glycol, glycerin and
sorbitol to prepare a water miscible medicine mix.
[0567] Immediate Release Tablets/Capsules
[0568] These are solid oral dosage forms made by conventional and
novel processes. These units are taken orally without water for
immediate dissolution and delivery of the medication. The active
ingredient is mixed in a liquid containing ingredient such as
sugar, gelatin, pectin, and sweeteners. These liquids are
solidified into solid tablets or caplets by freeze drying and solid
state extraction techniques. The drug compounds may be compressed
with viscoelastic and thermoelastic sugars and polymers or
effervescent components to produce porous matrices intended for
immediate release, without the need of water.
[0569] It should be apparent to one of ordinary skill in the art
that changes and modifications can be made to this invention
without departing from the spirit or scope of the invention as it
is set forth herein.
Biological Evaluation
[0570] In order that this invention may be better understood, the
following examples are set forth. These examples are for the
purpose of illustration only, and are not to be construed as
limiting the scope of the invention in any manner. All publications
mentioned herein are incorporated by reference in their
entirety.
[0571] Demonstration of the activity of the compounds of the
present invention may be accomplished through in vitro, ex vivo,
and in vivo assays that are well known in the art. For example, to
demonstrate the efficacy of a pharmaceutical agent for the
treatment of diabetes and related disorders such as Syndrome X,
impaired glucose tolerance, impaired fasting glucose, and
hyperinsulinemia, the following assays may be used.
In Vitro Assay
[0572] Insulin Secretion from INS-1 Cells
[0573] INS-1 cells were isolated from X-ray induced rat insulinoma
(Asfari, et al., Endocrinology 130:167, 1992). INS-1 cells were
seeded at 30,000 cells per well in Biocoat Collagen1 Cellware
96-well plates and incubated for 4-5 days. The cells were then
treated for 2 days with complete media (RPM 1640, 10% Fetal Bovine
Serum, 100 .mu.g/mL Penicillin/Streptomycin, 0.5 mM sodium
pyruvate, 10 mM HEPES, and 50 .mu.M beta-mercaptoethanol) adjusted
to 3 mM glucose. After the two-day treatment, the cells were washed
with Krebs-Ringer-Bicarbonate-HEPES (KRBH) containing 3 mM glucose.
The cells were then incubated for 30 min in the same buffer. The
cells were incubated for an additional 2 h in the presence of the
desired concentration of glucose and compounds. The supernatants
were harvested.
[0574] To determine the amount of insulin secreted, the
supernatants were mixed with anti-insulin antibody and a tracer
amount of .sup.125I-insulin in phosphate buffered saline containing
0.5% bovine serum albumin. Protein A coated SPA (scintillation
proximity assay) beads were added. The plates were incubated for
5-20 h and counted on a scintillation counter to measure insulin
levels. Activity for compounds at a given concentration was
expressed as a fold-stimulation of insulin secretion relative to
controls.
[0575] The compounds of the invention (measured at 10 .mu.M) were
found to be active in the INS-1 assay.
Insulin Secretion from Dispersed Rat Islet Cells
[0576] Insulin secretion of dispersed rat islets mediated by a
number of compounds of the present invention was measured as
follows. Islets of Langerhans, isolated from male Sprague-Dawley
rats (200-250 g), were digested using collagenase. The dispersed
islet cells were treated with trypsin, seeded into 96 V-bottom
plates, and pelleted. The cells were then cultured overnight in
media with or without compounds of this invention. The media was
aspirated, and the cells were pre-incubated with Krebs-Ringer-HEPES
buffer containing 3 mM glucose for 30 minutes at 37.degree. C. The
pre-incubation buffer was removed, and the cells were incubated at
37.degree. C. with Krebs-Ringer-HEPES buffer containing the
appropriate glucose concentration (e.g., 8 mM) with or without
compounds for an appropriate time. In some studies, an appropriate
concentration of GLP-1 or forskolin was also included. A portion of
the supernatant was removed and its insulin content was measured by
SPA. The results were expressed as "fold over control" (FOC).
In Vivo Assay
[0577] Effect of Compounds on Intraperitoneal Glucose Tolerance in
Rats
[0578] The in vivo activities of the compounds of this invention
when administered via oral gavage were examined in rats. Rats
fasted overnight were given an oral dose of vehicle control or
compound. Three hours later, basal blood glucose was measured, and
the rats were given 2 g/kg of glucose intraperitoneally. Blood
glucose was measured again after 15, 30, and 60 min. A
representative compound of this invention significantly reduced
blood glucose levels relative to the vehicle following the IPGTT
(Intraperitoneal Glucose Tolerance Test).
Target Identification
[0579] Use of Formula (I) Compounds to Identify Biological
Targets
[0580] Compounds of Formula (I) of the current invention are also
useful for identifying their associated biological target(s) (e.g.,
nucleic acids, peptides, polypeptides, proteins, carbohydrates,
lipids, or other molecules) effecting the functional response of
insulin secretion. Such targets, or protein molecules that are
modulated by the compounds of present invention can be identified
by several means.
[0581] For example, one such method of target identification can be
accomplished, by photoaffinity labeling techniques well-known in
the art. In such a procedure, compounds of Formula (I) that contain
a photoactive group, such as a benzoylphenyl group, are prepared
and additionally labeled with a radioactive isotope such as
tritium. As an example, a suitable Formula (I) compound useful for
such experiments is a radioactively tagged derivative of the
benzophenone analog described in Example 207. The preparation of
such a compound is shown in Reaction Scheme M below, starting from
the compound of Formula (X). The chloro-containing starting
material may be made using a procedure similar to that described
for Example 142. In stepwise fashion, this starting material is
functionalized with a benzoyl group and allowed to undergo a
tritium-halogen exchange reaction, to provide a probe molecule of
Formula (XIII). The methods for replacement of a chlorine atom by
tritium are well know in the art and may be done without affecting
the integrity of the keto group of the benzophenone moiety (e.g.,
Mesange, et al. Bioconj. Chem. 13:766-772, 2002; Held, et al.,
Labelled Compd. Radiopharm. 39:501-508, 1997; Kaspersen, et al.,
Rec. Trav. Chim. Pays-Bas 112:191-199, 1993; Hergert, et al.,
Pharmazie 38:28-29, 1983).
[0582] This probe molecule is then allowed to come in contact with
pancreatic beta-cell lysate homogenate (or any biological sample,
such as a sample obtained from an organism (e.g., mammal) or from
components (e.g., cells, biological tissue or fluid) of an
organism, cell line or tissue culture sample; or the sample may be
a sample derived from a patient including, but are not limited to,
tissue or cells therefrom) containing the suspected target(s),
incubated for a period of time sufficient to effect association of
the probe molecule with the target protein, then the mixture is
irradiated with light at the wavelength of the photoactive group of
the probe molecule. The protein and probe molecule that become
covalently bound as a result of the irradiation is then purified
using standard methods, facilitated by the radioactivity of
probe/target complex as a means to differentiate it from the rest
of the lysate mixture. Identification of the purified protein (the
probe/target complex) is then conducted using methods well
described in the art (see, e.g., Dorman, et al., Tibtech. 18:64-77,
2000). ##STR514##
[0583] Another method using the compounds of Formula (I) to
identify the biological target effecting the functional response of
insulin secretion is the so called drug "pull-down" experiments
(see, e.g., Graves, et al., Rec. Prog. Horm. Res. 58:1-24, 2003).
Formula (I) compounds containing functional groups that are
suitable for chemical coupling (e.g., carboxylic acid groups, amino
groups, alcohol groups) may be coupled to a commercially available
polymer (resins) containing a suitably reactive linker group. For
example, polymeric beads containing an amino linker may be allowed
to react with a Formula (I) compound where X.dbd.COOH to form an
amide, said amide being bound to the polymeric beads and thus,
immobilized. The polymeric beads containing immobilized Formula (I)
compound may then be used as bait for appropriate pancreatic
beta-cell tissue lysates, by allowing the polymer beads to come in
contact with the lysate, incubating for a period of time sufficient
for the target proteins to form a complex with the polymer,
removing the unbound protein material from the polymer, and
cleaving of the bound protein from the polymer. Thus, purified
protein target(s) of interest may then be identified by mass
spectrometric analysis using techniques well know in the art (see,
e.g., Kim, et al., Biochem. Mol. Biol. 36:299-304, 2003.
[0584] All publications and patents mentioned in the above
specification are incorporated herein by reference. Various
modifications and variations of the described compositions and
methods of the invention will be apparent to those skilled in the
art without departing from the scope and spirit of the invention.
Although the invention has been described in connection with
specific preferred embodiments, it should be understood that the
invention as claimed should not be unduly limited to such specific
embodiments. Indeed, various modifications of the above-described
modes for carrying out the invention which are obvious to those
skilled in the field of molecular biology or related fields are
intended to be within the scope of the following claims. Those
skilled in the art will recognize, or be able to ascertain using no
more than routine experimentation, many equivalents to the specific
embodiments of the invention described herein. Such equivalents are
intended to be encompassed by the following claims.
* * * * *