U.S. patent application number 11/963115 was filed with the patent office on 2008-05-01 for thrombopoietin activity modulating compounds and methods.
This patent application is currently assigned to Ligand Pharmaceuticals, Inc.. Invention is credited to Jyun-Hung Chen, Jackline E. Dalgard, E. Adam Kallel, Thomas Lau, Matthew H. McNeill, Todd A. Miller, Bao N. Nguyen, Richard J. Penuliar, Dean P. Phillips, Daniel A. Ruppar, Lin Zhi.
Application Number | 20080103190 11/963115 |
Document ID | / |
Family ID | 35610075 |
Filed Date | 2008-05-01 |
United States Patent
Application |
20080103190 |
Kind Code |
A1 |
Chen; Jyun-Hung ; et
al. |
May 1, 2008 |
THROMBOPOIETIN ACTIVITY MODULATING COMPOUNDS AND METHODS
Abstract
Disclosed herein are compounds, pharmaceutical compositions
comprising the same, methods of modulating the activity a
thrombopoietin receptor using the same, methods of identifying
compounds as thrombopoietin receptor modulators, and methods of
treating disease by administering a compound of the invention to a
patient in need thereof.
Inventors: |
Chen; Jyun-Hung; (San Diego,
CA) ; Kallel; E. Adam; (Escondido, CA) ; Lau;
Thomas; (San Diego, CA) ; McNeill; Matthew H.;
(San Clemente, CA) ; Miller; Todd A.; (San Marcos,
CA) ; Nguyen; Bao N.; (San Diego, CA) ;
Penuliar; Richard J.; (San Diego, CA) ; Phillips;
Dean P.; (San Marcos, CA) ; Ruppar; Daniel A.;
(San Antonio, TX) ; Zhi; Lin; (San Diego, CA)
; Dalgard; Jackline E.; (Del Mar, CA) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Assignee: |
Ligand Pharmaceuticals,
Inc.
10275 Science Center Drive
San Diego
CA
92121-1117
|
Family ID: |
35610075 |
Appl. No.: |
11/963115 |
Filed: |
December 21, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11937392 |
Nov 8, 2007 |
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11963115 |
Dec 21, 2007 |
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11256572 |
Oct 21, 2005 |
7314887 |
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11963115 |
Dec 21, 2007 |
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60621879 |
Oct 25, 2004 |
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60675001 |
Apr 25, 2005 |
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Current U.S.
Class: |
514/418 ;
435/375; 435/4; 548/486 |
Current CPC
Class: |
C07D 409/04 20130101;
C07D 471/04 20130101; C07D 403/12 20130101; A61P 7/00 20180101;
C07D 209/40 20130101; C07D 239/04 20130101; C07D 401/04 20130101;
C07D 417/12 20130101; A61P 21/04 20180101; C07D 277/54 20130101;
A61P 25/00 20180101; C07D 277/04 20130101; C07D 239/60 20130101;
C07D 405/04 20130101; A61P 43/00 20180101; C07D 217/24 20130101;
A61P 7/04 20180101 |
Class at
Publication: |
514/418 ;
435/375; 435/004; 548/486 |
International
Class: |
A61K 31/404 20060101
A61K031/404; A61P 7/00 20060101 A61P007/00; C07D 209/30 20060101
C07D209/30; C12N 5/00 20060101 C12N005/00; G01N 33/53 20060101
G01N033/53 |
Claims
1. An isolated compound that is a TPO receptor agonist and is not a
TPO receptor partial agonist.
2. The compound of claim 1 that is a selective TPO receptor
agonist.
3. The compound of claim 1 that is a selective TPO receptor binding
compound.
4. The compound of claim 1 that is a tissue-specific modulator.
5. A compound that is a TPO receptor agonist, is not TPO and is not
a TPO receptor partial agonist.
6. The compound of claim 5 that is a selective TPO receptor
agonist.
7. The compound of claim 5 that is a selective TPO receptor binding
compound.
8. The compound of claim 5 that is a tissue-specific modulator.
9. A method for modulating a TPO activity in a cell comprising
contacting a cell with a compound of claim 1.
10. A method for identifying a compound that modulates a TPO
activity, comprising contacting a cell that expresses a TPO
receptor with a compound of claim 1; and monitoring an effect of
the compound on the cell.
11. A method of treating thrombocytopenia in a patient in need
thereof with a compound of claim 1.
12. The method of claim 9, wherein the thrombocytopenia results
from radiation or chemotherapy.
13. The method of claim 9, further comprising harvesting cells from
the patient.
14. A method for modulating a TPO activity in a cell comprising
contacting a cell with a compound of claim 5.
15. A method for identifying a compound that modulates a TPO
activity, comprising contacting a cell that expresses a TPO
receptor with a compound of claim 5; and monitoring an effect of
the compound on the cell.
16. A method of treating thrombocytopenia in a patient in need
thereof with a compound of claim 5.
17. The method of claim 14, wherein the thrombocytopenia results
from radiation or chemotherapy.
18. The method of claim 14, further comprising harvesting cells
from the patient.
19. A pharmaceutical composition comprising a compound of claim
1.
20. A pharmaceutical composition comprising a compound of claim 5.
Description
RELATED APPLICATIONS
[0001] This application is related to U.S. application Ser. No.
11/937,392, filed on Nov. 8, 2007, and is a continuation of U.S.
application Ser. No. 11/256,572, filed on Oct. 21, 2005, to be
issued as U.S. Pat. No. 7,314,887, which applications claim the
benefit of U.S. Provisional Patent Application No. 60/621,879,
filed on Oct. 25, 2004, and U.S. Provisional Patent Application No.
60/675,001, filed on Apr. 25, 2005, all by Zhi et al. and entitled
"THROMBOPOIETIN ACTIVITY MODULATING COMPOUNDS AND METHODS." This
applications claims priority to all of the aforementioned
applications and all of the aforementioned applications are
incorporated by reference herein in their entirety, including any
drawings.
FIELD OF THE INVENTION
[0002] This invention relates to compounds that modulate one or
more thrombopoietin activity and/or bind to thrombopoietin
receptors; and to methods for making and using such compounds.
BACKGROUND
[0003] Thrombopoietin (TPO), also referred to as c-Mp1 ligand, mp1
ligand, megapoietin, and megakaryocyte growth and development
factor, is a glycoprotein that has been shown to be involved in
production of platelets. See e.g., Wendling, F., et. al.,
Biotherapy 10(4):269-77 (1998); Kuter D. J. et al., The Oncologist,
1:98-106 (1996); and Metcalf, Nature 369: 519-520 (1994). TPO has
been cloned and its amino acid sequence and the cDNA sequence
encoding it have been described. See e.g., U.S. Pat. No. 5,766,581;
Kuter, D. J. et al., Proc. Natl. Acad. Sci., 91:11104-11108 (1994);
de Sauvage F. V., et al., Nature, 369: 533-538 (1994); Lok, S. et
al., Nature 369:565-568 (1994); and Wending, F. et al., Nature,
369: 571-574 (1994).
[0004] In certain instances, TPO activity results from binding of
TPO to the TPO receptor (also called MPL). The TPO receptor has
been cloned and its amino acid sequence has been described. See
e.g., Vigon et al., Proc. Natl. Acad. Sci., 89:5640-5644
(1992).
[0005] In certain instances, TPO modulators may be useful in
treating a variety of hematopoietic conditions, including, but not
limited to, thrombocytopenia. See e.g., Baser et al. Blood
89:3118-3128 (1997); Fanucchi et al. New Engl. J. Med. 336:404-409
(1997). For example, patients undergoing certain chemotherapies,
including but not limited to chemotherapy and/or radiation therapy
for the treatment of cancer, may have reduced platelet levels. In
certain instances, treating such patients with a selective TPO
modulator increases platelet levels. In certain instances,
selective TPO modulators stimulate production of glial cells, which
may result in repair of damaged nerve cells.
[0006] Certain TPO mimics have been described previously. See e.g.,
WO 03/103686A1; and WO 01/21180.
SUMMARY OF THE INVENTION
[0007] In certain embodiments, the present invention provides a
compound of Formula I: ##STR1## or a pharmaceutically acceptable
salt, ester, amide, or prodrug thereof, wherein:
[0008] R.sup.1 is selected from CO.sub.2R.sup.10,
CONR.sup.10R.sup.10, SO.sub.3R.sup.10, and a carboxylic acid
bioisostere;
[0009] R.sup.2 and R.sup.3 are each independently selected from
null, hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally
substituted C.sub.1-C.sub.4 aliphatic, an optionally substituted
C.sub.1-C.sub.4 haloaliphatic, an optionally substituted
C.sub.1-C.sub.4 heteroaliphatic, an optionally substituted ring,
and (CH.sub.2).sub.mR.sup.14; or R.sup.2 and R.sup.3 taken together
form an optionally substituted olefin; or R.sup.2 and R.sup.3 are
linked to form an optionally substituted C.sub.3-C.sub.8 ring;
[0010] R.sup.4 is selected from hydrogen, F, Cl, Br,
C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4 haloaliphatic,
C.sub.1-C.sub.4 heteroaliphatic, and a ring;
[0011] R.sup.5 is selected from hydrogen, OR.sup.10, SR.sup.10,
NHR.sup.11, and CO.sub.2H;
[0012] R.sup.6 is selected from hydrogen, OR.sup.12,
NR.sup.12R.sup.13, F, Cl, Br, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 heteroalkyl, and a
ring;
[0013] R.sup.7 is selected from hydrogen, an optionally substituted
C.sub.1-C.sub.8 aliphatic, an optionally substituted
C.sub.1-C.sub.8 haloaliphatic, an optionally substituted
C.sub.1-C.sub.8 heteroaliphatic, an optionally substituted
C.sub.1-C.sub.8 heterohaloaliphatic, an optionally substituted
ring, and (CH.sub.2).sub.mR.sup.14;
[0014] R.sup.10 is selected from hydrogen, an optionally
substituted C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4
haloaliphatic, C.sub.1-C.sub.4 heteroaliphatic, and a ring;
[0015] R.sup.11 is selected from hydrogen, SO.sub.2R.sup.15,
C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4 haloaliphatic,
C.sub.1-C.sub.4 heteroaliphatic, and a ring;
[0016] R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 aliphatic, an
optionally substituted C.sub.1-C.sub.4 haloaliphatic, an optionally
substituted C.sub.1-C.sub.4 heteroaliphatic, an optionally
substituted ring, and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12
and R.sup.13 is an optionally substituted C.sub.2-C.sub.6 aliphatic
or an optionally substituted ring and the other of R.sup.12 and
R.sup.13 is null; or R.sup.12 and R.sup.13 are linked to form an
optionally substituted C.sub.3-C.sub.8 ring;
[0017] R.sup.14 is selected from an optionally substituted aryl and
an optionally substituted heteroaryl;
[0018] R.sup.15 is selected from hydrogen, C.sub.1-C.sub.3
aliphatic, C.sub.1-C.sub.3 haloaliphatic, and a ring;
[0019] Y is a 1-4 atom spacer comprising one or more groups
selected from an optionally substituted C.sub.1-C.sub.6 aliphatic,
an optionally substituted C.sub.1-C.sub.6 heteroaliphatic, an
optionally substituted phenyl, an optionally substituted
heteroaryl, an optionally substituted C.sub.3-C.sub.5 heterocycle,
and an optionally substituted alicyclic,
[0020] provided that Y is not --N.dbd.CR.sup.6-- orientated to form
a dihydropyrazole;
[0021] Z is selected from: [0022] a 2-5 atom spacer selected from
an optionally substituted C.sub.6-C.sub.10 aryl and an optionally
substituted C.sub.1-C.sub.8 heteroaryl, and [0023] a 1-5 atom
spacer of selected from an optionally substituted C.sub.1-C.sub.6
aliphatic, an optionally substituted C.sub.1-C.sub.6
heteroaliphatic, and an optionally substituted C.sub.1-C.sub.6
haloaliphatic;
[0024] m is 0, 1, or 2; and
[0025] n is 0 or 1.
[0026] In certain embodiments, the invention provides a compound of
Formula I or a pharmaceutically acceptable salt, ester, amide, or
prodrug thereof, wherein:
[0027] R.sup.1 is selected from CO.sub.2R.sup.10,
CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic acid
bioisostere selected from tetrazole, NHSO.sub.2R.sup.15,
OC(S)NR.sup.10R.sup.11, SC(O)NR.sup.10R.sup.11, and ##STR2##
[0028] wherein A, B, and C are each independently selected from O,
S, and N;
[0029] R.sup.2 and R.sup.3 are each independently selected from
hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally substituted
C.sub.1-C.sub.4 alkyl, an optionally substituted C.sub.1-C.sub.4
haloalkyl, an optionally substituted C.sub.1-C.sub.4 heteroalkyl,
an optionally substituted ring, and (CH.sub.2).sub.mR.sup.14; or
R.sup.2 and R.sup.3 taken together form an optionally substituted
olefin; or R.sup.2 and R.sup.3 are linked to form an optionally
substituted C.sub.3-C.sub.8 ring;
[0030] R.sup.4 is selected from hydrogen, F, Cl, Br,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
heteroalkyl, and a non-aromatic ring;
[0031] R.sup.7 is selected from hydrogen, an optionally substituted
C.sub.1-C.sub.8 alkyl, an optionally substituted C.sub.1-C.sub.8
haloalkyl, an optionally substituted C.sub.1-C.sub.8 heteroalkyl,
an optionally substituted C.sub.1-C.sub.8 heterohaloalkyl, an
optionally substituted aromatic ring, and
(CH.sub.2).sub.mR.sup.14;
[0032] R.sup.10 is selected from hydrogen, an optionally
substituted C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 heteroalkyl, and a non-aromatic ring;
[0033] R.sup.11 is selected from hydrogen, SO.sub.2R.sup.15,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
heteroalkyl, and a non-aromatic ring;
[0034] R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 alkyl, an
optionally substituted C.sub.1-C.sub.4 haloalkyl, an optionally
substituted C.sub.1-C.sub.4 heteroalkyl, an optionally substituted
non-aromatic ring, and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12
and R.sup.13 is an optionally substituted C.sub.2-C.sub.6 alkyl or
an optionally substituted non-aromatic ring, and the other of
R.sup.12 and R.sup.13 is null; or R.sup.12 and R.sup.13 are linked
to form an optionally substituted C.sub.3-C.sub.8 ring;
[0035] R.sup.15 is selected from hydrogen, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, and aryl;
[0036] Y is a 1-4 atom spacer comprising one or more groups
selected from an optionally substituted C.sub.1-C.sub.6 alkyl, an
optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally
substituted C.sub.2-C.sub.6 alkenyl, an optionally substituted
C.sub.2-C.sub.6 heteroalkenyl, an optionally substituted phenyl, an
optionally substituted heteroaryl, an optionally substituted
C.sub.3-C.sub.5 heterocycle, an optionally substituted cycloalkyl,
and an optionally substituted cycloalkenyl; and
[0037] Z is selected from: [0038] a 2-5 atom spacer selected from
an optionally substituted C.sub.6-C.sub.10 aryl and an optionally
substituted C.sub.1-C.sub.8 heteroaryl, and [0039] a 1-5 atom
spacer of selected from an optionally substituted C.sub.1-C.sub.6
alkyl, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an
optionally substituted C.sub.1-C.sub.6 haloalkyl, an optionally
substituted C.sub.2-C.sub.6 alkenyl, an optionally substituted
C.sub.2-C.sub.6 heteroalkenyl, an optionally substituted
C.sub.2-C.sub.6 haloalkenyl, an optionally substituted
C.sub.2-C.sub.6 alkynyl, and an optionally substituted
C.sub.2-C.sub.6 heteroalkyl.
[0040] In certain embodiments, the present invention provides a
compound of Formula II: ##STR3## or a pharmaceutically acceptable
salt, ester, amide, or prodrug thereof, wherein:
[0041] R.sup.1 is selected from CO.sub.2R.sup.10,
CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic acid
bioisostere;
[0042] R.sup.2 and R.sup.3 are each independently selected from
null, hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally
substituted C.sub.1-C.sub.4 aliphatic, an optionally substituted
C.sub.1-C.sub.4 haloaliphatic, an optionally substituted
C.sub.1-C.sub.4 heteroaliphatic, an optionally substituted ring,
and (CH.sub.2).sub.mR.sup.14; or R.sup.2 and R.sup.3 taken together
form an optionally substituted olefin; or R.sup.2 and R.sup.3 are
linked to form an optionally substituted C.sub.3-C.sub.8 ring;
[0043] R.sup.4 is selected from hydrogen, F, Cl, Br,
C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4 haloaliphatic,
C.sub.1-C.sub.4 heteroaliphatic, and a ring;
[0044] R.sup.5 is selected from hydrogen, OR.sup.10, SR.sup.10,
NHR.sup.11, and CO.sub.2H;
[0045] R.sup.6 is selected from hydrogen, OR.sup.2,
NR.sup.12R.sup.13, F, Cl, Br, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 heteroalkyl, and a
ring;
[0046] R.sup.7 is selected from hydrogen, an optionally substituted
C.sub.1-C.sub.8 aliphatic, an optionally substituted
C.sub.1-C.sub.8 haloaliphatic, an optionally substituted
C.sub.1-C.sub.8 heteroaliphatic, an optionally substituted
C.sub.1-C.sub.8 heterohaloaliphatic, an optionally substituted
ring, and (CH.sub.2).sub.mR.sup.14;
[0047] R.sup.8 and R.sup.9 are each independently selected from
hydrogen, F, Cl, Br, CO.sub.2R.sup.10, NO.sub.2, CN,
SO.sub.2R.sup.10, (CH.sub.2).sub.mR.sup.14, C.sub.1-C.sub.4
aliphatic, C.sub.1-C.sub.4 haloaliphatic, C.sub.1-C.sub.4
heteroaliphatic, C.sub.1-C.sub.4 heterohaloaliphatic, and a
ring;
[0048] R.sup.10 is selected from hydrogen, an optionally
substituted C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4
haloaliphatic, C.sub.1-C.sub.4 heteroaliphatic, and a ring;
[0049] R.sup.11 is selected from hydrogen, SO.sub.2R.sup.15,
C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4 haloaliphatic,
C.sub.1-C.sub.4 heteroaliphatic, and a ring;
[0050] R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 aliphatic, an
optionally substituted C.sub.1-C.sub.4 haloaliphatic, an optionally
substituted C.sub.1-C.sub.4 heteroaliphatic, an optionally
substituted ring, and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12
and R.sup.13 is an optionally substituted C.sub.2-C.sub.6 aliphatic
or an optionally substituted ring and the other of R.sup.12 and
R.sup.13 is null; or R.sup.12 and R.sup.13 are linked to form an
optionally substituted C.sub.3-C.sub.8 ring;
[0051] R.sup.14 is selected from an optionally substituted aryl and
an optionally substituted heteroaryl;
[0052] R.sup.15 is selected from hydrogen, C.sub.1-C.sub.3
aliphatic, C.sub.1-C.sub.3 haloaliphatic, and a ring;
[0053] Q is selected from O and S;
[0054] X is selected from O, S, NR.sup.10, and
CR.sup.10R.sup.11;
[0055] Y is selected from: ##STR4##
[0056] Z is selected from: [0057] a 2-5 atom spacer selected from
an optionally substituted C.sub.6-C.sub.10 aryl and an optionally
substituted C.sub.1-C.sub.8 heteroaryl, and [0058] a 1-5 atom
spacer of selected from an optionally substituted C.sub.1-C.sub.6
aliphatic, an optionally substituted C.sub.1-C.sub.6
heteroaliphatic, and an optionally substituted C.sub.1-C.sub.6
haloaliphatic;
[0059] m is 0, 1, or 2; and
[0060] n is 0 or 1.
[0061] In certain embodiments, the invention provides a compound of
Formula II or a pharmaceutically acceptable salt, ester, amide, or
prodrug thereof, wherein:
[0062] R.sup.1 is selected from CO.sub.2R.sup.10,
CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic acid
bioisostere selected from tetrazole, NHSO.sub.2R.sup.15,
OC(S)NR.sup.10R.sup.11, SC(O)NR.sup.10R.sup.11, and ##STR5##
[0063] wherein A, B, and C are each independently selected from O,
S, and N;
[0064] R.sup.2 and R.sup.3 are each independently selected from
hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally substituted
C.sub.1-C.sub.4 alkyl, an optionally substituted C.sub.1-C.sub.4
haloalkyl, an optionally substituted C.sub.1-C.sub.4 heteroalkyl,
an optionally substituted ring, and (CH.sub.2).sub.mR.sup.14; or
R.sup.2 and R.sup.3 taken together form an optionally substituted
olefin; or R.sup.2 and R.sup.3 are linked to form an optionally
substituted C.sub.3-C.sub.8 ring; or one of R2 or R3 is null and
the other is
[0065] R.sup.4 is selected from hydrogen, F, Cl, Br,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, and
C.sub.1-C.sub.4 heteroalkyl and a non-aromatic ring;
[0066] R.sup.7 is selected from hydrogen, an optionally substituted
C.sub.1-C.sub.8 alkyl, an optionally substituted C.sub.1-C.sub.8
haloalkyl, an optionally substituted C.sub.1-C.sub.8 heteroalkyl,
an optionally substituted C.sub.1-C.sub.8 heterohaloalkyl, an
optionally substituted aromatic ring, and
(CH.sub.2).sub.mR.sup.14;
[0067] R.sup.8 and R.sup.9 are each independently selected from
hydrogen, F, Cl, Br, CO.sub.2R.sup.10, NO.sub.2, CN,
SO.sub.2R.sup.10, (CH.sub.2).sub.mR.sup.14, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 heteroalkyl,
C.sub.1-C.sub.4 heterohaloalkyl, and a ring;
[0068] R.sup.10 is selected from hydrogen, an optionally
substituted C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 heteroalkyl, and a non-aromatic ring;
[0069] R.sup.11 is selected from hydrogen, SO.sub.2R.sup.15,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, and
C.sub.1-C.sub.4 heteroalkyl;
[0070] R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 alkyl, an
optionally substituted C.sub.1-C.sub.4 haloalkyl, an optionally
substituted C.sub.1-C.sub.4 heteroalkyl, an optionally substituted
non-aromatic ring, and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12
and R.sup.13 is an optionally substituted C.sub.2-C.sub.6 alkyl or
an optionally substituted non-aromatic ring and the other of
R.sup.12 and R.sup.13 is null; or R.sup.12 and R.sup.13 are linked
to form an optionally substituted C.sub.3-C.sub.8 ring;
[0071] R.sup.15 is selected from hydrogen, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, and aryl; and
[0072] Z is selected from: [0073] a 2-5 atom spacer selected from
an optionally substituted C.sub.6-C.sub.10 aryl and an optionally
substituted C.sub.1-C.sub.8 heteroaryl, and [0074] a 1-5 atom
spacer of selected from an optionally substituted C.sub.1-C.sub.6
alkyl, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an
optionally substituted C.sub.1-C.sub.6 haloalkyl, an optionally
substituted C.sub.2-C.sub.6 alkenyl, an optionally substituted
C.sub.2-C.sub.6 heteroalkenyl, an optionally substituted
C.sub.2-C.sub.6 haloalkenyl, an optionally substituted
C.sub.2-C.sub.6 alkynyl, and an optionally substituted
C.sub.2-C.sub.6 heteroalkyl.
[0075] In certain embodiments, the present invention provides a
compound of Formula III: ##STR6## or a pharmaceutically acceptable
salt, ester, amide, or prodrug thereof, wherein:
[0076] R.sup.1 is selected from CO.sub.2R.sup.10,
CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic acid
bioisostere;
[0077] R.sup.2 and R.sup.3 are each independently selected from
null, hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally
substituted C.sub.1-C.sub.4 aliphatic, an optionally substituted
C.sub.1-C.sub.4 haloaliphatic, an optionally substituted
C.sub.1-C.sub.4 heteroaliphatic, an optionally substituted ring,
and (CH.sub.2).sub.mR.sup.14; or R.sup.2 and R.sup.3 taken together
form an optionally substituted olefin; or R.sup.2 and R.sup.3 are
linked to form an optionally substituted C.sub.3-C.sub.8 ring;
[0078] R.sup.4 is selected from hydrogen, F, Cl, Br,
C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4 haloaliphatic,
C.sub.1-C.sub.4 heteroaliphatic, and a ring;
[0079] R.sup.5 is selected from hydrogen, OR.sup.10, SR.sup.10,
NHR.sup.11, and CO.sub.2H;
[0080] R.sup.6 is selected from hydrogen, OR.sup.12,
NR.sup.12R.sup.13, F, Cl, Br, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 heteroalkyl;
[0081] R.sup.7 is selected from hydrogen, an optionally substituted
C.sub.1-C.sub.8 aliphatic, an optionally substituted
C.sub.1-C.sub.8 haloaliphatic, an optionally substituted
C.sub.1-C.sub.8 heteroaliphatic, an optionally substituted
C.sub.1-C.sub.8 heterohaloaliphatic, an optionally substituted
ring, and (CH.sub.2).sub.mR.sup.14;
[0082] R.sup.8 and R.sup.9 are each independently selected from
hydrogen, F, Cl, Br, CO.sub.2R.sup.10, NO.sub.2, CN,
SO.sub.2R.sup.10, (CH.sub.2).sub.mR.sup.14, C.sub.1-C.sub.4
aliphatic, C.sub.1-C.sub.4 haloaliphatic, C.sub.1-C.sub.4
heteroaliphatic, and C.sub.1-C.sub.4 heterohaloaliphatic;
[0083] R.sup.10 is selected from hydrogen, an optionally
substituted C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4
haloaliphatic, C.sub.1-C.sub.4 heteroaliphatic, and a ring;
[0084] R.sup.11 is selected from hydrogen, SO.sub.2R.sup.15,
C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4 haloaliphatic,
C.sub.1-C.sub.4 heteroaliphatic, and a ring;
[0085] R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 aliphatic, an
optionally substituted C.sub.1-C.sub.4 haloaliphatic, an optionally
substituted C.sub.1-C.sub.4 heteroaliphatic, an optionally
substituted ring, and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12
and R.sup.13 is an optionally substituted C.sub.2-C.sub.6 aliphatic
or an optionally substituted ring and the other of R.sup.12 and
R.sup.13 is null; or R.sup.12 and R.sup.13 are linked to form an
optionally substituted C.sub.3-C.sub.8 ring;
[0086] R.sup.14 is selected from an optionally substituted aryl and
an optionally substituted heteroaryl;
[0087] R.sup.15 is selected from hydrogen, C.sub.1-C.sub.3
aliphatic, C.sub.1-C.sub.3 haloaliphatic, and a ring;
[0088] m is 0, 1, or 2; and
[0089] n is 0 or 1.
[0090] In certain embodiments, the invention provides a compound of
Formula III or a pharmaceutically acceptable salt, ester, amide, or
prodrug thereof, wherein:
[0091] R.sup.1 is selected from CO.sub.2R.sup.10,
CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic acid
bioisostere selected from tetrazole, NHSO.sub.2R.sup.15,
OC(S)NR.sup.10R.sup.11, SC(O)NR.sup.10R.sup.11, and ##STR7##
[0092] wherein A, B, and C are each independently selected from O,
S, and N;
[0093] R.sup.2 and R.sup.3 are each independently selected from
hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally substituted
C.sub.1-C.sub.4 alkyl, an optionally substituted C.sub.1-C.sub.4
haloalkyl, an optionally substituted C.sub.1-C.sub.4 heteroalkyl,
an optionally substituted ring, and (CH.sub.2).sub.mR.sup.14; or
R.sup.2 and R.sup.3 taken together form an optionally substituted
olefin; or R.sup.2 and R.sup.3 are linked to form an optionally
substituted C.sub.3-C.sub.8 ring;
[0094] R.sup.4 is selected from hydrogen, F, Cl, Br,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
heteroalkyl, and a non-aromatic ring;
[0095] R.sup.7 is selected from hydrogen, an optionally substituted
C.sub.1-C.sub.8 alkyl, an optionally substituted C.sub.1-C.sub.8
haloalkyl, an optionally substituted C.sub.1-C.sub.8 heteroalkyl,
an optionally substituted C.sub.1-C.sub.8 heterohaloalkyl, an
optionally substituted aromatic ring, and
(CH.sub.2).sub.mR.sup.14;
[0096] R.sup.8 and R.sup.9 are each independently selected from
hydrogen, F, Cl, Br, CO.sub.2R.sup.10, NO.sub.2, CN,
SO.sub.2R.sup.10, (CH.sub.2).sub.mR.sup.14, C.sub.1-C.sub.4 alkyl
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 heteroalkyl, and
C.sub.1-C.sub.4 heterohaloalkyl;
[0097] R.sup.10 is selected from hydrogen, an optionally
substituted C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 heteroalkyl and a non-aromatic ring;
[0098] R.sup.11 is selected from hydrogen, SO.sub.2R.sup.5,
C.sub.1-C.sub.4 alkyl C.sub.1-C.sub.4 haloalkyl, and
C.sub.1-C.sub.4 heteroalkyl, and a non-aromatic ring;
[0099] R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 alkyl, an
optionally substituted C.sub.1-C.sub.4 haloalkyl, an optionally
substituted C.sub.1-C.sub.4 heteroalkyl, a non-aromatic ring, and
(CH.sub.2).sub.mR.sup.14; or one of R.sup.12 and R.sup.13 is an
optionally substituted C.sub.2-C.sub.6 alkyl or a non-aromatic
ring, and the other of R.sup.12 and R.sup.13 is null; or R.sup.12
and R.sup.13 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring; and
[0100] R.sup.15 is selected from hydrogen, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, and aryl.
[0101] In certain embodiments, a compound of Formula I, II, or III
is a selective TPO modulator. In certain such embodiments, a
compound of Formula I, II, or III is a TPO mimic.
[0102] In certain embodiments, the invention provides a selective
TPO modulator. In certain embodiments, the invention provides a
selective TPO receptor agonist. In certain embodiments, the
invention provides a selective TPO receptor antagonist. In certain
embodiments, the invention provides a selective TPO partial
agonist. In certain embodiments, the invention provides a selective
TPO receptor binding compound. In certain embodiments, the
invention provides a TPO mimic. In certain embodiments, the
invention provides a tissue-selective selective TPO modulator.
[0103] In certain embodiments, the invention provides methods for
modulating a TPO activity. Certain such methods comprise contacting
a cell with one or more compounds of the present invention. Such
methods include, but are not limited to, contacting TPO and/or a
TPO receptor with one or more compounds of the present
invention.
[0104] In certain embodiments, the invention provides a method for
identifying a compound that is capable of modulating TPO activity
comprising contacting a cell capable of a TPO activity with a
compound of the present invention and monitoring an effect on the
cell. In certain such embodiments, the cell expresses a TPO
receptor.
[0105] In certain embodiments, the invention provides methods of
treating a patient comprising administering to the patient a
compound of the present invention. In certain embodiments, such a
patient suffers from thrombocytopenia. In certain embodiments, one
or more compounds of the present invention are administered to a
patient before, during or after chemotherapy, bone marrow
transplantation, and/or radiation therapy. In certain embodiments,
one or more compounds of the invention are administered to a
patient suffering from aplastic anemia, bone marrow failure, and/or
idiopathic thrombocytopenia. In certain embodiments, one or more
compounds of the present invention are administered to a patient
suffering from a disease of the nervous system. In certain
embodiments, one or more compounds of the present invention are
administered to patient suffering from amyotrophic lateral
sclerosis, multiple sclerosis, or multiple dystrophy. In certain
embodiments, one or more compounds of the present invention are
administered to a patient with a nerve injury, including, but not
limited to, a spinal cord injury.
[0106] In certain embodiments, the invention provides
pharmaceutical compositions comprising one or more compounds of the
present invention and a physiologically acceptable carrier,
diluent, or excipient.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0107] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention
claimed. Herein, the use of the singular includes the plural unless
specifically stated otherwise. Herein, the use of "or" means
"and/or" unless stated otherwise. Furthermore, use of the term
"including" as well as other forms, such as "includes," and
"included," is not limiting.
[0108] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described. All documents, or portions of documents, cited in
the application including, but not limited to, patents, patent
applications, articles, books, manuals, and treatises are hereby
expressly incorporated by reference in their entirety for any
purpose.
DEFINITIONS
[0109] Unless specific definitions are provided, the nomenclatures
utilized in connection with, and the laboratory procedures and
techniques of, analytical chemistry, synthetic organic chemistry,
and medicinal and pharmaceutical chemistry described herein are
those known in the art. Standard chemical symbols are used
interchangeably with the full names represented by such symbols.
Thus, for example, the terms "hydrogen" and "H" are understood to
have identical meaning. Standard techniques may be used for
chemical syntheses, chemical analyses, pharmaceutical preparation,
formulation, and delivery, and treatment of patients. Standard
techniques may be used for recombinant DNA, oligonucleotide
synthesis, and tissue culture and transformation (e.g.,
electroporation, lipofection). Reactions and purification
techniques may be performed e.g., using kits according to
manufacturer's specifications or as commonly accomplished in the
art or as described herein. The foregoing techniques and procedures
may be generally performed according to conventional methods well
known in the art and as described in various general and more
specific references that are cited and discussed throughout the
present specification. See e.g., Sambrook et al. Molecular Cloning:
A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press,
Cold Spring Harbor, N.Y. (1989)), which is incorporated herein for
any purpose.
[0110] As used herein, the following terms are defined with the
following meanings, unless expressly stated otherwise.
[0111] The term "selective binding compound" refers to a compound
that selectively binds to any portion of one or more target.
[0112] The term "selective TPO receptor binding compound" refers to
a compound that selectively binds to any portion of a TPO
receptor.
[0113] The term "selectively binds" refers to the ability of a
selective binding compound to bind to a target receptor with
greater affinity than it binds to a non-target receptor. In certain
embodiments, specific binding refers to binding to a target with an
affinity that is at least 10, 50, 100, 250, 500, or 1000 times
greater than the affinity for a non-target.
[0114] The term "target receptor" refers to a receptor or a portion
of a receptor capable of being bound by a selective binding
compound. In certain embodiments, a target receptor is a TPO
receptor.
[0115] The term "modulator" refers to a compound that alters or
elicits an activity. For example, the presence of a modulator may
result in an increase or decrease in the magnitude of a certain
activity compared to the magnitude of the activity in the absence
of the modulator. In certain embodiments, a modulator is an
inhibitor, which decreases the magnitude of one or more activities.
In certain embodiments, an inhibitor completely prevents one or
more biological activities. In certain embodiments, a modulator is
an activator, which increases the magnitude of at least one
activity. In certain embodiments the presence of a modulator
results in a activity that does not occur in the absence of the
modulator.
[0116] The term "selective modulator" refers to a compound that
selectively modulates a target activity.
[0117] The term "selective TPO modulator" refers to a compound that
selectively modulates at least one TPO activity. The term selective
TPO modulator includes, but is not limited to "TPO mimic" which
refers to a compound, the presence of which results in at least one
TPO activity.
[0118] The term "selectively modulates" refers to the ability of a
selective modulator to modulate a target activity to a greater
extent than it modulates a non-target activity.
[0119] The term "target activity" refers to a biological activity
capable of being modulated by a selective modulator. Certain
exemplary target activities include, but are not limited to,
binding affinity; signal transduction; enzymatic activity;
transcription of one or more genes; the proliferation and/or
differentiation of cells, including, but not limited to progenitor
cells; generation of platelets; and alleviation of symptoms of a
disease or condition.
[0120] The term "TPO activity" refers to a biological activity that
results, either directly or indirectly from the presence of TPO.
Exemplary TPO activities include, but are not limited to,
proliferation and or differentiation of progenitor cells to produce
platelets; hematopoiesis; growth and/or development of glial cells;
repair of nerve cells; and alleviation of thrombocytopenia.
[0121] The term "thrombocytopenia" refers to a condition wherein
the concentration of platelets in the blood of a patient is below
what is considered normal for a healthy patient. In certain
embodiments, thrombocytopenia is a platelet count less than
450,000, 400,000, 350,000, 300,000, 250,000, 200,000, 150,000,
140,000, 130,000, 120,000, 110,000, 100,000, 75,000, or 50,000
platelets per microliter of blood.
[0122] The term "receptor mediated activity" refers any biological
activity that results, either directly or indirectly, from binding
of a ligand to a receptor.
[0123] The term "agonist" refers to a compound, the presence of
which results in a biological activity of a receptor that is the
same as the biological activity resulting from the presence of a
naturally occurring ligand for the receptor.
[0124] The term "partial agonist" refers to a compound, the
presence of which results in a biological activity of a receptor
that is of the same type as that resulting from the presence of a
naturally occurring ligand for the receptor, but of a lower
magnitude.
[0125] The term "antagonist" refers to a compound, the presence of
which results in a decrease in the magnitude of a biological
activity of a receptor. In certain embodiments, the presence of an
antagonist results in complete inhibition of a biological activity
of a receptor.
[0126] The term "aliphatic," alone or in combination, refers to a
straight or branched chain comprising at least one carbon atom.
Aliphatics include alkyls, alkenyls, and alkynyls. In certain
embodiments, aliphatics are optionally substituted. Aliphatics
include, but are not limited to, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl,
butenyl, ethynyl, butynyl, propynyl, and the like, each of which
may be optionally substituted. As used herein, aliphatic is not
intended to include cyclic groups.
[0127] The term "alkyl," alone or in combination, refers to a fully
saturated aliphatic. In certain embodiments, alkyls are optionally
substituted. In certain embodiments, an alkyl comprises 1 to 20
carbon atoms (whenever it appears herein, a numerical range, such
as "1 to 20" or "C.sub.1-C.sub.20", refers to each integer in the
given range; e.g., "C.sub.1-C.sub.20 alkyl" means that an alkyl
group comprising only 1 carbon atom, 2 carbon atoms, 3 carbon
atoms, etc., up to and including 20 carbon atoms). Examples of
alkyls include, but are not limited to, methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl,
pentyl, hexyl, heptyl, octyl and the like.
[0128] The term "alkenyl," alone or in combination, refers to an
aliphatic having one or more carbon-carbon double-bonds. In certain
embodiments, alkenyls are optionally substituted. Examples of
alkenyls include, but are not limited to, ethenyl, propenyl,
1,4-butadienyl, and the like.
[0129] The term "alkynyl," alone or in combination, refers to an
aliphatic having one or more carbon-carbon triple-bonds. In certain
embodiments, alkynyls are optionally substituted. Examples of
alkynyls include, but are not limited to, ethynyl, propynyl,
butynyl, and the like.
[0130] The term "haloaliphatic," alone or in combination, refers to
an aliphatic in which at least one hydrogen atom is replaced with a
halogen atom. In certain embodiments in which two or more hydrogen
atom are replaced with halogen atoms, the halogen atoms are all the
same as one another. In certain such embodiments, the halogen atoms
are not all the same as one another. Haloaliphatics include
haloalkyls, haloalkenyls, and haloalkynyls. In certain embodiments,
haloaliphatics are optionally substituted, in addition to the
hydrogen/halogen substitution. The term "haloaliphatic" also
includes perhaloaliphatic, in which all of the hydrogen atoms of
the aliphatic are replaced by halogen atoms. Examples of
perhaloaliphatic include trichloromethyl, pentacholorethyl,
etc.
[0131] The term "heteroaliphatic," alone or in combination, refers
to a group comprising an aliphatic and one or more heteroatoms.
Certain heteroaliphatics are acylaliphatics, in which the one or
more heteroatoms is not within an aliphatic chain. Heteroaliphatics
include heteroalkyls, including, but not limited to acylalkys;
heteroalkenyls, including, but not limited to, acylalkenyls; and
heteroalkynyls, including, but not limited acylalkynyls. Examples
of heteraliphatics include, but are not limited to,
CH.sub.3C(.dbd.O)CH.sub.2--, CH.sub.3C(.dbd.O)CH.sub.2CH.sub.2--,
CH.sub.3CH.sub.2C(.dbd.O)CH.sub.2CH.sub.2--,
CH.sub.3C(.dbd.O)CH.sub.2CH.sub.2CH.sub.2--,
CH.sub.3OCH.sub.2CH.sub.2--, CH.sub.3NHCH.sub.2--, and the like. In
certain embodiments, heteroaliphatics are optionally
substituted.
[0132] The term "heterohaloaliphatic" refers to a heteroaliphatic
in which at least one hydrogen atom is replaced with a halogen
atom. Heterohaloaliphatics include heterohaloalkyls,
heterohaloalkenyls, and heterohaloalkynyls. In certain embodiments,
heterohaloaliphatics are optionally substituted.
[0133] The term "olefin" refers to a C.dbd.C bond. The term
"together form an olefin" refers to instances where two groups are
bound to the same carbon atom and one of those two groups is .dbd.C
and the other of those two groups is null. For example, if R' and
R'' in the structure below together form an olefin: ##STR8## the
resulting structure is: ##STR9##
[0134] wherein R''' and R'''' represent hydrogen. Olefins may be
optional substituted, in which case R''' and R'''' above are
independently selected from hydrogen and an optional
substituent.
[0135] The term "carbocycle" refers to a group comprising a
covalently closed ring, wherein each of the atoms forming the ring
is a carbon atom. Carbocylic rings may be formed by three, four,
five, six, seven, eight, nine, or more than nine carbon atoms.
Carbocycles may be optionally substituted.
[0136] The term "heterocycle" refers to a group comprising a
covalently closed ring wherein at least one atom forming the ring
is a carbon atom and at least one atom forming the ring is a
heteroatom. Heterocyclic rings may be formed by three, four, five,
six, seven, eight, nine, or more than nine atoms. Any number of
those atoms may be heteroatoms (i.e., a heterocyclic ring may
comprise one, two, three, four, five, six, seven, eight, nine, or
more than nine heteroatoms). Herein, whenever the number of carbon
atoms in a heterocycle is indicated (e.g., C.sub.1-C.sub.6
heterocycle), at least one other atom (the heteroatom) must be
present in the ring. Designations such as "C.sub.1-C.sub.6
heterocycle" refer only to the number of carbon atoms in the ring
and do not refer to the total number of atoms in the ring. It is
understood that the heterocylic ring will have additional
heteroatoms in the ring. In heterocycles comprising two or more
heteroatoms, those two or more heteroatoms may be the same or
different from one another. Heterocycles may be optionally
substituted. Binding to a heterocycle can be at a heteroatom or via
a carbon atom. Examples of heterocycles include, but are not
limited to the following: ##STR10## wherein D, E, F, and G
independently represent a heteroatom. Each of D, E, F, and G may be
the same or different from one another.
[0137] The term "heteroatom" refers to an atom other than carbon or
hydrogen. Heteroatoms are typically independently selected from
oxygen, sulfur, nitrogen, and phosphorus, but are not limited to
those atoms. In embodiments in which two or more heteroatoms are
present, the two or more heteroatoms may all be the same as one
another, or some or all of the two or more heteroatoms may each be
different from the others.
[0138] The term "aromatic" refers to a group comprising a
covalently closed planar ring having a delocalized .pi.-electron
system comprising 4n+2.pi. electrons, where n is an integer.
Aromatic rings may be formed by five, six, seven, eight, nine, or
more than nine atoms. Aromatics may be optionally substituted.
Examples of aromatic groups include, but are not limited to phenyl,
naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl,
indenyl, and indanyl. The term aromatic includes, for example,
benzenoid groups, connected via one of the ring-forming carbon
atoms, and optionally carrying one or more substituents selected
from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic
heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an
alkylamido, an acyl, a C.sub.1-6 alkoxy, a C.sub.1-6 alkyl, a
C.sub.1-6 hydroxyalkyl, a C.sub.1-6 aminoalkyl, a C.sub.1-6
alkylamino, an alkylsulfenyl, an alkylsulfinyl, an alkylsulfonyl,
an sulfamoyl, or a trifluoromethyl. In certain embodiments, an
aromatic group is substituted at one or more of the para, meta,
and/or ortho positions. Examples of aromatic groups comprising
substitutions include, but are not limited to, phenyl,
3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,
3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl,
3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl,
hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl,
alkoxyphenyl, 4-morpholin-4-ylphenyl, 4-pyrrolidin-1-ylphenyl,
4-pyrazolylphenyl, 4-triazolylphenyl, and
4-(2-oxopyrrolidin-1-yl)phenyl.
[0139] The term "aryl" refers to an aromatic ring wherein each of
the atoms forming the ring is a carbon atom. Aryl rings may be
formed by five, six, seven, eight, nine, or more than nine carbon
atoms. Aryl groups may be optionally substituted.
[0140] The term "heteroaryl" refers to an aromatic heterocycle.
Heteroaryl rings may be formed by three, four, five, six, seven,
eight, nine, or more than nine atoms. Heteroaryls may be optionally
substituted. Examples of heteroaryl groups include, but are not
limited to, aromatic C.sub.3-8 heterocyclic groups comprising one
oxygen or sulfur atom or up to four nitrogen atoms, or a
combination of one oxygen or sulfur atom and up to two nitrogen
atoms, and their substituted as well as benzo- and pyrido-fused
derivatives, for example, connected via one of the ring-forming
carbon atoms. In certain embodiments, heteroaryl groups are
optionally substituted with one or more substituents, independently
selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl,
C.sub.1-6-alkoxy, C.sub.1-6-alkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-aminoalkyl, C.sub.1-6-alkylamino, alkylsulfenyl,
alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl.
Examples of heteroaryl groups include, but are not limited to,
unsubstituted and mono- or di-substituted derivatives of furan,
benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole,
oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole,
benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole,
indazole, tetrazole, quinoline, isoquinoline, pyridazine,
pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole,
1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole,
pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine,
cinnoline, phthalazine, quinazoline, and quinoxaline. In some
embodiments, the substituents are halo, hydroxy, cyano,
O--C.sub.1-6-alkyl, C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, and
amino-C.sub.1-6-alkyl.
[0141] The term "non-aromatic ring" refers to a group comprising a
covalently closed ring that is not aromatic.
[0142] The term "alicyclic" refers to a group comprising a
non-aromatic ring wherein each of the atoms forming the ring is a
carbon atom. Alicyclic rings may be formed by three, four, five,
six, seven, eight, nine, or more than nine carbon atoms. In certain
embodiments, alicyclics are optionally substituted. In certain
embodiments, an alicyclic comprises one or more unsaturated bonds.
Alicyclics include cycloalkyls, cycloalkenyls, and cycloalkynyls.
Examples of alicyclics include, but are not limited to,
cyclopropane, cyclobutane, cyclopentane, cyclopentene,
cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene,
1,4-cyclohexadiene, cycloheptane, and cycloheptene. In certain
embodiments, alicylcic rings are optionally substituted.
[0143] The term "non-aromatic heterocycle" refers to a group
comprising a non-aromatic ring wherein one or more atoms forming
the ring is a heteroatom. Non-aromatic heterocyclic rings may be
formed by three, four, five, six, seven, eight, nine, or more than
nine atoms. Non-aromatic heterocycles may be optionally
substituted. In certain embodiments, non-aromatic heterocycles
comprise one or more carbonyl or thiocarbonyl groups such as, for
example, oxo- and thio-containing groups. Examples of non-aromatic
heterocycles include, but are not limited to, lactams, lactones,
cyclic imides, cyclic thioimides, cyclic carbamates,
tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine,
1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine,
1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,
tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,
barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,
dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,
tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,
pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,
imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole,
1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine,
oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane.
[0144] The term "arylalkyl" refers to a group comprising an aryl
group bound to an alkyl group.
[0145] The term "ring" refers to any covalently closed structure.
Rings include, for example, carbocycles (e.g., aryls and
alicyclics), heterocycles (e.g., heteroaryls and non-aromatic
heterocycles), aromatics (e.g., aryls and heteroaryls), and
non-aromatics (e.g., alicyclics and non-aromatic heterocycles).
Rings may be optionally substituted. Rings may form part of a ring
system.
[0146] The term "ring system" refers to two or more rings, wherein
two or more of the rings are fused. The term "fused" refers to
structures in which two or more rings share one or more bonds.
[0147] The term "null" refers to a group being absent from a
structure. For example, in the structure ##STR11## where in certain
instances X is N, if X is N, one of R' or R'' is null, meaning that
only three groups are bound to the N.
[0148] The term "carboxylic acid bioisostere" refers to a group
that is biologically equivalent to a carboxylic acid. For example,
carboxylic acid bioisosteres include, but are not limited to,
tetrazole, NHSO.sub.2R.sup.15, OC(S)NR.sup.10R.sup.11,
SC(O)NR.sup.10R.sup.11, thiazolidinedione, oxazolidinedione, and
1-oxa-2,4-diazolidine-3,5-dione. In certain embodiments, a
carboxylic acid bioisoster comprises the following structure:
##STR12## wherein A, B, and C are each independently selected from
O, S, and N.
[0149] The term "spacer" refers to an atom or group of atoms that
separate two or more groups from one another by a desired number of
atoms. For example, in certain embodiments, it may be desirable to
separate two or more groups by one, two, three, four, five, six, or
more than six atoms. In such embodiments, any atom or group of
atoms may be used to separate those groups by the desired number of
atoms. In certain embodiments, spacers are optionally substituted.
In certain embodiments, a spacer comprises an aliphatic. In certain
embodiments, a spacer comprises atoms that are part of a ring.
[0150] Solely for the purposes of illustration, and without
limiting the above definition, some examples of spacers are
provided. Examples of 1-atom spacers include, but are not limited
to, the following: ##STR13## where A and B represent groups which
are separated by the desired number of atoms. Examples of 2-atom
spacers include, but are not limited to, the following: ##STR14##
where A and B represent groups which are separated by the desired
number of atoms. Examples of 3-atom spacers include, but are not
limited to, the following: ##STR15## where A and B represent groups
that are separated by the desired number of atoms.
[0151] In certain embodiments, a spacer separates atoms in a ring.
For example, in the structure: ##STR16## where Q is a 1-atom
spacer, the resulting ring is a three-membered ring comprising A,
B, and Q, where Q may be optionally substituted. An example of such
a structure includes, but is not limited to: ##STR17## If Q is a
2-atom spacer, then a four-membered ring results; if Q is a three
atom spacer, then a five-membered ring results; if Q is a four atom
spacer, then a six-membered ring results; if Q is a five atom
spacer, then a seven-membered ring results; if Q is a six atom
spacer, then an eight-membered ring results; and so on. In certain
embodiments, a spacer in a ring comprises a ring, such that the
ring formed by the spacer and the ring comprised by the spacer are
fused. For example, referring to the structure above where Q is a
3-atom spacer comprising a fused ring includes, but is not limited
to, structures such as: ##STR18## where the fused ring can be fused
at any bond of the spacer. Such a fused ring may be optionally
substituted and may be heterocyclic or carbocyclic.
[0152] As is evident from the above examples, the atoms of a spacer
that create the desired separation may themselves be part of a
group. That group may be, for example, an aliphatic,
heteroaliphatic, haloaliphatic, heterohaloaliphatic, alicyclic,
aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, or
substituted alkyl all of which are optionally substituted. Thus,
the term "1-5 atom spacer" refers to a spacer that separates two
groups by 1, 2, 3, 4, or 5 atoms and does not indicate the total
size of the group that constitutes the spacer.
[0153] The term "linked to form a ring" refers to the circumstance
where two atoms that are bound either to a single atom or to atoms
that are themselves ultimately bound, are each bound to a linking
group, such that the resulting structure forms a ring. That
resulting ring comprises the two atoms, the atom (or atoms) that
previously linked those atoms, and the linker. For example, if A
and B below are "linked to form a ring" ##STR19## the resulting
ring includes A, B, the carbon atom to which both A and B are
bound, and a linking group. Unless otherwise indicated, that
linking group may be of any length and may be optionally
substituted. Referring to the above example, resulting structures
include, but are not limited to: ##STR20## and the like. In certain
embodiments, the two atoms that are linked to form a ring are not
bound to the same atom. For example, if A and B, below, are linked
to form a ring: ##STR21## the resulting ring comprises A, B, the 3
carbon atoms that already link A and B, and a linking group.
Examples of resulting structures include, but are not limited to:
##STR22## and the like.
[0154] The substituent "R" appearing by itself and without a number
designation refers to a substituent selected from alkyl,
cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and
non-aromatic heterocycle (bonded through a ring carbon).
[0155] The term "O-carboxy" refers to a group of formula
RC(.dbd.O)O--.
[0156] The term "C-carboxy" refers to a group of formula
--C(.dbd.O)OR.
[0157] The term "acetyl" refers to a group of formula
--C(.dbd.O)CH.sub.3.
[0158] The term "trihalomethanesulfonyl" refers to a group of
formula X.sub.3CS(.dbd.O).sub.2-- where X is a halogen.
[0159] The term "cyano" refers to a group of formula --CN.
[0160] The term "isocyanato" refers to a group of formula
--NCO.
[0161] The term "thiocyanato" refers to a group of formula
--CNS.
[0162] The term "isothiocyanato" refers to a group of formula
--NCS.
[0163] The term "sulfonyl" refers to a group of formula
--S(.dbd.O)--R.
[0164] The term "S-sulfonamido" refers to a group of formula
--S(.dbd.O).sub.2NR.
[0165] The term "N-sulfonamido" refers to a group of formula
RS(.dbd.O).sub.2NH--.
[0166] The term "trihalomethanesulfonamido" refers to a group of
formula X.sub.3CS(.dbd.O).sub.2NR--.
[0167] The term "O-carbamyl" refers to a group of formula
--OC(.dbd.O)--NR.
[0168] The term "N-carbamyl" refers to a group of formula
ROC(.dbd.O)NH--.
[0169] The term "O-thiocarbamyl" refers to a group of formula
--OC(.dbd.S)--NR.
[0170] The term "N-thiocarbamyl" refers to a group of formula
ROC(.dbd.S)NH--.
[0171] The term "C-amido" refers to a group of formula
--C(.dbd.O)--NR.sub.2.
[0172] The term "N-amido" refers to a group of formula
RC(.dbd.O)NH--.
[0173] The term "ester" refers to a chemical moiety with formula
--(R).sub.n--COOR', where R and R' are independently selected from
alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon)
and non-aromatic heterocycle (bonded through a ring carbon), where
n is 0 or 1.
[0174] The term "amide" refers to a chemical moiety with formula
--(R).sub.n--C(O)NHR' or --(R).sub.n--NHC(O)R', where R and R' are
independently selected from alkyl, cycloalkyl, aryl, heteroaryl
(bonded through a ring carbon) and heteroalicyclic (bonded through
a ring carbon), where n is 0 or 1. In certain embodiments, an amide
may be an amino acid or a peptide.
[0175] The terms "amine," "hydroxy," and "carboxyl" include such
groups that have been esterified or amidified. Procedures and
specific groups used to achieve esterification and amidification
are known to those of skill in the art and can readily be found in
reference sources such as Greene and Wuts, Protective Groups in
Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York,
N.Y., 1999, which is incorporated herein in its entirety.
[0176] Unless otherwise indicated, the term "optionally
substituted," refers to a group in which none, one, or more than
one of the hydrogen atoms has been replaced with one or more
group(s) are independently selected from: alkyl, heteroalkyl,
haloalkyl, heteroholoalkyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy,
mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl,
O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,
N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,
isocyanato, thiocyanato, isothiocyanato, nitro, silyl,
trihalomethanesulfonyl, and amino, including mono- and
di-substituted amino groups, and the protected derivatives of amino
groups. Such protective derivatives (and protecting groups that may
form such protective derivatives) are known to those of skill in
the art and may be found in references such as Greene and Wuts,
above. In embodiments in which two or more hydrogen atoms have been
substituted, the substituent groups may be linked to form a
ring.
[0177] The term "carrier" refers to a compound that facilitates the
incorporation of another compound into cells or tissues. For
example, dimethyl sulfoxide (DMSO) is a commonly used carrier for
improving incorporation of certain organic compounds into cells or
tissues.
[0178] The term "pharmaceutical agent" refers to a chemical
compound or composition capable of inducing a desired therapeutic
effect in a patient. In certain embodiments, a pharmaceutical agent
comprises an active agent, which is the agent that induces the
desired therapeutic effect. In certain embodiments, a
pharmaceutical agent comprises a prodrug. In certain embodiments, a
pharmaceutical agent comprises inactive ingredients such as
carriers, excipients, and the like.
[0179] The term "pharmaceutical composition" refers to a
pharmaceutical agent together with one or more inactive ingredient
for pharmaceutical administration, such as a carrier, excipient, or
the like.
[0180] The term "therapeutically effective amount" refers to an
amount of a pharmaceutical agent or composition sufficient to
achieve a desired therapeutic effect.
[0181] The term "prodrug" refers to an pharmaceutical agent that is
converted from a less active form into a corresponding more active
form in vivo.
[0182] The term "pharmaceutically acceptable" refers to a
formulation of a compound that does not significantly abrogate the
biological activity, a pharmacological activity and/or other
properties of the compound when the formulated compound is
administered to a patient. In certain embodiments, a
pharmaceutically acceptable formulation does not cause significant
irritation to a patient.
[0183] The term "co-administer" refers to administering more than
one pharmaceutical agent to a patient. In certain embodiments,
co-administered pharmaceutical agents are administered together in
a single dosage unit. In certain embodiments, co-administered
pharmaceutical agents are administered separately. In certain
embodiments, co-administered pharmaceutical agents are administered
at the same time. In certain embodiments, co-administered
pharmaceutical agents are administered at different times.
[0184] The term "patient" includes human and animal subjects.
[0185] The term "substantially pure" means an object species (e.g.,
compound) is the predominant species present (i.e., on a molar
basis it is more abundant than any other individual species in the
composition). In certain embodiments, a substantially purified
fraction is a composition wherein the object species comprises at
least about 50 percent (on a molar basis) of all species present.
In certain embodiments, a substantially pure composition will
comprise more than about 80%, 85%, 90%, 95%, or 99% of all species
present in the composition. In certain embodiments, the object
species is purified to essential homogeneity (contaminant species
cannot be detected in the composition by conventional detection
methods) wherein the composition consists essentially of a single
species.
[0186] The term "tissue-selective" refers to the ability of a
compound to modulate a biological activity in one tissue to a
greater or lesser degree than it modulates a biological activity in
another tissue. The biological activities in the different tissues
may be the same or they may be different. The biological activities
in the different tissues may be mediated by the same type of target
receptor. For example, in certain embodiments, a tissue-selective
compound may modulate receptor mediated biological activity in one
tissue and fail to modulate, or modulate to a lesser degree,
receptor mediated biological activity in another tissue type.
[0187] The term "monitoring" refers to observing an effect or
absence of any effect. In certain embodiments, one monitors cells
after contacting those cells with a compound of the present
invention. Examples of effects that may be monitored include, but
are not limited to, changes in cell phenotype, cell proliferation,
receptor activity, or the interaction between a receptor and a
compound known to bind to the receptor.
[0188] The term "cell phenotype" refers to physical or biological
characteristics of a cell. Examples of characteristics that
constitute phenotype included, but are not limited to, cell size,
cell proliferation, cell differentiation, cell survival, apoptosis
(cell death), or the utilization of a metabolic nutrient (e.g.,
glucose uptake). Certain changes or the absence of changes in cell
phenotype are readily monitored using techniques known in the
art.
[0189] The term "cell proliferation" refers to the rate at which
cells divide. In certain embodiments, cells are in situ in an
organism. In certain embodiments, cell are grown in vitro in a
vessel. The number of cells growing in a vessel can be quantified
by a person skilled in the art (e.g., by counting cells in a
defined area using a microscope or by using laboratory apparatus
that measure the density of cells in an appropriate medium). One
skilled in that art can calculate cell proliferation by determining
the number of cells at two or more times.
[0190] The term "contacting" refers to bringing two or more
materials into close enough proximity that they may interact. In
certain embodiments, contacting can be accomplished in a vessel
such as a test tube, a petri dish, or the like. In certain
embodiments, contacting may be performed in the presence of
additional materials. In certain embodiments, contacting may be
performed in the presence of cells. In certain of such embodiments,
one or more of the materials that are being contacted may be inside
a cell. Cells may be alive or may dead. Cells may or may not be
intact.
Certain Compounds
[0191] Certain compounds that modulate one or more TPO activity
and/or bind to TPO receptors play a role in health. In certain
embodiments, compounds of the present invention are useful for
treating any of a variety of diseases or conditions.
[0192] In certain embodiments, the present invention provides
selective TPO modulators. In certain embodiments, the invention
provides selective TPO receptor binding agents. In certain
embodiments, the invention provides methods of making and methods
of using selective TPO modulators and/or selective TPO receptor
binding agents. In certain embodiments, selective TPO modulators
are agonists, partial agonists, and/or antagonists for the TPO
receptor.
[0193] In certain embodiments, the present invention relates to
compounds of Formula I, II, or III: ##STR23## or a pharmaceutically
acceptable salt, ester, amide, or prodrug thereof.
[0194] In certain embodiments, R.sup.1 is selected from hydrogen,
CO.sub.2R.sup.10, CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a
carboxylic acid bioisostere. In certain embodiments in which
R.sup.1 is a carboxylic acid bioisostere, R.sup.1 is selected from
tetrazole, NHSO.sub.2R.sup.15, OC(S)NR.sup.10R.sup.11,
SC(O)NR.sup.10R.sup.11, thiazolidinedione, oxazolidinedione, and
1-oxa-2,4-diazolidine-3,5-dione.
[0195] In certain embodiments, R.sup.2 and R.sup.3 are each
independently selected from hydrogen, OR.sup.12, NR.sup.12R.sup.13,
an optionally substituted C.sub.1-C.sub.4 aliphatic, an optionally
substituted C.sub.1-C.sub.4 haloaliphatic, an optionally
substituted C.sub.1-C.sub.4 heteroaliphatic,
(CH.sub.2).sub.mR.sup.14, an optionally substituted ring, and null.
In certain such embodiments, R.sup.2 and R.sup.3 are each
independently selected from an optionally substituted
C.sub.1-C.sub.4 alkyl, an optionally substituted C.sub.1-C.sub.4
haloalkyl, an optionally substituted C.sub.1-C.sub.4 heteroalkyl.
In certain embodiments, R.sup.2 and R.sup.3 taken together form an
optionally substituted olefin. In certain embodiments, R.sup.2 and
R.sup.3 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring. In certain such embodiments, R.sup.2 and
R.sup.3 are linked to form an optionally substituted carbocycle, an
optionally substituted heterocycle, an optionally substituted
aromatic, or an optionally substituted non-aromatic ring. In
certain such embodiments, R.sup.2 and R.sup.3 are linked to form an
optionally substituted aryl, an optionally substituted heteroaryl,
an optionally substituted alicyclic, or an optionally substituted
non-aromatic heterocyclic. In certain embodiments, R.sup.2 and
R.sup.3 are linked to form an optionally substituted aryl or an
optionally substituted heteroaryl. In certain embodiments, R.sup.2
and R.sup.3 are linked to form an optionally substituted aryl. In
certain embodiments, R.sup.2 and R.sup.3 are linked to form an
aryl.
[0196] In certain embodiments, R.sup.4 is selected from hydrogen,
F, Cl, Br, optionally substituted C.sub.1-C.sub.4 aliphatic,
optionally substituted C.sub.1-C.sub.4 haloaliphatic, optionally
substituted C.sub.1-C.sub.4 heteroaliphatic, and an optionally
substituted ring. In certain such embodiments, R.sup.4 is selected
from optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 haloalkyl, and optionally substituted
C.sub.1-C.sub.4 heteroalkyl.
[0197] In certain embodiments, R.sup.5 is selected from hydrogen,
OR.sup.10, SR.sup.10, NHR.sup.11, and CO.sub.2H.
[0198] In certain embodiments, R.sup.6 is selected from hydrogen,
OR.sup.2, NR.sup.12R.sup.13, F, Cl, Br, optionally substituted
C.sub.1-C.sub.4 aliphatic, optionally substituted C.sub.1-C.sub.4
haloaliphatic, optionally substituted C.sub.1-C.sub.4
heteroaliphatic, and an optionally substituted ring. In certain
such embodiments, R.sup.6 is selected from optionally substituted
C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.1-C.sub.4
haloalkyl, and optionally substituted C.sub.1-C.sub.4 heteroalkyl.
In certain embodiments, R.sup.6 is selected from an optionally
substituted carbocycle, an optionally substituted heterocycle, and
optionally substituted aromatic, and an optionally substituted
non-aromatic ring. In certain such embodiments, R.sup.6 is selected
from an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted alicyclic, and an optionally
substituted non-aromatic heterocyclic. In certain embodiments,
R.sup.6 is selected from an optionally substituted aryl and an
optionally substituted heteroaryl. In certain embodiments, R.sup.6
is selected from an optionally substituted aryl. In certain
embodiments, R.sup.6 is an aryl.
[0199] In certain embodiments, R.sup.7 is selected from hydrogen,
an optionally substituted C.sub.1-C.sub.8 aliphatic, an optionally
substituted C.sub.1-C.sub.8 haloaliphatic, an optionally
substituted C.sub.1-C.sub.8 heteroaliphatic, an optionally
substituted C.sub.1-C.sub.8 heterohaloaliphatic, an optionally
substituted ring, and (CH.sub.2).sub.mR.sup.14. In certain such
embodiments, R.sup.7 is selected from an optionally substituted
C.sub.1-C.sub.8 alkyl, an optionally substituted C.sub.1-C.sub.8
haloalkyl, an optionally substituted C.sub.1-C.sub.8 heteroalkyl,
and an optionally substituted C.sub.1-C.sub.8 heterohaloalkyl. In
certain embodiments, R.sup.7 is selected from an optionally
substituted carbocycle, an optionally substituted heterocycle, and
optionally substituted aromatic, and an optionally substituted
non-aromatic ring. In certain such embodiments, R.sup.7 is selected
from an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted alicyclic, and an optionally
substituted non-aromatic heterocyclic. In certain embodiments,
R.sup.7 is selected from an optionally substituted aryl and an
optionally substituted heteroaryl. In certain embodiments, R.sup.7
is selected from an optionally substituted aryl. In certain such
embodiments, R.sup.7 is selected from an aryl ring optionally fused
to one or more additional rings. In certain embodiments, R.sup.7 is
an aryl. In certain embodiments, R.sup.7 is an optionally
substituted phenyl ring.
[0200] In certain embodiments, R.sup.8 and R.sup.9 are each
independently selected from hydrogen, F, Cl, Br, optionally
substituted C.sub.1-C.sub.4 aliphatic, optionally substituted
C.sub.1-C.sub.4 haloaliphatic, optionally substituted
C.sub.1-C.sub.4 heteroaliphatic, optionally substituted
C.sub.1-C.sub.4 heterohaloaliphatic, and an optionally substituted
ring. In certain such embodiments, R.sup.8 and/or R.sup.9 is
independently selected from optionally substituted C.sub.1-C.sub.4
alkyl, optionally substituted C.sub.1-C.sub.4 haloalkyl, optionally
substituted C.sub.1-C.sub.4 heteroalkyl, and optionally substituted
C.sub.1-C.sub.4 heterohaloalkyl. In certain embodiments, R.sup.8
and/or R.sup.9 is selected from an optionally substituted
carbocycle, an optionally substituted heterocycle, and optionally
substituted aromatic, and an optionally substituted non-aromatic
ring. In certain such embodiments, R.sup.8 and/or R.sup.9 is
selected from an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted alicyclic, and an
optionally substituted non-aromatic heterocyclic. In certain
embodiments, R.sup.8 and/or R.sup.9 is selected from an optionally
substituted aryl and an optionally substituted heteroaryl. In
certain embodiments, R.sup.8 and/or R.sup.9 is selected from an
optionally substituted aryl. In certain embodiments, R.sup.8 and/or
R.sup.9 is an aryl.
[0201] In certain embodiments, R.sup.10 is selected from hydrogen,
optionally substituted C.sub.1-C.sub.4 aliphatic, optionally
substituted C.sub.1-C.sub.4 haloaliphatic, optionally substituted
C.sub.1-C.sub.4 heteroaliphatic, optionally substituted
C.sub.1-C.sub.4 heterohaloaliphatic, an optionally substituted
ring. In certain such embodiments, R.sup.10 is selected from
optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 haloalkyl, optionally substituted
C.sub.1-C.sub.4 heteroalkyl, and optionally substituted
C.sub.1-C.sub.4 heterohaloalkyl. In certain embodiments, R.sup.10
is selected from an optionally substituted ring. In certain such
embodiments, R.sup.10 is selected from an optionally substituted
carbocycle, an optionally substituted heterocycle, and optionally
substituted aromatic, and an optionally substituted non-aromatic
ring. In certain such embodiments, R.sup.10 is selected from an
optionally substituted aryl, an optionally substituted heteroaryl,
an optionally substituted alicyclic, and an optionally substituted
non-aromatic heterocyclic. In certain embodiments, R.sup.10 is
selected from an optionally substituted aryl and an optionally
substituted heteroaryl. In certain embodiments, R.sup.10 is
selected from an optionally substituted aryl. In certain
embodiments, R.sup.10 is an aryl.
[0202] In certain embodiments, R.sup.11 is selected from hydrogen,
SO.sub.2R.sup.15, optionally substituted C.sub.1-C.sub.4 aliphatic,
optionally substituted C.sub.1-C.sub.4 haloaliphatic, optionally
substituted C.sub.1-C.sub.4 heteroaliphatic, optionally substituted
C.sub.1-C.sub.4 heterohaloaliphatic, and an optionally substituted
ring. In certain such embodiments, R.sup.11 is selected from
optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 haloalkyl, optionally substituted
C.sub.1-C.sub.4 heteroalkyl, and optionally substituted
C.sub.1-C.sub.4 heterohaloalkyl. In certain embodiments, R.sup.11
is selected from an optionally substituted ring. In certain such
embodiments, R.sup.11 is selected from an optionally substituted
carbocycle, an optionally substituted heterocycle, and optionally
substituted aromatic, and an optionally substituted non-aromatic
ring. In certain such embodiments, R.sup.11 is selected from an
optionally substituted aryl, an optionally substituted heteroaryl,
an optionally substituted alicyclic, and an optionally substituted
non-aromatic heterocyclic. In certain embodiments, R.sup.11 is
selected from an optionally substituted aryl and an optionally
substituted heteroaryl. In certain embodiments, R.sup.11 is
selected from an optionally substituted aryl. In certain
embodiments, R.sup.11 is an aryl.
[0203] In some embodiments, R.sup.12 and R.sup.13 are each
independently selected from hydrogen, optionally substituted
C.sub.1-C.sub.4 aliphatic, optionally substituted C.sub.1-C.sub.4
haloaliphatic, optionally substituted C.sub.1-C.sub.4
heteroaliphatic, optionally substituted C.sub.1-C.sub.4
heterohaloaliphatic, an optionally substituted ring, and
(CH.sub.2).sub.mR.sup.4. In certain such embodiments, R.sup.12
and/or R.sup.13 is independently selected from optionally
substituted C.sub.1-C.sub.4 alkyl, optionally substituted
C.sub.1-C.sub.4 haloalkyl, optionally substituted C.sub.1-C.sub.4
heteroalkyl, and optionally substituted C.sub.1-C.sub.4
heterohaloalkyl. In certain embodiments, R.sup.12 and/or R.sup.13
is selected from an optionally substituted carbocycle, an
optionally substituted heterocycle, and optionally substituted
aromatic, and an optionally substituted non-aromatic ring. In
certain such embodiments, R.sup.12 and/or R.sup.13 is selected from
an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted alicyclic, and an optionally
substituted non-aromatic heterocyclic. In certain embodiments,
R.sup.12 and/or R.sup.13 is selected from an optionally substituted
aryl and an optionally substituted heteroaryl. In certain
embodiments, R.sup.12 and/or R.sup.3 is selected from an optionally
substituted aryl. In certain embodiments, R.sup.12 and/or R.sup.13
is an aryl. In certain embodiments, one of R.sup.12 or R.sup.13 is
a ring and the other of R.sup.12 and R.sup.13 is hydrogen.
[0204] In certain embodiments, R.sup.12 and R.sup.13 are linked to
form an optionally substituted C.sub.2-C.sub.8 heterocycle. In
certain embodiments, R.sup.12 and R.sup.13 are linked to form an
optionally substituted C.sub.2-C.sub.8 heteroaryl. In certain
embodiments, R.sup.12 and R.sup.13 are linked to form an optionally
substituted C.sub.2-C.sub.8 non-aromatic heterocycle.
[0205] In certain embodiments, R.sup.14 is selected from an
optionally substituted ring. In certain such embodiments, R.sup.14
is selected from an optionally substituted carbocycle, an
optionally substituted heterocycle, and optionally substituted
aromatic, and an optionally substituted non-aromatic ring. In
certain such embodiments, R.sup.14 is selected from an optionally
substituted aryl, an optionally substituted heteroaryl, an
optionally substituted alicyclic, and an optionally substituted
non-aromatic heterocyclic. In certain embodiments, R.sup.14 is
selected from an optionally substituted aryl and an optionally
substituted heteroaryl. In certain embodiments, R.sup.14 is
selected from an optionally substituted aryl. In certain
embodiments, R.sup.14 is an aryl.
[0206] In certain embodiments, R.sup.15 is selected from hydrogen,
optionally substituted C.sub.1-C.sub.3 aliphatic, optionally
substituted C.sub.1-C.sub.3 haloaliphatic, and optionally
substituted ring. In certain such embodiments, R.sup.15 is selected
from optionally substituted C.sub.1-C.sub.3 alkyl, and optionally
substituted C.sub.1-C.sub.3 haloalkyl. In certain embodiments,
R.sup.15 is an optionally substituted aryl. In certain embodiments,
R.sup.15 is selected from an alkyl, a haloalkyl, an alicyclic, and
an aryl. In certain embodiments, R is selected from an optionally
substituted ring. In certain such embodiments, R.sup.15 is selected
from an optionally substituted carbocycle, an optionally
substituted heterocycle, and optionally substituted aromatic, and
an optionally substituted non-aromatic ring. In certain such
embodiments, R.sup.15 is selected from an optionally substituted
aryl, an optionally substituted heteroaryl, an optionally
substituted alicyclic, and an optionally substituted non-aromatic
heterocyclic. In certain embodiments, R.sup.15 is selected from an
optionally substituted aryl and an optionally substituted
heteroaryl. In certain embodiments, R.sup.15 is selected from an
optionally substituted aryl. In certain embodiments, R.sup.15 is an
aryl.
[0207] In certain embodiments, Y is a 1, 2, 3, 4, 5, 7, or 8 atom
spacer. In certain embodiments, Y is a 1-4 atom spacer selected
from optionally substituted C.sub.1-C.sub.6 aliphatic and
optionally substituted C.sub.1-C.sub.6 heteroaliphatic. In certain
such embodiments, Y is a 1-4 atom spacer selected from optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6
alkenyl, and optionally substituted C.sub.2-C.sub.6
heteroalkenyl.
[0208] In certain embodiments, Y is a 1-4 atom spacer comprising a
ring. In certain such embodiments, Y is selected from optionally
substituted phenyl, optionally substituted monocyclic heteroaryl,
optionally substituted C.sub.3-C.sub.5 heterocycle, and optionally
substituted alicyclic, including, but not limited to, optionally
substituted cycloalkyl and optionally substituted cycloalkenyl.
[0209] In certain embodiments, Y is a 2-6 atom spacer comprising
both (1) a ring selected from optionally substituted phenyl,
optionally substituted monocyclic heteroaryl, optionally
substituted C.sub.3-C.sub.5 heterocycle, and optionally substituted
alicyclic and (2) 1-4 atoms selected from optionally substituted
C.sub.1-C.sub.6 aliphatic, and optionally substituted
C.sub.1-C.sub.6 heteroaliphatic.
[0210] In certain embodiments, Y is not --N.dbd.CR.sup.6--
orientated to form the dihydropyrazole. Thus, in such embodiments,
the ring that includes Y cannot be: ##STR24##
[0211] In certain embodiments, Y is selected from: ##STR25##
[0212] In certain embodiments, Q is selected from O and S.
[0213] In certain embodiments, X is selected from O, S, NR.sup.10,
and CR.sup.10R.sup.10;
[0214] In certain embodiments, Z is a 1 to 5 atom spacer. In
certain embodiments, Z is a 2-5 atom spacer selected from an
optionally substituted C.sub.6-C.sub.10 aryl and an optionally
substituted C.sub.1-C.sub.8 heteroaryl. In certain embodiments, Z
is a 1-5 atom spacer selected from an optionally substituted
C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6
heteroalkyl, an optionally substituted C.sub.1-C.sub.6 haloalkyl,
an optionally substituted C.sub.2-C.sub.6 alkenyl, an optionally
substituted C.sub.2-C.sub.6 heteroalkenyl, an optionally
substituted C.sub.2-C.sub.6 haloalkenyl, an optionally substituted
C.sub.2-C.sub.6 alkynyl, and an optionally substituted
C.sub.2-C.sub.6 heteroalkyl.
[0215] In certain embodiments, m is 0, 1, or 2.
[0216] In certain embodiments, n is 0 or 1. In embodiments in which
n is 0, R.sup.1 binds directly to Z and R.sup.2 and/or R.sup.3 are
null, as appropriate. For example, if Z is a phenyl ring and n is
0, then R.sup.1 binds directly to the phenyl ring and both R.sup.1
and R.sup.2 are null.
[0217] In embodiments in which two or more of a particular group
are present, the identities of those two or more particular groups
are selected independently and, thus, may be the same or different
from one another. For example, certain compounds of the invention
comprise two or more R.sup.14 groups. The identities of those two
or more R.sup.14 groups are each selected independently. Thus, in
certain embodiments, those R.sup.14 groups are all the same as one
another; in certain embodiments, those R.sup.14 groups are all
different from one another; and in certain embodiments, some of
those R.sup.14 groups are the same as one another and some are
different from one another. This independent selection applies to
any group that is present in a compound more than once.
[0218] One of ordinary skill in the art will recognize that the
complete lists of possible identities for each above-listed group
(all R groups, Y, Q, Z, m, and n) may be narrowed to provide
shorter lists of possible identities. For example, since in certain
embodiments R.sup.1 is selected from hydrogen, CO.sub.2R.sup.10,
CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic acid
bioisostere, it is to be understood that in certain embodiments,
R.sup.1 may be selected from CO.sub.2R.sup.10, CONR.sup.10R.sup.11,
and SO.sub.3R.sup.10, because each of those possible identities is
included on the longer list of possible identities. One of ordinary
skill in the art will also recognize that broader terms include
combinations of narrower terms, which may be substituted and
selected. For example, in certain embodiments, R.sup.2 is selected
from an optionally substituted C.sub.1-C.sub.4 aliphatic. Because
aliphatics include, but are not limited to, alkyls and alkenes, in
certain embodiments, R.sup.2 may be selected from an optionally
substituted C.sub.1-C.sub.4 alkyl and an optionally substituted
C.sub.1-C.sub.4 alkenyl. Similarly, in certain embodiments, R.sup.2
is selected from an optionally substituted C.sub.2-C.sub.3 alkyl
and an optionally substituted C.sub.2-C.sub.4 alkenyl, because
those alkyls and alkenyls are included in the definition of
C.sub.1-C.sub.4 aliphatics.
[0219] One of ordinary skill in the art will also understand that
the above listed groups may be selected in any combination. For
example, in certain embodiments, R.sup.1 is selected from hydrogen,
CO.sub.2R.sup.10, CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a
carboxylic acid bioisostere; and R.sup.2 is selected from hydrogen,
OR.sup.12, NR.sup.12R.sup.13, an optionally substituted
C.sub.1-C.sub.4 aliphatic, an optionally substituted
C.sub.1-C.sub.4 haloaliphatic, an optionally substituted
C.sub.1-C.sub.4 heteroaliphatic, (CH.sub.2).sub.mR.sup.14, an
optionally substituted ring, and null. Therefore, in certain
embodiments, R.sup.1 may be selected from hydrogen, and
CO.sub.2R.sup.10; and at the same time R may be selected from
hydrogen, OR.sup.12, NR.sup.12R.sup.13, and an optionally
substituted C.sub.1-C.sub.4 aliphatic, because those lists of
possible identities are included within the previous lists of
possible identities. Such selection of combinations are included
for all groups herein.
[0220] In certain embodiments, a compound of Formula I, II, or III
is a selective TPO modulator. In certain embodiments, a compound of
Formula I, II, or III is a selective TPO receptor agonist. In
certain embodiments, a compound of Formula I, II, or III is a
selective TPO receptor antagonist. In certain embodiments, a
compound of Formula I, II, or III is a selective TPO receptor
partial agonist. In certain embodiments, a compound of Formula I,
II, or III is a tissue-specific selective TPO modulator. In certain
embodiments, a compound of Formula I, II, or III is a selective TPO
receptor binding compound. In certain embodiments, a compound of
Formula I, II, or III is a TPO mimic.
[0221] In certain embodiments, the invention provides compounds
including, but not limited to: [0222]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydraz-
ino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 101); [0223]
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-biphenyl-3-carboxylic acid (Compound 102); [0224]
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-ethyl-phenyl)-1,2-dihydro-indol-3-ylidene]--
hydrazino}-biphenyl-3-carboxylic acid (Compound 103); [0225]
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol--
3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 104);
[0226]
3'-{N'-[1-(3-Fluoro-4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]--
hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 105);
[0227]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydraz-
ino}-2'-hydroxy-biphenyl-4-carboxylic acid (Compound 106); [0228]
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-biphenyl-4-carboxylic acid (Compound 107); [0229]
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-ethyl-phenyl)-1,2-dihydro-indol-3-ylidene]--
hydrazino}-biphenyl-4-carboxylic acid (Compound 108); [0230]
3'-{N'-[1-(4-tert-Butyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydraz-
ino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 109); [0231]
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-
-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 110);
[0232]
3'-[N'-(1-Benzyl-5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-2-
'-hydroxy-biphenyl-3-carboxylic acid (Compound 111); [0233]
3'-[N'-(1-Benzyl-5-methyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-2-
'-hydroxy-biphenyl-3-carboxylic acid (Compound 112); [0234]
3'-[N'-(1-Benzyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-2'-hydroxy-
-biphenyl-3-carboxylic acid (Compound 113); [0235]
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-
-ylidene]-hydrazino}-biphenyl-4-carboxylic acid (Compound 114);
[0236]
3'-{N'-[1-(3,4-Dichloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydraz-
ino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 115); [0237]
2'-Hydroxy-3'-{N'-[1-(4-methyl-3-trifluoromethyl-phenyl)-2-oxo-1,2-dihydr-
o-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound
116); [0238]
3'-{N'-[1-(3-Fluoro-4-trifluoromethyl-phenyl)-2-oxo-1,2-dihydro-i-
ndol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 117); [0239]
3'-{N'-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylid-
ene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
118); [0240]
3'-{N'-[3-(3,4-Dimethyl-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ylid-
ene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
119); [0241]
2'-Hydroxy-3'-{N'-[1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 120);
[0242]
3'-{N'-[1-(2-Fluoro-4-trifluoromethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-y-
lidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
121); [0243]
3'-{N'-[1-(2-Fluoro-4-methyl-phenyl)-2-oxo-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
122); [0244]
3'-{N'-[1-(4-Chloro-3-trifluoromethyl-phenyl)-2-oxo-1,2-dihydro-i-
ndol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 123); [0245]
3'-{N'-[1-(4-Butyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}--
2'-hydroxy-biphenyl-3-carboxylic acid (Compound 124); [0246]
3'-{N'-[1-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}-
-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 125); [0247]
2'-Hydroxy-3'-[N'-(2-oxo-1-m-tolyl-1,2-dihydro-indol-3-ylidene)-hydrazino-
]-biphenyl-3-carboxylic acid (Compound 126); [0248]
3'-{N'-[1-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}-
-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 127); [0249]
3'-[N'-(1-Benzyl-5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]--
2'-hydroxy-biphenyl-3-carboxylic acid (Compound 128); [0250]
2'-Hydroxy-3'-{N'-[2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-
-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 129);
[0251]
3'-{N'-[5-Chloro-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 130);
[0252]
3'-{N'-[6-Chloro-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-yliden-
e]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 131);
[0253]
3'-{N'-[5-Fluoro-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-
-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 132); [0254]
3'-{N'-[5-Methoxy-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 133); [0255]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-5-fluoro-2-oxo-1,2-dihydro-indol-3-yliden-
e]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 134);
[0256]
3'-{N'-[1-(4-Fluoro-3-trifluoromethyl-phenyl)-5-fluoro-2-oxo-1,2--
dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 135); [0257]
3'-{N'-[1-(3,5-Dichloro-phenyl)-5-fluoro-2-oxo-1,2-dihydro-indol-3-yliden-
e]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 136);
[0258]
3'-{N'-[1-(4-Propyl-phenyl)-6-chloro-2-oxo-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
137); and
[0259] a pharmaceutically acceptable salt, ester, amide, or prodrug
of any of those compounds. In certain embodiments, such compounds
are selective TPO modulators.
[0260] In certain embodiments, the invention provides compounds
including, but not limited to: [0261]
(.+-.)-2'-Hydroxy-3'-(N'-{2-oxo-1-[4-(2,2,2-trifluoro-1-hydroxy-ethyl)-ph-
enyl]-1,2-dihydro-indol-3-ylidene}-hydrazino)-biphenyl-3-carboxylic
acid (Compound 138); [0262]
(.+-.)-2'-Hydroxy-3'-(N'-{2-oxo-1-[4-(2,2,2-trifluoro-1-methoxy-ethyl)-ph-
enyl]-1,2-dihydro-indol-3-ylidene}-hydrazino)-biphenyl-3-carboxylic
acid (Compound 139); [0263]
2'-Hydroxy-3'-(N'-{2-oxo-1-[4-(2,2,2-trifluoro-ethyl)-phenyl]-1,2-dihydro-
-indol-3-ylidene}-hydrazino)-biphenyl-3-carboxylic acid (Compound
140); [0264]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-4,5-dimethyl-2-oxo-1,2-dihydro-in-
dol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 141); [0265]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-5-fluoro-4-methyl-2-oxo-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 142); [0266]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-5-fluoro-6-methyl-2-oxo-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 143); [0267]
5-(4-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-ind-
ol-3-ylidene]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4-dione
(Compound 144); [0268]
5-(4-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydr-
azino}-3-hydroxy-benzylidene)-thiazolidine-2,4-dione (Compound
145); [0269]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-4-fluoro-2-oxo-6-trifluoromethyl--
1,2-dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 146); [0270]
3'-{N'-[4-Chloro-1-(3,4-dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihy-
dro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 147); [0271]
5-(4-{N'-[1-(3,4-Dimethyl-phenyl)-4-fluoro-2-oxo-6-trifluoromethyl-1,2-di-
hydro-indol-3-ylidene]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4--
dione (Compound 148); [0272]
5-(4-{N'-[4-Chloro-1-(3,4-dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-di-
hydro-indol-3-ylidene]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4--
dione (Compound 149); [0273]
3-(4-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-ind-
ol-3-ylidene]-hydrazino}-3-hydroxy-phenyl)-acrylic acid (Compound
150); [0274]
1-(3,4-Dimethyl-phenyl)-3-{[2-hydroxy-4-(4-oxo-2-thioxo-thiazolid-
in-5-ylidenemethyl)-phenyl]-hydrazono}-6-trifluoromethyl-1,3-dihydro-indol-
-2-one (Compound 151); [0275]
1-(3,4-Dimethyl-phenyl)-4-fluoro-3-{[2-hydroxy-4-(4-oxo-2-thioxo-thiazoli-
din-5-ylidenemethyl)-phenyl]-hydrazono}-6-trifluoromethyl-1,3-dihydro-indo-
l-2-one (Compound 152); [0276]
5-(3-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-ind-
ol-3-ylidene]-hydrazino}-2-hydroxy-benzylidene)-thiazolidine-2,4-dione
(Compound 153); [0277]
3'-{N'-[5-Chloro-2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]-h-
ydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 154);
[0278]
2'-Hydroxy-3'-{N'-[1-(4-methylsulfanyl-phenyl)-2-oxo-1,2-dihydro-indol-3--
ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 155);
[0279]
2'-Hydroxy-3'-{N'-[1-(4-methoxymethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-y-
lidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 156);
[0280]
(.+-.)-2'-Hydroxy-3'-(N'-{2-oxo-1-[4-(2,2,2-trifluoro-1-hydroxy-1-methyl--
ethyl)-phenyl]-1,2-dihydro-indol-3-ylidene}-hydrazino)-biphenyl-3-carboxyl-
ic acid (Compound 157); [0281]
3'-{N'-[5-Fluoro-1-(4-methyl-3-trifluoromethyl-phenyl)-2-oxo-1,2-dihydro--
indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 158); [0282]
2'-Hydroxy-3'-(N'-{2-oxo-1-[4-(2,2,2-trifluoro-1-methoxy-1-methyl-ethyl)--
phenyl]-1,2-dihydro-indol-3-ylidene}-hydrazino)-biphenyl-3-carboxylic
acid (Compound 159); [0283]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-fluoro-2-oxo-1,2-dihydro-indol-3-yliden-
e]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 160);
[0284]
3'-{N'-[6-Fluoro-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-
-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 161); [0285]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-5-trifluoromethyl-1,2-dihy-
dro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 162); [0286]
3'-{N'-[6-Fluoro-2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]-h-
ydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 163);
[0287]
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-5-trifluoromethyl-1,2-dihydr-
o-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound
164); [0288]
3'-{N'-[4,5-Difluoro-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-ind-
ol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 165); [0289]
2'-Hydroxy-3'-[N'-(2-oxo-1-piperidin-4-yl-1,2-dihydro-indol-3-ylidene)-hy-
drazino]-biphenyl-3-carboxylic acid (Compound 166); [0290]
3'-{N'-[5-Fluoro-1-(2-fluoro-4-methyl-phenyl)-2-oxo-1,2-dihydro-indol-3-y-
lidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
167); [0291]
2'-Hydroxy-3'-[N'-(1-methyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hy-
drazino]-biphenyl-3-carboxylic acid (Compound 168); [0292]
3'-[N'-(1-Cyclopentyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-2'-hy-
droxy-biphenyl-3-carboxylic acid (Compound 169); [0293]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-methyl-2-oxo-1,2-dihydro-indol-3-yliden-
e]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 170);
[0294]
2'-Hydroxy-3'-[N'-(2-oxo-1-phenyl-1,2-dihydro-indol-3-ylidene)-hy-
drazino]-biphenyl-3-carboxylic acid (Compound 171); [0295]
3'-[N'-(6-Fluoro-2-oxo-1-phenyl-2,3-dihydro-1H-indol-3-yl)-hydrazino]-2'--
hydroxy-biphenyl-3-carboxylic acid (Compound 172); [0296]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-isopropyl-2-oxo-1,2-dihydro-indol-3-yli-
dene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
173); [0297]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-4-isopropyl-2-oxo-1,2-dihydro-ind-
ol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 174); [0298]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-4-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 175); [0299]
5'-Chloro-3'-{N'-[1-(3,4-dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dih-
ydro-indol-3-ylidene]-hydrazino}-4-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 176); [0300]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-6-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 177); [0301]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-4,5-difluoro-2-oxo-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
178); [0302]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihyd-
ro-indol-3-ylidene]-hydrazino}-2'-hydroxy-3-methyl-biphenyl-4-carboxylic
acid (Compound 179); [0303]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-2,3-dihydro-1H-in-
dol-3-yl]-hydrazino}-2-fluoro-2'-hydroxy-biphenyl-4-carboxylic acid
(Compound 180); [0304]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-4-fluoro-2-oxo-6-trifluoromethyl-2,3-dihy-
dro-1H-indol-3-yl]-hydrazino}-4-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 181); [0305]
5'-Chloro-3'-{N'-[1-(3,4-dimethyl-phenyl)-4-fluoro-2-oxo-6-trifluoromethy-
l-1,2-dihydro-indol-3-ylidene]-hydrazino}-4-fluoro-2'-hydroxy-biphenyl-3-c-
arboxylic acid (Compound 182); [0306]
3-[(3'-Carboxy-2-hydroxy-biphenyl-3-yl)-hydrazono]-1-(3,5-dimethyl-phenyl-
)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester
(Compound 183); [0307]
3-[(3'-Carboxy-4'-fluoro-2-hydroxy-biphenyl-3-yl)-hydrazono]-1-(3,5-dimet-
hyl-phenyl)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl
ester (Compound 184); [0308]
3-[(3'-Carboxy-4'-fluoro-2-hydroxy-biphenyl-3-yl)-hydrazono]-1-(3,4-dimet-
hyl-phenyl)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl
ester (Compound 185); [0309]
3-[(3'-Carboxy-5-chloro-4'-fluoro-2-hydroxy-biphenyl-3-yl)-hydrazono]-1-(-
3,5-dimethyl-phenyl)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid
methyl ester (Compound 186); [0310]
3'-{N'-[1-(2-Cyano-thiophen-3-yl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydr-
azino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 187); [0311]
2'-Hydroxy-3'-[N'-(2-oxo-1-thiophen-3-yl-1,2-dihydro-indol-3-ylidene)-hyd-
razino]-biphenyl-3-carboxylic acid (Compound 188); [0312]
3-[(3'-Carboxy-2-hydroxy-biphenyl-3-yl)-hydrazono]-1-(3,4-dimethyl-phenyl-
)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester
(Compound 189); [0313]
3'-{N'-[1-(4-Chloro-3-trifluoromethyl-phenyl)-6-cyano-2-oxo-1,2-dihydro-i-
ndol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 190); [0314]
5'-Chloro-3'-{N'-[6-cyano-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol--
3-ylidene]-hydrazino}-4-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 191); [0315]
3'-{N'-[6-Cyano-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-4-fluoro-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 192); [0316]
(.+-.)-1-(3,4-Dimethyl-phenyl)-3-{[2-hydroxy-3'-(2,2,2-trifluoro-
-1-hydroxy-ethyl)-biphenyl-3-yl]-hydrazono}-6-methanesulfonyl-1,3-dihydro--
indol-2-one (Compound 193); [0317]
3'-{N'-[6-Cyano-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 194);
[0318]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-5-nitro-2-oxo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 195);
[0319]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-methanesulfonyl-2-oxo-1,2-dihydro-indo-
l-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 196); [0320]
3'-{N'-[6-Cyano-1-(3,4-dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 197);
[0321]
3'-{N'-[1-(5-Cyano-pyridin-3-yl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydr-
azino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 198); [0322]
3'-[N'-(1-Furan-3-yl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-2'-hyd-
roxy-biphenyl-3-carboxylic acid (Compound 199); [0323]
3'-[N'-(1-Benzo[1,3]dioxol-5-yl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydraz-
ino]-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 200); [0324]
2'-Hydroxy-3'-{N'-[1-(3-methyl-thiophen-2-yl)-2-oxo-1,2-dihydro-indol-3-y-
lidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 201);
[0325]
2'-Hydroxy-3'-[N'-(2-oxo-1-thiophen-2-yl-1,2-dihydro-indol-3-ylidene)-hyd-
razino]-biphenyl-3-carboxylic acid (Compound 202); [0326]
2'-Hydroxy-3'-{N'-[1-(4-isopropyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dih-
ydro-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid
(Compound 203); [0327]
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-6-trifluoromethyl-1,2-dihydr-
o-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound
204); [0328]
3'-{N'-[1-(4-Ethyl-phenyl)-5,7-difluoro-2-oxo-1,2-dihydro-indol-3-
-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 205); [0329]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-5,7-difluoro-2-oxo-1,2-dihydro-i-
ndol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 206); [0330]
3'-{N'-[5,7-Difluoro-2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-yliden-
e]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 207);
[0331]
3'-{N'-[5,7-Difluoro-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-ind-
ol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 208); [0332]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 209); [0333]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-ethyl-2-oxo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 210);
[0334]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-methoxy-2-oxo-1,2-dihydro-indol-3-ylid-
ene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
211); [0335]
3'-{N'-[5-Chloro-1-(3,4-dimethyl-phenyl)-2-oxo-6-trifluoromethyl--
1,2-dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 212); [0336]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6,7-dimethyl-2-oxo-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
213); [0337]
2-(3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-di-
hydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-4-yl)-2-methyl-propi-
onic acid (Compound 214); [0338]
(-)-2-(3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydr-
o-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-4-yl)-propionic
acid (Compound 215) and
(+)-2-(3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydr-
o-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-4-yl)-propionic
acid (Compound 215a); [0339]
(.+-.)-(3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihyd-
ro-indol-3-ylidene]-hydrazino}-2'-hydroxy-5'-methyl-biphenyl-4-yl)-propion-
ic acid (Compound 216); [0340]
(.+-.)-2-(3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dih-
ydro-indol-3-ylidene]-hydrazino}-5'-fluoro-2'-hydroxy-biphenyl-4-yl)-propi-
onic acid (Compound 217); [0341]
5-(4-{N'-[1-(3,4-Dimethyl-phenyl)-5,7-difluoro-2-oxo-1,2-dihydro-indol-3--
ylidene]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4-dione
(Compound 218); [0342]
5-(4-{N'-[1-(4-Ethyl-phenyl)-5,7-difluoro-2-oxo-1,2-dihydro-indol-3-ylide-
ne]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4-dione
(Compound 219); [0343]
5-(4-{N'-[5,7-Difluoro-2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylid-
ene]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4-dione
(Compound 220); [0344]
5-(3-Hydroxy-4-{N'-[1-(4-isopropyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-di-
hydro-indol-3-ylidene]-hydrazino}-benzylidene)-thiazolidine-2,4-dione
(Compound 221); [0345]
5-(3-Hydroxy-4-{N'-[1-(4-isopropyl-phenyl)-2-oxo-5,7-difluoro-1,2-dihydro-
-indol-3-ylidene]-hydrazino}-benzylidene)-thiazolidine-2,4-dione
(Compound 222); [0346]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-5'-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 223); [0347]
5'-Chloro-3'-{N'-[1-(3,4-dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dih-
ydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 224); [0348]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-5'-methyl-biphenyl-3-carboxylic
acid (Compound 225); [0349]
2'-Hydroxy-3'-{N'-[2-oxo-6-trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1-
,2-dihydro-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid
(Compound 226); [0350]
3'-{N'-[1-(4-Ethyl-3-methyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-i-
ndol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 227); [0351]
3'-{N'-[1-(4-Chloro-3-trifluoromethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-
-dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 228); [0352]
3'-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-5'-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 229); [0353]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-4,5'-difluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 230);
[0354]
3'-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihyd-
ro-indol-3-ylidene]-hydrazino}-4,5'-difluoro-2'-hydroxy-biphenyl-3-carboxy-
lic acid (Compound 231); [0355]
4,5'-Difluoro-2'-hydroxy-3'-{N'-[2-oxo-6-trifluoromethyl-1-(4-trifluorome-
thyl-phenyl)-1,2-dihydro-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic
acid (Compound 232); [0356]
3'-{N'-[1-(4-Fluoro-3,5-dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihy-
dro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 233); [0357]
2'-Hydroxy-3'-{N'-[1-(4-methoxy-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihyd-
ro-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound
234); [0358]
3'-{N'-[1-(4-Fluoro-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-i-
ndol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 235); [0359]
3'-{N'-[1-(3,5-Dimethoxy-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indo-
l-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 236); [0360]
3'-{N'-[1-(3,4-Dimethoxy-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indo-
l-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 237); [0361]
3'-{N'-[1-(3,5-Difluoro-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 238); [0362]
5'-Fluoro-3'-{N'-[1-(4-fluoro-3,5-dimethyl-phenyl)-2-oxo-6-trifluoromethy-
l-1,2-dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 239); [0363]
4,5'-Difluoro-3'-{N'-[1-(4-fluoro-3,5-dimethyl-phenyl)-2-oxo-6-trifluorom-
ethyl-1,2-dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carbox-
ylic acid (Compound 240); [0364]
2'-Hydroxy-3'-{N'-[1-(4-methoxy-3,5-dimethyl-phenyl)-2-oxo-6-trifluoromet-
hyl-1,2-dihydro-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic
acid (Compound 241); [0365]
2'-Hydroxy-3'-{N'-[1-(4-hydroxy-3,5-dimethyl-phenyl)-2-oxo-6-trifluoromet-
hyl-1,2-dihydro-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic
acid (Compound 242); [0366]
3'-{N'-[1-(4-Cyclohexyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydraz-
ino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 243); [0367]
2'-Hydroxy-3'-[N'-(2-oxo-1-pyridin-2-yl-1,2-dihydro-indol-3-ylidene)-hydr-
azino]-biphenyl-3-carboxylic acid (Compound 244); [0368]
2'-Hydroxy-3'-[N'-(2-oxo-1-pyridin-3-yl-1,2-dihydro-indol-3-ylidene)-hydr-
azino]-biphenyl-3-carboxylic acid (Compound 245); [0369]
3'-{N'-[1-(4-Ethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
246); [0370]
3'-{N'-[1-(4-Ethyl-phenyl)-4-fluoro-2-oxo-6-trifluoromethyl-1,2-d-
ihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 247); [0371]
3-[(3'-Carboxy-2-hydroxy-biphenyl-3-yl)-hydrazono]-1-(3,5-dimethyl-phenyl-
)-2-oxo-2,3-dihydro-1-H-indole-5-carboxylic acid methyl ester
(Compound 248); [0372]
3'-{N'-[1-(3-Chloro-4-methyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro--
indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 249); [0373]
5-(4-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-ind-
ol-3-ylidene]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4-dione
(Compound 250); [0374]
2'-Hydroxy-3'-(N'-{2-oxo-1-[4-(4,4,4-trifluoro-butyl)-phenyl]-1,2-dihydro-
-indol-3-ylidene}-hydrazino)-biphenyl-3-carboxylic acid (Compound
251); [0375]
3'-{N'-[1-(3,5-Dimethyl-phenyl)-4-fluoro-2-oxo-6-trifluoromethyl--
1,2-dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 252); [0376]
3'-{N'-[1-(4-tert-Butyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 253); [0377]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-4-carboxylic acid
(Compound 254); [0378]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-bromo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 255);
[0379]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indo-
l-3-ylidene]-hydrazino}-3-fluoro-2'-hydroxy-biphenyl-4-carboxylic
acid (Compound 256); [0380]
3'-{N'-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-di-
hydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 257); [0381]
3'-{N'-[1-(3,4-Dichloro-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 258); [0382]
3'-{N'-[1-(3,5-Dichloro-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 259); [0383]
3-(4-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-ind-
ol-3-ylidene]-hydrazino}-3-hydroxy-phenyl)-2-methyl-acrylic acid
(Compound 260); [0384]
3-(4-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-ind-
ol-3-ylidene]-hydrazino}-3-hydroxy-phenyl)-2-methyl-acrylic acid
(Compound 261); [0385]
2'-Hydroxy-3'-[N'-(2-oxo-7-phenyl-1,2-dihydro-indol-3-ylidene)-hydrazino]-
-biphenyl-3-carboxylic acid (Compound 262); [0386]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethoxy-1,2-dihydro-indo-
l-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 263); [0387]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-(1,1,2,2-tetrafluoro-ethoxy)-1,2--
dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 264); [0388]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-5-methyl-2-oxo-1,2-dihydro-indol-3-yliden-
e]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 265);
[0389]
3'-{N'-[1-(4-Isopropyl-phenyl)-5-methyl-2-oxo-1,2-dihydro-indol-3-
-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 266); [0390]
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-phenyl-2-oxo-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 267); [0391]
3'-{N'-[1-(3-Trifluoromethyl-phenyl)-6-trifluoromethyl-2-oxo-1,2-dihydro--
indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 268); [0392]
3'-{N'-[1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethoxy-2-oxo-1,2-dihydr-
o-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 269); [0393]
3'-{N'-[1-(3,5-Dimethyl-phenyl)-6-trifluoromethyl-2-oxo-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 270); [0394]
3'-{N'-[1-(3-Trifluoromethyl-phenyl)-4,6-dimethyl-2-oxo-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 271); [0395]
3'-{N'-[1-(3-Trifluoromethyl-phenyl)-5,6-dimethyl-2-oxo-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 272); [0396]
3'-{N'-[1-(3,5-Dimethyl-phenyl)-6-trifluoromethyl-2-oxo-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-5'-chloro-4-fluoro-biphenyl-3-carboxylic
acid (Compound 273); [0397]
3'-{N'-[1-(3,5-Dimethyl-phenyl)-6-trifluoromethyl-2-oxo-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-4-fluoro-biphenyl-3-carboxylic
acid (Compound 274); [0398]
3'-{N'-[6-Chloro-1-(3,4-dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-yliden-
e]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 275);
[0399]
3'-{N'-[5-Fluoro-2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
276); [0400]
3'-{N'-[5-Cyano-1-(3,4-dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-
-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 277); [0401]
3'-{N'-[6-Chloro-1-(3,5-dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 278); [0402]
4-Fluoro-3'-{N'-[1-(3-fluoro-4-methyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-
-dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 279); and
[0403] a pharmaceutically acceptable salt ester, amide or prodrug
of any of those compounds.
[0404] In certain embodiments, the invention provides compounds
including, but not limited to: [0405]
3'-{N'-[1-(4-Chloro-3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihyd-
roindol-3-ylidene]hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 280); [0406]
3'-{N'-[1-(3,5-Dimethylphenyl)-4-fluoro-2-oxo-6-trifluoromethyl-1,2-dihyd-
roindol-3-ylidene]hydrazino}-2'-hydroxybiphenyl-4-fluoro-3-carboxylic
acid (Compound 281); [0407]
3'-{N'-[1-Benzo[1,3]dioxo-5-yl-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3-
-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound
282); [0408]
3'-{N'-[1-Benzo[1,3]dioxo-5-yl-2-oxo-6-trifluoromethyl-1,2-dihydr-
oindol-3-ylidene]hydrazino}-2'-hydroxybiphenyl-2-fluoro-3-carboxylic
acid (Compound 283); [0409]
3'-{N'-[1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3-
-ylidene]hydrazino}-2'-hydroxybiphenyl-2-hydroxy-3-carboxylic acid
(Compound 284); [0410]
3'-{N'-[1-(3-Methoxycarbonylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroin-
dol-3-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid
(Compound 285); [0411]
3'-{N'-[1-(3-Methoxycarbonylphenyl)-2-oxo-1,2-dihydroindol-3-ylidene]hydr-
azino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 286); [0412]
3'-{N'-[7-Aza-1-(3,4-dimethylphenyl)-2-oxo-1,2-dihydroindol-3-ylidene]hyd-
razino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 287); [0413]
3'-{N'-[1-(3,5-Dimethylphenyl)-2-oxo-1,2-dihydroindol-6-trifluoromethyl-3-
-ylidene]hydrazino}-2'-hydroxybiphenyl-3-(2-methyl-2-propionic
acid) (Compound 288); [0414]
3'-{N'-[1,3-N,N-Dimethylbarbitur-5-ylidene]hydrazino}-2'-hydroxybiphenyl--
3-carboxylic acid (Compound 289); [0415]
3'-{N'-[1-N-(4-Trifluoromethylbenzyl)-2,8-dioxo-1,2,7,8-tetrahydroisoquin-
olin-7-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid
(Compound 290); [0416]
3'-{N'-[1-N-(4-Methylbenzyl)-2,8-dioxo-1,2,7,8-tetrahydroisoquinolin-7-yl-
idene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound
291); [0417]
3'-{N'-[1-N-Benzyl-2,8-dioxo-1,2,7,8-tetrahydroisoquinolin-7-ylid-
ene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 292);
[0418]
3'-{N'-[1-N-(4-Trifluoromethylphenyl)-2,8-dioxo-1,2,7,8-tetrahydr-
oisoquinolin-7-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic
acid (Compound 293); [0419]
3'-{N'-[1-N-(3-Trifluoromethylphenyl)-2,8-dioxo-1,2,7,8-tetrahydroisoquin-
olin-7-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid
(Compound 294); [0420]
3'-{N'-[1-N-(3,5-Dimethylphenyl)-2,8-dioxo-1,2,7,8-tetrahydroisoquinolin--
7-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound
295); [0421]
3'-{N'-[1-N-Phenyl-2,8-dioxo-1,2,7,8-tetrahydroisoquinolin-7-ylid-
ene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 296);
[0422]
3'-{N'-[1-N-(3,4-Dimethylphenyl)-2,8-dioxo-1,2,7,8-tetrahydroisoq-
uinolin-7-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid
(Compound 297); [0423]
3'-{N'-[1-N-(3,4-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-
-3-ylidene]hydrazino}-2'-fluorobiphenyl-3-carboxylic acid (Compound
298); [0424]
3-(3-{N'-[1-N-(3,4-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-di-
hydroindol-3-ylidene]hydrazino}-2-hydroxyphenyl)-2(Z)-propenoic
acid (Compound 299); [0425]
3-(3-{N'-[1-N-(3,4-Dimethylphenyl)-2-oxo-4-fluoro-6-trifluoromethyl-1,2-d-
ihydroindol-3-ylidene]hydrazino}-2-hydroxyphenyl)-2(Z)-propenoic
acid (Compound 300); [0426]
5-(3-{N'-[1-(3,4-Dimethylphenyl)-2-oxo-4-fluoro-6-trifluoromethyl-1,2-dih-
ydroindol-3-ylidene]hydrazino}-2-hydroxybenzylidene)thiazolidine-2,4-dione
(Compound 301); [0427]
2-Chloro-3-(4-{N'-[1-(3,4-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dih-
ydroindol-3-ylidene]hydrazino}-3-hydroxyphenyl)-2-propenoic acid
(Compound 302); [0428]
2-Ethyl-3-(4-{N'-[1-(3,4-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihy-
droindol-3-ylidene]hydrazino}-3-hydroxyphenyl)-2-propenoic acid
(Compound 303); [0429]
1-N-Methyl-5-(4-{N'-[1-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-d-
ihydroindol-3-ylidene]hydrazino}-3-hydroxybenzylidene)-1,3-diazolidine-2,4-
-dione (Compound 304); [0430]
5-(4-{N'-[1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-
-3-ylidene]hydrazino}-3-hydroxybenzylidene)-1,3-diazolidine-2,4-dione
(Compound 305); [0431]
2-Fluoro-3-(4-{N'-[1-(3,4-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dih-
ydroindol-3-ylidene]hydrazino}-3-hydroxyphenyl)-2-propenoic acid
(Compound 306); [0432]
(.+-.)-2-Methoxy-3-(4-{N'-[1-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-
-1,2-dihydroindol-3-ylidene]hydrazino}-3-hydroxyphenyl)propanoic
acid (Compound 307); [0433]
4-(3-{N'-[1-(3,4-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-
-3-ylidene]hydrazino}-2-hydroxyphenyl)butanoic acid (Compound 308);
[0434]
3-(2-{N'-[1-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihy-
droindol-3-ylidene]hydrazino}-3-hydroxyphenoxy)propanoic acid
(Compound 309); [0435]
4-(4-{N'-[1-(3,4-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-
-3-ylidene]hydrazino}-3-hydroxyphenyl)butanoic acid (Compound 310);
and a pharmaceutically acceptable salt ester, amide or prodrug of
any of those compounds.
[0436] In certain embodiments, the present invention provides any
single compound selected from any of the above lists of compounds.
In certain embodiments, the present invention provides any number
and any combination of compounds selected from the above lists of
compounds.
[0437] Certain compounds of the present inventions may exist as
stereoisomers including optical isomers. The present disclosure is
intended to include all stereoisomers and both the racemic mixtures
of such stereoisomers as well as the individual enantiomers that
may be separated according to methods that are known in the art or
that may be excluded by synthesis schemes known in the art designed
to yield predominantly one enantomer relative to another.
Certain Synthesis Methods
[0438] In certain embodiments, certain compounds of the present
invention can by synthesized using the following Schemes.
##STR26##
[0439] The process of Scheme I is a multi-step synthetic sequence
that commences with the palladium catalyzed cross-coupling of a
phenylboronic acid such as structure 2 and an aryl bromide such as
structure 1 to form the biaryl structure 3. Deprotection of the
methyl ether is followed by nitration and hydrogenation to give the
biphenyl amino acid such as structure 4. The amino group is then
diazotized under standard conditions and is treated with the
appropriate coupling partner to give the final product of structure
6. ##STR27##
[0440] The process of Scheme II is a multi-step synthetic sequence
that commences with the copper catalyzed cross-coupling of an
oxindole such as structure 7 and an aryl or alkyl bromide to
provide an N-substituted oxindole of structure 8. This is then
followed by coupling the N-substituted oxindole with the diazonium
salt of the biphenyl amino acid such as structure 4 to give the
final product of structure 9. ##STR28##
[0441] The process of Scheme III is a multi-step synthetic sequence
that commences with the reductive amination of an aniline such as
structure 10 with a benzaldehyde and conversion into the
chloroacetanilide of structure 11 with chloroacetyl chloride.
Palladium catalyzed ring closure gives the N-benzyl oxindole such
as structure 12, which is then coupled to the diazonium salt of the
biphenyl amino acid of structure 4 to give the final product of
structure 9. ##STR29##
[0442] The process of Scheme IV is a multi-step synthetic sequence
that commences with the conversion of an amine of structure 13 into
an N-aryl rhodanine of structure 14 with bis(carboxymethyl)
trithiocarbonate. The rhodanine is then coupled to the diazonium
salt of the biphenyl amino acid such as structure 4 to give the
final product of structure 15. ##STR30##
[0443] In Scheme V, a hydroxynitrobenzaldehyde such as structure 16
is converted into either a cinnamate such as structure 17 or
thiazolidinedione derivative of structure 19. The requisite
nitro-group is reduced and then converted into a diazonium salt and
coupled to the corresponding N-aryl oxindole of structure 8 to give
the final compound of structure 20.
[0444] One of skill in the art will recognize that analogous
synthesis schemes may be used to synthesize similar compounds. One
of skill will recognize that compounds of the present invention may
be synthesized using other synthesis schemes. In certain
embodiments, the invention provides a salt corresponding to any of
the compounds provided herein.
[0445] In certain embodiments, the invention provides a salt
corresponding to a selective TPO modulator. In certain embodiments,
the invention provides a salt corresponding to a selective TPO
receptor binding agent. In certain embodiments, a salt is obtained
by reacting a compound with an acid, such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid, and the like. In certain embodiments, a salt is
obtained by reacting a compound with a base to form a salt such as
an ammonium salt, an alkali metal salt, such as a sodium or a
potassium salt, an alkaline earth metal salt, such as a calcium or
a magnesium salt, a salt of organic bases such as choline,
dicyclohexylamine, N-methyl-D-glucamine,
tris(hydroxymethyl)methylamine, 4-(2-hydroxyethyl)-morpholine,
1-(2-hydroxyethyl)-pyrrolidine, ethanolamine and salts with amino
acids such as arginine, lysine, and the like. In certain
embodiments, a salt is obtained by reacting a free acid form of a
selective TPO modulator or selective TPO binding agent with
multiple molar equivalents of a base, such as bis-sodium,
bis-ethanolamine, and the like.
[0446] In certain embodiments, a salt corresponding to a compound
of the present invention is selected from acetate, ammonium,
benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,
borate, bromide, calcium edetate, camsylate, carbonate, chloride,
cholinate, clavulanate, citrate, dihydrochloride, diphosphate,
edetate, edisylate, estolate, esylate, fumarate, gluceptate,
gluconate, glutamate, glycollylarsanilate, hexylresorcinate,
hydrabanine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isethionate, lactate, lactobionate, laurate, magnesium,
malate, maleate, mandelate, mucate, napsylate, nitrate,
N-methylglucamine, oxalate, pamoate (embonate), palmitate,
pantothenate, phosphate, polygalacturonate, potassium, salicylate,
sodium, stearate, subaceatate, succinate, sulfate, tannate,
tartrate, teoclate, tosylate, triethiodide, tromethamine,
trimethylammonium, and valerate salts.
[0447] In certain embodiments, one or more carbon atoms of a
compound of the present invention are replaced with silicon. See
e.g., WO 03/037905A1; Tacke and Zilch, Endeavour, New Series, 10,
191-197 (1986); and Bains and Tacke, Curr. Opin. Drug Discov Devel.
July:6(4):526-43 (2003). In certain embodiments, compounds of the
present invention comprising one or more silicon atoms possess
certain desired properties, including, but not limited to, greater
stability and/or longer half-life in a patient, when compared to
the same compound in which none of the carbon atoms have been
replaced with a silicon atom.
Certain Assays
[0448] In certain embodiments, compounds of the present invention
may be used in a any of a variety of assays. For example, compounds
of the present invention may be tested for potency as selective TPO
modulators in a luciferase assay, such as those described in Lamb,
et al., Nucleic Acids Research, 23: 3283-3289 (1995) and/or Seidel
et al., Proc. Nat. Acad. Sci. USA; 92: 3041-3045 (1995).
[0449] Certain compounds of the present invention may be used in in
vitro proliferation and/or differentiation assays, such as those
described by Bartley et al., Cell, 77: 1117-1124 (1994) and/or
Cwirla, et al., Science, 276: 1696-1699 (1997).
Certain Pharmaceutical Compositions
[0450] In certain embodiments, at least one selective TPO
modulator, or pharmaceutically acceptable salt, ester, amide,
and/or prodrug thereof, combined with one or more pharmaceutically
acceptable carriers, forms a pharmaceutical composition. Techniques
for formulation and administration of compounds of the present
invention may be found for example, in "Remington's Pharmaceutical
Sciences," Mack Publishing Co., Easton, Pa., 18th edition,
1990.
[0451] In certain embodiments, a pharmaceutical composition
comprising one or more compounds of the present invention is
prepared using known techniques, including, but not limited to
mixing, dissolving, granulating, dragee-making, levigating,
emulsifying, encapsulating, entrapping or tabletting processes.
[0452] In certain embodiments, a pharmaceutical composition
comprising one or more compounds of the present invention is a
liquid (e.g., a suspension, elixir and/or solution). In certain of
such embodiments, a liquid pharmaceutical composition comprising
one or more compounds of the present invention is prepared using
ingredients known in the art, including, but not limited to, water,
glycols, oils, alcohols, flavoring agents, preservatives, and
coloring agents.
[0453] In certain embodiments, a pharmaceutical composition
comprising one or more compounds of the present invention is a
solid (e.g., a powder, tablet, and/or capsule). In certain of such
embodiments, a solid pharmaceutical composition comprising one or
more compounds of the present invention is prepared using
ingredients known in the art, including, but not limited to,
starches, sugars, diluents, granulating agents, lubricants,
binders, and disintegrating agents.
[0454] In certain embodiments, a pharmaceutical composition
comprising one or more compounds of the present invention is
formulated as a depot preparation. Certain such depot preparations
are typically longer acting than non-depot preparations. In certain
embodiments, such preparations are administered by implantation
(for example subcutaneously or intramuscularly) or by intramuscular
injection. In certain embodiments, depot preparations are prepared
using suitable polymeric or hydrophobic materials (for example an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0455] In certain embodiments, a pharmaceutical composition
comprising one or more compounds of the present invention comprises
a delivery system. Examples of delivery systems include, but are
not limited to, liposomes and emulsions. Certain delivery systems
are useful for preparing certain pharmaceutical compositions
including those comprising hydrophobic compounds. In certain
embodiments, certain organic solvents such as dimethylsulfoxide are
used.
[0456] In certain embodiments, a pharmaceutical composition
comprising one or more compounds of the present invention comprises
one or more tissue-specific delivery molecules designed to deliver
the one or more compounds of the present invention to specific
tissues or cell types. For example, in certain embodiments,
pharmaceutical compositions include liposomes coated with a
tissue-specific antibody.
[0457] In certain embodiments, a pharmaceutical composition
comprising one or more compounds of the present invention comprises
a co-solvent system. Certain of such co-solvent systems comprise,
for example, benzyl alcohol, a nonpolar surfactant, a
water-miscible organic polymer, and an aqueous phase. In certain
embodiments, such co-solvent systems are used for hydrophobic
compounds. A non-limiting example of such a co-solvent system is
the VPD co-solvent system, which is a solution of absolute ethanol
comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant
Polysorbate 80.TM., and 65% w/v polyethylene glycol 300. The
proportions of such co-solvent systems may be varied considerably
without significantly altering their solubility and toxicity
characteristics. Furthermore, the identity of co-solvent components
may be varied: for example, other surfactants may be used instead
of Polysorbate 80.TM.; the fraction size of polyethylene glycol may
be varied; other biocompatible polymers may replace polyethylene
glycol, e.g., polyvinyl pyrrolidone; and other sugars or
polysaccharides may substitute for dextrose.
[0458] In certain embodiments, a pharmaceutical composition
comprising one or more compounds of the present invention comprises
a sustained-release system. A non-limiting example of such a
sustained-release system is a semi-permeable matrix of solid
hydrophobic polymers. In certain embodiments, sustained-release
systems may, depending on their chemical nature, release compounds
over a period of hours, days, weeks or months.
[0459] In certain embodiments, a pharmaceutical composition
comprising a compound of the present invention is prepared for oral
administration. In certain of such embodiments, a pharmaceutical
composition is formulated by combining one or more compounds of the
present invention with one or more pharmaceutically acceptable
carriers. Certain of such carriers enable compounds of the
invention to be formulated as tablets, pills, dragees, capsules,
liquids, gels, syrups, slurries, suspensions and the like, for oral
ingestion by a patient. In certain embodiments, pharmaceutical
compositions for oral use are obtained by mixing one or more
compounds of the present invention and one or more solid excipient.
Suitable excipients include, but are not limited to, fillers, such
as sugars, including lactose, sucrose, mannitol, or sorbitol;
cellulose preparations such as, for example, maize starch, wheat
starch, rice starch, potato starch, gelatin, gum tragacanth, methyl
cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In
certain embodiments, such a mixture is optionally ground and
auxiliaries are optionally added. In certain embodiments,
pharmaceutical compositions are formed to obtain tablets or dragee
cores. In certain embodiments, disintegrating agents (e.g.,
cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt
thereof, such as sodium alginate) are added.
[0460] In certain embodiments, dragee cores are provided with
coatings. In certain of such embodiments, concentrated sugar
solutions may be used, which may optionally contain gum arabic,
talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol,
and/or titanium dioxide, lacquer solutions, and suitable organic
solvents or solvent mixtures. Dyestuffs or pigments may be added to
tablets or dragee coatings.
[0461] In certain embodiments, pharmaceutical compositions for oral
administration are push-fit capsules made of gelatin. Certain of
such push-fit capsules comprise one or more compounds of the
present invention in admixture with one or more filler such as
lactose, binders such as starches, and/or lubricants such as talc
or magnesium stearate and, optionally, stabilizers. In certain
embodiments, pharmaceutical compositions for oral administration
are soft, sealed capsules made of gelatin and a plasticizer, such
as glycerol or sorbitol. In certain soft capsules, one or more
compounds of the present invention are be dissolved or suspended in
suitable liquids, such as fatty oils, liquid paraffin, or liquid
polyethylene glycols. In addition, stabilizers may be added.
[0462] In certain embodiments, pharmaceutical compositions are
prepared for buccal administration. Certain of such pharmaceutical
compositions are tablets or lozenges formulated in conventional
manner.
[0463] In certain embodiments, a pharmaceutical composition is
prepared for administration by injection (e.g., intravenous,
subcutaneous, intramuscular, etc.). In certain of such embodiments,
a pharmaceutical composition comprises a carrier and is formulated
in aqueous solution, such as water or physiologically compatible
buffers such as Hanks's solution, Ringer's solution, or
physiological saline buffer. In certain embodiments, other
ingredients are included (e.g., ingredients that aid in solubility
or serve as preservatives). In certain embodiments, injectable
suspensions are prepared using appropriate liquid carriers,
suspending agents and the like. Certain pharmaceutical compositions
for injection are presented in unit dosage form, e.g., in ampoules
or in multi-dose containers. Certain pharmaceutical compositions
for injection are suspensions, solutions or emulsions in oily or
aqueous vehicles, and may contain formulatory agents such as
suspending, stabilizing and/or dispersing agents. Certain solvents
suitable for use in pharmaceutical compositions for injection
include, but are not limited to, lipophilic solvents and fatty
oils, such as sesame oil, synthetic fatty acid esters, such as
ethyl oleate or triglycerides, and liposomes. Aqueous injection
suspensions may contain substances that increase the viscosity of
the suspension, such as sodium carboxymethyl cellulose, sorbitol,
or dextran. Optionally, such suspensions may also contain suitable
stabilizers or agents that increase the solubility of the compounds
to allow for the preparation of highly concentrated solutions.
[0464] In certain embodiments, a pharmaceutical composition is
prepared for transmucosal administration. In certain of such
embodiments penetrants appropriate to the barrier to be permeated
are used in the formulation. Such penetrants are generally known in
the art.
[0465] In certain embodiments, a pharmaceutical composition is
prepared for administration by inhalation. Certain of such
pharmaceutical compositions for inhalation are prepared in the form
of an aerosol spray in a pressurized pack or a nebulizer. Certain
of such pharmaceutical compositions comprise a propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
certain embodiments using a pressurized aerosol, the dosage unit
may be determined with a valve that delivers a metered amount. In
certain embodiments, capsules and cartridges for use in an inhaler
or insufflator may be formulated. Certain of such formulations
comprise a powder mixture of a compound of the invention and a
suitable powder base such as lactose or starch.
[0466] In certain embodiments, a pharmaceutical composition is
prepared for rectal administration, such as a suppositories or
retention enema. Certain of such pharmaceutical compositions
comprise known ingredients, such as cocoa butter and/or other
glycerides.
[0467] In certain embodiments, a pharmaceutical composition is
prepared for topical administration. Certain of such pharmaceutical
compositions comprise bland moisturizing bases, such as ointments
or creams. Exemplary suitable ointment bases include, but are not
limited to, petrolatum, petrolatum plus volatile silicones, lanolin
and water in oil emulsions such as Eucerin.TM., available from
Beiersdorf (Cincinnati, Ohio). Exemplary suitable cream bases
include, but are not limited to, Nivea.TM. Cream, available from
Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose Cream.TM.,
available from Johnson & Johnson (New Brunswick, N.J.),
hydrophilic ointment (USP) and Lubriderm.TM., available from Pfizer
(Morris Plains, N.J.).
[0468] In certain embodiments, a pharmaceutical composition
comprising one or more compounds of the present invention comprises
an active ingredient in a therapeutically effective amount. In
certain embodiments, the therapeutically effective amount is
sufficient to prevent, alleviate or ameliorate symptoms of a
disease or to prolong the survival of the subject being treated.
Determination of a therapeutically effective amount is well within
the capability of those skilled in the art.
[0469] In certain embodiments, one or more compounds of the present
invention is formulated as a prodrug. In certain embodiments, upon
in vivo administration, a prodrug is chemically converted to the
biologically, pharmaceutically or therapeutically more active form
of the compound. In certain embodiments, prodrugs are useful
because they are easier to administer than the corresponding active
form. For example, in certain instances, a prodrug may be more
bioavailable (e.g., through oral administration) than is the
corresponding active form. In certain instances, a prodrug may have
improved solubility compared to the corresponding active form. In
certain embodiments, prodrugs are less water soluble than the
corresponding active form. In certain instances, such prodrugs
possess superior transmittal across cell membranes, where water
solubility is detrimental to mobility. In certain embodiments, a
prodrug is an ester. In certain such embodiments, the ester is
metabolically hydrolyzed to carboxylic acid upon administration. In
certain instances the carboxylic acid containing compound is the
corresponding active form. In certain embodiments, a prodrug
comprises a short peptide (polyaminoacid) bound to an acid group.
In certain of such embodiments, the peptide is cleaved upon
administration to form the corresponding active form.
[0470] In certain embodiments, a prodrug is produced by modifying a
pharmaceutically active compound such that the active compound will
be regenerated upon in vivo administration. The prodrug can be
designed to alter the metabolic stability or the transport
characteristics of a drug, to mask side effects or toxicity, to
improve the flavor of a drug or to alter other characteristics or
properties of a drug. By virtue of knowledge of pharmacodynamic
processes and drug metabolism in vivo, those of skill in this art,
once a pharmaceutically active compound is known, can design
prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal
Chemistry A Biochemical Approach, Oxford University Press, New
York, pages 388-392).
[0471] In certain embodiments, a pharmaceutical composition
comprising one or more compounds of the present invention is useful
for treating a conditions or disorders in a mammalian, and
particularly in a human, patient. Suitable administration routes
include, but are not limited to, oral, rectal, transmucosal,
intestinal, enteral, topical, suppository, through inhalation,
intrathecal, intraventricular, intraperitoneal, intranasal,
intraocular and parenteral (e.g., intravenous, intramuscular,
intramedullary, and subcutaneous). In certain embodiments,
pharmaceutical intrathecals are administered to achieve local
rather than systemic exposures. For example, pharmaceutical
compositions may be injected directly in the area of desired effect
(e.g., in the renal or cardiac area).
[0472] In certain embodiments, a pharmaceutical composition
comprising one or more compounds of the present invention is
administered in the form of a dosage unit (e.g., tablet, capsule,
bolus, etc.). In certain embodiments, such dosage units comprise a
selective TPO modulator in a dose from about 1 .mu.g/kg of body
weight to about 50 mg/kg of body weight. In certain embodiments,
such dosage units comprise a selective TPO modulator in a dose from
about 2 .mu.g/kg of body weight to about 25 mg/kg of body weight.
In certain embodiments, such dosage units comprise a selective TPO
modulator in a dose from about 10 .mu.g/kg of body weight to about
5 mg/kg of body weight. In certain embodiments, pharmaceutical
compositions are administered as needed, once per day, twice per
day, three times per day, or four or more times per day. It is
recognized by those skilled in the art that the particular dose,
frequency, and duration of administration depends on a number of
factors, including, without limitation, the biological activity
desired, the condition of the patient, and tolerance for the
pharmaceutical composition.
[0473] In certain embodiments, the formulation, route of
administration and dosage for a pharmaceutical composition of the
present invention can be chosen in view of a particular patient's
condition. (See e.g., Fingl et al. 1975, in "The Pharmacological
Basis of Therapeutics", Ch. 1 p. 1). In certain embodiments, a
pharmaceutical composition is administered as a single dose. In
certain embodiments, a pharmaceutical composition is administered
as a series of two or more doses administered over one or more
days.
[0474] In certain embodiments, a pharmaceutical composition of the
present invention is administered to a patient between about 0.1%
and 500%, more preferably between about 25% and 75% of an
established human dosage. Where no human dosage is established, a
suitable human dosage may be inferred from ED.sub.50 or ID.sub.50
values, or other appropriate values derived from in vitro or in
vivo studies.
[0475] In certain embodiments, a daily dosage regimen for a patient
comprises an oral dose of between 0.1 mg and 2000 mg of a compound
of the present invention. In certain embodiments, a daily dosage
regimen is administered as a single daily dose. In certain
embodiments, a daily dosage regimen is administered as two, three,
four, or more than four doses.
[0476] In certain embodiments, a pharmaceutical composition of the
present invention is administered by continuous intravenous
infusion. In certain of such embodiments, from 0.1 mg to 500 mg of
a composition of the present invention is administered per day.
[0477] In certain embodiments, a pharmaceutical composition of the
invention is administered for a period of continuous therapy. For
example, a pharmaceutical composition of the present invention may
be administered over a period of days, weeks, months, or years.
[0478] Dosage amount, interval between doses, and duration of
treatment may be adjusted to achieve a desired effect. In certain
embodiments, dosage amount and interval between doses are adjusted
to maintain a desired concentration on compound in a patient. For
example, in certain embodiments, dosage amount and interval between
doses are adjusted to provide plasma concentration of a compound of
the present invention at an amount sufficient to achieve a desired
effect. In certain of such embodiments the plasma concentration is
maintained above the minimal effective concentration (MEC). In
certain embodiments, pharmaceutical compositions of the present
invention are administered with a dosage regimen designed to
maintain a concentration above the MEC for 10-90% of the time,
between 30-90% of the time, or between 50-90% of the time.
[0479] In certain embodiments in which a pharmaceutical composition
is administered locally, the dosage regimen is adjusted to achieve
a desired local concentration of a compound of the present
invention.
[0480] In certain embodiments, a pharmaceutical composition may be
presented in a pack or dispenser device which may contain one or
more unit dosage forms containing the active ingredient. The pack
may for example comprise metal or plastic foil, such as a blister
pack. The pack or dispenser device may be accompanied by
instructions for administration. The pack or dispenser may also be
accompanied with a notice associated with the container in form
prescribed by a governmental agency regulating the manufacture,
use, or sale of pharmaceuticals, which notice is reflective of
approval by the agency of the form of the drug for human or
veterinary administration. Such notice, for example, may be the
labeling approved by the U.S. Food and Drug Administration for
prescription drugs, or the approved product insert. Compositions
comprising a compound of the invention formulated in a compatible
pharmaceutical carrier may also be prepared, placed in an
appropriate container, and labeled for treatment of an indicated
condition.
[0481] In certain embodiments, a pharmaceutical composition is in
powder form for constitution with a suitable vehicle, e.g., sterile
pyrogen-free water, before use.
Certain Combination Therapies
[0482] In certain embodiments, one or more pharmaceutical
compositions of the present invention are co-administered with one
or more other pharmaceutical agents. In certain embodiments, such
one or more other pharmaceutical agents are designed to treat the
same disease or condition as the one or more pharmaceutical
compositions of the present invention. In certain embodiments, such
one or more other pharmaceutical agents are designed to treat a
different disease or condition as the one or more pharmaceutical
compositions of the present invention. In. certain embodiments,
such one or more other pharmaceutical agents are designed to treat
an undesired effect of one or more pharmaceutical compositions of
the present invention. In certain embodiments, one or more
pharmaceutical compositions of the present invention are
co-administered with another pharmaceutical agent to treat an
undesired effect of that other pharmaceutical agent. In certain
embodiments, one or more pharmaceutical compositions of the present
invention and one or more other pharmaceutical agents are
administered at the same time. In certain embodiments, one or more
pharmaceutical compositions of the present invention and one or
more other pharmaceutical agents are administered at the different
times. In certain embodiments, one or more pharmaceutical
compositions of the present invention and one or more other
pharmaceutical agents are prepared together in a single
formulation. In certain embodiments, one or more pharmaceutical
compositions of the present invention and one or more other
pharmaceutical agents are prepared separately.
[0483] Examples of pharmaceutical agents that may be
co-administered with a pharmaceutical composition of the present
invention include, but are not limited to, anti-cancer treatments,
including, but not limited to, chemotherapy and radiation
treatment; corticosteroids, including but not limited to
prednisone; immunoglobulins, including, but not limited to
intravenous immunoglobulin (IVIg); analgesics (e.g.,
acetaminophen); anti-inflammatory agents, including, but not
limited to non-steroidal anti-inflammatory drugs (e.g., ibuprofen,
COX-1 inhibitors, and COX-2, inhibitors); salicylates; antibiotics;
antivirals; antifungal agents; antidiabetic agents (e.g.,
biguanides, glucosidase inhibitors, insulins, sulfonylureas, and
thiazolidenediones); adrenergic modifiers; diuretics; hormones
(e.g., anabolic steroids, androgen, estrogen, calcitonin,
progestin, somatostan, and thyroid hormones); immunomodulators;
muscle relaxants; antihistamines; osteoporosis agents (e.g.,
biphosphonates, calcitonin, and estrogens); prostaglandins,
antineoplastic agents; psychotherapeutic agents; sedatives; poison
oak or poison sumac products; antibodies; and vaccines.
Certain Indications
[0484] In certain embodiments, the invention provides methods of
treating a patient comprising administering one or more compounds
of the present invention. In certain embodiments, such patient
suffers from thrombocytopenia. In certain such embodiments,
thrombocytopenia results from chemotherapy and/or radiation
treatment. In certain embodiments, thrombocytopenia results bone
marrow failure resulting from bone marrow transplantation and/or
aplastic anemia. In certain embodiments thrombocytopenia is
idiopathic. In certain embodiments, one or more compounds of the
present invention are administered to a patient to in conjunction
with harvesting peripheral blood progenitor cells and/or in
conjunction with platelet apheresis. Such administration may be
done before, during, and/or after such harvesting.
[0485] In certain embodiments, one or more compounds of the present
invention are administered to a patient who suffers from a
condition affecting the nervous system, including, but are not
limited to, diseases affecting the nervous system and injuries to
the nervous system. Such diseases, include, but not limited to,
amyotrophic lateral sclerosis, multiple sclerosis, and multiple
dystrophy. Injury to the nervous system include, but are not
limited to spinal cord injury or peripheral nerve damage,
including, but not limited to, injury resulting from trauma or from
stroke. In certain embodiments, one or more compounds of the
present invention are used to promote growth and/or development of
glial cells. Such glial cells may repair nerve cells. In certain
embodiments, compounds of the present invention are used to treat
psychological disorders, including, but not limited to, cognitive
disorders. In certain embodiments, one or more compounds of the
invention are administered to enhance athletic performance.
EXAMPLES
[0486] The following examples, including experiments and results
achieved, are provided for illustrative purposes only and are not
to be construed as limiting the present invention.
Example 1
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazi-
no}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 101)
[0487] ##STR31##
[0488] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.07 (s, 1H), 13.03
(s, 1H), 9.26 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7,
1.6, 1.3 Hz, 1H), 7.79 (ddd, J=7.7, 1.6, 1.3 Hz, 1H), 7.73 (dd,
J=7.9, 1.6 Hz, 1H), 7.72 (m, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.35 (d,
J=8.1 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.28 (td, J=7.7, 1.3 Hz,
1H), 7.23 (dd, J=8.1, 2.1 Hz, 1H), 7.18 (td, J=7.7, 0.9 Hz, 1H),
7.11 (t, J=7.9 Hz, 1H), 7.00 (dd, J=7.9, 1.6 Hz, 1H), 6.85 (m, 1H),
2.31 (s, 3H), 2.30 (s, 3H).
Example 2
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]--
hydrazino}-biphenyl-3-carboxylic acid (Compound 102)
[0489] ##STR32##
[0490] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.07 (s, 1H), 13.03
(s, 1H), 9.27 (s, 1H), 8.11 (t, J=1.6 Hz, 1H), 7.94 (dt, J=7.7, 1.6
Hz, 1H), 7.79 (dt, J=7.7, 1.6 Hz, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.73
(d, J=7.9 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H),
7.41 (d, J=8.5 Hz, 2H), 7.29 (td, J=7.7, 1.3 Hz, 1H), 7.19 (td,
J=7.7, 1.0 Hz, 1H), 7.11 (t, J=7.9 Hz, 1H), 7.00 (dd, J=7.7, 1.3
Hz, 1H), 6.87 (dd, J=7.7, 1.0 Hz, 1H), 2.66 (t, J=7.3 Hz, 2H), 1.66
(sext, J=7.3 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H).
Example 3
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-ethyl-phenyl)-1,2-dihydro-indol-3-ylidene]-h-
ydrazino}-biphenyl-3-carboxylic acid (Compound 103)
[0491] ##STR33##
[0492] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.06 (s, 1H), 13.03
(s, 1H), 9.27 (s, 1H), 8.11 (t, J=1.5 Hz, 1H), 7.94 (dt, J=7.8, 1.5
Hz, 1H), 7.79 (dt, J=7.8, 1.5 Hz, 1H), 7.73 (dd, J=7.8 Hz, 1H),
7.73 (dd, J=7.8 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.45 (d, J=8.6 Hz,
2H), 7.43 (d, J=8.6 Hz, 2H), 7.29 (td, J=7.9, 1.0 Hz, 1H), 7.19
(td, J=7.9, 1.0 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.00 (dd, J=7.9,
1.0 Hz, 1H), 6.87 (dd, J=7.9, 1.0 Hz, 1H), 2.71 (q, J=7.6 Hz, 2H),
1.25 (t, J=7.6 Hz, 3H).
Example 4
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-
-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 104)
[0493] ##STR34##
[0494] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.03 (s, 1H), 9.30 (s,
1H), 8.11 (t, J=1.8 Hz, 1H), 7.94 (ddd, J=7.8, 1.8, 1.2 Hz, 1H),
7.79 (ddd, J=7.8, 1.8, 1.2 Hz, 1H), 7.75 (dd, J=7.7, 1.0 Hz, 1H),
7.74 (dd, J=7.8, 1.6 Hz, 1H), 7.72 (d, J=8.9 Hz, 2H), 7.60 (t,
J=7.8 Hz, 1H), 7.31 (td, J=7.7, 1.0 Hz, 1H), 7.22 (td, J=7.7, 1.0
Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 7.01 (dd, J=7.8, 1.6 Hz, 1H), 6.94
(dd, J=7.7, 1.0 Hz, 1H).
Example 5
3'-{N'-[1-(3-Fluoro-4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-h-
ydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 105)
[0495] ##STR35##
[0496] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.03 (s, 1H), 9.28 (s,
1H), 8.12 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2 Hz, 1H),
7.79 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.74-7.71 (m, 2H), 7.60 (t,
J=7.7 Hz, 1H), 7.50 (dd, J=12.3, 2.2 Hz, 1H), 7.38 (t, J=8.8 Hz,
1H), 7.35 (dd, J=8.8, 2.2 Hz, 1H), 7.29 (td, J=7.7, 1.0 Hz, 1H),
7.19 (td, J=7.7, 1.0 Hz, 1H), 7.11 (t, J=7.7 Hz, 1H), 7.00 (dd,
J=7.7, 1.6 Hz, 1H), 6.87 (dd, J=7.7, 1.0 Hz, 1H), 3.93 (s, 3H).
Example 6
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazi-
no}-2'-hydroxy-biphenyl-4-carboxylic acid (Compound 106)
[0497] ##STR36##
[0498] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.07 (s, 1H), 12.96
(s, 1H), 9.30 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.74 (dd, J=7.8, 1.6
Hz, 1H), 7.72 (dd, J=7.7, 1.0 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.35
(d, J=8.0 Hz, 1H), 7.30 (m, 1H), 7.27 (td, J=7.7, 1.0 Hz, 1H), 7.23
(dd, J=8.0, 2.1 Hz, 1H), 7.18 (td, J=7.7, 1.0 Hz, 1H), 7.12 (t,
J=7.8 Hz, 1H), 7.01 (dd, J=7.8, 1.6 Hz, 1H), 6.85 (dd, J=7.7, 1.0
Hz, 1H), 2.31 (s, 3H), 2.30 (s, 3H).
Example 7
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]--
hydrazino}-biphenyl-4-carboxylic acid (Compound 107)
[0499] ##STR37##
[0500] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.06 (s, 1H), 12.96
(s, 1H), 9.31 (s, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.75-7.72 (m, 2H),
7.68 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.41 (d, J=8.6 Hz,
2H), 7.29 (td, J=7.7, 1.0 Hz, 1H), 7.19 (td, J=7.7, 1.0 Hz, 1H),
7.12 (t, J=7.8 Hz, 1H), 7.01 (dd, J=7.8, 1.6 Hz, 1H), 6.87 (dd,
J=7.7, 1.0 Hz, 1H), 2.66 (t, J=7.4 Hz, 2H), 1.66 (sext, J=7.4 Hz,
2H), 0.95 (t, J=7.4 Hz, 3H).
Example 8
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-ethyl-phenyl)-1,2-dihydro-indol-3-ylidene]-h-
ydrazino}-biphenyl-4-carboxylic acid (Compound 108)
[0501] ##STR38##
[0502] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.21 (s, 1H), 8.47 (s,
1H), 8.11 (d, J=8.5 Hz, 2H), 7.79 (dd, J=7.8, 1.6 Hz, 1H), 7.76 (m,
1H), 7.68 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5
Hz, 2H), 7.29 (td, J=7.7, 1.1 Hz, 1H), 7.19 (td, J=7.7, 1.1 Hz,
1H), 7.12 (t, J=7.8 Hz, 1H), 7.02 (dd, J=7.8, 1.6 Hz, 1H), 6.92
(dd, J=7.7, 1.1 Hz, 1H), 2.75 (q, J=7.6 Hz, 2H), 1.29 (t, J=7.6 Hz,
3H).
Example 9
3'-{N'-[1-(4-tert-Butyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazi-
no}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 109)
[0503] ##STR39##
[0504] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, acetone-d.sub.6) .delta. 13.22 (s, 1H), 8.20
(s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.80-7.74 (m, 3H), 7.64 (d, J=8.0
Hz, 2H), 7.58 (m, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.29 (t, J=7.7 Hz,
1H), 7.19 (t, J=7.7 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.00 (m, 1H),
6.92 (d, J=7.7 Hz, 1H), 1.38 (s, 9H).
Example 10
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-trifluoromethyl-phenyl)-1,2-dihydro-indol-3--
ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 110)
[0505] ##STR40##
[0506] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.04 (s, 1H), 9.32 (s,
1H), 8.12 (t, J=1.5 Hz, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.94 (dt,
J=7.7, 1.5 Hz, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.79 (dt, J=7.7, 1.5
Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.74 (dd, J=7.6, 1.2 Hz, 1H), 7.59
(t, J=7.7 Hz, 1H), 7.32 (td, J=7.6, 1.2 Hz, 1H), 7.24 (td, J=7.6,
1.2 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.02
(dd, J=7.6, 1.2 Hz, 1H).
Example 11
3'-[N'-(1-Benzyl-5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-2'-
-hydroxy-biphenyl-3-carboxylic acid (Compound 111)
[0507] ##STR41##
[0508] This compound was prepared as described in Scheme III.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.10 (s, 1H), 13.03
(s, 1H), 9.36 (s, 1H), 8.13 (t, J=1.7 Hz, 1H), 7.95 (ddd, J=7.7,
1.7, 1.3 Hz, 1H), 7.80 (ddd, J=7.7, 1.7, 1.3 Hz, 1H), 7.76 (dd,
J=7.7, 1.6 Hz, 1H), 7.68 (d, J=2.1 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H),
7.37-7.32 (m, 4H), 7.30 (dd, J=8.5, 2.1 Hz, 1H), 7.27 (m, 1H), 7.11
(t, J=7.7 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.03 (dd, J=7.7, 1.6 Hz,
1H), 5.05 (s, 2H).
Example 12
3'-[N'-(1-Benzyl-5-methyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-2'-
-hydroxy-biphenyl-3-carboxylic acid (Compound 112)
[0509] ##STR42##
[0510] This compound was prepared as described in Scheme III.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.04 (s, 1H), 13.03
(s, 1H), 9.25 (s, 1H), 8.13 (t, J=1.5 Hz, 1H), 7.94 (dt, J=7.8, 1.5
Hz, 1H), 7.80 (m, 1H), 7.69 (dd, J=7.8, 1.6 Hz, 1H), 7.60 (t, J=7.8
Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 7.37-7.31 (m, 4H), 7.27 (m, 1H),
7.10 (t, J=7.8 Hz, 1H), 7.07 (dd, J=8.1, 1.8 Hz, 1H), 6.99 (dd,
J=7.8, 1.6 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 5.01 (s, 2H), 2.33 (s,
3H).
Example 13
3'-[N'-(1-Benzyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-2'-hydroxy--
biphenyl-3-carboxylic acid (Compound 113)
[0511] ##STR43##
[0512] This compound was prepared as described in Scheme III.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.07 (s, 1H), 13.04
(s, 1H), 9.28 (s, 1H), 8.13 (t, J=1.5 Hz, 1H), 7.94 (dm, J=7.7 Hz,
1H), 7.80 (dm, J=7.7 Hz, 1H), 7.70 (dd, J=7.8, 1.3 Hz, 1H), 7.65
(d, J=7.8 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.39-7.32 (m, 4H),
7.29-7.24 (m, 2H), 7.14-7.09 (m, 2H), 7.07 (d, J=7.8 Hz, 1H), 7.00
(dd, J=7.8, 1.3 Hz, 1H), 5.05 (s, 2H).
Example 14
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-trifluoromethyl-phenyl)-1,2-dihydro-indol-3--
ylidene]-hydrazino}-biphenyl-4-carboxylic acid (Compound 114)
[0513] ##STR44##
[0514] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.03 (s, 1H), 12.96
(s, 1H), 9.36 (s, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.98 (d, J=8.3 Hz,
2H), 7.83 (d, J=8.3 Hz, 2H), 7.77 (dd, J=7.7, 1.2 Hz, 1H), 7.75
(dd, J=7.8, 1.6 Hz, 1H), 7.68 (d, J=8.3 Hz, 2H), 7.32 (td, J=7.7,
1.2 Hz, 1H), 7.24 (td, J=7.7, 0.7 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H),
7.03 (dd, J=7.8, 1.6 Hz, 1H) 7.04 (dd, J=7.7, 0.7 Hz, 1H).
Example 15
3'-{N'-[1-(3,4-Dichloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazi-
no}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 115)
[0515] ##STR45##
[0516] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.04 (s, 1H), 13.01
(s, 1H), 9.32 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.95 (dt, J=7.7, 1.4
Hz, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.79 (m,
1H), 7.75 (ddd, J=7.6, 1.0, 0.5 Hz, 1H), 7.73 (dd, J=7.7, 1.6 Hz,
1H), 7.61 (dd, J=8.5, 2.4 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.31
(td, J=7.6, 1.0 Hz, 1H), 7.22 (td, J=7.6, 0.8 Hz, 1H), 7.12 (t,
J=7.7 Hz, 1H), 6.98 (ddd, J=7.6, 0.8, 0.5 Hz, 1H), 7.01 (dd, J=7.7,
1.6 Hz, 1H).
Example 16
2'-Hydroxy-3'-{N'-[1-(4-methyl-3-trifluoromethyl-phenyl)-2-oxo-1,2-dihydro-
-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound
116)
[0517] ##STR46##
[0518] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.04 (s, 1H), 13.02
(s, 1H), 9.30 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.8,
1.6, 1.2 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.79 (ddd, J=7.8, 1.6,
1.2 Hz, 1H), 7.77 (dd, J=8.3, 2.0 Hz, 1H), 7.76-7.72 (m, 2H), 7.68
(d, J=8.3 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.30 (td, J=7.7, 1.2 Hz,
1H), 7.21 (td, J=7.7, 0.9 Hz, 1H), 7.12 (t, J=7.7 Hz, 1H), 7.01
(dd, J=7.7, 1.6 Hz, 1H), 6.92 (dm, J=7.7 Hz, 1H), 2.54 (q, J=1.4
Hz, 3H).
Example 17
3'-{N'-[1-(3-Fluoro-4-trifluoromethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
117)
[0519] ##STR47##
[0520] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.04 (s, 1H), 13.01
(s, 1H), 9.35 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 8.03 (t, J=8.4 Hz,
1H), 7.94 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.86 (dd, J=11.8, 1.5 Hz,
1H), 7.80 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.77 (dd, J=7.7, 1.0 Hz,
1H), 7.74 (dd, J=7.7, 1.6 Hz, 1H), 7.68 (dd, J=8.4, 1.5 Hz, 1H),
7.60 (t, J=7.7 Hz, 1H), 7.34 (td, J=7.7, 1.0 Hz, 1H), 7.25 (td,
J=7.7, 1.0 Hz, 1H), 7.14 (dd, J=7.7, 1.0 Hz, 1H), 7.12 (t, J=7.7
Hz, 1H), 7.02 (dd, J=7.7, 1.6 Hz, 1H).
Example 18
3'-{N'-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylide-
ne]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
118)
[0521] ##STR48##
[0522] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.04 (s, 1H), 12.99
(s, 1H), 9.34 (s, 1H), 8.38-8.37 (m, 2H), 8.27 (m, 1H), 8.12 (t,
J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.79 (ddd,
J=7.7, 1.6, 1.2 Hz, 1H), 7.78 (ddd, J=7.7, 1.3, 0.6 Hz, 1H), 7.75
(dd, J=7.8, 1.7 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.34 (td, J=7.7,
1.3 Hz, 1H), 7.25 (td, J=7.7, 1.0 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H),
7.02 (dd, J=7.8, 1.7 Hz, 1H), 7.02 (ddd, J=7.7, 1.0, 0.6 Hz,
1H).
Example 19
3'-{N'-[3-(3,4-Dimethyl-phenyl)-4-oxo-2-thioxo-thiazolidin-5-ylidene]-hydr-
azino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 119)
[0523] ##STR49##
[0524] This compound was prepared as described in Scheme IV.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.83 (s, 1H), 10.76
(s, 1H), 9.35 (s, 1H), 8.15 (t, J=1.5 Hz, 1H), 7.91 (m, 1H), 7.79
(dt, J=7.7, 1.5 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.34 (m, 1H), 7.29
(d, J=7.9 Hz, 1H), 7.14-6.96 (m, 4H), 2.28 (s, 3H), 2.26 (s,
3H).
Example 20
2'-Hydroxy-3'-{N'-[1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-yliden-
e]-hydrazino}-biphenyl-3-carboxylic acid (Compound 120)
[0525] ##STR50##
[0526] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.06 (s, 1H), 9.27 (s,
1H), 8.11 (t, J=1.7 Hz, 1H), 7.94 (ddd, J=7.7, 1.7, 1.2 Hz, 1H),
7.79 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.73 (dd, J=7.7, 1.3 Hz, 1H),
7.73 (dd, J=7.7, 1.6 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.47 (d,
J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.29 (td, J=7.7, 1.3 Hz,
1H), 7.19 (td, J=7.7, 0.8 Hz, 1H), 7.11 (t, J=7.7 Hz, 1H), 7.00
(dd, J=7.7, 1.6 Hz, 1H), 6.88 (dd, J=7.7, 0.8 Hz, 1H), 3.00 (sept,
J=6.9 Hz, 1H), 1.27 (d, J=6.9 Hz, 6H).
Example 21
3'-{N'-[1-(2-Fluoro-4-trifluoromethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
121)
[0527] ##STR51##
[0528] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.95 (s, 1H), 9.34 (s,
1H), 8.11 (t, J=1.7 Hz, 1H), 8.09 (m, 1H), 7.96 (t, J=8.0 Hz, 1H),
7.94 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.86 (m, 1H), 7.79 (ddd, J=7.7,
1.7, 1.2 Hz, 1H), 7.77 (m, 1H), 7.75 (dd, J=8.0, 1.5 Hz, 1H), 7.60
(t, J=7.7 Hz, 1H), 7.32 (td, J=7.6, 1.4 Hz, 1H), 7.24 (td, J=7.6,
0.9 Hz, 1H), 7.13 (t, J=7.7 Hz, 1H), 7.03 (dd, J=7.7, 1.6 Hz, 1H),
6.86 (dm, J=7.6 Hz, 1H).
Example 22
3'-{N'-[1-(2-Fluoro-4-methyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hy-
drazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 122
[0529] ##STR52##
[0530] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.99 (s, 1H), 9.29 (s,
1H), 8.11 (t, J=1.7 Hz, 1H), 7.94 (ddd, J=7.7, 1.7, 1.2 Hz, 1H),
7.79 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.75-7.72 (m, 2H), 7.59 (t,
J=7.7 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.37 (dd, J=11.3, 1.4 Hz,
1H), 7.29 (td, J=7.7, 1.2 Hz, 1H), 7.25 (dm, J=8.0 Hz, 1H), 7.21
(td, J=7.7, 1.0 Hz, 1H) 7.12 (t, J=7.7 Hz, 1H), 7.01 (dd, J=7.7,
1.6 Hz, 1H), 6.71 (dm, J=7.7 Hz, 1H), 2.43 (s, 3H).
Example 23
3'-{N'-[1-(4-Chloro-3-trifluoromethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
123)
[0531] ##STR53##
[0532] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.99 (s, 1H), 9.32 (s,
1H), 8.12 (m, 2H), 7.98 (d, J=8.7 Hz, 1H), 7.94 (dd, J=8.7, 2.2 Hz,
1H), 7.94 (m, 1H), 7.79 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.76 (dd,
J=7.6, 1.0 Hz, 1H), 7.74 (dd, J=7.9, 1.6 Hz, 1H), 7.60 (t, J=7.7
Hz, 1H), 7.32 (td, J=7.6, 1.4 Hz, 1H), 7.23 (td, J=7.6, 1.0 Hz,
1H), 7.12 (t, J=7.9 Hz, 1H), 7.03-7.00 (m, 2H).
Example 24
3'-{N'-[1-(4-Butyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}-2-
'-hydroxy-biphenyl-3-carboxylic acid (Compound 124)
[0533] ##STR54##
[0534] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.22 (s, 1H), 8.19 (t,
J=1.6 Hz, 1H), 8.03 (dt, J=7.8, 1.6 Hz, 1H), 7.79 (dt, J=7.8, 1.6
Hz, 1H), 7.78 (dd, J=7.8, 1.6 Hz, 1H), 7.76 (dd, J=7.7, 1.0 Hz,
1H), 7.60 (t, J=7.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4
Hz, 2H), 7.29 (td, J=7.7, 1.0 Hz, 1H), 7.19 (td, J=7.7, 1.0 Hz,
1H), 7.12 (t, J=7.8 Hz, 1H), 7.01 (dd, J=7.8, 1.6 Hz, 1H), 6.92 (d,
J=7.7, 1.0 Hz, 1H), 2.72 (t, J=7.5 Hz, 2H), 1.67 (m, 2H), 1.40 (m,
2H), 0.95 (t, J=7.5 Hz, 3H).
Example 25
3'-{N'-[1-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}--
2'-hydroxy-biphenyl-3-carboxylic acid (Compound 125)
[0535] ##STR55##
[0536] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.03 (s, 1H), 9.31 (s,
1H), 8.12 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2 Hz, 1H),
7.79 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.74 (ddd, J=7.6, 1.2, 0.6 Hz,
1H), 7.73 (dd, J=7.7, 1.6 Hz, 1H), 7.65 (ddd, J=8.5, 8.0, 6.6 Hz,
1H), 7.60 (t, J=7.7 Hz, 1H), 7.49 (ddd, J=9.9, 2.6, 2.0 Hz, 1H)
7.42 (ddd, J=8.0, 2.0, 0.8 Hz, 1H), 7.36 (tdd, J=8.5, 2.6, 0.8 Hz,
1H), 7.31 (td, J=7.6, 1.2 Hz, 1H), 7.21 (td, J=7.6, 0.8 Hz, 1H),
7.11 (t, J=7.7 Hz, 1H), 7.01 (dd, J=7.7, 1.6 Hz, 1H), 6.96 (ddd,
J=7.6, 0.8, 0.6 Hz, 1H).
Example 26
2'-Hydroxy-3'-[N'-(2-oxo-1-m-tolyl-1,2-dihydro-indol-3-ylidene)-hydrazino]-
-biphenyl-3-carboxylic acid (Compound 126)
[0537] ##STR56##
[0538] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.22 (s, 1H), 8.20 (t,
J=1.6 Hz, 1H), 8.03 (dt, J=7.8, 1.6 Hz, 1H), 7.80-7.77 (m, 2H),
7.76 (dd, J=7.7, 1.0 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.48 (t,
J=7.8 Hz, 1H), 7.38 (t, J=1.6 Hz, 1H), 7.35 (m, 1H), 7.30 (m, 1H),
7.29 (td, J=7.7, 1.0 Hz, 1H), 7.19 (td, J=7.7, 1.0 Hz, 1H), 7.12
(t, J=7.8 Hz, 1H), 7.01 (dd, J=7.8, 1.7 Hz, 1H), 6.93 (dd, J=7.7,
1.0 Hz, 1H), 2.44 (s, 3H).
Example 27
3'-{N'-[1-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazino}--
2'-hydroxy-biphenyl-3-carboxylic acid (Compound 127)
[0539] ##STR57##
[0540] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.04 (s, 1H), 9.28 (s,
1H), 8.11 (t, J=1.6 Hz, 1H), 7.94 (dt, J=7.9, 1.6 Hz, 1H), 7.78
(dt, J=7.9, 1.6 Hz, 1H), 7.74 (dd, J=7.8, 1.0 Hz, 1H), 7.73 (dd,
J=7.9, 1.6 Hz, 1H), 7.63-7.57 (m, 3H), 7.44 (t, J=8.6 Hz, 2H), 7.29
(td, J=7.8, 1.0 Hz, 1H), 7.20 (td, J=7.8, 1.0 Hz, 1H), 7.11 (t,
J=7.9 Hz, 1H), 7.00 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=7.8 Hz,
1H).
Example 28
3'-[N'-(1-Benzyl-5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-2-
'-hydroxy-biphenyl-3-carboxylic acid (Compound 128)
[0541] ##STR58##
[0542] This compound was prepared as described in Scheme III.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.10 (s, 1H), 9.27 (s,
1H), 8.13 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H),
7.74 (d, J=6.5 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.36-7.32 (m, 4H),
7.28-7.25 (m, 1H), 7.24 (d, J=2.5 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H),
7.00 (d, J=8.0 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.84 (dd, J=2.5,
9.0 Hz, 1H), 5.01 (s, 2H), 3.79 (s, 3H).
Example 29
2'-Hydroxy-3'-{N'-[2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3--
ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 129)
[0543] ##STR59##
[0544] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.03 (s, 1H), 9.32 (s,
1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.95-7.91 (m, 4H), 7.81-7.73 (m,
3H), 7.60 (t, J=7.5 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.23 (t, J=7.5
Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.02 (dd, J=1.5, 7.5 Hz, 1H), 6.95
(d, J=7.5 Hz, 1H).
Example 30
3'-{N'-[5-Chloro-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 130
[0545] ##STR60##
[0546] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.09 (s, 2H), 9.35 (s,
1H), 8.11 (d, J=1.5 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.79 (d, J=8.3
Hz, 2H), 7.76 (d, J=2.0 Hz, 1H), 7.60 (t, 1H), 7.46 (q, J=6.0 Hz,
4H), 7.30 (dd, J=8.3, 2.4 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 7.03
(dd, J=7.8, 1.5 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 3.00 (sept, J=7.0
Hz, 1H), 1.27 (d, J=6.8 Hz, 8H).
Example 31
3'-{N'-[6-Chloro-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
131)
[0547] ##STR61##
[0548] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.05 (s, 1H), 9.30 (s,
1H), 8.11 (t, J=1.5 Hz, 1H), 7.94 (qn, J=2.3 Hz, 1H), 7.79 (dt,
J=7.8, 1.5 Hz, 1H), 7.73 (dd, J=7.8, 1.5 Hz, 2H), 7.59 (t, J=7.8
Hz, 1H), 7.48 (m, 4H), 7.24 (dd, J=8.1, 1.7 Hz, 1H), 7.11 (t, 1H),
7.02 (dd, J=7.6, 1.7 Hz, 1H), 6.82 (d, J=1.5 Hz, 1H), 3.00 (sept,
J=6.8 Hz, 1H), 1.27 (d, J=6.8 Hz, 6H).
Example 32
3'-{N'-[5-Fluoro-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
132)
[0549] ##STR62##
[0550] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.12 (s, 1H), 13.04
(s, 1H), 9.34 (s, 1H), 8.11 (t, 1H), 7.94 (t, 1H), 7.78 (dt, J=9.1,
5.2 Hz, 2H), 7.58 (m, 2H), 7.46 (m, 4H), 7.09-7.09 (m, 2H), 7.03
(dd, J=7.8, 2.0 Hz, 1H), 6.87 (dd, J=8.8, 3.9 Hz, 1H), 3.00 (sept,
J=7.0 Hz, 1H), 1.27 (d, J=6.8 Hz, 6H).
Example 33
3'-{N'-[5-Methoxy-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
133)
[0551] ##STR63##
[0552] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.09 (s, 1H), 13.03
(s, 1H), 9.26 (s, 1H), 8.11 (t, J=1.5 Hz, 1H), 7.94 (d, J=7.8 Hz,
1H), 7.78 (dt, J=9.9, 5.5 Hz, 2H), 7.60 (t, J=7.8 Hz, 1H), 7.45 (q,
J=5.4 Hz, 4H), 7.32 (d, J=2.4 Hz, 1H), 7.11 (t, 1H), 7.00 (dd,
J=7.6, 1.7 Hz, 1H), 6.86 (dd, J=8.5, 2.7 Hz, 1H), 6.82 (d, J=8.8
Hz, 1H), 3.83 (s, 3H), 3.00 (sept, J=6.8 Hz, 1H), 1.27 (d, J=6.8
Hz, 6H).
Example 34
3'-{N'-[1-(3,4-Dimethyl-phenyl-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
134)
[0553] ##STR64##
[0554] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.13 (s, 1H), 13.03
(s, 1H), 9.33 (s, 1H), 8.12 (t, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.79
(dt, J=4.8, 3.8 Hz, 2H), 7.60 (t, J=7.8 Hz, 1H), 7.56 (dd, J=8.1,
2.7 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.23
(dd, J=8.1, 2.2 Hz, 1H), 7.14-7.08 (m, 2H), 7.03 (dd, J=7.8, 1.5
Hz, 1H), 6.85 (q, J=4.2 Hz, 1H), 2.31 (s, 3H), 2.30 (s, 3H).
Example 35
3'-{N'-[1-(4-Fluoro-3-trifluoromethyl-phenyl)-5-fluoro-2-oxo-1,2-dihydro-i-
ndol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 135)
[0555] ##STR65##
[0556] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.03 (s, 1H), 13.00
(s, 1H), 9.31 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 8.06 (dd, J=6.6, 2.7
Hz, 1H), 7.99 (dd, J=8.8, 4.4, 2.7 Hz, 1H), 7.94 (ddd, J=7.8, 1.6,
1.3 Hz, 1H), 7.80-7.72 (m, 4H), 7.60 (t, J=7.8 Hz, 1H), 7.31 (td,
J=7.7, 1.3 Hz, 1H), 7.22 (td, J=7.7, 1.0 Hz, 1H), 7.12 (t, J=7.8
Hz, 1H), 7.01 (dd, J=7.8, 1.6 Hz, 1H), 6.94 (ddd, J=7.7, 1.0, 0.6
Hz, 1H).
Example 36
3'-{N'-[1-(3,5-Dichloro-phenyl)-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
136)
[0557] ##STR66##
[0558] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.02 (s, 1H), 12.99
(s, 1H), 9.33 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7,
1.6, 1.1 Hz, 1H), 7.80 (ddd, J=7.7, 1.6, 1.1 Hz, 1H), 7.78 (t,
J=1.9 Hz, 1H), 7.76-7.72 (m, 4H), 7.60 (t, J=7.7 Hz, 1H), 7.32 (td,
J=7.6, 1.2 Hz, 1H), 7.23 (td, J=7.6, 0.7 Hz, 1H), 7.12 (t, J=7.8
Hz, 1H), 7.01 (dd, J=7.8, 1.7 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H).
Example 37
3'-{N'-[1-(4-Propyl-phenyl)-6-chloro-2-oxo-1,2-dihydro-indol-3-ylidene]-hy-
drazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 137)
[0559] ##STR67##
[0560] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.05 (s, 1H), 13.02
(s, 1H), 9.32 (s, 1H), 8.11 (t, J=1.7 Hz, 1H), 7.94 (ddd, J=7.7,
1.7, 1.2 Hz, 1H), 7.79 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.73 (dd,
J=8.0, 1.8 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H),
7.45 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H), 7.23 (dd, J=8.0,
1.9 Hz, 1H), 7.11 (dd, J=7.7, 8.0 Hz, 1H), 7.02 (dd, J=7.7, 1.8 Hz,
1H), 6.81 (d, J=1.9 Hz, 1H), 2.66 (t, J=7.4 Hz, 2H), 1.66 (sext,
J=7.4 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H).
Example 38
(.+-.)-2'-Hydroxy-3'-(N'-{2-oxo-1-[4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phe-
nyl]-1,2-dihydro-indol-3-ylidene}-hydrazino)-biphenyl-3-carboxylic
acid (Compound 138)
[0561] ##STR68##
[0562] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.05 (s, 1H), 13.03
(s, 1H), 9.29 (s, 1H), 8.12 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.79
(d, J=7.8 Hz, 1H), 7.76-7.70 (m, 4H), 7.62-7.59 (m, 3H), 7.30 (t,
J=7.6 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.12 (t, J=7.9 Hz, 1H),
7.02-6.99 (m, 2H), 6.93 (d, J=7.8 Hz, 1H), 5.32 (m, 1H), 3.17 (d,
J=5.3 Hz, 1H).
Example 39
(.+-.)-2'-Hydroxy-3'-(N'-{2-oxo-1-[4-(2,2,2-trifluoro-1-methoxy-ethyl)-phe-
nyl]-1,2-dihydro-indol-3-ylidene}-hydrazino)-biphenyl-3-carboxylic
acid (Compound 139)
[0563] ##STR69##
[0564] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.06 (s, 1H), 13.03
(s, 1H), 9.30 (s, 1H), 8.12 (s, 1H), 7.94 (d, J=7.0 Hz, 1H), 7.79
(d, J=7.0 Hz, 1H), 7.75 (m, 2H), 7.68 (m, 4H), 7.60 (t, J=7.0 Hz,
1H), 7.31 (t, J=7.4 Hz, 1H), 7.22 (t, J=7.4 Hz, 1H), 7.12 (t, J=7.6
Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 6.97 (m, 1H), 5.22 (q, J=6.7 Hz,
1H), 3.42 (s, 3H).
Example 40
2'-Hydroxy-3'-(N'-{2-oxo-1-[4-(2,2,2-trifluoro-ethyl)-phenyl]-1,2-dihydro--
indol-3-ylidene}-hydrazino)-biphenyl-3-carboxylic acid (Compound
140)
[0565] ##STR70##
[0566] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.05 (s, 1H), 13.02
(s, 1H), 9.28 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.94 (ddd, J=7.7,
1.7, 1.2 Hz, 1H), 7.79 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.74 (m, 2H),
7.62-7.56 (m, 5H), 7.30 (td, J=7.6, 1.2 Hz, 1H), 7.21 (td, J=7.6,
0.8 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 7.01 (dd, J=7.8, 1.6 Hz, 1H),
6.92 (d, J=7.8, 1H), 3.79 (q, J=11.5 Hz, 2H).
Example 41
3'-{N'-[1-(3,4-Dimethyl-phenyl)-4,5-dimethyl-2-oxo-1,2-dihydro-indol-3-yli-
dene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
141)
[0567] ##STR71##
[0568] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, CD3OD) .delta. 8.17 (s, 1H), 8.00 (d, J=7.7
Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.54 (t,
J=7.7 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.21 (s, 1H), 7.15 (d, J=7.7
Hz, 1H), 7.08 (t, J=7.7 Hz, 1H), 7.02 (m, 1H), 6.95 (d, J=7.7 Hz,
1H), 6.57 (m, 1H), 2.72 (s, 3H), 2.35 (s, 3H), 2.34 (s, 3H), 2.33
(s, 3H).
Example 42
3'-{N'-[1-(3,4-Dimethyl-phenyl)-5-fluoro-4-methyl-2-oxo-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 142)
[0569] ##STR72##
[0570] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.29 (s, 1H), 8.11 (s,
1H), 7.91 (d, J=7.3 Hz, 1H), 7.74 (d, J=7.3 Hz, 1H), 7.61 (d, J=7.8
Hz, 1H), 7.54 (t, J=7.3 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.28 (s,
1H), 7.21 (dd, J=8.0, 1.7 Hz, 1H), 7.10 (m, 1H), 7.06 (t, J=9.3 Hz,
1H), 7.01 (d, J=7.8 Hz, 1H), 6.65 (dd, J=8.6, 3.8 Hz, 1H), 2.63 (br
s, 3H), 2.31 (s, 3H), 2.30 (s, 3H).
Example 43
3'-{N'-[1-(3,4-Dimethyl-phenyl)-5-fluoro-6-methyl-2-oxo-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 143)
[0571] ##STR73##
[0572] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.28 (s, 1H), 8.11 (t,
J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.79 (ddd,
J=7.6, 1.6, 1.2 Hz, 1H), 7.74 (dd, J=7.9, 1.6 Hz, 1H), 7.59 (t,
J=7.7 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.28
(d, J=2.1 Hz, 1H), 7.22 (dd, J=8.0, 2.1 Hz, 1H), 7.11 (t, J=7.9 Hz,
1H), 7.01 (dd, J=7.9, 1.6 Hz, 1H), 6.74 (d, J=5.8 Hz, 1H), 2.31 (s,
3H), 2.30 (s, 3H), 2.24 (d, J=1.8 Hz, 3H).
Example 44
5-(4-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indo-
l-3-ylidene]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4-dione
(Compound 144)
[0573] ##STR74##
[0574] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 13.13 (s, 1H), 12.57 (s, 1H),
10.88 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.70
(s, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.33 (br
s, 1H), 7.28-7.24 (m, 2H), 7.16 (br s, 1H), 6.96 (s, 1H), 2.33 (s,
3H), 2.31 (s, 3H).
Example 45
5-(4-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydra-
zino}-3-hydroxy-benzylidene)-thiazolidine-2,4-dione (Compound
145)
[0575] ##STR75##
[0576] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 13.00 (s, 1H), 12.54 (s, 1H),
10.74 (s, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.68
(s, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.32-7.29 (m, 2H), 7.25-7.22 (m,
2H), 7.19 (t, J=7.5, 1H), 7.15 (d, J=1.8 Hz, 1H), 6.86 (d, J=7.5
Hz, 1H), 2.32 (s, 3H), 2.31 (s, 3H).
Example 46
3'-{N'-[1-(3,4-Dimethyl-phenyl)-4-fluoro-2-oxo-6-trifluoromethyl-1,2-dihyd-
ro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 146)
[0577] ##STR76##
[0578] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.37 (s, 1H), 13.05
(s, 1H), 9.49 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.95 (ddd, J=7.7,
1.6, 1.2 Hz, 1H), 7.80 (ddd, J=7.7, 1.6, 1.3 Hz, 1H), 7.67 (dd,
J=7.9, 1.6 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.50 (d, J=9.5 Hz, 1H),
7.39 (d, J=8.0 Hz, 1H), 7.32 (d, J=2.1 Hz, 1H), 7.26 (dd, J=8.0,
2.1 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 7.08 (dd, J=7.9, 1.6 Hz, 1H),
6.81 (s, 1H), 2.32 (s, 3H), 2.31 (s, 3H).
Example 47
3'-{N'-[4-Chloro-1-(3,4-dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihyd-
ro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 147)
[0579] ##STR77##
[0580] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.45 (s, 1H), 13.06
(s, 1H), 9.51 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.95 (ddd, J=7.7,
1.6, 1.2 Hz, 1H), 7.80 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.74 (dd,
J=7.8, 1.5 Hz, 1H), 7.62 (m, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.39 (d,
J=8.2 Hz, 1H), 7.32 (d, J=2.1 Hz, 1H), 7.26 (dd, J=8.2, 2.1 Hz,
1H), 7.16 (t, J=7.8 Hz, 1H), 7.09 (dd, J=7.8, 1.5 Hz, 1H), 6.89 (m,
1H), 2.32 (s, 3H), 2.31 (s, 3H).
Example 48
5-(4-{N'-[1-(3,4-Dimethyl-phenyl)-4-fluoro-2-oxo-6-trifluoromethyl-1,2-dih-
ydro-indol-3-ylidene]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4-d-
ione (Compound 148)
[0581] ##STR78##
[0582] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 13.26 (s, 1H), 12.57 (s, 1H),
10.91 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.66 (s, 1H), 7.51 (d, J=9.4
Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 7.27 (s,
1H), 7.25 (d, J=1.9 Hz, 1H), 7.17 (d, J=1.9 Hz, 1H), 6.80 (s, 1H),
2.33 (s, 3H), 2.31 (s, 3H).
Example 49
5-(4-{N'-[4-Chloro-1-(3,4-dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dih-
ydro-indol-3-ylidene]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4-d-
ione (Compound 149)
[0583] ##STR79##
[0584] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 13.33 (s, 1H), 12.58 (s, 1H),
10.94 (s, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.70 (s, 1H), 7.63 (s, 1H),
7.39 (d, J=8.0 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 7.27 (dt, J=8.3,
1.9 Hz, 1H), 7.26 (d, J=8.0, 1H), 7.17 (d, J=1.9 Hz, 1H), 6.88 (s,
1H), 2.33 (s, 3H), 2.31 (s, 3H).
Example 50
3-(4-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indo-
l-3-ylidene]-hydrazino}-3-hydroxy-phenyl)-acrylic acid (Compound
150)
[0585] ##STR80##
[0586] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 13.12 (s, 1H), 12.33 (s, 1H),
10.68 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H),
7.53-7.52 (m, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.33-7.31 (m, 2H), 7.26
(dd, J=8.3, 2.1 Hz, 1H), 7.15 (d, J=1.8 Hz, 1H), 6.95 (s, 1H), 6.33
(d, J=15.9 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H).
Example 51
1-(3,4-Dimethyl-phenyl)-3-{[2-hydroxy-4-(4-oxo-2-thioxo-thiazolidin-5-ylid-
enemethyl)-phenyl]-hydrazono}-6-trifluoromethyl-1,3-dihydro-indol-2-one
(Compound 151)
[0587] ##STR81##
[0588] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 13.81 (s, 1H), 13.14 (s, 1H),
10.90 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H),
7.56-7.55 (m, 2H), 7.39 (d, J=8.0 Hz, 1H), 7.33 (d, J=2.1 Hz, 1H),
7.29-7.27 (m, 2H), 7.15 (d, J=1.8 Hz, 1H), 6.96 (m, 1H), 2.33 (s,
3H), 2.31 (s, 3H).
Example 52
1-(3,4-Dimethyl-phenyl)-4-fluoro-3-{[2-hydroxy-4-(4-oxo-2-thioxo-thiazolid-
in-5-ylidenemethyl)-phenyl]-hydrazono}-6-trifluoromethyl-1,3-dihydro-indol-
-2-one (Compound 152)
[0589] ##STR82##
[0590] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 13.81 (s, 1H), 13.27 (s, 1H),
10.94 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J=9.9
Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.32-7.30 (m, 2H), 7.26 (dd,
J=8.0, 1.6 Hz, 1H), 7.16 (s, 1H), 6.81 (s, 1H), 2.33 (s, 3H), 2.31
(s, 3H).
Example 53
5-(3-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indo-
l-3-ylidene]-hydrazino}-2-hydroxy-benzylidene)-thiazolidine-2,4-dione
(Compound
[0591] ##STR83##
[0592] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 13.16 (s, 1H), 8.05 (s, 1H),
7.91 (d, J=7.7 Hz, 1H), 7.81 (m, 1H), 7.53 (d, J=7.7, 1H), 7.39 (d,
J=8.2 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.27 (dd, J=8.2, 2.0 Hz,
1H), 7.17-7.12 (m, 2H), 6.95 (s, 1H), 2.33 (s, 3H), 2.31 (s,
3H).
Example 54
3'-{N'-[5-Chloro-2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]-hy-
drazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 154)
[0593] ##STR84##
[0594] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.09 (s, 1H), 13.02 (s, 1H),
9.35 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.8, 1.6, 1.2
Hz, 1H), 7.81-7.78 (m, 2H), 7.76 (d, J=2.2 Hz, 1H), 7.60 (t, J=7.8
Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.30 (dd,
J=8.4, 2.2 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 7.03 (dd, J=7.8, 1.6
Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 2.65 (t, J=7.4 Hz, 2H), 1.66
(sext, J=7.4 Hz, 2H), 0.94 (t, J=7.4 Hz, 3H).
Example 55
2'-Hydroxy-3'-{N'-[1-(4-methylsulfanyl-phenyl)-2-oxo-1,2-dihydro-indol-3-y-
lidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 155)
[0595] ##STR85##
[0596] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.05 (s, 1H), 13.03 (s, 1H),
9.28 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.94 (ddd, J=7.7, 1.7, 1.2
Hz, 1H), 7.79 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.74-7.72 (m, 2H),
7.60 (t, J=7.7 Hz, 1H), 7.49 (d, J=9.0 Hz, 2H), 7.46 (d, J=9.0 Hz,
2H), 7.29 (td, J=7.7, 1.2 Hz, 1H), 7.20 (td, J=7.7, 0.8 Hz, 1H),
7.11 (t, J=7.8 Hz, 1H), 7.00 (dd, J=7.8, 1.6 Hz, 1H), 6.88 (dd,
J=7.7, 0.8 Hz, 1H), 2.55 (s, 3H).
Example 56
2'-Hydroxy-3'-{N'-[1-(4-methoxymethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 156)
[0597] ##STR86##
[0598] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.07 (s, 1H), 13.03 (s, 1H),
9.28 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.94 (ddd, J=7.7, 1.7, 1.2
Hz, 1H), 7.79 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.74 (m, 1H), 7.73
(dd, J=7.9, 1.6 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.54 (d, J=9.0 Hz,
2H), 7.52 (d, J=9.0 Hz, 2H), 7.29 (td, J=7.8, 1.2 Hz, 1H), 7.20
(td, J=7.8, 0.8 Hz, 1H), 7.12 (t, J=7.9 Hz, 1H), 7.01 (dd, J=7.9,
1.6 Hz, 1H), 6.90 (dd, J=7.8, 0.8 Hz, 1H), 4.52 (s, 2H), 3.36 (s,
3H).
Example 57
(.+-.)-2'-Hydroxy-3'-(N'-{2-oxo-1-[4-(2,2,2-trifluoro-1-hydroxy-1-methyl-e-
thyl)-phenyl]-1,2-dihydro-indol-3-ylidene}-hydrazino)-biphenyl-3-carboxyli-
c acid (Compound 157)
[0599] ##STR87##
[0600] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.06 (s, 1H), 13.03 (s, 1H),
9.29 (s, 1H), 8.12 (s, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.83-7.72 (m,
5H), 7.62-7.58 (m, 3H), 7.30 (t, J=7.9 Hz, 1H), 7.21 (t, J=7.9 Hz,
1H), 7.12 (t, J=7.8 Hz, 1H), 7.01 (d, J=7.8 Hz, 1H), 6.93 (d, J=7.9
Hz, 1H), 6.77 (s, 1H), 1.76 (s, 3H).
Example 58
3'-{N'-[5-Fluoro-1-(4-methyl-3-trifluoromethyl-phenyl)-2-oxo-1,2-dihydro-i-
ndol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 158
[0601] ##STR88##
[0602] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.07 (s, 1H), 13.03 (s, 1H),
9.37 (s, 1H), 8.12 (s, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.88 (s, 1H),
7.81-7.75 (m, 3H), 7.68 (d, J=8.1 Hz, 1H), 7.63-7.57 (m, 2H),
7.15-7.09 (m, 2H), 7.04 (d, J=7.6 Hz, 1H), 6.93 (m, 1H), 2.54 (s,
3H).
Example 59
2'-Hydroxy-3'-(N'-{2-oxo-1-[4-(2,2,2-trifluoro-1-methoxy-1-methyl-ethyl)-p-
henyl]-1,2-dihydro-indol-3-ylidene}-hydrazino)-biphenyl-3-carboxylic
acid (Compound
[0603] ##STR89##
[0604] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.05 (s, 1H), 13.02 (s, 1H),
9.29 (s, 1H), 8.12 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.81-7.72 (m,
5H), 7.68-7.65 (m, 2H), 7.60 (t, J=7.8 Hz, 1H), 7.31 (t, J=7.6 Hz,
1H), 7.22 (t, J=7.6 Hz, 1H), 7.12 (t, J=7.9 Hz, 1H), 7.03 (d, J=7.8
Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 3.24 (s, 3H), 1.85 (s, 3H).
Example 60
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
160)
[0605] ##STR90##
[0606] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.03 (s, 1H), 12.99 (s, 1H),
9.27 (s, 1H), 8.12 (t, J=1.5 Hz, 1H), 7.94 (ddd, J=7.7, 1.5, 1.2
Hz, 1H), 7.79 (ddd, J=7.7, 1.5, 1.2 Hz, 1H), 7.74 (dd, J=8.4, 5.3
Hz, 1H), 7.72 (dd, J=7.8, 1.4 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.36
(d, J=8.0 Hz, 1H), 7.31 (d, J=1.8 Hz, 1H), 7.25 (dd, J=7.8, 1.8 Hz,
1H), 7.11 (t, J=7.8 Hz, 1H), 7.03-6.98 (m, 2H), 6.66 (dd, J=9.3,
2.2 Hz, 1H), 2.31 (s, 3H), 2.30 (s, 3H).
Example 61
3'-{N'-[6-Fluoro-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
161)
[0607] ##STR91##
[0608] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.02 (s, 1H), 12.98 (s, 1H),
9.28 (s, 1H), 8.11 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.8, 1.6, 1.1
Hz, 1H), 7.79 (m, 1H), 7.75 (dd, J=7.7, 4.9 Hz, 1H), 7.73 (dd,
J=7.8, 1.5 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.48 (d, J=9.2 Hz, 2H),
7.46 (d, J=9.2 Hz, 2H), 7.11 (t, J=7.8 Hz, 1H), 7.02 (m, 1H), 7.00
(dd, J=7.8, 1.5 Hz, 1H), 6.69 (dd, J=9.3, 2.2 Hz, 1H), 3.01 (sept,
J=6.9 Hz, 1H), 1.27 (d, J=6.9 Hz, 6H).
Example 62
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-5-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 162)
[0609] ##STR92##
[0610] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.12 (s, 1H), 12.99 (s, 1H),
9.38 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 8.03 (m, 1H), 7.94 (ddd,
J=7.8, 1.6, 1.1 Hz, 1H), 7.85 (dd, J=7.8, 1.5 Hz, 1H), 7.80 (ddd,
J=7.8, 1.6, 1.1 Hz, 1H), 7.62 (m, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.37
(d, J=8.0 Hz, 1H), 7.33 (d, J=1.9 Hz, 1H), 7.26 (dd, J=8.0, 1.9 Hz,
1H), 7.13 (t, J=7.8 Hz, 1H), 7.05 (dd, J=7.8, 1.5 Hz, 1H), 7.01 (d,
J=8.3 Hz, 1H), 2.32 (s, 3H), 2.31 (s, 3H).
Example 63
3'-{N'-[6-Fluoro-2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]-hy-
drazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 163)
[0611] ##STR93##
[0612] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.98 (s, 1H), 9.28 (s, 1H),
8.11 (t, J=1.7 Hz, 1H), 7.94 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.79
(ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.75 (dd, J=7.5, 4.7 Hz, 1H), 7.72
(dd, J=7.8, 1.6 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.45 (d, J=8.5 Hz,
2H), 7.42 (d, J=8.5 Hz, 2H), 7.11 (t, J=7.8 Hz, 1H), 7.02 (m, 1H),
7.00 (dd, J=7.8, 1.6 Hz, 1H), 6.68 (dd, J=9.4, 2.3 Hz, 1H), 2.66
(t, J=7.4 Hz, 2H), 1.66 (sext, J=7.4 Hz, 2H), 0.95 (t, J=7.4 Hz,
3H).
Example 64
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-5-trifluoromethyl-1,2-dihydro-
-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound
164)
[0613] ##STR94##
[0614] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.11 (s, 1H), 12.99 (s, 1H),
9.38 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 8.03 (d, J=1.5 Hz, 1H), 7.95
(ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.85 (dd, J=8.2, 1.5 Hz, 1H), 7.80
(ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.62 (m, 1H), 7.60 (t, J=7.7 Hz,
1H), 7.46 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.13 (t, J=7.8
Hz, 1H), 7.05 (dd, J=7.8, 1.6 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 2.66
(t, J=7.4 Hz, 2H), 1.67 (sext, J=7.4 Hz, 2H), 0.95 (t, J=7.4 Hz,
3H).
Example 65
3'-{N'-[4,5-Difluoro-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylid-
ene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
165)
[0615] ##STR95##
[0616] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.25 (s, 1H), 13.01 (s, 1H),
9.39 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2
Hz, 1H), 7.79 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.64 (dd, J=7.8, 1.6
Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 2H), 7.43 (d,
J=8.7 Hz, 2H), 7.29 (dt, J=11.2, 8.5 Hz, 1H), 7.14 (t, J=7.8 Hz,
1H), 7.05 (dd, J=7.8, 1.6 Hz, 1H), 6.65 (dd, J=8.5, 3.1 Hz, 1H),
3.00 (sept, J=7.0 Hz, 1H), 1.27 (d, J=7.0 Hz, 6H).
Example 66
2'-Hydroxy-3'-[N'-(2-oxo-1-piperidin-4-yl-1,2-dihydro-indol-3-ylidene)-hyd-
razino]-biphenyl-3-carboxylic acid (Compound 166)
[0617] ##STR96##
[0618] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.15 (s, 1H), 8.13 (t, J=1.4
Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.66-7.63
(m, 2H), 7.51 (t, J=7.8 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.28 (td,
J=7.6, 1.0 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H),
6.96 (dd, J=7.6, 1.5 Hz, 1H), 4.42 (m, 1H), 3.26 (m, 2H), 2.84 (m,
2H), 2.45 (m, 2H), 1.76 (m, 2H).
Example 67
3'-{N'-[5-Fluoro-1-(2-fluoro-4-methyl-phenyl)-2-oxo-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
167)
[0619] ##STR97##
[0620] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.05 (s, 1H), 13.02 (s, 1H),
9.37 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.94 (ddd, J=7.8, 1.7, 1.3
Hz, 1H), 7.79 (m, 1H), 7.78 (dd, J=7.8, 1.5 Hz, 1H), 7.60 (t, J=7.8
Hz, 1H), 7.58 (dd, J=8.2, 2.7 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.37
(dd, J=11.3, 1.2 Hz, 1H), 7.25 (dd, J=8.1, 1.2 Hz, 1H), 7.13 (t,
J=7.8 Hz, 1H), 7.11 (ddd, J=9.2, 8.7, 2.7 Hz, 1H), 7.04 (dd, J=7.8,
1.5 Hz, 1H, 6.72 (ddd, J=8.7, 4.1, 1.0 Hz, 1H), 2.43 (s, 3H).
Example 68
2'-Hydroxy-3'-[N'-(1-methyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]--
biphenyl-3-carboxylic acid (Compound 168)
[0621] ##STR98##
[0622] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.05 (s, 1H), 13.03 (s, 1H),
9.24 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.94 (ddd, J=7.7, 1.7, 1.1
Hz, 1H), 7.79 (ddd, J=7.7, 1.7, 1.1 Hz, 1H), 7.68 (dd, J=7.9, 1.6
Hz, 1H), 7.63 (dd, J=7.7, 1.0 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.35
(td, J=7.7, 1.0 Hz, 1H), 7.16-7.12 (m, 2H), 7.09 (t, J=7.9 Hz, 1H),
6.98 (dd, J=7.9, 1.6 Hz, 1H), 3.28 (s, 3H).
Example 69
3'-[N'-(1-Cyclopentyl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazino]-2'-hyd-
roxy-biphenyl-3-carboxylic acid (Compound 169)
[0623] ##STR99##
[0624] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.12 (s, 1H), 13.00 (s, 1H),
9.23 (s, 1H), 8.13 (t, J=1.7 Hz, 1H), 7.94 (ddd, J=7.8, 1.7, 1.1
Hz, 1H), 7.79 (ddd, J=7.6, 1.7, 1.1 Hz, 1H), 7.68 (dd, J=7.8, 1.6
Hz, 1H), 7.65 (dd, J=7.6, 1.1 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.32
(td, J=7.6, 1.1 Hz, 1H), 7.21 (dd, J=7.6, 0.8 Hz, 1H), 7.13 (td,
J=7.6, 0.8 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 6.98 (dd, J=7.8, 1.6
Hz, 1H), 4.76 (qn, J=8.5 Hz, 1H), 2.10 (m, 2H), 1.97-1.89 (m, 4H),
1.68 (m, 2H).
Example 70
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-methyl-2-oxo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
170)
[0625] ##STR100##
[0626] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) 12.98 (s, 2H), 9.22 (s, 1H),
8.12 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.79
(ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.70 (dd, J=8.0, 1.5 Hz, 1H), 7.60
(dd, J=7.7, 1.6 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.35 (d, J=8.0 Hz,
1H), 7.28 (d, J=1.9 Hz, 1H), 7.21 (dd, J=8.0, 1.9 Hz, 1H), 7.10 (t,
J=7.7 Hz, 1H), 7.00 (m, 1H), 6.98 (dd, J=7.7, 1.6 Hz, 1H), 6.65 (m,
1H), 2.31 (s, 6H), 2.30 (s, 3H).
Example 71
2'-Hydroxy-3'-[N'-(2-oxo-1-phenyl-1,2-dihydro-indol-3-ylidene)-hydrazino]--
biphenyl-3-carboxylic acid (Compound 171)
[0627] ##STR101##
[0628] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.07 (s, 1H), 13.04 (s, 1H),
9.28 (s, 1H), 8.12 (t, J=1.5 Hz, 1H), 7.94 (ddd, J=7.6, 1.5, 1.1
Hz, 1H), 7.79 (ddd, J=7.6, 1.5, 1.1 Hz, 1H), 7.76-7.72 (m, 2H),
7.61 (td, J=7.4, 1.0 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 7.55 (dd,
J=7.4, 1.0 Hz, 2H), 7.50 (tt, J=7.4, 1.0 Hz, 1H), 7.30 (td, J=7.6,
1.1 Hz, 1H), 7.20 (td, J=7.6, 0.6 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H),
7.01 (dd, J=7.8, 1.5 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H)
Example 72
3'-[N'-(6-Fluoro-2-oxo-1-phenyl-2,3-dihydro-1H-indol-3-yl)-hydrazino]-2'-h-
ydroxy-biphenyl-3-carboxylic acid (Compound 172)
[0629] ##STR102##
[0630] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.04 (s, 1H), 12.98 (s, 1H),
9.30 (s, 1H), 8.12 (t, J=1.5 Hz, 1H), 7.94 (ddd, J=7.7, 1.5, 0.9
Hz, 1H), 7.79 (ddd, J=7.7, 1.5, 0.9 Hz, 1H), 7.76 (dd, J=8.5, 5.7
Hz, 1H), 7.73 (dd, J=7.8, 1.2 Hz, 1H), 7.64-7.55 (m, 5H), 7.51 (t,
J=7.3 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.05-6.99 (m, 2H), 6.71 (dd,
J=9.4, 2.2 Hz, 1H).
Example 73
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-isopropyl-2-oxo-1,2-dihydro-indol-3-ylid-
ene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
173)
[0631] ##STR103##
[0632] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) 13.03 (s, 1H), 13.00 (s, 1H),
9.23 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.8, 1.6, 1.2
Hz, 1H), 7.79 (ddd, J=7.8, 1.6, 1.2 Hz, 1H), 7.70 (dd, J=7.8, 1.6
Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.36 (d,
J=8.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.0, 2.0 Hz,
1H), 7.10 (t, J=7.8 Hz, 1H), 7.08 (dd, J=7.9, 1.2 Hz, 1H), 6.98
(dd, J=7.8, 1.6 Hz, 1H), 6.68 (d, J=1.2 Hz, 1H), 2.89 (sept, J=6.8
Hz, 1H), 2.31 (s, 3H), 2.31 (s, 3H), 1.17 (d, J=6.8 Hz, 6H).
Example 74
3'-{N'-[1-(3,4-Dimethyl-phenyl)-4-isopropyl-2-oxo-1,2-dihydro-indol-3-ylid-
ene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
174)
[0633] ##STR104##
[0634] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) 13.29 (s, 1H), 8.13 (s, 1H),
7.94 (d, J=7.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.61-7.54 (m, 2H),
7.35 (d, J=8.3 Hz, 1H), 7.28 (m, 1H), 7.22 (m, 2H), 7.16-7.10 (m,
2H), 6.98 (dd, J=7.6, 1.1 Hz, 1H), 6.65 (d, J=7.6 Hz, 1H), 3.99 (m,
1H), 2.31 (s, 3H), 2.30 (s, 3H), 1.38 (d, J=6.9 Hz, 6H).
Example 75
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-4-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 175)
[0635] ##STR105##
[0636] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.22 (s, 1H), 9.44 (s, 1H),
8.01 (dd, J=7.0, 2.4 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.78 (dd,
J=7.8, 1.5 Hz, 1H), 7.78 (m, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.41 (dd,
J=10.4, 8.4 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.33 (d, J=1.9 Hz,
1H), 7.27 (dd, J=7.9, 1.9 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 7.05
(dd, J=7.8, 1.5 Hz, 1H), 6.96 (s, 1H), 2.32 (s, 3H), 2.31 (s,
3H).
Example 76
5'-Chloro-3'-{N'-[1-(3,4-dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihy-
dro-indol-3-ylidene]-hydrazino}-4-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 176)
[0637] ##STR106##
[0638] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) 13.38 (s, 1H), 13.11 (s, 1H),
9.70 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 8.02 (dd, J=6.9, 2.4 Hz, 1H),
7.80 (ddd, J=8.5, 4.6, 2.4 Hz, 1H), 7.76 (d, J=2.6 Hz, 1H), 7.54
(d, J=8.0 Hz, 1H), 7.42 (dd, J=10.7, 8.5 Hz, 1H), 7.39 (d, J=7.9
Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.27 (dd, J=7.9, 2.0 Hz, 1H), 7.08
(d, J=2.6 Hz, 1H), 6.95 (s, 1H), 2.32 (s, 3H), 2.31 (s, 3H).
Example 77
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-6-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 177)
[0639] ##STR107##
[0640] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) 13.19 (s, 1H), 13.13 (s, 1H),
9.56 (s, 1H), 7.98 (m, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.82 (dd,
J=7.7, 1.1 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.44 (m, 1H), 7.38 (d,
J=8.0 Hz, 1H), 7.33 (d, J=1.7 Hz, 1H), 7.26 (dd, J=8.0, 1.7 Hz,
1H), 7.11 (t, J=7.7 Hz, 1H), 7.00 (dd, J=7.7, 1.1 Hz, 1H), 6.95 (s,
1H), 2.32 (s, 3H), 2.31 (s, 3H).
Example 78
3'-{N'-[1-(3,4-Dimethyl-phenyl)-4,5-difluoro-2-oxo-1,2-dihydro-indol-3-yli-
dene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
178)
[0641] ##STR108##
[0642] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.27 (s, 1H), 13.05 (s, 1H),
9.40 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.94 (ddd, J=7.7, 1.7, 1.2
Hz, 1H), 7.79 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.64 (dd, J=7.9, 1.6
Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.29 (dt,
J=1.1, 8.5 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.22 (dd, J=8.2, 2.1
Hz, 1H), 7.14 (t, J=7.9 Hz, 1H), 7.05 (dd, J=7.9, 1.6 Hz, 1H), 6.63
(dd, J=8.5, 3.2 Hz, 1H), 2.31 (s, 3H), 2.29 (s, 3H).
Example 79
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-3-methyl-biphenyl-4-carboxylic
acid (Compound 179)
[0643] ##STR109##
[0644] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.23 (s, 1H), 12.83 (s, 1H),
9.43 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.78
(dd, J=7.8, 1.5 Hz, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.49 (s, 1H), 7.46
(d, J=7.9 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H),
7.27 (dd, J=7.9, 1.8 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 7.05 (dd,
J=7.8, 1.6 Hz, 1H), 6.96 (s, 1H), 2.59 (s, 3H), 2.32 (s, 3H), 2.31
(s, 3H).
Example 80
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-2,3-dihydro-1H-ind-
ol-3-yl]-hydrazino}-2-fluoro-2'-hydroxy-biphenyl-4-carboxylic acid
(Compound 180)
[0645] ##STR110##
[0646] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.31 (s, 1H), 13.19 (s, 1H),
9.58 (s, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.85 (dd, J=7.8, 1.5 Hz, 1H),
7.82 (dd, J=7.8, 1.5 Hz, 1H), 7.75 (dd, J=10.4, 1.5 Hz, 1H), 7.58
(t, J=7.8 Hz, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H),
7.33 (d, J=1.9 Hz, 1H), 7.27 (dd, J=8.0, 1.9 Hz, 1H, 7.12 (t, J=7.8
Hz, 1H), 6.99 (dd, J=7.8, 1.5 Hz, 1H), 6.95 (s, 1H), 2.32 (s, 3H),
2.31 (s, 3H).
Example 81
3'-{N'-[1-(3,4-Dimethyl-phenyl)-4-fluoro-2-oxo-6-trifluoromethyl-2,3-dihyd-
ro-1H-indol-3-yl]-hydrazino}-4-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 181)
[0647] ##STR111##
[0648] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.36 (s, 1H), 8.00 (dd, J=6.9,
2.1 Hz, 1H), 7.78 (m, 1H), 7.66 (dd, J=7.7, 1.4 Hz, 1H), 7.50 (d,
J=9.5 Hz, 1H), 7.41 (m, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.32 (d, J=1.6
Hz, 1H), 7.26 (dd, J=8.1, 1.6 Hz, 1H), 7.14 (t, J=7.7 Hz, 1H), 7.07
(dd, J=7.7, 1.4 Hz, 1H), 6.80 (s, 1H), 2.32 (s, 3H), 2.31 (s,
3H).
Example 82
5'-Chloro-3'-{N'-[1-(3,4-dimethyl-phenyl)-4-fluoro-2-oxo-6-trifluoromethyl-
-1,2-dihydro-indol-3-ylidene]-hydrazino}-4-fluoro-2'-hydroxy-biphenyl-3-ca-
rboxylic acid (Compound 182)
[0649] ##STR112##
[0650] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.38 (s, 1H), 13.22 (s, 1H),
9.78 (s, 1H), 8.01 (dd, J=7.0, 2.3 Hz, 1H), 7.80 (ddd, J=8.6, 4.2,
2.3 Hz, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.51 (d, J=9.5 Hz, 1H), 7.42
(dd, J=10.5, 8.6 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.31 (d, J=1.6
Hz, 1H), 7.25 (dd, J=8.0, 1.6 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 6.80
(s, 1H), 2.32 (s, 3H), 2.30 (s, 3H).
Example 83
3-[(3'-Carboxy-2-hydroxy-biphenyl-3-yl)-hydrazono]-1-(3,5-dimethyl-phenyl)-
-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester
(Compound 183)
[0651] ##STR113##
[0652] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.26 (s, 1H), 13.05
(s, 1H), 9.42 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.95 (ddd, J=7.7,
1.6, 1.2 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.81 (dd, J=7.9, 1.4 Hz,
1H), 7.80 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.77 (dd, J=7.8, 1.6 Hz,
1H), 7.61 (t, J=7.7 Hz, 1H), 7.29 (d, J=1.4 Hz, 1H), 7.18 (s, 1H),
7.16 (s, 2H), 7.14 (t, J=7.8 Hz, 1H), 7.06 (dd, J=7.8, 1.6 Hz, 1H),
3.83 (s, 3H), 2.38 (s, 6H).
Example 84
3-[(3'-Carboxy-4'-fluoro-2-hydroxy-biphenyl-3-yl)-hydrazono]-1-(3,5-dimeth-
yl-phenyl)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl
ester (Compound 184)
[0653] ##STR114##
[0654] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.35 (s, 1H), 13.24
(s, 1H), 9.43 (s, 1H), 8.01 (dd, J=7.2, 2.6 Hz, 1H), 7.85 (d, J=7.9
Hz, 1H), 7.81 (dd, J=7.9, 1.3 Hz, 1H), 7.79 (m, 1H), 7.77 (dd,
J=7.8, 1.6 Hz, 1H), 7.42 (dd, J=10.7, 8.5 Hz, 1H), 7.28 (d, J=1.3
Hz, 1H), 7.18 (s, 1H), 7.16 (s, 2H), 7.13 (t, J=7.8 Hz, 1H), 7.05
(dd, J=7.8, 1.6 Hz, 1H), 3.83 (s, 3H), 2.37 (s, 6H).
Example 85
3-[(3'-Carboxy-4'-fluoro-2-hydroxy-biphenyl-3-yl)-hydrazono]-1-(3,4-dimeth-
yl-phenyl)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl
ester (Compound 185)
[0655] ##STR115##
[0656] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.34 (s, 1H), 13.24
(s, 1H), 9.43 (s, 1H), 8.01 (dd, J=7.1, 2.1 Hz, 1H), 7.85 (d, J=7.9
Hz, 1H), 7.81 (m, 1H), 7.79 (m, 1H), 7.77 (m, 1H), 7.41 (dd,
J=10.5, 8.8 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.32 (d, J=1.8 Hz,
1H), 7.27 (d, J=1.0 Hz, 1H), 7.26 (m, 1H), 7.13 (t, J=7.8 Hz, 1H),
7.05 (dd, J=7.8, 1.6 Hz, 1H), 3.82 (s, 3H), 2.33 (s, 3H), 2.31 (s,
3H).
Example 86
3-[(3'-Carboxy-5-chloro-4'-fluoro-2-hydroxy-biphenyl-3-yl-hydrazono]-1-(3,-
5-dimethyl-phenyl)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid
methyl ester (Compound 186)
[0657] ##STR116##
[0658] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, CD.sub.3OD-d.sub.4) .delta. 8.05 (dd, J=6.7,
1.2 Hz, 1H), 7.89-7.81 (m, 2H), 7.75-7.70 (m, 2H), 7.40 (s, 1H),
7.29 (dd, J=10.3, 8.7 Hz, 1H), 7.18 (s, 1H), 7.09 (s, 2H), 6.97 (d,
J=1.7 Hz, 1H), 3.86 (s, 3H), 2.41 (s, 6H).
Example 87
3'-{N'-[1-(2-Cyano-thiophen-3-yl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydra-
zino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 187)
[0659] ##STR117##
[0660] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, CD.sub.3OD-d.sub.4) .delta. 8.05 (t, J=1.5
Hz, 1H), 8.03 (d, J=5.3 Hz, 1H), 7.89 (ddd, J=7.7, 1.5, 1.0 Hz,
1H), 7.74 (ddd, J=7.6, 1.1, 0.6 Hz, 1H), 7.73 (dd, J=7.8, 1.6 Hz,
1H), 7.56 (ddd, J=7.7, 1.5, 1.0 Hz, 1H), 7.41 (t, J=7.7 Hz, 1H),
7.37 (d, J=5.3 Hz, 1H), 7.28 (td, J=7.6, 1.1 Hz, 1H), 7.20 (td,
J=7.6, 0.8 Hz, 1H), 7.03 (t, J=7.8 Hz, 1H), 6.97 (dd, J=7.8, 1.6
Hz, 1H), 6.93 (ddd, J=7.8, 0.8, 0.6 Hz, 1H).
Example 88
2'-Hydroxy-3'-[N'-(2-oxo-1-thiophen-3-yl-1,2-dihydro-indol-3-ylidene)-hydr-
azino]-biphenyl-3-carboxylic acid (Compound 188)
[0661] ##STR118##
[0662] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, CD.sub.3OD-d.sub.4) .delta. 8.15 (t, J=1.6
Hz, 1H), 7.99 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.74 (dd, J=7.8, 1.6
Hz, 1H), 7.73 (m, 1H), 7.71 (ddd, J=7.7, 1.6, 1.2 Hz, 1H),
7.65-7.62 (m, 2H), 7.52 (t, J=7.7 Hz, 1H), 7.33 (dd, J=3.9, 2.7 Hz,
1H), 7.28 (td, J=7.6, 1.2 Hz, 1H), 7.18 (td, J=7.6, 0.8 Hz, 1H),
7.07 (t, J=7.8 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 6.98 (dd, J=7.8,
1.6 Hz, 1H).
Example 89
3-[(3'-Carboxy-2-hydroxy-biphenyl-3-yl)-hydrazono]-1-(3,4-dimethyl-phenyl)-
-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester
(Compound 189)
[0663] ##STR119##
[0664] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.25 (s, 1H), 13.05
(s, 1H), 9.42 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.95 (ddd, J=7.8,
1.6, 1.2 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.81 (dd, J=8.0, 1.4 Hz,
1H), 7.79 (ddd, J=7.8, 1.6, 1.2 Hz, 1H), 7.77 (dd, J=7.9, 1.6 Hz,
1H), 7.60 (t, J=7.8 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.32 (d, J=2.0
Hz, 1H), 7.28 (d, J=1.4 Hz, 1H), 7.26 (dd, J=8.0, 2.0 Hz, 1H), 7.14
(t, J=7.9 Hz, 1H), 7.06 (dd, J=7.9, 1.6 Hz, 1H), 3.82 (s, 3H), 2.33
(s, 3H), 2.31 (s, 3H).
Example 90
3'-{N'-[1-(4-Chloro-3-trifluoromethyl-phenyl)-6-cyano-2-oxo-1,2-dihydro-in-
dol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 190)
[0665] ##STR120##
[0666] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.20 (s, 1H), 13.02
(s, 1H), 9.49 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 8.11 (d, J=2.4 Hz,
1H), 7.98 (d, J=8.5 Hz, 1H), 7.95 (ddd, J=7.7, 1.7, 1.3 Hz, 1H),
7.94 (dd, J=8.5, 2.4 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.79 (dd,
J=7.8, 1.6 Hz, 1H), 7.79 (m, 1H), 7.66 (dd, J=7.8, 1.3 Hz, 1H),
7.60 (t, J=7.7 Hz, 1H), 7.51 (d, J=1.3 Hz, 1H), 7.15 (t, J=7.8 Hz,
1H), 7.09 (dd, J=7.8, 1.6 Hz, 1H).
Example 91
5'-Chloro-3'-{N'-[6-cyano-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-
-ylidene]-hydrazino}-4-fluoro-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 191)
[0667] ##STR121##
[0668] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.37 (s, 1H), 13.14
(s, 1H), 9.74 (s, 1H), 8.01 (dd, J=7.0, 2.4 Hz, 1H), 7.99 (d, J=7.8
Hz, 1H), 7.80 (ddd, J=8.5, 4.6, 2.4 Hz, 1H), 7.77 (d, J=2.6 Hz,
1H), 7.64 (dd, J=7.8, 1.3 Hz, 1H), 7.49 (d, J=9.1 Hz, 2H), 7.47 (d,
J=9.1 Hz, 2H), 7.42 (dd, J=10.7, 8.5 Hz, 1H), 7.24 (d, J=1.3 Hz,
1H), 7.09 (d, J=2.6 Hz, 1H), 3.01 (sept, J=6.9 Hz, 1H), 1.28 (d,
J=6.9 Hz, 6H).
Example 92
3'-{N'-[6-Cyano-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]--
hydrazino}-4-fluoro-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
192)
[0669] ##STR122##
[0670] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, CD.sub.3OD-d.sub.4) .delta. 7.91 (dd, J=6.8,
2.4 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.73 (dd, J=7.7, 1.6 Hz, 1H),
7.62 (ddd, J=8.5, 4.6, 2.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.47
(m, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.21 (dd, J=10.3, 8.5 Hz, 1H),
7.09 (d, J=1.0 Hz, 1H), 7.05 (t, J=7.7 Hz, 1H), 7.00 (dd, J=7.7,
1.6 Hz, 1H), 3.02 (sept, J=6.9 Hz, 1H), 1.32 (d, J=6.9 Hz, 6H).
Example 93
(.+-.)-1-(3,4-Dimethyl-phenyl)-3-{[2-hydroxy-3'-(2,2,2-trifluoro-1-hydroxy-
-ethyl)-biphenyl-3-yl]-hydrazono}-6-methanesulfonyl-1,3-dihydro-indol-2-on-
e (Compound 193)
[0671] ##STR123##
[0672] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, CD.sub.3OD-d.sub.4) .delta. 7.88 (d, J=7.7
Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.65 (s, 1H), 7.58 (m, 1H),
7.53-7.44 (m, 3H), 7.37 (d, J=8.0 Hz, 1H), 7.25 (s, 1H), 7.19 (d,
J=8.0 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.99
(s, 1H), 5.10 (q, J=7.0 Hz, 1H), 2.37 (s, 3H), 2.37 (s, 3H).
Example 94
3'-{N'-[6-Cyano-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]--
hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 194)
[0673] ##STR124##
[0674] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, CD.sub.3OD-d.sub.4) .delta. 8.06 (s, 1H),
7.90 (d, J=7.8 Hz, 1H), 7.78 (m, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.62
(m, 1H), 7.44 (m, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.2 Hz,
2H), 7.04 (s, 1H), 7.00 (t, J=7.6 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H),
2.94 (sept, J=7.0 Hz, 1H), 1.23 (d, J=7.0 Hz, 6H).
Example 95
3'-{N'-[1-(3,4-Dimethyl-phenyl)-5-nitro-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
195)
[0675] ##STR125##
[0676] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.10 (s, 1H), 12.93
(s, 1H), 8.47 (d, J=2.3 Hz, 1H), 8.16 (dd, J=8.7, 2.3 Hz, 1H), 8.10
(t, J=1.6 Hz, 1H), 7.93 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.85 (dd,
J=7.8, 1.7 Hz, 1H), 7.78 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.58 (t,
J=7.7 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.32-7.21 (m, 2H), 7.12 (t,
J=7.8 Hz, 1H), 7.05 (dd, J=7.8, 1.7 Hz, 1H), 6.99 (d, J=8.7 Hz,
1H), 2.30 (s, 3H), 2.28 (s, 3H).
Example 96
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-methanesulfonyl-2-oxo-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 196)
[0677] ##STR126##
[0678] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, CD.sub.3OD-d.sub.4) .delta. 8.43 (s, 2H),
8.11 (t, J=1.2 Hz, 1H), 7.94 (dt, J=7.6, 1.2 Hz, 1H), 7.71 (dd,
J=7.8, 1.6 Hz, 1H), 7.69 (dd, J=7.4, 0.9 Hz, 1H), 7.66 (dt, J=7.6,
1.2 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H),
7.22-7.18 (m, 2H), 7.14 (dd, J=7.9, 2.0 Hz, 1H), 7.12 (m, 1H), 7.03
(t, J=7.8 Hz, 1H), 6.94 (dd, J=7.8, 1.6 Hz, 1H), 6.81 (d, J=7.8 Hz,
1H), 3.30 (s, 3H), 2.31 (s, 6H).
Example 97
3'-{N'-[6-Cyano-1-(3,4-dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
197)
[0679] ##STR127##
[0680] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.25 (d, J=7.8 Hz, 1H),
8.22 (t, J=1.5 Hz, 1H), 7.87-7.82 (m, 2H), 7.51 (t, J=7.8 Hz, 1H),
7.41 (dd, J=7.7, 1.3 Hz, 1H), 7.31-7.26 (m, 2H), 7.22 (d, J=1.9 Hz,
1H), 7.15 (dd, J=7.9, 1.9 Hz, 1H), 6.99 (dd, J=7.6, 1.5 Hz, 1H),
6.92-6.88 (m, 2H), 2.27 (s, 6H).
Example 98
3'-{N'-[1-(5-Cyano-pyridin-3-yl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydraz-
ino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 198)
[0681] ##STR128##
[0682] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.91 (m, 1H), 8.85 (m,
0.5H), 8.72 (m, 0.5H), 8.43 (t, J=2.0 Hz, 0.5H), 8.30 (t, J=2.1 Hz,
0.5H), 8.06 (m, 0.5H), 8.02 (t, J=1.5 Hz, 0.5H), 7.90 (t, J=1.6 Hz,
0.5H), 7.73 (m, 0.5H), 7.72-7.53 (m, 3H), 7.37 (t, J=7.6 Hz, 0.5H),
7.30 (t, J=7.7 Hz, 0.5H), 7.12 (m, 1H), 7.03 (m, 0.5H), 6.95-6.61
(m, 3.5H).
Example 99
3'-[N'-(1-Furan-3-yl-2-oxo-1,2-dihydro-indol-3-ylidene-hydrazino]-2'-hydro-
xy-biphenyl-3-carboxylic acid (Compound 199)
[0683] ##STR129##
[0684] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, CD.sub.3OD-d.sub.4) .delta. 8.07 (s, 1H),
7.90 (m, 2H), 7.66-7.59 (m, 4H), 7.42 (t, J=7.7 Hz, 1H), 7.21 (t,
J=7.6 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 6.97
(t, J=7.6 Hz, 1H), 6.88 (dd, J=7.6, 1.3 Hz, 1H), 6.74 (dd, J=2.0,
0.7 Hz, 1H).
Example 100
3'-[N'-(1-Benzo[1,3]dioxol-5-yl-2-oxo-1,2-dihydro-indol-3-ylidene)-hydrazi-
no]-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 200)
[0685] ##STR130##
[0686] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.02 (s, 1H), 8.09 (t,
J=1.6 Hz, 1H), 7.92 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.76 (ddd,
J=7.7, 1.6, 1.2 Hz, 1H), 7.70 (dd, J=7.8, 1.6 Hz, 1H), 7.70 (m,
1H), 7.57 (t, J=7.7 Hz, 1H), 7.27 (td, J=7.7, 1.1 Hz, 1H), 7.16 (t,
J=7.8 Hz, 1H), 7.13-7.07 (m, 3H), 6.99-6.96 (m, 2H), 6.82 (d, J=8.1
Hz, 1H), 6.13 (s, 2H). Mixture .about.90:10
Example 101
2'-Hydroxy-3'-{N'-[1-(3-methyl-thiophen-2-yl)-2-oxo-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-biphenyl-3-carboxylic acid (Compound 201)
[0687] ##STR131##
[0688] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 12.94 (s, 1H), 8.10 (s,
1H), 7.92 (d, J=7.6 Hz, 1H), 7.79-7.69 (m, 3H), 7.63-7.54 (m, 2H),
7.30 (t, J=7.6 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.14-7.06 (m, 2H),
6.99 (d, J=7.4 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 2.01 (s, 3H).
Example 102
2'-Hydroxy-3'-[N'-(2-oxo-1-thiophen-2-yl-1,2-dihydro-indol-3-ylidene)-hydr-
azino]-biphenyl-3-carboxylic acid (Compound 202)
[0689] ##STR132##
[0690] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.96 (s, 1H), 9.33 (s,
1H), 8.11 (s, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H),
7.74-7.69 (m, 2H), 7.63 (dd, J=5.5, 1.4 Hz, 1H), 7.58 (t, J=7.6 Hz,
1H), 7.36-7.28 (m, 2H), 7.25-7.15 (m, 2H), 7.10 (t, J=7.8 Hz, 1H),
7.08 (d, J=7.8 Hz, 1H), 7.00 (dd, J=7.6, 1.2 Hz, 1H),
Example 103
2'-Hydroxy-3'-{N'-[1-(4-isopropyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihy-
dro-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid
(Compound 203)
[0691] ##STR133##
[0692] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.23 (s, 1H), 13.04 (s, 1H),
9.43 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.95 (ddd, J=7.7, 1.6, 1.2
Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.80 (dd, J=7.7, 1.6, 1.2 Hz, 1H),
7.79 (d, J=7.6 Hz, 1H), 7.78 (dd, J=7.9, 1.6 Hz, 1H), 7.60 (t,
J=7.7 Hz, 1H), 7.55 (d, J=8.0, 1.1 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H),
7.48 (d, J=8.8 Hz, 2H), 7.14 (t, J=7.9 Hz, 1H), 7.06 (dd, J=7.9,
1.6 Hz, 1H), 7.00 (d, J=1.1 Hz, 1H), 3.01 (sept, J=6.8 Hz, 1H),
1.28 (d, J=6.8 Hz, 6H).
Example 104
2'-Hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-6-trifluoromethyl-1,2-dihydro-
-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound
204)
[0693] ##STR134##
[0694] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.23 (s, 1H), 13.04 (s, 1H),
9.43 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.95 (d, J=7.7, 1.6, 1.2 Hz,
1H), 7.93 (d, J=8.0 Hz, 1H), 7.80 (dd, J=7.7, 1.6, 1.2 Hz, 1H),
7.78 (dd, J=7.7, 1.5 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.55 (m, 1H),
7.47 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 7.14 (t, J=7.7 Hz,
1H), 7.06 (dd, J=7.7, 1.5 Hz, 1H), 6.98 (m, 1H), 2.67 (t, J=7.4 Hz,
2H), 1.67 (sext, J=7.4 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H).
Example 105
3'-{N'-[1-(4-Ethyl-phenyl)-5,7-difluoro-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
205)
[0695] ##STR135##
[0696] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.15 (s, 1H), 13.03 (s, 1H),
9.40 (s, 1H), 8.11 (t, J=1.6 Hz, 1H), 7.94 (d, J=7.7, 1.6, 1.1 Hz,
1H), 7.79 (m, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.48 (dd, J=7.8, 2.3 Hz,
1H), 7.41 (dd, J=8.3, 1.4 Hz, 2H), 7.36 (d, J=8.3 Hz, 2H), 7.21
(ddd, J=11.6, 9.7, 2.3 Hz, 1H) 7.13 (t, J=7.8 Hz, 1H), 7.05 (dd,
J=7.8, 1.3 Hz, 1H), 2.69 (q, J=7.5 Hz, 2H), 1.24 (t, J=7.5 Hz,
3H).
Example 106
3'-{N'-[1-(3,4-Dimethyl-phenyl)-5,7-difluoro-2-oxo-1,2-dihydro-indol-3-yli-
dene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
206
[0697] ##STR136##
[0698] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.16 (s, 1H), 12.99 (s, 1H),
9.40 (s, 1H), 8.11 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2
Hz, 1H), 7.79 (m, 1H), 7.78 (dd, J=7.8, 1.5 Hz, 1H), 7.60 (t, J=7.7
Hz, 1H), 7.47 (dd, J=7.7, 2.3 Hz, 1H), 7.28 (m, 2H), 7.23-7.17 (m,
1H), 7.13 (t, J=7.8 Hz, 1H), 7.05 (dd, J=7.8, 1.5 Hz, 1H), 2.29 (s,
3H), 2.27 (s, 3H).
Example 107
3'-{N'-[5,7-Difluoro-2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
207)
[0699] ##STR137##
[0700] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.15 (s, 1H), 13.03 (s, 1H),
9.40 (s, 1H), 8.11 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2
Hz, 1H), 7.79 (m, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.48 (dd, J=7.8, 2.4
Hz, 1H), 7.40 (dd, J=8.3, 1.7 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.21
(ddd, J=11.6, 9.7, 2.4 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 7.05 (dd,
J=7.8, 1.6 Hz, 1H), 2.64 (t, J=7.4 Hz, 2H), 1.65 (sext, J=7.4 Hz,
2H), 0.93 (t, J=7.4 Hz, 3H).
Example 108
3'-{N'-[5,7-Difluoro-1-(4-isopropyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylid-
ene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
208)
[0701] ##STR138##
[0702] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.15 (s, 1H), 13.04 (s, 1H),
9.41 (s, 1H), 8.11 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.1
Hz, 1H), 7.79 (m, 1H), 7.78 (dd, J=7.8, 1.7 Hz, 1H), 7.60 (t, J=7.7
Hz, 1H), 7.48 (dd, J=7.8, 2.2 Hz, 1H), 7.42 (dd, J=8.8, 1.4 Hz,
2H), 7.39 (d, J=8.8 Hz, 2H), 7.21 (ddd, J=11.8, 9.5, 2.2 Hz, 1H),
7.13 (t, J=7.8 Hz, 1H), 7.05 (dd, J=7.8, 1.7 Hz, 1H), 2.98 (sept,
J=6.9 Hz, 1H), 1.26 (d, J=6.9 Hz, 6H).
Example 109
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 209)
[0703] ##STR139##
[0704] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.22 (s, 1H), 13.02 (s, 1H),
9.41 (s, 1H), 8.10 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2
Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.79 (dd, J=7.7, 1.6, 1.2 Hz, 1H),
7.76 (dd, J=7.8, 1.5 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.52 (m, 1H),
7.37 (d, J=8.0 Hz, 1H), 7.31 (m, 1H), 7.25 (dd, J=8.0, 1.9 Hz, 1H),
7.12 (t, J=7.8 Hz, 1H), 7.04 (dd, J=7.8, 1.5 Hz, 1H), 6.94 (m, 1H),
2.30 (s, 3H), 2.29 (s, 3H).
Example 110
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-ethyl-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
210)
[0705] ##STR140##
[0706] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO) .delta. 13.04 (s, 1H), 12.99 (s, 1H),
9.23 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.6, 1.6, 1.2
Hz, 1H), 7.79 (ddd, J=7.6, 1.6, 1.2 Hz, 1H), 7.70 (dd, J=7.8, 1.6
Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.36 (d,
J=8.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.22 (dd, J=8.0, 2.0 Hz,
1H), 7.10 (t, J=7.8 Hz, 1H), 7.04 (m, 1H), 6.98 (dd, J=7.8, 1.6 Hz,
1H), 6.67 (m, 1H), 2.61 (q, J=7.6 Hz, 2H), 2.31 (s, 3H), 2.30 (s,
3H), 1.14 (t, J=7.6 Hz, 3H).
Example 111
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-methoxy-2-oxo-1,2-dihydro-indol-3-yliden-
e]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
211)
[0707] ##STR141##
[0708] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO) .delta. 12.85 (s, 1H), 9.16 (s, 1H),
8.09 (t, J=1.7 Hz, 1H), 7.91 (ddd, J=7.6, 1.7, 1.2 Hz, 1H), 7.76
(ddd, J=7.6, 1.7, 1.2 Hz, 1H), 7.66 (dd, J=7.9, 1.6 Hz, 1H), 7.62
(d, J=8.4 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H),
7.28 (d, J=2.1 Hz, 1H), 7.21 (dd, J=8.0, 2.1 Hz, 1H), 7.07 (t,
J=7.9 Hz, 1H), 6.93 (dd, J=7.9, 1.6 Hz, 1H), 6.74 (dd, J=8.4, 2.2
Hz, 1H), 6.33 (d, J=2.2 Hz, 1H), 3.73 (s, 3H), 2.29 (s, 3H), 2.28
(s, 3H).
Example 112
3'-{N'-[5-Chloro-1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihyd-
ro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 212)
[0709] ##STR142##
[0710] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO) .delta. 13.25 (s, 1H), 13.01 (s, 1H),
9.49 (s, 1H), 8.10 (t, J=1.7 Hz, 1H), 8.01 (s, 1H), 7.93 (ddd,
J=7.7, 1.7, 1.1 Hz, 1H), 7.83 (dd, J=7.8, 1.9 Hz, 1H), 7.77 (ddd,
J=7.7, 1.7, 1.1 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.36 (d, 8.0 Hz,
1H), 7.31 (d, 2.0 Hz, 1H), 7.25 (dd, J=8.0, 2.0 Hz, 1H), 7.12 (t,
J=7.8 Hz, 1H), 7.07 (dd, J=7.8, 1.9 Hz, 1H), 7.02 (s, 1H).
Example 113
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6,7-dimethyl-2-oxo-1,2-dihydro-indol-3-yli-
dene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
213)
[0711] ##STR143##
[0712] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO) .delta. 13.03 (s, 1H), 12.94 (s, 1H),
9.17 (s, 1H), 8.10 (t, J=1.5 Hz, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.77
(d, J=7.7 Hz, 1H), 7.69 (dd, J=7.8, 1.2 Hz, 1H), 7.58 (t, J=7.7 Hz,
1H), 7.48 (d, J=7.5 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.20 (d, J=1.8
Hz, 1H), 7.14 (dd, J=7.9, 1.8 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 7.02
(d, J=7.8 Hz, 1H), 6.96 (d, J=7.5 Hz, 1H), 2.31 (s, 3H), 2.28 (s,
3H), 2.23 (s, 3H), 1.62 (s, 3H).
Example 114
2-(3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-ind-
ol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-4-yl)-2-methyl-propionic
acid (Compound 214)
[0713] ##STR144##
[0714] This compound was prepared as in Scheme II. .sup.1H NMR (300
MHz, DMSO) .delta. 13.23 (s, 1H), 12.39 (s, 1H), 9.35 (s, 1H), 7.92
(d, J=7.9 Hz, 1H), 7.74 (dd, J=7.8, 1.7 Hz, 1H), 7.55 (d, J=8.5 Hz,
2H), 7.53 (m, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.0 Hz, 1H),
7.33 (d, J=2.2 Hz, 1H), 7.27 (dd, J=8.0, 2.2 Hz, 1H), 7.11 (t,
J=7.8 Hz, 1H), 7.03 (dd, J=7.8, 1.7 Hz, 1H), 6.96 (m, 1H), 2.32 (s,
3H), 2.31 (s, 3H), 1.52 (s, 6H).
Example 115
(-)-2-(3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-
-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-4-yl)-propionic
acid (Compound 215) and
(+)-2-(3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydr-
o-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-4-yl)-propionic
acid (Compound 215a)
[0715] ##STR145##
[0716] These compounds were prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO) .delta. 13.23 (s, 1H), 12.36 (s, 1H),
9.34 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.74 (dd, J=7.8, 1.6 Hz, 1H),
7.53 (d, J=8.4 Hz, 2H), 7.53 (m, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.38
(d, J=8.2 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.27 (dd, J=8.2, 2.0 Hz,
1H), 7.11 (t, J=7.8 Hz, 1H), 7.02 (dd, J=7.8, 1.6 Hz, 1H), 6.96 (m,
1H), 3.73 (q, J=7.0 Hz, 1H), 2.32 (s, 3H), 2.31 (s, 3H), 1.40 (d,
J=7.0 Hz, 3H).
Example 116
(.+-.)-(3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydr-
o-indol-3-ylidene]-hydrazino}-2'-hydroxy-5'-methyl-biphenyl-4-yl)-propioni-
c acid (Compound 216)
[0717] ##STR146##
[0718] This compound was prepared as in Scheme II. .sup.1H NMR (300
MHz, DMSO) .delta. 13.21 (s, 1H), 12.34 (s, 1H), 9.07 (s, 1H), 7.94
(d, J=8.0 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H),
7.52 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.3 Hz,
2H), 7.33 (d, J=2.0 Hz, 1H), 7.27 (dd, J=8.0, 2.0 Hz, 1H), 6.96 (m,
1H), 6.85 (d, J=1.6 Hz, 1H), 3.73 (q, J=7.0 Hz, 1H), 2.35 (s, 3H),
2.32 (s, 3H), 2.31 (s, 3H), 1.40 (d, J=7.0 Hz, 3H).
Example 117
(.+-.)-2-(3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihy-
dro-indol-3-ylidene]-hydrazino}-5'-fluoro-2'-hydroxy-biphenyl-4-yl)-propio-
nic acid (Compound 217)
[0719] ##STR147##
[0720] This compound was prepared as in Scheme II. .sup.1H NMR (300
MHz, DMSO) .delta. 13.13 (s, 1H), 12.37 (s, 1H), 9.26 (s, 1H), 7.99
(d, J=7.8 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.55 (m, 1H), 7.53 (dd,
J=9.7, 3.1 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.39 (m, 1H), 7.33 (d,
J=2.0 Hz, 1H), 7.27 (dd, J=7.9, 2.0 Hz, 1H), 6.96 (m, 1H), 6.86
(dd, J=9.4, 3.1 Hz, 1H), 3.74 (q, J=7.1 Hz, 1H), 2.32 (s, 3H), 2.31
(s, 3H) 1.40 (d, J=7.1 Hz, 3H).
Example 118
5-(4-{N'-[1-(3,4-Dimethyl-phenyl)-5,7-difluoro-2-oxo-1,2-dihydro-indol-3-y-
lidene]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4-dione
(Compound 218)
[0721] ##STR148##
[0722] This compound was prepared as in Scheme V. .sup.1H NMR (300
MHz, DMSO) .delta. 13.03 (s, 1H), 12.56 (s, 1H), 10.86 (s, 1H),
7.80 (d, J=8.4 Hz, 1H), 7.68 (s, 1H), 7.46 (dd, J=7.6, 2.3 Hz, 1H),
7.30-7.18 (m, 5H), 7.14 (d, J=1.6 Hz, 1H), 2.30 (s, 3H), 2.28 (s,
3H).
Example 119
5-(4-{N'-[1-(4-Ethyl-phenyl)-5,7-difluoro-2-oxo-1,2-dihydro-indol-3-yliden-
e]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4-dione
(Compound 219)
[0723] ##STR149##
[0724] This compound was prepared as in Scheme V. .sup.1H NMR (500
MHz, DMSO) .delta. 13.03 (s, 1H), 12.56 (s, 1H), 10.87 (s, 1H),
7.80 (d, J=8.3 Hz, 1H), 7.68 (s, 1H), 7.47 (dd, J=7.5, 1.8 Hz, 1H),
7.41 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 7.27-7.21 (m, 2H),
7.14 (s, 1H), 2.70 (q, J=7.6 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H).
Example 120
5-(4-{N'-[5,7-Difluoro-2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylide-
ne]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4-dione
(Compound 220)
[0725] ##STR150##
[0726] This compound was prepared as in Scheme V. .sup.1H NMR (500
MHz, DMSO) .delta. 13.03 (s, 1H), 12.56 (s, 1H), 10.87 (s, 1H),
7.80 (d, J=8.3 Hz, 1H), 7.69 (s, 1H), 7.46 (dd, J=7.7, 2.3 Hz, 1H),
7.40 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 7.26-7.20 (m, 2H),
7.14 (d, J=1.6 Hz, 1H), 2.64 (t, J=7.4 Hz, 2H), 1.65 (q, J=7.4 Hz,
2H), 0.93 (t, J=7.4 Hz, 3H).
Example 121
5-(3-Hydroxy-4-{N'-[1-(4-isopropyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dih-
ydro-indol-3-ylidene]-hydrazino}-benzylidene)-thiazolidine-2,4-dione
(Compound 221)
[0727] ##STR151##
[0728] This compound was prepared as in Scheme V. .sup.1H NMR (500
MHz, DMSO) .delta. 13.13 (s, 1H), 12.57 (s, 1H), 10.89 (s, 1H),
7.92 (d, J=7.8 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.69 (s, 1H), 7.55
(d, J=7.8 Hz, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H),
7.25 (dd, J=8.4, 1.6 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 6.99 (s, 1H),
3.02 (sept, J=6.9 Hz, 1H), 1.28 (d, J=6.9 Hz, 6H).
Example 122
5-(3-Hydroxy-4-{N'-[1-(4-isopropyl-phenyl)-2-oxo-5,7-difluoro-1,2-dihydro--
indol-3-ylidene]-hydrazino}-benzylidene)-thiazolidine-2,4-dione
(Compound 222)
[0729] ##STR152##
[0730] This compound was prepared as in Scheme V. .sup.1H NMR (500
MHz, DMSO) .delta. 13.05 (s, 1H), 12.56 (s, 1H), 10.87 (s, 1H),
7.81 (d, J=8.4 Hz, 1H), 7.69 (s, 1H), 7.48 (dd, J=7.7, 2.1 Hz, 1H),
7.42 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.27-7.21 (m, 2H),
7.15 (d, J=1.6 Hz, 1H), 2.99 (sept, J=7.0 Hz, 1H), 1.26 (d, J=7.0
Hz, 6H).
Example 123
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-5'-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 223)
[0731] ##STR153##
[0732] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.14 (s, 1H), 13.08 (s, 1H),
9.35 (s, 1H), 8.15 (m, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.96 (dd,
J=7.7, 1.2 Hz, 1H), 7.82 (m, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.57 (dd,
J=9.2, 3.0 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H),
7.33 (d, J=1.5 Hz, 1H), 7.27 (dd, J=8.1, 1.5 Hz, 1H), 6.95 (s, 1H),
6.92 (dd, J=9.2, 3.0 Hz, 1H), 2.32 (s, 3H), 2.31 (s, 3H).
Example 124
5'-Chloro-3'-{N'-[1-(3,4-dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihy-
dro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 224)
[0733] ##STR154##
[0734] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.12 (s, 1H), 13.09 (s, 1H),
9.68 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.97
(ddd, J=7.7, 1.7, 1.1 Hz, 1H), 7.81 (ddd, J=7.7, 1.7, 1.1 Hz, 1H),
7.76 (d, J=2.6 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.54 (d, J=7.8 Hz,
1H), 7.39 (d, J=8.0 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.27 (dd,
J=8.0, 2.0 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 6.95 (s, 1H), 2.32 (s,
3H), 2.31 (s, 3H).
Example 125
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-5'-methyl-biphenyl-3-carboxylic
acid (Compound 225)
[0735] ##STR155##
[0736] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.22 (s, 1H), 13.04 (s, 1H),
9.16 (s, 1H), 8.11 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2
Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.79 (ddd, J=7.7, 1.6, 1.2 Hz,
1H), 7.61 (d, J=1.9 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.53 (d, J=7.8
Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.33 (d, J=1.9 Hz, 1H), 7.27 (dd,
J=8.0, 1.9 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J=1.9 Hz, 1H), 2.37 (s,
3H), 2.32 (s, 3H), 2.31 (s, 3H).
Example 126
2'-Hydroxy-3'-{N'-[2-oxo-6-trifluoromethyl-1-(4-trifluoromethyl-phenyl)-1,-
2-dihydro-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid
(Compound 226)
[0737] ##STR156##
[0738] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.20 (s, 1H), 13.06 (s, 1H),
9.48 (s, 1H), 8.12 (m, 1H), 8.01 (d, J=8.4 Hz, 2H), 7.98-7.94 (m,
2H), 7.86 (d, J=8.4 Hz, 2H), 7.81-7.78 (m, 2H), 7.61 (t, J=7.7 Hz,
1H), 7.59 (d, J=7.5 Hz, 1H), 7.20 (s, 1H), 7.15 (t, J=7.8 Hz, 1H),
7.08 (dd, J=7.8, 1.2 Hz, 1H).
Example 127
3'-{N'-[1-(4-Ethyl-3-methyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-in-
dol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 227)
[0739] ##STR157##
[0740] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.24 (s, 1H), 13.05 (s, 1H),
9.43 (s, 1H), 8.12 (m, 1H), 7.96-7.91 (m, 2H), 7.81-7.77 (m, 2H),
7.61 (t, J=7.7 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.40 (d, J=7.9 Hz,
1H), 7.34-7.30 (m, 2H), 7.14 (t, J=7.8 Hz, 1H), 7.06 (d, J=7.8 Hz,
1H), 6.97 (s, 1H), 2.69 (q, J=7.5 Hz, 2H), 2.35 (s, 3H), 1.23 (t,
J=7.5 Hz, 3H).
Example 128
3'-{N'-[1-(4-Chloro-3-trifluoromethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2--
dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 228)
[0741] ##STR158##
[0742] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.16 (s, 1H), 13.05 (s, 1H),
9.48 (s, 1H), 8.14 (d, J=2.1 Hz, 1H), 8.12 (t, J=1.5 Hz, 1H),
8.01-7.93 (m, 4H), 7.81-7.78 (m, 2H), 7.61 (t, J=7.7 Hz, 1H), 7.58
(d, J=8.0 Hz, 1H), 7.23 (s, 1H), 7.15 (t, J=7.7 Hz, 1H), 7.08 (dd,
J=7.7, 1.3 Hz, 1H).
Example 129
3'-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-5'-fluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 229)
[0743] ##STR159##
[0744] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.14 (s, 1H), 13.09 (s, 1H),
9.35 (s, 1H), 8.16 (t, J=1.6 Hz, 1H), 8.00 (d, J=7.9 Hz, 1H), 7.97
(ddd, J=7.8, 1.6, 1.0 Hz, 1H), 7.82 (ddd, J=7.8, 1.6, 1.0 Hz, 1H),
7.62 (t, J=7.8 Hz, 1H), 7.57 (dd, J=9.5, 3.1 Hz, 1H), 7.56 (m, 1H),
7.17 (s, 1H), 7.16 (s, 2H), 6.98 (s, 1H), 6.92 (dd, J=9.3, 3.1 Hz,
1H), 2.37 (s, 6H).
Example 130
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-4,5'-difluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 230)
[0745] ##STR160##
[0746] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.37 (s, 1H), 13.11 (s, 1H),
9.35 (s, 1H), 8.04 (dd, J=1.5, 7.0 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H),
7.82-7.79 (m, 1H), 7.56-7.53 (m, 2H), 7.41 (t, J=10.5 Hz, 1H), 7.37
(d, J=8.5 Hz, 1H), 7.31 (s, 1H), 7.26 (d, J=8 Hz, 1H), 6.94 (s,
1H), 6.91 (dd, J=2.5, 9.5 Hz, 1H), 2.29 (s, 6H).
Example 131
3'-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-4,5'-difluoro-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 231)
[0747] ##STR161##
[0748] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.37 (s, 1H), 13.11 (s, 1H),
9.35 (s, 1H), 8.04 (dd, J=1.5, 7.0 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H),
7.82-7.79 (m, 1H), 7.56-7.53 (m, 2H), 7.41 (t, J=10.5 Hz, 1H), 7.16
(s, 1H), 7.15 (s, 1H), 6.96 (s, 1H), 6.91 (dd, J=2.5, 9.5 Hz, 1H),
2.35 (s, 6H).
Example 132
4,5'-Difluoro-2'-hydroxy-3'-{N'-[2-oxo-6-trifluoromethyl-1-(4-trifluoromet-
hyl-phenyl)-1,2-dihydro-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic
acid (Compound 232)
[0749] ##STR162##
[0750] This compound was prepared as described in Scheme II.
.sup.1H NMR.sup.1H NMR (500 MHz, DMSO) .delta. 13.37 (s, 1H), 13.07
(s, 1H), 9.39 (s, 1H), 8.04 (dd, J=1.5, 7.0 Hz, 1H), 7.97 (d, J=9.0
Hz, 1H), 7.82-7.79 (m, 1H), 7.59-7.56 (m, 2H), 7.42 (t, J=9.5 Hz,
1H), 7.18 (s, 1H), 6.92 (dd, J=3.0, 9.5 Hz, 1H).
Example 133
3'-{N'-[1-(4-Fluoro-3,5-dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihyd-
ro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 233)
[0751] ##STR163##
[0752] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.20 (s, 1H), 13.04 (s, 1H),
9.42 (s, 1H), 8.10 (s, 1H), 7.94-7.89 (m, 2H), 7.79-7.75 (m, 2H),
7.59 (t, J=13 Hz, 1H), 7.52 (d, J=13.5 Hz, 1H), 7.30 (d, J=10.5 Hz,
1H), 7.12 (t, J=13 Hz, 1H), 7.04 (dd, J=2.0, 12.5 Hz, 1H), 6.98 (s,
1H), 2.29 (s, 6H).
Example 134
2'-Hydroxy-3'-{N'-[1-(4-methoxy-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydr-
o-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic acid (Compound
234)
[0753] ##STR164##
[0754] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.21 (s, 1H), 13.04 (s, 1H),
9.41 (s, 1H), 8.10 (s, 1H), 7.92 (dd, J=7.5, 12 Hz, 2H), 7.77 (t,
J=7.5 Hz, 2H), 7.59 (t, J=7.5 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.47
(d, J=8.5 Hz, 2H), 7.16 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H),
7.05 (dd, J=1.0, 8.0 Hz, 1H), 6.92 (s, 1H), 3.84 (s, 3H).
Example 135
3'-{N'-[1-(4-Fluoro-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
235)
[0755] ##STR165##
[0756] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.19 (s, 1H), 13.04 (s, 1H),
9.43 (s, 1H), 8.10 (s, 1H), 7.93 (t, J=6.0 Hz, 2H), 7.78 (t, J=6.0
Hz, 2H), 7.65-7.62 (m, 2H), 7.59 (t, J=7.0 Hz, 1H), 7.54 (d, J=8.5
Hz, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.13 (t, J=8.0 Hz, 1H), 7.05 (dd,
J=1.5, 8.0 Hz, 1H), 6.99 (s, 1H).
Example 136
3'-{N'-[1-(3,5-Dimethoxy-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 236)
[0757] ##STR166##
[0758] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.21 (s, 1H), 13.04 (s, 1H),
9.44 (s, 1H), 8.11 (s, 1H), 7.92 (dd, J=8.0, 10.5 Hz, 2H), 7.78 (t,
J=7.5 Hz, 2H), 7.59 (t, J=7.5 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.13
(t, J=8.0 Hz, 1H), 7.06-7.04 (m, 2H), 6.73 (s, 2H), 6.66 (s, 1H),
3.79 (s, 6H).
Example 137
3'-{N'-[1-(3,4-Dimethoxy-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 237)
[0759] ##STR167##
[0760] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.23 (s, 1H), 13.04 (s, 1H),
9.42 (s, 1H), 8.11 (s, 1H), 7.92 (dd, J=7.5, 14.0 Hz, 2H), 7.78 (t,
J=7.5 Hz, 2H), 7.59 (t, J=7.5 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H),
7.17-7.04 (m, 5H), 6.96 (s, 1H), 3.84 (s, 3H), 3.76 (s, 3H).
Example 138
3'-{N'-[1-(3,5-Difluoro-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 238)
[0761] ##STR168##
[0762] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.16 (s, 1H), 13.04 (s, 1H),
9.48 (s, 1H), 8.11 (s, 1H), 7.94 (d, J=7.5 Hz, 2H), 7.80-7.77 (m,
2H), 7.60 (t, J=7.5, Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.46-7.44 (m,
3H), 7.22 (s, 1H), 7.13 (t, J=7.5 Hz, 1H), 7.06 (d, J=7.5 Hz,
1H).
Example 139
5'-Fluoro-3'-{N'-[1-(4-fluoro-3,5-dimethyl-phenyl)-2-oxo-6-trifluoromethyl-
-1,2-dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 239)
[0763] ##STR169##
[0764] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.11 (s, 1H), 13.07 (s, 1H),
9.34 (s, 1H), 8.14 (s, 1H), 7.97 (dd, J=7.5, 16.0 Hz, 2H), 7.81 (d,
J=7.5 Hz, 1H), 7.60 (t, J=7.5, Hz, 1H), 7.57-7.54 (m, 2H), 7.31 (d,
J=6.0 Hz, 2H), 6.98 (s, 1H), 6.91 (dd, J=2.5, 9.5 Hz, 1H), 2.29 (s,
6H).
Example 140
4,5'-Difluoro-3'-{N'-[1-(4-fluoro-3,5-dimethyl-phenyl)-2-oxo-6-trifluorome-
thyl-1,2-dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxy-
lic acid (Compound 240)
[0765] ##STR170##
[0766] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.37 (s, 1H), 13.10 (s, 1H),
9.35 (s, 1H), 8.04 (dd, J=2.0, 7.0 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H),
7.82-7.79 (m, 1H), 7.57-7.54 (m, 2H), 7.42 (t, J=9.0 Hz, 1H), 7.30
(d, J=6.5 Hz, 2H), 6.98 (s, 1H), 6.91 (dd, J=2.5, 9.5 Hz, 1H), 2.29
(s, 6H).
Example 141
2'-Hydroxy-3'-{N'-[1-(4-methoxy-3,5-dimethyl-phenyl)-2-oxo-6-trifluorometh-
yl-1,2-dihydro-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic
acid (Compound 241)
[0767] ##STR171##
[0768] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.21 (s, 1H), 13.03 (s, 1H),
9.40 (s, 1H), 8.10 (s, 1H), 7.91 (dd, J=8.0, 15.0 Hz, 2H), 7.77 (t,
J=7.5 Hz, 2H), 7.59 (t, J=8.0 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.21
(s, 2H), 7.12 (t, J=8.0 Hz, 1H), 7.04 (dd, J=1.5, 7.5 Hz, 1H), 6.96
(s, 1H), 3.73 (s, 3H), 2.29 (s, 6H).
Example 142
2'-Hydroxy-3'-{N'-[1-(4-hydroxy-3,5-dimethyl-phenyl)-2-oxo-6-trifluorometh-
yl-1,2-dihydro-indol-3-ylidene]-hydrazino}-biphenyl-3-carboxylic
acid (Compound 242)
[0769] ##STR172##
[0770] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.22 (s, 1H), 13.03 (s, 1H),
9.39 (s, 1H), 8.69 (s, 1H), 8.10 (s, 1H), 7.93 (d, J=8.0 Hz, 1H),
7.88 (d, J=8.0 Hz, 1H), 7.78-7.75 (m, 2H), 7.58 (t, J=8.0 Hz, 1H),
7.50 (d, J=8.5 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H), 7.06 (s, 2H), 7.03
(dd, J=1.5, 7.5 Hz, 1H), 6.89 (s, 1H), 2.21 (s, 6H).
Example 143
3'-{N'-[1-(4-Cyclohexyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazi-
no}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 243)
[0771] ##STR173##
[0772] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.06 (s, 1H), 9.27 (s,
1H), 8.11 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H),
7.73 (m, 2H), 7.60 (t, J=7.8 Hz, 1H), 7.44 (s, 4H), 7.29 (t, J=7.6
Hz, 1H), 7.19 (t, J=7.6 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.00 (d,
J=7.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 2.61 (m, 1H), 1.85 (m, 4H),
1.72 (m, 1H), 1.44 (m, 4H), 1.26 (m, 1H).
Example 144
2'-Hydroxy-3'-[N'-(2-oxo-1-pyridin-2-yl-1,2-dihydro-indol-3-ylidene)-hydra-
zino]-biphenyl-3-carboxylic acid (Compound 244)
[0773] ##STR174##
[0774] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.08 (s, 1H), 9.34 (s,
1H), 8.66 (ddd, J=4.9, 1.9, 0.9 Hz, 1H), 8.13 (t, J=1.6 Hz, 1H),
8.07 (ddd, J=7.6, 8.0, 1.9 Hz, 1H), 7.95 (ddd, J=7.7, 1.6, 1.2 Hz,
1H), 7.89 (dt, J=8.0, 1.0 Hz, 1H), 7.81 (ddd, J=7.7, 1.6, 1.2 Hz,
1H), 7.77-7.74 (m, 2H), 7.67 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.7 Hz,
1H), 7.47 (ddd, J=7.6, 4.9, 1.0 Hz, 1H), 7.34 (td, J=7.8, 1.3 Hz,
1H), 7.25 (td, J=7.8, 0.9 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 7.02
(dd, J=7.8, 1.6 Hz, 1H).
Example 145
2'-Hydroxy-3'-[N'-(2-oxo-1-pyridin-3-yl-1,2-dihydro-indol-3-ylidene)-hydra-
zino]-biphenyl-3-carboxylic acid (Compound 245)
[0775] ##STR175##
[0776] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.02 (s, 1H), 9.33 (s,
1H), 8.81 (s, 1H), 8.69 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 8.05 (ddd,
J=8.2, 2.0, 1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2 Hz, 1H),
7.82-7.73 (m, 3H), 7.67 (m, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.32 (td,
J=7.6, 1.4 Hz, 1H), 7.23 (td, J=7.6, 1.0 Hz, 1H), 7.12 (t, J=7.8
Hz, 1H), 7.02 (dd, J=7.8, 1.7 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H).
Example 146
3'-{N'-[1-(4-Ethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-3-yli-
dene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
246)
[0777] ##STR176##
[0778] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.21 (s, 1H), 13.04
(s, 1H), 9.42 (s, 1H), 8.10 (s, 1H), 7.96-7.88 (m, 2H), 7.80-7.74
(m, 2H), 7.58 (t, J=7.7 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.46 (s,
4H), 7.12 (t, J=7.8 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 6.96 (s, 1H),
2.70 (q, J=7.6 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H).
Example 147
3'-{N'-[1-(4-Ethyl-phenyl)-4-fluoro-2-oxo-6-trifluoromethyl-1,2-dihydro-in-
dol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 247)
[0779] ##STR177##
[0780] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.36 (s, 1H), 13.05
(s, 1H), 9.50 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.95 (ddd, J=7.7,
1.6, 1.2 Hz, 1H), 7.80 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.67 (dd,
J=7.8, 1.6 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.51 (d, J=9.5 Hz, 1H),
7.47 (s, 4H), 7.15 (t, J=7.8 Hz, 1H), 7.08 (dd, J=7.8, 1.6 Hz, 1H),
6.83 (s, 1H), 2.72 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H).
Example 148
3-[(3'-Carboxy-2-hydroxy-biphenyl-3-yl)-hydrazono]-1-(3,5-dimethyl-phenyl)-
-2-oxo-2,3-dihydro-1-H-indole-5-carboxylic acid methyl ester
(Compound 248
[0781] ##STR178##
[0782] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.07 (s, 1H), 13.05
(s, 1H), 9.37 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.97-7.89 (m,
2H), 7.83-7.77 (m, 2H), 7.60 (t, J=7.8 Hz, 1H), 7.46 (s, 4H), 7.13
(t, J=7.8 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 6.97 (d, J=8.6 Hz, 1H),
3.89 (s, 3H), 2.72 (q, J=7.5 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H).
Example 149
3'-{N'-[1-(3-Chloro-4-methyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-i-
ndol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 249)
[0783] ##STR179##
[0784] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.19 (s, 1H), 13.05
(s, 1H), 9.46 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.95 (ddd, J=7.6,
1.7, 1.2 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.80 (ddd, J=7.6, 1.7,
1.2 Hz, 1H), 7.78 (dd, J=7.8, 1.6 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H),
7.61 (t, J=7.6 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.56 (dq, J=7.9,
0.7 Hz, 1H), 7.49 (dd, J=8.2, 2.1 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H),
7.07 (dd, J=7.8, 1.6 Hz, 1H), 7.04 (m, 1H), 2.44 (s, 3H).
Example 150
5-(4-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indo-
l-3-ylidene]-hydrazino}-3-hydroxy-benzylidene)-thiazolidine-2,4-dione
(Compound 250)
[0785] ##STR180##
[0786] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 13.12 (s, 1H), 12.57 (s, 1H),
10.88 (s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.68
(s, 1H), 7.54 (dq, J=7.9, 0.8 Hz, 1H), 7.24 (dd, J=8.4, 1.8 Hz,
1H), 7.18 (s, 1H), 7.17-7.15 (m, 3H), 6.97 (m, 1H), 2.37 (s,
6H).
Example 151
2'-Hydroxy-3'-(N'-{2-oxo-1-[4-(4,4,4-trifluoro-butyl)-phenyl]-1,2-dihydro--
indol-3-ylidene}-hydrazino)-biphenyl-3-carboxylic acid (Compound
251)
[0787] ##STR181##
[0788] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.02 (s, 1H), 9.26 (s,
1H), 8.12 (t, J=1.7 Hz, 1H), 7.95 (ddd, J=7.7, 1.7, 1.2 Hz, 1H),
7.79 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.69 (dd, J=7.8, 1.6 Hz, 1H),
7.65 (dd, J=7.6, 1.2 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.35 (td,
J=7.6, 1.2 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.14 (td, J=7.6, 0.8
Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.98 (dd, J=7.8, 1.6 Hz, 1H), 3.90
(t, J=7.0 Hz, 2H), 2.39 (m, 2H), 1.88 (m, 2H).
Example 152
3'-{N'-[1-(3,5-Dimethyl-phenyl)-4-fluoro-2-oxo-6-trifluoromethyl-1,2-dihyd-
ro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 252)
[0789] ##STR182##
[0790] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.37 (s, 1H), 13.06
(s, 1H), 9.49 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.95 (ddd, J=7.7,
1.7, 1.2 Hz, 1H), 7.80 (ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.67 (dd,
J=7.8, 1.6 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.50 (d, J=9.5 Hz, 1H),
7.18 (m, 1H), 7.16 (m, 2H), 7.15 (t, J=7.8 Hz, 1H), 7.08 (dd,
J=7.8, 1.6 Hz, 1H), 6.83 (s, 1H), 2.37 (s, 6H).
Example 153
3'-{N'-[1-(4-tert-Butyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 253)
[0791] ##STR183##
[0792] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.23 (s, 1H), 13.05
(s, 1H), 9.44 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.95 (ddd, J=7.7,
1.7, 1.1 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.80 (ddd, J=7.7, 1.7,
1.1 Hz, 1H), 7.78 (dd, J=7.8, 1.6 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H),
7.61 (t, J=7.7 Hz, 1H), 7.55 (dq, J=7.8, 0.7 Hz, 1H), 7.50 (d,
J=8.7 Hz, 2H), 7.14 (t, J=7.8 Hz, 1H), 7.06 (dd, J=7.8, 1.6 Hz,
1H), 7.01 (q, J=0.8 Hz, 1H), 1.36 (s, 9H).
Example 154
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-4-carboxylic acid
(Compound 254)
[0793] ##STR184##
[0794] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.09 (d, J=8.2 Hz, 2H),
7.89 (d, J=7.9 Hz, 1H), 7.81 (dd, J=7.9, 1.6 Hz, 1H), 7.63 (d,
J=8.2 Hz, 2H), 7.47 (d, J=7.9 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.26
(d, J=1.8 Hz, 1H), 7.19 (dd, J=8.0, 1.8 Hz, 1H), 7.10 (t, J=7.9 Hz,
1H), 7.04 (dd, J=7.9, 1.6 Hz, 1H), 6.99 (s, 1H), 2.38 (s, 3H), 2.37
(s, 3H).
Example 155
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-bromo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
255)
[0795] ##STR185##
[0796] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.08 (s, 1H), 13.04
(s, 1H), 9.33 (s, 1H), 8.12 (m, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.79
(m, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.60 (t,
J=7.7 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.31
(d, J=1.8 Hz, 1H), 7.24 (dd, J=8.0, 1.8 Hz, 1H), 7.12 (t, J=7.9 Hz,
1H), 7.03 (m, 1H), 6.91 (m, 1H), 2.32 (s, 3H), 2.31 (s, 3H).
Example 156
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-3-fluoro-2'-hydroxy-biphenyl-4-carboxylic
acid (Compound 256)
[0797] ##STR186##
[0798] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.27 (s, 1H), 13.22
(s, 1H), 9.59 (s, 1H), 7.97-7.91 (m, 2H), 7.81 (dd, J=7.7, 1.5 Hz,
1H), 7.54 (d, J=7.6 Hz, 1H), 7.51-7.47 (m, 2H), 7.39 (d, J=8.0 Hz,
1H), 7.33 (d, J=1.8 Hz, 1H), 7.27 (dd, J=8.0, 1.8 Hz, 1H), 7.15 (t,
J=7.7 Hz, 1H), 7.10 (dd, J=7.7, 1.5 Hz, 1H), 6.96 (s, 1H), 2.32 (s,
3H), 2.31 (s, 3H).
Example 157
3'-{N'-[1-(3,5-Bis-trifluoromethyl-phenyl-2-oxo-6-trifluoromethyl-1,2-dihy-
dro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 257)
[0799] ##STR187##
[0800] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.24 (s, 2H), 8.11 (s,
2H), 7.99-7.92 (m, 2H), 7.81 (m, 1H), 7.65 (m, 1H), 7.56-7.45 (m,
2H), 7.18 (s, 1H), 7.11-7.02 (m, 2H).
Example 158
3'-{N'-[1-(3,4-Dichloro-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 258)
[0801] ##STR188##
[0802] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.17 (s, 1H), 13.05
(s, 1H), 9.47 (s, 1H), 8.12 (t, J=1.7, Hz, 1H), 7.97-7.93 (m, 3H),
7.91 (d, J=8.5 Hz, 1H), 7.81-7.77 (m, 2H), 7.64 (dd, J=8.5, 2.4 Hz,
1H), 7.61 (t, J=7.7 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.18 (s, 1H),
7.14 (t, J=7.7 Hz, 1H), 7.07 (dd, J=7.7, 1.6 Hz, 1H).
Example 159
3'-{N'-[1-(3,5-Dichloro-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 259)
[0803] ##STR189##
[0804] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.13 (s, 1H), 7.97 (d,
J=7.7 Hz, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.79 (m, 1H), 7.66 (d, J=7.7
Hz, 1H), 7.62-7.59 (m, 3H), 7.54-7.47 (m, 2H), 7.16-7.02 (m,
3H).
Example 160
3-(4-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indo-
l-3-ylidene]-hydrazino}-3-hydroxy-phenyl)-2-methyl-acrylic acid
(Compound 260)
[0805] ##STR190##
[0806] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 13.14 (s, 1H), 12.45 (s, 1H),
10.61 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H),
7.55-7.51 (m, 2H), 7.18 (s, 1H), 7.16 (s, 2H), 7.12-7.09 (m, 2H),
6.98 (s, 1H), 2.37 (s, 6H), 2.08 (d, J=1.0 Hz, 3H).
Example 161
3-(4-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indo-
l-3-ylidene]-hydrazino}-3-hydroxy-phenyl)-2-methyl-acrylic acid
(Compound 261)
[0807] ##STR191##
[0808] This compound was prepared as described in Scheme V. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 13.13 (s, 1H), 12.45 (s, 1H),
10.61 (s, 1H), 7.90 (m, 1H), 7.75 (m, 1H), 7.56-7.50 (m, 2H), 7.39
(m, 1H), 7.33 (s, 1H), 7.26 (m, 1H), 7.13-7.08 (m, 2H), 6.96 (s,
1H), 2.32 (s, 3H), 2.31 (s, 3H), 2.08 (s, 3H).
Example 162
2'-Hydroxy-3'-[N'-(2-oxo-7-phenyl-1,2-dihydro-indol-3-ylidene)-hydrazino]--
biphenyl-3-carboxylic acid (Compound 262)
[0809] ##STR192##
[0810] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.16 (s, 1H), 10.91
(s, 1H), 8.15 (t, J=1.4 Hz, 1H), 7.95 (ddd, J=7.8, 1.4, 1.2 Hz,
1H), 7.79 (ddd, J=7.8, 1.4, 1.2 Hz, 1H), 7.72 (dd, J=7.9, 1.5 Hz,
1H), 7.63 (dd, J=7.6, 1.2 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H),
7.56-7.46 (m, 4H), 7.41 (m, 1H), 7.26 (dd, J=7.6, 1.2 Hz, 1H), 7.18
(t, J=7.6 Hz, 1H), 7.11 (t, J=7.9 Hz, 1H), 6.99 (dd, J=7.9, 1.5 Hz,
1H).
Example 163
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-trifluoromethoxy-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 263)
[0811] ##STR193##
[0812] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.27 (s, 1H), 13.02
(s, 1H), 9.39 (s, 1H), 8.12 (s, 1H), 7.95 (m, 1H), 7.80 (m, 1H),
7.65-7.58 (m, 2H), 7.42-7.24 (m, 4H), 7.22-7.11 (m, 2H), 7.04 (m,
1H), 6.89 (m, 1H), 2.32 (s, 3H), 2.30 (s, 3H).
Example 164
3'-{N'-[1-(3,4-Dimethyl-phenyl)-2-oxo-6-(1,1,2,2-tetrafluoro-ethoxy)-1,2-d-
ihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 264)
[0813] ##STR194##
[0814] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO) .delta. 13.07 (s, 1H), 13.04 (s, 1H),
9.33 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2
Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.79 (ddd, J=7.7, 1.6, 1.2 Hz,
1H), 7.74 (dd, J=7.8, 1.6 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.37 (d,
J=8.1 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.25 (dd, J=8.1, 2.0 Hz,
1H), 7.12 (t, J=7.8 Hz, 1H), 7.09 (dd, J=8.2, 2.1 Hz, 1H), 7.02
(dd, J=7.8, 1.6 Hz, 1H), 6.78 (tt, J=52.1, 3.1 Hz, 1H), 6.63 (d,
J=2.1 Hz, 1H), 2.32 (s, 3H), 2.30 (s, 3H).
Example 165
3'-{N'-[1-(3,4-Dimethyl-phenyl)-5-methyl-2-oxo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
265)
[0815] ##STR195##
[0816] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.04 (s, 2H), 9.26 (s,
1H), 8.12 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2 Hz, 1H),
7.78 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.72 (dd, J=7.9, 1.6 Hz, 1H),
7.59 (t, J=7.7 Hz, 1H), 7.55 (s, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.28
(d, J=2.0 Hz, 1H), 7.22 (dd, J=8.1, 2.0 Hz, 1H), 7.11 (t, J=7.9,
Hz, 1H), 7.09 (m, 1H), 6.99 (dd, J=7.9, 1.6 Hz, 1H), 6.76 (d, J=8.0
Hz, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H).
Example 166
3'-{N'-[1-(4-Isopropyl-phenyl)-5-methyl-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
266)
[0817] ##STR196##
[0818] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.03 (s, 2H), 9.26 (s,
1H), 8.11 (t, J=1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2 Hz, 1H),
7.79 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.72 (dd, J=7.9, 1.6 Hz, 1H),
7.59 (t, J=7.7 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.43
(d, J=8.6 Hz, 2H), 7.11 (t, J=7.9 Hz, 1H), 7.10 (m, 1H), 6.99 (dd,
J=7.9, 1.6 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 3.00 (sept, J=6.9 Hz,
1H), 2.37 (s, 3H), 1.26 (d, J=6.9 Hz, 6H).
Example 167
3'-{N'-[1-(3,4-Dimethyl-phenyl)-6-phenyl-2-oxo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
267)
[0819] ##STR197##
[0820] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.10 (s, 1H), 13.05
(s, 1H), 9.30 (s, 1H), 8.13 (t, J=1.6 Hz, 1H), 7.95 (ddd, J=7.7,
1.6, 1.2 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.80 (ddd, J=7.7, 1.6,
1.2 Hz, 1H), 7.75 (dd, J=7.9, 1.5 Hz, 1H), 7.62-7.57 (m, 3H), 7.48
(dd, J=7.8, 1.8 Hz, 1H), 7.47-7.42 (m, 2H), 7.39-7.34 (m, 3H), 7.30
(dd, J=7.8, 2.2 Hz, 1H), 7.13 (t, J=7.9 Hz, 1H), 7.02-7.00 (m, 2H),
2.32 (s, 3H), 2.31 (s, 3H).
Example 168
3'-{N'-[1-(3-Trifluoromethyl-phenyl)-6-trifluoromethyl-2-oxo-1,2-dihydro-i-
ndol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 268)
[0821] ##STR198##
[0822] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.19 (s, 1H), 13.05
(s, 1H), 9.47 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 8.03 (s, 1H),
7.97-7.93 (m, 3H), 7.93-7.86 (m, 2H), 7.80 (dd, J=7.8, 1.6 Hz, 1H),
7.80 (ddd, J=7.8, 1.7, 1.2 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.58
(dq, J=7.8, 0.8 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.10 (d, J=0.7 Hz,
1H), 7.08 (dd, J=7.8, 1.6 Hz, 1H).
Example 169
3'-{N'-[1-(4-Trifluoromethoxy-phenyl)-5-trifluoromethoxy-2-oxo-1,2-dihydro-
-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 269)
[0823] ##STR199##
[0824] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.10 (s, 1H), 13.05
(s, 1H), 9.40 (s, 1H), 8.12 (t, J=1.6 Hz, 1H), 7.95 (ddd, J=7.7,
1.6, 1.2 Hz, 1H), 7.82 (dd, J=7.8, 1.6 Hz, 1H), 7.80 (ddd, J=7.7,
1.6, 1.2 Hz, 1H), 7.74 (m, 1H), 7.73 (d, J=9.0 Hz, 2H), 7.62 (dq,
J=9.0, 0.9 Hz, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.28 (ddq, J=8.6, 2.1,
0.9 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 7.05 (dd, J=7.8, 1.6 Hz, 1H),
7.02 (d, J=8.6 Hz, 1H).
Example 170
3'-{N'-[1-(3,5-Dimethyl-phenyl)-6-trifluoromethyl-2-oxo-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 270)
[0825] ##STR200##
[0826] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.24 (s, 1H), 13.05
(s, 1H), 9.43 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.95 (ddd, J=7.7,
1.7, 1.2 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.80 (ddd, J=7.7, 1.7,
1.2 Hz, 1H), 7.78 (dd, J=7.7, 1.7 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H),
7.54 (dq, J=7.8, 0.8 Hz, 1H), 7.18-7.16 (m, 3H), 7.14 (t, J=7.7 Hz,
1H), 7.07 (dd, J=7.7, 1.7 Hz, 1H), 6.98 (m, 1H), 2.37 (s, 3H), 2.37
(s, 3H).
Example 171
3'-{N'-[1-(3-Trifluoromethyl-phenyl)-4,6-dimethyl-2-oxo-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 271)
[0827] ##STR201##
[0828] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.04 (s, 1H), 13.03
(s, 1H), 9.23 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.95 (m, 1H), 7.94
(ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.89-7.83 (m, 3H), 7.79 (ddd, J=7.7,
1.7, 1.2 Hz, 1H), 7.61 (dd, J=8.1, 1.4 Hz, 1H), 7.60 (t, J=7.7 Hz,
1H), 7.12 (t, J=7.8 Hz, 1H), 6.98 (dd, J=7.8, 1.6 Hz, 1H), 6.87 (s,
1H), 6.57 (s, 1H), 2.65 (s, 3H), 2.29 (s, 3H).
Example 172
3'-{N'-[1-(3-Trifluoromethyl-phenyl)-5,6-dimethyl-2-oxo-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 272)
[0829] ##STR202##
[0830] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.04 (s, 1H), 12.91
(s, 1H), 9.25 (s, 1H), 8.12 (t, J=1.7 Hz, 1H), 7.95 (m, 1H), 7.94
(ddd, J=7.7, 1.7, 1.2 Hz, 1H), 7.90-7.84 (m, 3H), 7.79 (ddd, J=7.7,
1.7, 1.2 Hz, 1H), 7.71 (dd, J=8.0, 1.4 Hz, 1H), 7.60 (t, J=7.7 Hz,
1H), 7.55 (s, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.99 (dd, J=7.8, 1.6 Hz,
1H), 6.76 (s, 1H), 2.29 (s, 3H), 2.25 (s, 3H).
Example 173
3'-{N'-[1-(3,5-Dimethyl-phenyl)-6-trifluoromethyl-2-oxo-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-5'-chloro-4-fluoro-biphenyl-3-carboxylic
acid (Compound
[0831] ##STR203##
[0832] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.39 (s, 1H), 13.11
(s, 1H), 9.69 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 8.02 (dd, J=7.0, 2.5
Hz, 1H), 7.81 (ddd, J=8.5, 4.6, 2.5 Hz, 1H), 7.76 (d, J=2.6 Hz,
1H), 7.54 (dq, J=8.0, 0.7 Hz, 1H), 7.43 (dd, J=10.7, 8.5 Hz, 1H),
7.17 (s, 1H), 7.16 (s, 2H), 7.08 (d, J=2.6 Hz, 1H), 6.97 (s, 1H),
2.37 (s, 6H).
Example 174
3'-{N'-[1-(3,5-Dimethyl-phenyl)-6-trifluoromethyl-2-oxo-1,2-dihydro-indol--
3-ylidene]-hydrazino}-2'-hydroxy-4-fluoro-biphenyl-3-carboxylic
acid (Compound 274)
[0833] ##STR204##
[0834] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.35 (s, 1H), 13.23
(s, 1H), 9.44 (s, 1H), 8.01 (dd, J=7.2, 2.4 Hz, 1H), 7.92 (d, J=8.0
Hz, 1H), 7.79 (ddd, J=8.6, 4.6, 2.4 Hz, 1H), 7.79 (dd, J=7.8, 1.5
Hz, 1H), 7.54 (dq, J=8.0, 0.8 Hz, 1H), 7.42 (dd, J=10.7, 8.6 Hz,
1H), 7.17 (s, 1H), 7.16 (s, 2H), 7.13 (t, J=7.8 Hz, 1H), 7.05 (dd,
J=7.8, 1.5 Hz, 1H), 6.98 (s, 1H), 2.37 (s, 6H).
Example 175
3'-{N'-[6-Chloro-1-(3,4-dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
275)
[0835] ##STR205##
[0836] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.06 (s, 1H), 13.00
(s, 1H), 9.33 (s, 1H), 8.12 (s, 1H), 7.94 (m, 1H), 7.81-7.70 (m,
3H), 7.60 (t, J=7.9 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.31 (m, 1H),
7.27-7.21 (m, 2H), 7.12 (t, J=7.8 Hz, 1H), 7.02 (d, J=7.8, 1H),
6.79 (m, 1H), 2.31 (s, 3H), 2.31 (s, 3H).
Example 176
3'-{N'-[5-Fluoro-2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]-hy-
drazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound 276)
[0837] ##STR206##
[0838] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, acetone-d.sub.6) .delta. 8.19 (t, J=1.5 Hz,
1H), 8.03 (m, 1H), 7.83 (dd, J=7.8, 1.6 Hz, 1H), 7.77 (m, 1H), 7.59
(t, J=7.6 Hz, 1H), 7.53 (dd, J=8.3, 2.6 Hz, 1H), 7.47 (d, J=8.8 Hz,
2H), 7.43 (d, J=8.8 Hz, 2H), 7.13 (t, J=7.8 Hz, 1H), 7.06-7.02 (m,
2H), 6.92 (dd, J=8.8, 4.3 Hz, 1H), 2.69 (dd, J=7.9, 7.3 Hz, 2H),
1.71 (m, 2H), 0.98 (t, J=7.3 Hz, 3H).
Example 177
3'-{N'-[5-Cyano-1-(3,4-dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
277)
[0839] ##STR207##
[0840] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, methanol-d.sub.4) .delta. 8.46 (s, 1H), 8.14
(m, 1H), 8.05 (s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.82 (dd, J=7.7, 1.4
Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.58 (m, 1H), 7.52 (t, J=7.6 Hz,
1H), 7.36 (m, 1H), 7.25 (s, 1H), 7.19 (m, 1H), 7.10 (t, J=7.7 Hz,
1H), 7.03 (dd, J=7.7, 1.4 Hz, 1H), 6.99 (m, 1H), 2.36 (s, 6H).
Example 178
3'-{N'-[6-Chloro-1-(3,5-dimethyl-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidene-
]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid (Compound
278)
[0841] ##STR208##
[0842] was prepared as described in Scheme II. .sup.1H NMR (300
MHz, acetone-d.sub.6) .delta. 13.22 (s, 1H), 8.49 (s, 1H), 8.19 (t,
J=1.6 Hz, 1H), 8.04 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.82-7.77 (m,
2H), 7.76 (d, J=8.0 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.21 (dd,
J=8.0, 1.8 Hz, 1H), 7.19-7.15 (m, 3H), 7.13 (t, J=7.7 Hz, 1H), 7.04
(dd, J=7.7, 1.6 Hz, 1H), 6.90 (d, J=1.8 Hz, 1H), 2.40 (s, 6H).
Example 179
4-Fluoro-3'-{N'-[1-(3-fluoro-4-methyl-phenyl)-2-oxo-6-trifluoromethyl-1,2--
dihydro-indol-3-ylidene]-hydrazino}-2'-hydroxy-biphenyl-3-carboxylic
acid (Compound 279)
[0843] ##STR209##
[0844] This compound was prepared as described in Scheme II.
.sup.1H NMR (300 MHz, acetone-d.sub.6) .delta. 8.09 (dd, J=7.0, 2.4
Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.85 (dd, J=7.8, 1.6 Hz, 1H), 7.80
(ddd, J=8.5, 4.5, 2.4 Hz, 1H), 7.57-7.50 (m, 2H), 7.44-7.32 (m,
3H), 7.20 (m, 1H), 7.15 (t, J=7.8, 1H), 7.07 (dd, J=7.8, 1.6 Hz,
1H), 2.37 (d, J=1.9 Hz, 3H).
Example 180
3'-{N'-[1-(4-Chloro-3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydr-
oindol-3-ylidene]hydrazino}-2'-hydroxy-biphenyl-3-carboxylic acid
(Compound 280)
[0845] ##STR210##
[0846] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, CDCl.sub.3) 7.75 (s, 1H), 7.45-7.41 (m, 2H),
7.39 (m, 1H), 7.09 (m, 1H), 3.25 (t, J=7.3, 2H), 3.03 (t, J=7.3,
2H), 1.81 (sext, J=7.3, 2H), 1.63 (sext, J=7.3, 2H), 1.12 (t,
J=7.3, 3H), 1.01 (t, J=7.3, 3H).
Example 181
3'-{N'-[1-(3,5-Dimethylphenyl)-4-fluoro-2-oxo-6-trifluoromethyl-1,2-dihydr-
oindol-3-ylidene]hydrazino}-2'-hydroxybiphenyl-4-fluoro-3-carboxylic
acid (Compound 281)
[0847] ##STR211##
[0848] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.35 (s, 1H), 8.01 (dd, J=7.1,
2.4, 1H), 7.78 (ddd, J=8.5, 4.5, 2.4, 1H), 7.66 (dd, J=7.9, 1.6,
1H), 7.50 (d, J=9.4, 1H), 7.41 (dd, J=10.7, 8.5, 1H), 7.18 (s, 1H),
7.15 (s, 2H), 7.14 (t, J=7.9, 1H), 7.07 (dd, J=7.9, 1.6, 1H), 6.83
(q, J=0.7, 1H), 2.37 (s, 6H).
Example 182
3'-{N'-[1-Benzo[1,3]dioxo-5-yl-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3--
ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound
282)
[0849] ##STR212##
[0850] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.21 (s, 1H), 13.05 (s, 1H),
9.43 (s, 1H), 8.12 (t, J=1.6, 1H), 7.95 (ddd, J=7.7, 1.6, 1.2, 1H),
7.92 (d, J=7.8, 1H), 7.80 (dd, J=7.7, 1.6, 1.2, 1H), 7.78 (dd,
J=7.9, 1.6, 1H), 7.60 (t, J=7.7, 1H), 7.54 (dq, J=7.8, 0.8, 1H),
7.18 (d, J=2.1, 1H), 7.14 (d, J=8.2, 1H), 7.14 (t, J=7.9, 1H), 7.06
(dd, J=7.9, 1.6, 1H), 7.03 (dd, J=8.2, 2.1, 1H), 6.98 (q, J=0.6,
1H), 6.16 (s, 2H).
Example 183
3'-{N'-[1-Benzo[1,3]dioxo-5-yl-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3--
ylidene]hydrazino}-2'-hydroxybiphenyl-2-fluoro-3-carboxylic acid
(Compound 283)
[0851] ##STR213##
[0852] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.35 (s, 1H), 13.19 (s, 1H),
9.45 (s, 1H), 8.01 (dd, J=7.2, 2.5, 1H), 7.91 (d, J=7.9, 1H), 7.79
(ddd, J=8.5, 4.6, 2.5, 1H), 7.77 (dd, J=7.8, 1.6, 1H), 7.54 (dq,
J=7.9, 0.7 Hz, 1H), 7.42 (dd, J=10.7, 8.5, 1H), 7.18 (d, J=2.1,
1H), 7.14 (d, J=8.2, 1H), 7.13 (t, J=7.8, 1H), 7.05 (dd, J=7.8,
1.6, 1H), 7.03 (dd, J=8.2, 2.1, 1H), 6.98 (q, J=0.9, 1H), 6.16 (s,
2H).
Example 184
3'-{N'-[1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3--
ylidene]hydrazino}-2'-hydroxybiphenyl-2-hydroxy-3-carboxylic acid
(Compound 284)
[0853] ##STR214##
[0854] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.23 (s, 1H), 9.31 (s, 1H),
7.97 (d, J=2.3, 1H), 7.92 (d, J=7.9, 1H), 7.73 (dd, J=7.8, 1.5,
1H), 7.69 (dd, J=8.6, 2.3, 1H), 7.54 (dq, J=7.9, 0.7, 1H), 7.17 (s,
1H), 7.16 (s, 2H), 7.10 (t, J=7.8, 1H), 7.06 (d, J=8.6, 1H), 7.02
(dd, J=7.8, 1.5, 1H), 6.98 (d, J=0.9, 1H), 2.37 (s, 6H).
Example 185
3'-{N'-[1-(3-Methoxycarbonylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroind-
ol-3-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid
(Compound 285)
[0855] ##STR215##
[0856] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.05 (s, 1H), 9.45 (s, 1H),
8.15 (t, J=1.7, 1H), 8.12 (t, J=1.7, 1H), 8.10 (ddd, J=7.8, 1.7,
1.2, 1H), 7.95 (m, 2H), 7.90 (m, 1H), 7.80 (t, J=7.8, 1H),
7.82-7.78 (m, 2H), 7.61 (t, J=7.8, 1H), 7.57 (dq, J=7.9, 0.8, 1H),
7.15 (t, J=7.8, 1H), 7.08 (m, 1H), 7.07 (dd, J=7.8, 1.6, 1H), and
3.90 (s, 3H).
Example 186
3'-{N'-[1-(3-Methoxycarbonylphenyl)-2-oxo-1,2-dihydroindol-3-ylidene]hydra-
zino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 286)
[0857] ##STR216##
[0858] This compound was prepared as described in Scheme II.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.04 (s, 1H), 9.30 (s, 1H),
8.12 (t, J=1.7, 1H), 8.12 (t, J=1.7, 1H), 8.06 (ddd, J=7.8, 1.7,
1.2, 1H), 7.94 (ddd, J=7.8, 1.7, 1.2, 1H), 7.88 (m, 1H), 7.80 (ddd,
J=7.8, 1.7, 1.2, 1H), 7.77 (t, J=7.8, 1H), 7.76 (dd, J=7.6, 0.8,
1H), 7.74 (dd, J=7.8, 1.6, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.31 (td,
J=7.6, 1.3, 1H), 7.22 (td, J=7.6, 0.8, 1H), 7.12 (t, J=7.8, 1H),
7.01 (dd, J=7.8, 1.6, 1H), 6.95 (d, J=7.6, 1H), 4.11 (s, 1H) and
3.90 (s, 3H).
Example 187
3'-{N'-[7-Aza-1-(3,4-dimethylphenyl)-2-oxo-1,2-dihydroindol-3-ylidene]hydr-
azino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 287)
[0859] ##STR217##
[0860] This compound was prepared as described in Scheme I. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.10 (s, 1H), 13.04 (s, 1H), 9.36 (s,
1H), 8.16 (dd, J=5.1, 1.6 Hz, 1H), 8.12 (t, J=1.6 Hz, 1H), 8.04
(dd, J=7.4, 1.6 Hz, 1H), 7.94 (ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.80
(ddd, J=7.7, 1.6, 1.2 Hz, 1H), 7.74 (dd, J=7.8, 1.6 Hz, 1H), 7.60
(t, J=7.7 Hz, 1H), 7.34 (d, J=1.8 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H),
7.28 (dd, J=8.1, 1.8 Hz, 1H), 7.21 (dd, J=7.4, 5.1 Hz, 1H), 7.13
(t, J=7.8 Hz, 1H), 7.03 (dd, J=7.8, 1.6 Hz, 1H), 2.30 (s, 3H), 2.29
(s, 3H).
Example 188
3'-{N'-[1-(3,5-Dimethylphenyl)-2-oxo-1,2-dihydroindol-6-trifluoromethyl-3--
ylidene]hydrazino}-2'-hydroxybiphenyl-3-(2-methyl-2-propionic acid)
(Compound 288)
[0861] ##STR218##
[0862] This compound was prepared as described in Scheme I. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.25 (s, 1H), 12.39 (s, 1H), 9.35 (s,
1H), 7.92 (d, J=7.8 Hz, 1H), 7.75 (dd, J=8.0, 1.5 Hz, 1H),
7.56-7.53 (m, 2H), 7.46-7.42 (m, 2H), 7.35 (m, 1H), 7.17 (s, 3H),
7.12 (t, J=7.8 Hz, 1H), 7.02 (dd, J=7.8, 1.6 Hz, 1H), 6.99 (q,
J=0.7 Hz, 1H), 2.37 (s, 6H), 1.52 (s, 6H).
Example 189
3'-{N'-[1,3-N,N-Dimethylbarbitur-5-ylidene]hydrazino}-2'-hydroxybiphenyl-3-
-carboxylic acid (Compound 289)
[0863] ##STR219##
[0864] This compound was prepared as described in Scheme I. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 8.14 (t, J=1.3 Hz, 1H), 7.95 (d, J=7.7
Hz, 1H), 7.81 (dt, J=7.7, 1.3 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.61
(t, J=7.7 Hz, 1H), 7.18 (dd, J=7.7, 1.2 Hz, 1H), 7.13 (m, 1H), 3.22
(s, 6H).
Example 190
3'-{N'-[1-N-(4-Trifluoromethylbenzyl)-2,8-dioxo-1,2,7,8-tetrahydroisoquino-
lin-7-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid
(Compound 290)
[0865] ##STR220##
[0866] This compound was prepared as described in Scheme I. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 14.24 (s, 1H), 13.06 (s, 1H), 9.49 (s,
1H), 8.36 (d, J=7.9 Hz, 1H), 8.16-8.12 (m, 2H), 7.95 (d, J=7.7 Hz,
1H), 7.88 (dd, J=7.8, 1.0 Hz, 1H), 7.84-7.79 (m, 2H), 7.68 (d,
J=8.2 Hz, 2H), 7.61 (t, J=7.7 Hz, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.55
(td, J=7.7, 0.9 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.10 (dd, J=7.8,
1.0 Hz, 1H), 5.28 (s, 2H).
Example 191
3'-{N'-[1-N-(4-Methylbenzyl)-2,8-dioxo-1,2,7,8-tetrahydroisoquinolin-7-yli-
dene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound
291)
[0867] ##STR221##
[0868] This compound was prepared as described in Scheme I. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 14.28 (s, 1H), 13.06 (s, 1H), 9.49 (s,
1H), 8.34 (d, J=8.0 Hz, 1H), 8.15-8.12 (m, 2H), 7.96 (dm, J=7.8 Hz,
1H), 7.87 (dm, J=7.8 Hz, 1H), 7.82-7.78 (m, 2H), 7.61 (t, J=7.8 Hz,
1H), 7.54 (td, J=7.7, 0.9 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.15 (t,
J=7.8 Hz, 1H), 7.10 (m, 1H), 7.12 (d, J=8.2 Hz, 2H), 5.16 (s, 2H),
2.25 (s, 3H).
Example 192
3'-{N'-[1-N-Benzyl-2,8-dioxo-1,2,7,8-tetrahydroisoquinolin-7-ylidene]hydra-
zino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 292)
[0869] ##STR222##
[0870] This compound was prepared as described in Scheme I. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 14.28 (s, 1H), 13.06 (s, 1H), 9.49 (s,
1H), 8.35 (d, J=7.9 Hz, 1H), 8.16-8.12 (m, 2H), 7.95 (dd, J=7.7,
1.2 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.82-7.78 (m, 2H), 7.61 (t,
J=7.7 Hz, 1H), 7.55 (td, J=7.6, 0.8 Hz, 1H), 7.36 (d, J=7.4 Hz,
2H), 7.32 (t, J=7.4 Hz, 2H), 7.25 (t, J=7.4 Hz, 1H), 7.15 (t, J=7.8
Hz, 1H), 7.10 (dd, J=7.8, 1.2 Hz, 1H), 5.21 (s, 2H).
Example 193
3'-{N'-[1-N-(4-Trifluoromethylphenyl)-2,8-dioxo-1,2,7,8-tetrahydroisoquino-
lin-7-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid
(Compound 293)
[0871] ##STR223##
[0872] This compound was prepared as described in Scheme I. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 14.11 (s, 1H), 13.05 (s, 1H), 9.41 (s,
1H), 8.42 (d, J=8.0 Hz, 1H), 8.15-8.11 (m, 2H), 7.95 (dd, J=7.7,
1.3 Hz, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.90 (dd, J=7.8, 1.3 Hz, 1H),
7.85 (ddd, J=8.0, 7.6, 1.3 Hz, 1H), 7.79 (dd, J=7.7, 1.3 Hz, 1H),
7.67 (d, J=8.2 Hz, 2H), 7.61 (t, J=7.7 Hz, 1H), 7.58 (td, J=7.6,
1.3 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 7.09 (dd, J=7.8, 1.3 Hz,
1H).
Example 194
3'-{N'-[1-N-(3-Trifluoromethylphenyl)-2,8-dioxo-1,2,7,8-tetrahydroisoquino-
lin-7-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid
(Compound 294)
[0873] ##STR224##
[0874] This compound was prepared as described in Scheme I. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 14.11 (s, 1H), 13.05 (s, 1H), 9.41 (s,
1H), 8.42 (d, J=7.9 Hz, 1H), 8.15-8.11 (m, 2H), 7.95 (dm, J=7.7 Hz,
1H), 7.92-7.83 (m, 4H), 7.81-7.77 (m, 2H), 7.75 (d, J=7.7 Hz, 1H),
7.61 (t, J=7.7 Hz, 1H), 7.58 (td, J=7.5, 1.0 Hz, 1H), 7.17 (t,
J=7.8 Hz, 1H), 7.09 (dd, J=7.8, 1.2 Hz, 1H).
Example 195
3'-{N'-[1-N-(3,5-Dimethylphenyl)-2,8-dioxo-1,2,7,8-tetrahydroisoquinolin-7-
-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound
295)
[0875] ##STR225##
[0876] This compound was prepared as described in Scheme I. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 14.18 (s, 1H), 13.06 (s, 1H), 9.38 (s,
1H), 8.38 (dd, J=7.6, 0.9 Hz, 1H), 8.12-8.09 (m, 2H), 7.94 (dt,
J=7.7, 1.4 Hz, 1H), 7.88 (dd, J=7.9, 1.3 Hz, 1H), 7.82 (td, J=7.6,
0.9 Hz, 1H), 7.78 (dt, J=7.7, 1.4 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H),
7.56 (td, J=7.6, 0.9 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 7.10 (s, 1H),
7.08 (dd, J=7.9, 1.3 Hz, 1H), 6.96 (s, 2H), 2.32 (s, 6H).
Example 196
3'-{N'-[1-N-Phenyl-2,8-dioxo-1,2,7,8-tetrahydroisoquinolin-7-ylidene]hydra-
zino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 296)
[0877] ##STR226##
[0878] This compound was prepared as described in Scheme I. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 14.16 (s, 1H), 13.04 (s, 1H), 9.38 (s,
1H), 8.40 (dd, J=7.7, 0.9 Hz, 1H), 8.14-8.10 (m, 2H), 7.94 (dt,
J=7.7, 1.4 Hz, 1H), 7.89 (dd, J=7.8, 1.3 Hz, 1H), 7.83 (td, J=7.7,
0.9 Hz, 1H), 7.78 (dt, J=7.7, 1.4 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H),
7.57 (td, J=7.7, 0.9 Hz, 1H), 7.53 (t, J=7.5 Hz, 2H), 7.47 (t,
J=7.5 Hz, 1H), 7.38 (m, 2H), 7.15 (t, J=7.8 Hz, 1H), 7.08 (dd,
J=7.8, 1.3 Hz, 1H).
Example 197
3'-{N'-[1-N-(3,4-Dimethylphenyl)-2,8-dioxo-1,2,7,8-tetrahydroisoquinolin-7-
-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound
297)
[0879] ##STR227##
[0880] This compound was prepared as described in Scheme I. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 14.19 (s, 1H), 13.04 (s, 1H), 9.39 (s,
1H), 8.41 (dd, J=7.6, 0.9 Hz, 1H), 8.14-8.10 (m, 2H), 7.94 (dt,
J=7.6, 1.4 Hz, 1H), 7.90 (dd, J=7.8, 1.2 Hz, 1H), 7.85 (td, J=7.6,
0.9 Hz, 1H), 7.78 (dt, J=7.6, 1.4 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H),
7.57 (td, J=7.6, 0.9 Hz, 1H), 7.27 (d, J=7.4 Hz, 1H), 7.22 (t,
J=7.8 Hz, 1H), 7.18-7.12 (m, 2H), 7.08 (dd, J=7.8, 1.2 Hz, 1H),
2.33 (s, 3H), 1.95 (s, 3H).
Example 198
3'-{N'-[1-N-(3,4-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol--
3-ylidene]hydrazino}-2'-fluorobiphenyl-3-carboxylic acid (Compound
298)
[0881] ##STR228##
[0882] This compound was prepared as described in Scheme I. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.06 (s, 1H), 8.13 (m, 1H), 8.00 (dt,
J=7.8, 1.3 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.90 (m, 1H), 7.85 (m,
1H), 7.64 (t, J=7.7 Hz, 1H), 7.56 (dq, J=7.9, 0.7 Hz, 1H), 7.42 (t,
J=7.9 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.30
(m, 1H), 7.26 (dd, J=8.0, 2.0 Hz, 1H), 6.95 (q, J=0.6 Hz, 1H), 2.31
(s, 3H), 2.29 (s, 3H).
Example 199
3-(3-{N'-[1-N-(3,4-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindo-
l-3-ylidene]hydrazino}-2-hydroxyphenyl)-2(Z)-propenoic acid
(Compound 299)
[0883] ##STR229##
[0884] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.26 (s, 1H), 8.13 (d, J=9.6 Hz, 1H),
8.03 (m, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.57 (dq, J=7.9, 0.7 Hz, 1H),
7.48-7.44 (m, 2H), 7.40 (d, J=8.1 Hz, 1H), 7.36 (d, J=2.2 Hz, 1H),
7.29 (dd, J=8.1, 2.2 Hz, 1H), 6.99 (m, 1H), 6.59 (d, J=9.6 Hz, 1H),
2.33 (s, 3H), 2.32 (s, 3H).
Example 200
3-(3-{N'-[1-N-(3,4-Dimethylphenyl)-2-oxo-4-fluoro-6-trifluoromethyl-1,2-di-
hydroindol-3-ylidene]hydrazino}-2-hydroxyphenyl)-2(Z)-propenoic
acid (Compound 300)
[0885] ##STR230##
[0886] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.39 (s, 1H), 8.13 (d, J=9.6 Hz, 1H),
7.90 (m, 1H), 7.55 (d, J=9.5 Hz, 1H), 7.49-7.47 (m, 2H), 7.40 (d,
J=8.0 Hz, 1H), 7.35 (d, J=1.9 Hz, 1H), 7.29 (dd, J=8.0, 1.9 Hz,
1H), 6.84 (s, 1H), 6.59 (d, J=9.6 Hz, 1H), 2.33 (s, 3H), 2.32 (s,
3H).
Example 201
5-(3-{N'-[1-(3,4-Dimethylphenyl)-2-oxo-4-fluoro-6-trifluoromethyl-1,2-dihy-
droindol-3-ylidene]hydrazino}-2-hydroxybenzylidene)thiazolidine-2,4-dione
(Compound 301)
[0887] ##STR231##
[0888] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.29 (s, 1H), 8.06 (s, 1H), 7.70 (m,
1H), 7.50 (d, J=9.6 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.32 (d, J=2.1
Hz, 1H), 7.26 (dd, J=8.1, 2.1 Hz, 1H), 7.17-7.14 (m, 2H), 6.80 (q,
J=0.7 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H).
Example 202
2-Chloro-3-(4-{N'-[1-(3,4-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihy-
droindol-3-ylidene]hydrazino}-3-hydroxyphenyl)-2-propenoic acid
(Compound 302)
[0889] ##STR232##
[0890] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.13 (s, 1H), 10.74 (s, 1H), 7.92 (d,
J=8.2 Hz, 1H), 7.85 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.72 (d, J=1.4
Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.45 (dd, J=8.6, 1.4 Hz, 1H), 7.39
(d, J=8.0 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H), 7.27 (dd, J=8.0, 1.6 Hz,
1H), 6.96 (m, 1H), 2.33 (s, 3H), 2.31 (s, 3H).
Example 203
2-Ethyl-3-(4-{N'-[1-(3,4-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihyd-
roindol-3-ylidene]hydrazino}-3-hydroxyphenyl)-2-propenoic acid
(Compound 303)
[0891] ##STR233##
[0892] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, Acetone-d.sub.6) 13.32 (s, 1H), 10.78 (s, 1H), 9.52
(s, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.61 (s,
1H), 7.52 (d, J=7.9 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.37 (br s,
1H), 7.31 (br d, J=8.1 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J=8.6 Hz,
1H), 7.10 (s, 1H), 2.61 (q, J=7.3 Hz, 2H), 2.37 (s, 6H), 1.20 (t,
J=7.3 Hz, 3H).
Example 204
1-N-Methyl-5-(4-{N'-[1-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-di-
hydroindol-3-ylidene]hydrazino}-3-hydroxybenzylidene)-1,3-diazolidine-2,4--
dione (Compound 304)
[0893] ##STR234##
[0894] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.17 (s, 1H), 13.13 (s, 1H), 11.43 (s,
1H), 11.35 (s, 1H), 10.64 (s, 1H), 10.58 (s, 1H), 7.92-7.88 (m,
3H), 7.72 (d, J=8.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.53 (m, 2H),
7.50 (d, J=8.3 Hz, 1H), 7.18 (s, 2H), 7.16 (s, 4H), 7.01 (d, J=8.3
Hz, 1H), 6.98 (m, 2H), 6.95 (s, 1H), 6.59 (s, 1H), 6.35 (s, 1H),
3.10 (s, 3H), 2.93 (s, 3H), 2.37 (s, 12H).
Example 205
5-(4-{N'-[1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol--
3-ylidene]hydrazino}-3-hydroxybenzylidene)-1,3-diazolidine-2,4-dione
(Compound 305)
[0895] ##STR235##
[0896] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.14 (s, 1H), 11.21 (s, 1H), 10.57 (s,
1H), 10.48 (s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H),
7.51 (d, J=7.9 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.15 (s, 1H), 7.14
(s, 2H), 7.05 (s, 1H), 6.96 (s, 1H), 6.32 (s, 1H), 2.35 (s,
6H).
Example 206
2-Fluoro-3-(4-{N'-[1-(3,4-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihy-
droindol-3-ylidene]hydrazino}-3-hydroxyphenyl)-2-propenoic acid
(Compound 306)
[0897] ##STR236##
[0898] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.56 (s, 1H), 13.12 (s, 1H), 10.69 (s,
1H), 7.91 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.54 (d, J=8.0
Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.36 (s, 1H), 7.33 (br s, 1H),
7.29-7.25 (m, 2H), 6.95 (d, J=36.7 Hz, 1H), 6.95 (m, 1H), 2.33 (s,
3H), 2.31 (s, 3H).
Example 207
(.+-.)-2-Methoxy-3-(4-{N'-[1-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl--
1,2-dihydroindol-3-ylidene]hydrazino}-3-hydroxyphenyl)propanoic
acid (Compound 307)
[0899] ##STR237##
[0900] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.10 (s, 1H), 10.43 (s, 1H), 7.86 (d,
J=7.9 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.51 (dq, J=7.9, 0.7 Hz,
1H), 7.16 (s, 1H), 7.15 (s, 2H), 6.97 (q, J=0.6 Hz, 1H), 6.83 (d,
J=1.6 Hz, 1H), 6.80 (dd, J=8.3, 1.6 Hz, 1H), 3.88 (dd, J=8.0, 4.6
Hz, 1H), 3.25 (s, 3H), 2.91 (dd, J=14.2, 4.6 Hz, 1H), 2.80 (dd,
J=14.2, 8.0 Hz, 1H), 2.37 (s, 6H).
Example 208
4-(3-{N'-[1-(3,4-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol--
3-ylidene]hydrazino}-2-hydroxyphenyl)butanoic acid (Compound
308)
[0901] ##STR238##
[0902] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.18 (s, 1H), 12.08 (s, 1H), 9.26 (s,
1H), 7.89 (d, J=7.9 Hz, 1H), 7.60 (dd, J=7.8, 1.6 Hz, 1H), 7.52
(dq, J=7.9, 0.7 Hz, 1H), 7.17 (s, 1H), 7.16 (s, 2H), 6.96 (m, 1H),
6.95 (t, J=7.8 Hz, 1H), 6.88 (dd, J=7.8, 1.6 Hz, 1H), 2.65 (t,
J=7.6 Hz, 2H), 2.37 (s, 6H), 2.25 (t, J=7.6 Hz, 2H), 1.77 (qn,
J=7.6 Hz, 2H).
Example 209
3-(2-{N'-[1-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol--
3-ylidene]hydrazino}-3-hydroxyphenoxy)propanoic acid (Compound
309)
[0903] ##STR239##
[0904] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) 13.0 (s, 1H), 12.4 (s, 1H), 10.1 (s,
1H), 7.84 (d, J=7.8 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.18 (s, 1H),
7.15 (s, 2H), 6.99 (dd, J=8.8, 8.8 Hz, 1H), 6.93 (s, 1H), 6.68 (d,
J=8.3 Hz, 1H), 6.30 (d, J=7.8 Hz, 1H), 4.28-4.26 (m, 2H), 2.77-2.75
(m, 2H), 2.37 (s, 6H).
Example 210
4-(4-{N'-[1-(3,4-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol--
3-ylidene]hydrazino}-3-hydroxyphenyl)butanoic acid (Compound
310)
[0905] ##STR240##
[0906] This compound was prepared as described in Scheme V. .sup.1H
NMR (500 MHz, CD.sub.3OD) 7.84 (d, J=7.8 Hz, 1H), 7.65 (d, J=8.4
Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.18 (s, 1H), 7.09 (s, 2H), 6.99
(s, 1H), 6.78 (d, J=7.8 Hz, 1H), 6.74 (s, 1H), 2.60-2.57 (m, 2H),
2.41 (s, 6H), 2.29-2.26 (m, 2H), 1.92-1.88 (m, 2H).
* * * * *