U.S. patent application number 15/077648 was filed with the patent office on 2017-02-16 for axl inhibitors for use in combination therapy for preventing, treating or managing metastatic cancer.
The applicant listed for this patent is Rigel Pharmaceuticals, Inc.. Invention is credited to Yasumichi Hitoshi, Sacha Holland, Donald G. Payan.
Application Number | 20170042891 15/077648 |
Document ID | / |
Family ID | 41683427 |
Filed Date | 2017-02-16 |
United States Patent
Application |
20170042891 |
Kind Code |
A1 |
Hitoshi; Yasumichi ; et
al. |
February 16, 2017 |
AXL INHIBITORS FOR USE IN COMBINATION THERAPY FOR PREVENTING,
TREATING OR MANAGING METASTATIC CANCER
Abstract
This invention is directed to methods of preventing, treating or
managing cancer, preferably metastatic cancer, in a patient. The
methods comprise administering an effective amount of an Axl
inhibitor in combination with the administration of an effective
amount of one or more chemotherapeutic agents.
Inventors: |
Hitoshi; Yasumichi;
(Brisbane, CA) ; Holland; Sacha; (San Francisco,
CA) ; Payan; Donald G.; (Hillsborough, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Rigel Pharmaceuticals, Inc. |
South San Francisco |
CA |
US |
|
|
Family ID: |
41683427 |
Appl. No.: |
15/077648 |
Filed: |
March 22, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13908874 |
Jun 3, 2013 |
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15077648 |
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12688746 |
Jan 15, 2010 |
8546433 |
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13908874 |
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61145448 |
Jan 16, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 33/24 20130101;
A61K 31/4196 20130101; A61K 31/502 20130101; A61K 31/502 20130101;
A61P 35/04 20180101; A61P 35/00 20180101; C07D 403/14 20130101;
C07D 403/04 20130101; A61P 43/00 20180101; A61K 33/24 20130101;
A61K 31/4196 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 45/06 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/502 20060101
A61K031/502; A61K 33/24 20060101 A61K033/24; A61K 45/06 20060101
A61K045/06 |
Claims
1. A method for treating or managing cancer in a patient in need
thereof, wherein the method comprises administering to the patient
a therapeutically effective amount of an Axl inhibitor and a
therapeutically effective amount of one or more chemotherapeutic
agents, wherein the Axl inhibitor is a compound of formula (I):
##STR00030## wherein: R.sup.1, R.sup.4 and R.sup.5 are each
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, aryl, aralkyl, --C(O)R.sup.8,
--C(O)N(R.sup.6)R.sup.7, and --C(.dbd.NR.sup.6)N(R.sup.6)R.sup.7;
R.sup.2 and R.sup.3 are each independently a polycyclic heteroaryl
containing more than 14 ring atoms optionally substituted by one or
more substituents selected from the group consisting of oxo,
thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted heteroaryl, optionally substituted
heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--CN, --R.sup.9--O--R.sup.10--C(O)OR,
--R.sup.9--O--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--S(O).sub.pR.sup.8 (where p is 0, 1 or 2),
--R.sup.9--O--R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--C(NR.sup.11)N(R.sup.11)H,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.8,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); or
R.sup.2 is a polycyclic heteroaryl containing more than 14 ring
atoms as described above and R.sup.3 is selected from the group
consisting of aryl and heteroaryl, where the aryl and the
heteroaryl are each independently optionally substituted by one or
more substitutents selected from the group consisting of alkyl,
alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); or
R.sup.3 is a polycyclic heteroaryl containing more than 14 ring
atoms as described above, and R.sup.2 is selected from the group
consisting of aryl and heteroaryl, where the aryl and the
heteroaryl are each independently optionally substituted by one or
more substitutents selected from the group consisting of alkyl,
alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); each
R.sup.6 and R.sup.7 is independently selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
aralkenyl, optionally substituted aralkynyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.10--OR.sup.8,
--R.sup.10--CN, --R.sup.10--NO.sub.2, --R.sup.10--N(R.sup.8).sub.2,
--R.sup.10--C(O)OR.sup.8 and --R.sup.10--C(O)N(R.sup.8).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; each R.sup.8 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, and optionally substituted heteroarylalkynyl;
each R.sup.9 is independently selected from the group consisting of
a direct bond, an optionally substituted straight or branched
alkylene chain, an optionally substituted straight or branched
alkenylene chain and an optionally substituted straight or branched
alkynylene chain; each R.sup.10 is independently selected from the
group consisting of an optionally substituted straight or branched
alkylene chain, an optionally substituted straight or branched
alkenylene chain and an optionally substituted straight or branched
alkynylene chain; each R.sup.11 is independently selected from the
group consisting of hydrogen, alkyl, cyano, nitro and --OR.sup.8;
each R.sup.12 is independently selected from the group consisting
of hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.10--OR.sup.8, --R.sup.10--CN,
--R.sup.10--NO.sub.2, --R.sup.10--N(R.sup.8).sub.2,
--R.sup.10--C(O)OR.sup.8 and --R.sup.10--C(O)N(R.sup.8).sub.2, or
two R.sup.12's, together with the common nitrogen to which they are
both attached, form an optionally substituted N-heterocyclyl or an
optionally substituted N-heteroaryl; each R.sup.13 is independently
selected from the group consisting of a direct bond, an optionally
substituted straight or branched alkylene chain and an optionally
substituted straight or branched alkenylene chain; and each
R.sup.14 is independently selected from the group consisting of an
optionally substituted straight or branched alkylene chain and an
optionally substituted straight or branched alkenylene chain; or a
stereoisomer, tautomer, pharmaceutically acceptable salt or N-oxide
thereof.
2. The method of claim 1 wherein the compound of formula (I) is
selected from the group consisting of:
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-tri-
azole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-
-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-
-triazole-3,5-diamine;
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazol-
e-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(7-(-
pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-tri-
azole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(7-(-
S)-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-t-
riazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole--
3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]ann-
ulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-
-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-
-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annu-
lene-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-tri-
azole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3-
,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7s-
)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-t-
riazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,-
4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2-
,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-
-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((5-chiorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((2-carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene--
2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,-
4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl-
)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-be-
nzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benz-
o[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1-
,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,-
2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,-
4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-pyrido[2,3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
5-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-pyrido[2,3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-tria-
zole-3,5-diamine;
1-(6,7-dihydro-5H-pyrido[2,3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-pyrido[2',3:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1-
,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-pyrido[2,3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-pyrido[2',3:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annul-
ene-2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-pyrido[2',3:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene--
2-yl)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine;
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-
-1H-1,2,4-triazole-3,5-diamine; and
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine.
3. The method of claim 1 wherein the one or more chemotherapeutic
agents is selected from the group consisting of antimetabolites,
alkylating agents, coordination compounds, platinum complexes, DNA
cross-linking compounds, inhibitors of transcription enzymes,
tyrosine kinase inhibitors, protein kinase inhibitors,
topoisomerase inhibitors, DNA minor-groove binding compounds, vinca
alkyloids, taxanes, antitumor antibiotics, hormones, aromatase
inhibitors, enzymes, growth factor receptors antibodies, cytokines,
cell surface markers antibodies, HDAC inhibitors, HSP 90
inhibitors, BCL-2 inhibitors, mTOR inhibitors, proteasome
inhibitors and monoclonal antibodies.
4. The method of claim 3 wherein the one or more chemotherapeutic
agents is selected from the group consisting of mechlorothamine,
cyclophosphamide, ifosfamide, melphalan, chlorambucil,
ethyleneimines, methylmelamines, procarbazine, dacarbazine,
temozolomide, busulfan, carmustine, lomustine, methotrexate,
fluorouracil, capecitabine, cytarabine, gemcitabine, cytosine
arabinoside, mecaptopurine, fludarabine, cladribine, thioguanine,
azathioprine, vinblastine, vincristine, paclitaxel, docetaxel,
colchicine, actinomycin D, daunorubicin, bleomycin, L-asparaginase,
cisplatin, carboplatin, oxaliplatin, prednisone, dexamethasone,
amino glutethimide, formestane, anastrozole, hydroxyprogesterone
caproate, medroxyprogesterone, tamoxifen, amsacrine, mitoxantrone,
topotecan, irinotecan, camptothecin, axtinib, bosutinib, cediranib,
dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib,
nilotinib, semaxanib, sunitinib, vandetanib, vatalanib, anti-Her2
antibodies, interferon-.alpha., interferon-.gamma., interleukin-2,
GM-CSF, anti-CTLA-4 antibodies, rituximab, anti-CD33 antibodies,
MGCD0103, vorinostat, 17-AAG, thalidomide, lenalidomide, rapamycin,
CCI-779, sorafenib, doxorubicine, gemcitabine, melphalan,
bortezomib, NPI052, gemtuzumab, alemtuzumab, ibritumomab tiuxaetan,
tositumomab, iodine-131 tositumomab, trastuzumab, bevacizumab,
rituximab, and anti-TRAIL death receptor antibodies.
5. The method of claim 1 wherein the Axl inhibitor and the one or
more chemotherapeutic agents are administered concurrently.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/908,874, filed Jun. 3, 2013 (now pending);
which is a divisional of U.S. patent application Ser. No.
12/688,746, filed Jan. 15, 2010 (now U.S. Pat. No. 8,546,433);
which claims the benefit under 35 U.S.C. .sctn.119(e) of U.S.
Provisional Patent Application No. 61/145,448, filed Jan. 16, 2009.
These applications are incorporated herein by reference in their
entireties.
FIELD OF THE INVENTION
[0002] This invention is directed to combination therapies for the
prevention, treatment, or management of metastatic cancer in a
patient having cancer or a patient having other proliferative
diseases or disorders.
BACKGROUND OF THE INVENTION
[0003] All of the protein kinases that have been identified to date
in the human genome share a highly conserved catalytic domain of
around 300 aa. This domain folds into a bi-lobed structure in which
resides ATP-binding and catalytic sites. The complexity of protein
kinase regulation allows many potential mechanisms of inhibition
including competition with activating ligands, modulation of
positive and negative regulators, interference with protein
dimerization, and allosteric or competitive inhibition at the
substrate or ATP binding sites.
[0004] Axl (also known as UFO, ARK, and Tyro7; nucleotide accession
numbers NM_021913 and NM_001699; protein accession numbers
NP_068713 and NP_001690) is a receptor protein tyrosine kinase
(RTK) that comprises a C-terminal extracellular ligand-binding
domain and N-terminal cytoplasmic region containing the catalytic
domain. The extracellular domain of Axl has a unique structure that
juxtaposes immunoglobulin and fibronectin Type III repeats and is
reminiscent of the structure of neural cell adhesion molecules. Axl
and its two close relatives, Mer/Nyk and Sky (Tyro3/Rse/Dtk),
collectively known as the Tyro3 family of RTK's, all bind and are
stimulated to varying degrees by the same ligand, Gas6 (growth
arrest specific-6), a .about.76 kDa secreted protein with
significant homology to the coagulation cascade regulator, Protein
S. In addition to binding to ligands, the Axl extracellular domain
has been shown to undergo homophilic interactions that mediate cell
aggregation, suggesting that one important function of Axl may be
to mediate cell-cell adhesion.
[0005] Axl is predominantly expressed in the vasculature in both
endothelial cells (EC's) and vascular smooth muscle cells (VSMC's)
and in cells of the myeloid lineage and is also detected in breast
epithelial cells, chondrocytes, Sertoli cells and neurons. Several
functions including protection from apoptosis induced by serum
starvation, TNF-.alpha. or the viral protein E1 A, as well as
migration and cell differentiation have been ascribed to Axl
signaling in cell culture. However, Axl-/- mice exhibit no overt
developmental phenotype and the physiological function of Axl in
vivo is not clearly established in the literature.
[0006] Angiogenesis (the formation of new blood vessels) is limited
to functions such as wound healing and the female reproductive
cycle in healthy adults. This physiological process has been
co-opted by tumors, thus securing an adequate blood supply that
feeds tumor growth and facilitates metastasis. Deregulated
angiogenesis also a feature of many other diseases (for example,
psoriasis, rheumatoid arthritis, endometriosis and blindness due to
age-related macular degeneration (AMD), retinopathy of prematurity
and diabetes) and often contributes to the progression or pathology
of the condition.
[0007] The overexpression of Axl and/or its ligand has also been
reported in a wide variety of solid tumor types including, but not
limited to, breast, renal, endometrial, ovarian, thyroid, non-small
cell lung carcinoma, and uveal melanoma as well as in myeloid
leukemia's. Furthermore, it possesses transforming activity in
NIH3T3 and 32D cells. It has been demonstrated that loss of Axl
expression in tumor cells blocks the growth of solid human
neoplasms in an in vivo MDA-MB-231 breast carcinoma xenograft
model. Taken together, these data suggest Axl signaling can
independently regulate EC angiogenesis and tumor growth and thus
represents a novel target class for tumor therapeutic
development.
[0008] The expression of Axl and Gas6 proteins is upregulated in a
variety of other disease states including endometriosis, vascular
injury and kidney disease and Axl signaling is functionally
implicated in the latter two indications. Axl-Gas6 signaling
amplifies platelet responses and is implicated in thrombus
formation. Axl may thus potentially represent a therapeutic target
for a number of diverse pathological conditions including solid
tumors, including, but not limited to, breast, renal, endometrial,
ovarian, thyroid, non-small cell lung carcinoma and uveal melanoma;
liquid tumors, including but not limited to, leukemias
(particularly myeloid leukemias) and lymphomas; endometriosis,
vascular disease/injury (including but not limited to restenosis,
atherosclerosis and thrombosis), psoriasis; visual impairment due
to macular degeneration; diabetic retinopathy and retinopathy of
prematurity; kidney disease (including but not limited to
glomerulonephritis, diabetic nephropathy and renal transplant
rejection), rheumatoid arthritis; osteoporosis, osteoarthritis and
cataracts.
[0009] U.S. Published Patent Application No. 20070213375, U.S.
Published Patent Application No. 20080153815, U.S. Published Patent
Application No. 20080188454, U.S. Published Patent Application No.
20080176847, U.S. Published Patent Application No. 20080188455,
U.S. Published Patent Application No. 20080182862, U.S. Published
Patent Application No. 20080188474, U.S. Published Patent
Application No. 20080117789, U.S. Published Patent Application No.
20090111816, PCT Published Patent Application No. WO 2007/0030680,
PCT Published Patent Application No. WO 2008/045978, PCT Published
Patent Application No. WO 2008/083353, PCT Published Patent
Application No. WO 2008/0083357, PCT Published Patent Application
No. WO 2008/083367, PCT Published Patent Application No. WO
2008/083354, PCT Published Patent Application No. WO 2008/083356,
PCT Published Patent Application No. WO 2008/080134, and PCT
Published Patent Application No. WO 2009/054864, the disclosures of
which are incorporated in full by reference herein in their
entireties, discloses compounds which are useful as Axl
inhibitors.
SUMMARY OF THE INVENTION
[0010] This invention is directed to combination therapies that
provide better therapeutic profiles than current single agent
therapies or other combination therapies utilizing Axl inhibitors.
Encompassed by the invention are combination therapies, of one or
more AXL inhibitors with one or more chemotherapeutic agents, that
have at least an additive potency or at least an additive
therapeutic effect. Preferably, the invention is directed to
combination therapies where the therapeutic efficacy is greater
than additive, e.g., a synergy exists between an AXL inhibitor and
one or more chemotherapeutic agents when co-administered.
Preferably, such combination therapies also reduce or avoid
unwanted or adverse effects. In certain embodiments, the
combination therapies of the invention provide an improved overall
therapy relative to the administration of the therapeutic agents by
themselves. In certain embodiments, doses of existing
chemotherapeutic agents can be reduced or administered less
frequently in using the combination therapies of the invention,
thereby increasing patient compliance, improving therapy and
reducing unwanted or adverse effects.
[0011] Accordingly, this invention is directed to combination
therapies designed to prevent, treat or manage cancer, preferably
metastatic cancer, in a patient, wherein the combination therapies
comprise administering an Axl inhibitor to the patient in need
thereof in combination with one or more chemotherapeutic agents. In
particular, this invention provides methods of preventing, treating
or managing cancer, preferably metastatic cancer, in a patient
comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents.
[0012] In one embodiment, the Axl inhibitor utilized in the
combination therapies of the invention is a compound of formula
(I):
##STR00001##
wherein: [0013] R.sup.1, R.sup.4 and R.sup.5 are each independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
aryl, aralkyl, --C(O)R.sup.8, --C(O)N(R.sup.6)R.sup.7, and
--C(.dbd.NR.sup.6)N(R.sup.6)R.sup.7; [0014] R.sup.2 and R.sup.3 are
each independently a polycyclic heteroaryl containing more than 14
ring atoms optionally substituted by one or more substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heteroaryl, optionally substituted heterocyclyl,
--R.sup.9--OR.sup.8, --R.sup.9--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--CN, --R.sup.9--O--R.sup.10--C(O)OR.sup.8,
--R.sup.9--O--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--S(O).sub.pR.sup.8 (where p is 0, 1 or 2),
--R.sup.9--O--R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--C(NR.sup.11)N(R.sup.11)H,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.8,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0015]
or R.sup.2 is a polycyclic heteroaryl containing more than 14 ring
atoms as described above and R.sup.3 is selected from the group
consisting of aryl and heteroaryl, where the aryl and the
heteroaryl are each independently optionally substituted by one or
more substitutents selected from the group consisting of alkyl,
alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); [0016]
or R.sup.3 is a polycyclic heteroaryl containing more than 14 ring
atoms as described above, and R.sup.2 is selected from the group
consisting of aryl and heteroaryl, where the aryl and the
heteroaryl are each independently optionally substituted by one or
more substitutents selected from the group consisting of alkyl,
alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sup.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); [0017]
each R.sup.6 and R.sup.7 is independently selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
aralkenyl, optionally substituted aralkynyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.10--OR.sup.8,
--R.sup.10--CN, --R.sup.10--NO.sub.2, --R.sup.10--N(R.sup.8).sub.2,
--R.sup.10--C(O)OR.sup.8 and --R.sup.10--C(O)N(R.sup.8).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0018] each R.sup.8 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, and optionally substituted heteroarylalkynyl;
[0019] each R.sup.9 is independently selected from the group
consisting of a direct bond, an optionally substituted straight or
branched alkylene chain, an optionally substituted straight or
branched alkenylene chain and an optionally substituted straight or
branched alkynylene chain; [0020] each R.sup.10 is independently
selected from the group consisting of an optionally substituted
straight or branched alkylene chain, an optionally substituted
straight or branched alkenylene chain and an optionally substituted
straight or branched alkynylene chain; [0021] each R.sup.11 is
independently selected from the group consisting of hydrogen,
alkyl, cyano, nitro and --OR.sup.8; [0022] each R.sup.12 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.10--OR.sup.8, --R.sup.10--CN, --R.sup.10--NO.sub.2,
--R.sup.10--N(R.sup.8).sub.2, --R.sup.10--C(O)OR.sup.8 and
--R.sup.10--C(O)N(R.sup.8).sub.2, or two R.sup.12's, together with
the common nitrogen to which they are both attached, form an
optionally substituted N-heterocyclyl or an optionally substituted
N-heteroaryl; [0023] each R.sup.13 is independently selected from
the group consisting of a direct bond, an optionally substituted
straight or branched alkylene chain and an optionally substituted
straight or branched alkenylene chain; and [0024] each R.sup.14 is
independently selected from the group consisting of an optionally
substituted straight or branched alkylene chain and an optionally
substituted straight or branched alkenylene chain; [0025] as an
isolated stereoisomer or mixture thereof or as a tautomer or
mixture thereof, or a pharmaceutically acceptable salt or N-oxide
thereof.
[0026] In another aspect, this invention provides in vivo assays to
determine the effectiveness of a compound of formula (I) in
combination with one or more chemotherapeutic agents in preventing,
treating or managing cancer, preferably metastatic cancer, in a
patient.
[0027] These and other aspects of the invention will be evident
upon reference to the following detailed description. To that end,
certain patent and other documents are cited herein to more
specifically set forth various aspects of this invention. Each of
these documents is hereby incorporated by reference in its
entirety.
BRIEF DESCRIPTION OF THE FIGURES
[0028] FIG. 1 shows the effect of an Axl inhibitor (i.e., Compound
A) on the number of macroscopic lung metastases in the mouse 4T1
breast tumor model of metastatic cancer.
[0029] FIG. 2 shows the effect of an Axl inhibitor (i.e., Compound
A) on the number of medium (.ltoreq.2 mm) macroscopic lung
metastases in the mouse 4T1 breast tumor model of metastatic
cancer.
[0030] FIG. 3 shows the effect of an Axl inhibitor (i.e., Compound
A) on the number of large (>3 mm) macroscopic lung metastases in
the mouse 4T1 breast tumor model of metastatic cancer.
[0031] FIG. 4 shows the effect of an Axl inhibitor (i.e., Compound
A) on the number of microscopic liver metastases in the mouse 4T1
breast tumor model of metastatic cancer.
[0032] FIG. 5 shows the effect of an Axl inhibitor (i.e., Compound
A) in combination with a chemotherapeutic agent (i.e., cisplatin)
on the volume of the primary tumor in the mouse 4T1 breast tumor
model of metastatic cancer.
[0033] FIG. 6 shows the effect of an Axl inhibitor (i.e., Compound
A) in combination with a chemotherapeutic agent (i.e., cisplatin)
on the number of micrometastasis in the liver in the mouse 4T1
breast tumor model of metastatic cancer.
[0034] FIG. 7 shows the effect of an Axl inhibitor (i.e., Compound
A) in combination with a chemotherapeutic agent (i.e., cisplatin)
on the number of large (>3 mm) metastases in the lung in the
mouse 4T1 breast tumor model of metastatic cancer.
[0035] FIG. 8 shows the percentage of mice bearing large (>3 mm)
metastases after treatment with an Axl inhibitor (i.e., Compound A)
in combination with a chemotherapeutic agent (i.e., cisplatin) in
the mouse 4T1 breast tumor model of metastatic cancer.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0036] As used in the specification and appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0037] "Amino" refers to the --NH.sub.2 radical.
[0038] "Carboxy" refers to the --C(O)OH radical.
[0039] "Cyano" refers to the --CN radical.
[0040] "Nitro" refers to the --NO.sub.2 radical.
[0041] "Oxa" refers to the --O-- radical.
[0042] "Oxo" refers to the .dbd.O radical.
[0043] "Thioxo" refers to the .dbd.S radical.
[0044] "Alkyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
no unsaturation, having from one to twelve carbon atoms, preferably
one to eight carbon atoms or one to six carbon atoms and which is
attached to the rest of the molecule by a single bond, for example,
methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl,
n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,
2-methylhexyl, and the like. For purposes of this invention, the
term "lower alkyl" refers to an alkyl radical having one to six
carbon atoms.
[0045] "Optionally substituted alkyl" refers to an alkyl radical,
as defined above, which is optionally substituted by one or more
substituents selected from the group consisting of halo, cyano,
nitro, oxo, thioxo, trimethylsilanyl, --OR.sup.20,
--OC(O)--R.sup.20, --N(R.sup.20).sub.2, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)N(R.sup.20).sub.2,
--N(R.sup.20)C(O)OR.sup.20, --N(R.sup.20)C(O)R.sup.20,
--N(R.sup.20)S(O).sub.2R.sup.20, --S(O).sub.tOR.sup.20 (where t is
1 or 2), --S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--S(O).sub.2N(R.sup.20).sub.2 where each R.sup.20 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl and optionally substituted heteroarylalkyl, or two
R.sup.20's, together with the common nitrogen to which they are
both attached, form an optionally substituted N-heterocyclyl or an
optionally substituted N-heteroaryl.
[0046] "Alkenyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
at least one double bond, having from two to twelve carbon atoms,
preferably one to eight carbon atoms and which is attached to the
rest of the molecule by a single bond, for example, ethenyl,
prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the
like.
[0047] "Optionally substituted alkenyl" refers to an alkenyl
radical, as defined above, which is optionally substituted by one
or more substituents selected from the group consisting of halo,
cyano, nitro, oxo, thioxo, trimethylsilanyl, --OR.sup.20,
--OC(O)--R.sup.20, --N(R.sup.20).sub.2, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)N(R.sup.20).sub.2,
--N(R.sup.20)C(O)OR.sup.20, --N(R.sup.20)C(O)R.sup.20,
--N(R.sup.20)S(O).sub.2R.sup.20, --S(O).sub.tOR.sup.20 (where t is
1 or 2), --S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--S(O).sub.2N(R.sup.20).sub.2 where each R.sup.20 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl and optionally substituted heteroarylalkyl, or two
R.sup.20's, together with the common nitrogen to which they are
both attached, form an optionally substituted N-heterocyclyl or an
optionally substituted N-heteroaryl.
[0048] "Alkynyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
at least one triple bond, optionally containing at least one double
bond, having from two to twelve carbon atoms, preferably one to
eight carbon atoms and which is attached to the rest of the
molecule by a single bond, for example, ethynyl, propynyl, butynyl,
pentynyl, hexynyl, and the like.
[0049] "Optionally substituted alkynyl" refers to an alkynyl
radical, as defined above, which is optionally substituted by one
or more substituents selected from the group consisting of halo,
cyano, nitro, oxo, thioxo, trimethylsilanyl, --OR.sup.20,
--OC(O)--R.sup.20, --N(R.sup.20).sub.2, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)N(R.sup.20).sub.2,
--N(R.sup.20)C(O)OR.sup.20, --N(R.sup.20)C(O)R.sup.20,
--N(R.sup.20)S(O).sub.2R.sup.20, --S(O).sub.tOR.sup.20 (where t is
1 or 2), --S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--S(O).sub.2N(R.sup.20).sub.2 where each R.sup.20 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl and optionally substituted heteroarylalkyl, or two
R.sup.20's, together with the common nitrogen to which they are
both attached, form an optionally substituted N-heterocyclyl or an
optionally substituted N-heteroaryl.
[0050] "Straight or branched alkylene chain" refers to a straight
or branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing no unsaturation and having from one to twelve
carbon atoms, for example, methylene, ethylene, propylene,
n-butylene, and the like. The alkylene chain is attached to the
rest of the molecule through a single bond and to the radical group
through a single bond. The points of attachment of the alkylene
chain to the rest of the molecule and to the radical group can be
through one carbon in the alkylene chain or through any two carbons
within the chain.
[0051] "Optionally substituted straight or branched alkylene chain"
refers to an alkylene chain, as defined above, which is optionally
substituted by one or more substituents selected from the group
consisting of halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl,
heteroaryl, oxo, thioxo, trimethylsilanyl, --OR.sup.20,
--OC(O)--R.sup.20, --N(R.sup.20).sub.2, --C(O)R.sup.20,
--C(O)OR.sup.20, --C(O)N(R.sup.20).sub.2,
--N(R.sup.20)C(O)OR.sup.20, --N(R.sup.20)C(O)R.sup.20,
--N(R.sup.20)S(O).sub.2R.sup.20, --S(O).sub.tOR.sup.20 (where t is
1 or 2), --S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--S(O).sub.2N(R.sup.20).sub.2 where each R.sup.20 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl and optionally substituted heteroarylalkyl, or two
R.sup.20's, together with the common nitrogen to which they are
both attached, form an optionally substituted N-heterocyclyl or an
optionally substituted N-heteroaryl.
[0052] "Straight or branched alkenylene chain" refers to a straight
or branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing at least one double bond and having from two
to twelve carbon atoms, for example, ethenylene, propenylene,
n-butenylene, and the like. The alkenylene chain is attached to the
rest of the molecule through a double bond or a single bond and to
the radical group through a double bond or a single bond. The
points of attachment of the alkenylene chain to the rest of the
molecule and to the radical group can be through one carbon or any
two carbons within the chain.
[0053] "Optionally substituted straight or branched alkenylene
chain" refers to an alkenylene chain, as defined above, which is
optionally substituted by one or more substituents selected from
the group consisting of halo, cyano, nitro, aryl, cycloalkyl,
heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl,
--OR.sup.20, --OC(O)--R.sup.20, --N(R.sup.20).sub.2,
--C(O)R.sup.20, --C(O)OR.sup.20, --C(O)N(R.sup.20).sub.2,
--N(R.sup.20)C(O)OR.sup.20, --N(R.sup.20)C(O)R.sup.20,
--N(R.sup.20)S(O).sub.2R.sup.20, --S(O).sub.tOR.sup.20 (where t is
1 or 2), --S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--S(O).sub.2N(R.sup.20).sub.2 where each R.sup.20 is independently
selected from the group consisting of hydrogen, alkyl, haloalkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl and optionally substituted heteroarylalkyl, or two
R.sup.20's, together with the common nitrogen to which they are
both attached, form an optionally substituted N-heterocyclyl or an
optionally substituted N-heteroaryl.
[0054] "Straight or branched alkynylene chain" refers to a straight
or branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing at least one triple bond and having from two
to twelve carbon atoms, for example, propynylene, n-butynylene, and
the like. The alkynylene chain is attached to the rest of the
molecule through a single bond and to the radical group through a
double bond or a single bond. The points of attachment of the
alkynylene chain to the rest of the molecule and to the radical
group can be through one carbon or any two carbons within the
chain.
[0055] "Optionally substituted straight or branched alkynylene
chain" refers to an alkynylene chain, as defined above, which is
optionally substituted by one or more substituents selected from
the group consisting of alkyl, alkenyl, halo, haloalkenyl, cyano,
nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo,
trimethylsilanyl, --OR.sup.20, --OC(O)--R.sup.20,
--N(R.sup.20).sub.2, --C(O)R.sup.20, --C(O)OR.sup.20,
--C(O)N(R.sup.20).sub.2, --N(R.sup.20)C(O)OR.sup.20,
--N(R.sup.20)C(O)R.sup.20, --N(R.sup.20)S(O).sub.2R.sup.20,
--S(O).sub.tOR.sup.20 (where t is 1 or 2), --S(O).sub.pR.sup.20
(where p is 0, 1 or 2), and --S(O).sub.2N(R.sup.20).sub.2 where
each R.sup.20 is independently selected from the group consisting
of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.20's, together with the common nitrogen to which they
are both attached, form an optionally substituted N-heterocyclyl or
an optionally substituted N-heteroaryl.
[0056] "Aryl" refers to a hydrocarbon ring system radical
comprising hydrogen, 6 to 14 carbon atoms and at least one aromatic
ring. For purposes of this invention, the aryl radical may be a
monocyclic, bicyclic, or tricyclic system and which may include
spiro ring systems. An aryl radical is commonly, but not
necessarily, attached to the parent molecule via an aromatic ring
of the aryl radical. For purposes of this invention, an "aryl"
radical as defined herein can not contain rings having more than 7
members and cannot contain rings wherein two non-adjacent ring
atoms thereof are connected through an atom or a group of atoms
(i.e., a bridged ring system). Aryl radicals include, but are not
limited to, aryl radicals derived from acenaphthylene, anthracene,
azulene, benzene, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, fluorene,
as-indacene, s-indacene, indane, indene, naphthalene, phenalene,
and phenanthrene.
[0057] "Optionally substituted aryl" refers to an aryl radical, as
defined above, which is optionally substituted by one or more
substituents selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, optionally substituted heteroarylalkynyl,
--R.sup.21--OR.sup.20, --R.sup.21--OC(O)--R.sup.20,
--R.sup.21--N(R.sup.20).sub.2, --R.sup.21--C(O)R.sup.20,
--R.sup.21--C(O)OR.sup.20, --R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--O--R.sup.22--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.20,
--R.sup.21--N(R.sup.20)C(O)R.sup.20,
--R.sup.21--N(R.sup.20)S(O).sub.2R.sup.20,
--R.sup.21--C(.dbd.NR.sup.20)N(R.sup.20).sub.2,
--R.sup.21--S(O).sub.tOR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--R.sup.21--S(O).sub.2N(R.sup.20).sub.2, where each R.sup.20 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.20's, together with the common nitrogen to which they
are both attached, form an optionally substituted N-heterocyclyl or
an optionally substituted N-heteroaryl, each R.sup.21 is
independently a direct bond or a straight or branched alkylene or
alkenylene chain, and R.sup.22 is a straight or branched alkylene
or alkenylene chain.
[0058] "Aralkyl" refers to a radical of the formula
--R.sub.b--R.sub.c where R.sub.b is an alkylene chain as defined
above and R.sub.c is one or more aryl radicals as defined above,
for example, benzyl, diphenylmethyl and the like.
[0059] "Optionally substituted aralkyl" refers to an aralkyl
radical, as defined above, wherein the alkylene chain of the
aralkyl radical is an optionally substituted alkylene chain, as
defined above, and each aryl radical of the aralkyl radical is an
optionally substituted aryl radical, as defined above.
[0060] "Aralkenyl" refers to a radical of the formula
--R.sub.d--R.sub.c where R.sub.d is an alkenylene chain as defined
above and R.sub.c is one or more aryl radicals as defined
above.
[0061] "Optionally substituted aralkenyl" refers to an aralkenyl
radical, as defined above, wherein the alkenylene chain of the
aralkenyl radical is an optionally substituted alkenylene chain, as
defined above, and each aryl radical of the aralkenyl radical is an
optionally substituted aryl radical, as defined above.
[0062] "Aralkynyl" refers to a radical of the formula
--R.sub.eR.sub.c where R.sub.e is an alkynylene chain as defined
above and R.sub.c is one or more aryl radicals as defined
above.
[0063] "Optionally substituted aralkynyl" refers to an aralkynyl
radical, as defined above, wherein the alkynylene chain of the
aralkynyl radical is an optionally substituted alkynylene chain, as
defined above, and each aryl radical of the aralkynyl radical is an
optionally substituted aryl radical, as defined above.
[0064] "Cycloalkyl" refers to a stable non-aromatic monocyclic or
polycyclic hydrocarbon radical consisting solely of carbon and
hydrogen atoms, which includes fused, spiro or bridged ring
systems, having from three to fifteen carbon atoms, preferably
having from three to ten carbon atoms, more preferably from five to
seven carbons and which is saturated or unsaturated and attached to
the rest of the molecule by a single bond. For purposes of this
invention, a bridged ring system is a system wherein two
non-adjacent ring atoms thereof are connected through an atom or a
group of atoms, wherein the atom or the group of atoms are the
bridging element. An example of a bridged cycloalkyl (monovalent)
radical is norbomanyl (also called bicyclo[2.2.1]heptanyl). For
purposes of this invention, a non-bridged ring system is a system
which does not contain a bridging element, as described above. For
purposes of this invention, a fused ring system is a system wherein
two adjacent ring atoms thereof are connected through an atom or a
group of atoms. An example of a fused cycloalkyl (monovalent)
radical is decahydronaphthalenyl (also called decalinyl). For
purposes of this invention, a spiro ring system is a system wherein
two rings are joined via a single carbon (quaternary) atom. An
example of a spiro cycloalkyl (monovalent) radical is
spiro[5.5]undecanyl. Monocyclic cycloalkyl radicals do not include
spiro, fused or bridged cycloalkyl radicals, but do include for
example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl. Polycyclic radicals include fused,
spiro or bridged cycloalkyl radicals, for example, C.sub.10
radicals such as adamantanyl (bridged) and decalinyl (fused), and
C.sub.7 radicals such as bicyclo[3.2.0]heptanyl (fused), norbomanyl
and norbornenyl (bridged), as well as substituted polycyclic
radicals, for example, substituted C.sub.7 radicals such as
7,7-dimethylbicyclo[2.2.1]heptanyl (bridged), and the like.
[0065] "Optionally substituted cycloalkyl" refers to a cycloalkyl
radical, as defined above, which is optionally substituted by one
or more substituents selected from the group consisting of alkyl,
alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, optionally substituted heteroarylalkynyl,
--R.sup.21--OR.sup.20, --R.sup.21--OC(O)--R.sup.20,
--R.sup.21--N(R.sup.20).sub.2, --R.sup.21--C(O)R.sup.20,
--R.sup.21--C(O)OR.sup.20, --R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.20,
--R.sup.21--N(R.sup.20)C(O)R.sup.20,
--R.sup.21--N(R.sup.20)S(O).sub.2R.sup.20,
--R.sup.21--C(.dbd.NR.sup.20)N(R.sup.20).sub.2,
--R.sup.21--S(O).sub.tOR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--R.sup.21--S(O).sub.2N(R.sup.20).sub.2, where each R.sup.20 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.20's, together with the common nitrogen to which they
are both attached, form an optionally substituted N-heterocyclyl or
an optionally substituted N-heteroaryl, and each R.sup.21 is
independently a direct bond or a straight or branched alkylene or
alkenylene chain.
[0066] "Cycloalkylalkyl" refers to a radical of the formula
--R.sub.bR.sub.g where R.sub.b is an alkylene chain as defined
above and R.sub.g is a cycloalkyl radical as defined above.
[0067] "Optionally substituted cycloalkylalkyl" refers to a
cycloalkylalkyl radical, as defined above, wherein the alkylene
chain of the cycloalkylalkyl radical is an optionally substituted
alkylene chain, as defined above, and the cycloalkyl radical of the
cycloalkylalkyl radical is an optionally substituted cycloalkyl
radical, as defined above.
[0068] "Cycloalkylalkenyl" refers to a radical of the formula
--R.sub.dR.sub.g where R.sub.d is an alkenylene chain as defined
above and R.sub.g is a cycloalkyl radical as defined above.
[0069] "Optionally substituted cycloalkylalkenyl" refers to a
cycloalkylalkenyl radical, as defined above, wherein the alkenylene
chain of the cycloalkylalkenyl radical is an optionally substituted
alkenylene chain, as defined above, and the cycloalkyl radical of
the cycloalkylalkenyl radical is an optionally substituted
cycloalkyl radical as defined above.
[0070] "Cycloalkylalkynyl" refers to a radical of the formula
--R.sub.eR.sub.g where R.sub.e is an alkynylene radical as defined
above and R.sub.g is a cycloalkyl radical as defined above.
[0071] "Optionally substituted cycloalkylalkynyl" refers to a
cycloalkylalkynyl radical, as defined above, wherein the alkynylene
chain of the cycloalkylalkynyl radical is an optionally substituted
alkynylene chain, as defined above, and the cycloalkyl radical of
the cycloalkylalkynyl radical is an optionally substituted
cycloalkyl radical as defined above.
[0072] "Halo" refers to bromo, chloro, fluoro or iodo.
[0073] "Haloalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more halo radicals, as defined above,
for example, trifluoromethyl, difluoromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl,
3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the
like.
[0074] "Haloalkenyl" refers to an alkenyl radical, as defined
above, that is substituted by one or more halo radicals, as defined
above.
[0075] "Haloalkynyl" refers to an alkynyl radical, as defined
above, that is substituted by one or more halo radicals, as defined
above.
[0076] "Heterocyclyl" refers to a stable 3- to 18-membered
non-aromatic ring system radical which comprises one to twelve
carbon atoms and from one to six heteroatoms selected from the
group consisting of nitrogen, oxygen and sulfur. Unless stated
otherwise specifically in the specification, the heterocyclyl
radical may be a monocyclic, bicyclic, tricyclic or tetracyclic
ring system, which may include spiro or bridged ring systems; and
the nitrogen, carbon or sulfur atoms in the heterocyclyl radical
may be optionally oxidized; the nitrogen atom may be optionally
quaternized; and the heterocyclyl radical may be partially or fully
saturated. Examples of a bridged heterocyclyl include, but are not
limited to, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl,
diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl,
diazabicyclo[3.3.1]nonanyl, diazabicyclo[3.2.2]nonanyl and
oxazabicyclo[2.2.1]heptanyl. A "bridged N-heterocyclyl" is a
bridged heterocyclyl containing at least one nitrogen, but which
optionally contains up to four additional heteroatoms selected from
O, N and S. For purposes of this invention, a non-bridged ring
system is a system wherein no two non-adjacent ring atoms thereof
are connected through an atom or a group of atoms. Examples of
heterocyclyl radicals include, but are not limited to, dioxolanyl,
1,4-diazepanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl,
isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,
octahydroisoindolyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl,
octahydro-1H-pyrrolo[2,3-c]pyridinyl,
octahydro-1H-pyrrolo[2,3-b]pyridinyl,
octahydro-1H-pyrrolo[3,4-b]pyridinyl,
octahydropyrrolo[3,4-c]pyrrolyl,
octahydro-1H-pyrido[1,2-a]pyrazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,
3,7-diazabicyclo[3.3.1]nonan-3-yl, piperidinyl, piperazinyl,
4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,
thiazolidinyl, tetrahydrofuranyl, thienyl[1,3]dithianyl,
trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,
1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, azetidinyl,
octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl,
decahydroprazino[1,2-a]azepinyl, azepanyl, azabicyclo[3.2.1]octyl,
and 2,7-diazaspiro[4.4]nonanyl.
[0077] "Optionally substituted heterocyclyl" refers to a
heterocyclyl radical, as defined above, which is optionally
substituted by one or more substituents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.21--OR.sup.20,
--R.sup.21--OC(O)--R.sup.20, --R.sup.21--N(R.sup.20).sub.2,
--R.sup.21--C(O)R.sup.20, --R.sup.21--C(O)OR.sup.20,
--R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.20,
--R.sup.21--N(R.sup.20)C(O)R.sup.20,
--R.sup.21--N(R.sup.20)S(O).sub.2R.sup.20,
--R.sup.21--C(.dbd.NR.sup.20)N(R.sup.20).sub.2,
--R.sup.21--S(O).sub.tOR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--R.sup.21--S(O).sub.2N(R.sup.20).sub.2, where each R.sup.20 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.20's, together with the common nitrogen to which they
are both attached, form an optionally substituted N-heterocyclyl or
an optionally substituted N-heteroaryl, and each R.sup.21 is
independently a direct bond or a straight or branched alkylene or
alkenylene chain.
[0078] "N-heterocyclyl" refers to a heterocyclyl radical as defined
above containing at least one nitrogen and where the point of
attachment of the N-heterocyclyl radical to the rest of the
molecule may be through a nitrogen atom in the N-heterocyclyl
radical or through a carbon in the N-heterocyclyl radical.
[0079] "Optionally substituted N-heterocyclyl" refers to an
N-heterocyclyl, as defined above, which is optionally substituted
by one or more substituents as defined above for optionally
substituted heterocyclyl.
[0080] "Heterocyclylalkyl" refers to a radical of the formula
--R.sub.bR.sub.h where R.sub.b is an alkylene chain as defined
above and R.sub.h is a heterocyclyl radical as defined above, and
when the heterocyclyl is a nitrogen-containing heterocyclyl, the
heterocyclyl may be attached to the alkylene chain at the nitrogen
atom.
[0081] "Optionally substituted heterocyclylalkyl" refers to a
heterocyclylalkyl radical, as defined above, wherein the alkylene
chain of the heterocyclylalkyl radical is an optionally substituted
alkylene chain, as defined above, and the heterocyclyl radical of
the heterocyclylalkyl radical is an optionally substituted
heterocyclyl radical, as defined above.
[0082] "Heterocyclylalkenyl" refers to a radical of the formula
--R.sub.dR.sub.h where R.sub.d is an alkenylene chain as defined
above and R.sub.h is a heterocyclyl radical as defined above, and
when the heterocyclyl is a nitrogen-containing heterocyclyl, the
heterocyclyl may be attached to the alkenylene chain at the
nitrogen atom.
[0083] "Optionally substituted heterocyclylalkenyl" refers to a
heterocyclylalkenyl radical, as defined above, wherein the
alkenylene chain of the heterocyclylalkenyl radical is an
optionally substituted alkenylene chain, as defined above, and the
heterocyclyl radical of the heterocyclylalkenyl radical is an
optionally substituted heterocyclyl radical, as defined above.
[0084] "Heterocyclylalkynyl" refers to a radical of the formula
--R.sub.eR.sub.h where R.sub.e is an alkynylene chain as defined
above and R.sub.h is a heterocyclyl radical as defined above, and
when the heterocyclyl is a nitrogen-containing heterocyclyl, the
heterocyclyl may be attached to the alkynylene chain at the
nitrogen atom.
[0085] "Optionally substituted heterocyclylalkynyl" refers to a
heterocyclylalkynyl radical, as defined above, wherein the
alkynylene chain of the heterocyclylalkynyl radical is an
optionally substituted alkynylene chain, as defined above, and the
heterocyclyl radical of the heterocyclylalkynyl radical is an
optionally substituted heterocyclyl radical, as defined above.
[0086] "Heteroaryl" refers to a 5- to 14-membered ring system
radical comprising hydrogen atoms, one to thirteen carbon atoms,
one to six heteroatoms selected from the group consisting of
nitrogen, oxygen and sulfur, and at least one aromatic ring. A
heteroaryl radical is commonly, but not necessarily, attached to
the parent molecule via an aromatic ring of the heteroaryl radical.
For purposes of this invention, the heteroaryl radical may be a
monocyclic, bicyclic or tricyclic ring system, which may include
spiro or bridged ring systems; and the nitrogen, carbon or sulfur
atoms in the heteroaryl radical may be optionally oxidized and the
nitrogen atom may be optionally quaternized. For purposes of this
invention, the aromatic ring of the heteroaryl radical need not
contain a heteroatom, as long as one ring of the heteroaryl radical
contains a heteroatom. For example benzo-fused heterocyclyls such
as 1,2,3,4-tetrahydroisoquinolin-7-yl are considered a "heteroaryl"
for the purposes of this invention. Except for the polycyclic
heteroaryls containing more than 14 ring atoms, as defined below, a
"heteroaryl" radical as defined herein can not contain rings having
more than 7 members and cannot contain rings wherein two
non-adjacent members thereof are connected through an atom or a
group of atoms (i.e., a bridged ring system). Examples of
heteroaryl radicals include, but are not limited to, azepinyl,
acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,
benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,
benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, benzo[b]azepinyl,
1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,
benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl,
benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl),
benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,
benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,
cyclopenta[d]pyrimidinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,
cyclopenta[4,5]thieno[2,3-d]pyrimidinyl such as
6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5,6-dihydrobenzo[h]quinazolinyl,
3,4-dihydro-2H-benzo[b][1,4]thiazinyl,
5,6-dihydrobenzo[h]cinnolinyl,
7',8'-dihydro-5'H-spiro[[1,3]dioxolane-2,6'-quinoline]-3'-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,
2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl,
3',4'-dihydrospiro[cyclobutane-1,2'-pyrido[3,2-b][1,4]oxazinyl,
dihydropyridooxazinyl such as
3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, dihydropyridothiazinyl
such as 3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, dibenzofuranyl,
dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,
furopyrimidinyl, furopyridazinyl, furopyrazinyl, isothiazolyl,
imidazolyl, imidazopyrimidinyl, imidazopyridazinyl,
imidazopyrazinyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl,
indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl
(isoquinolyl), indolizinyl, isoxazolyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,
3'-oxo-3',4'-dihydrospiro[cyclobutane-1,2'-pyrido[3,2-b][1,4]oxazine]yl,
7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridinyl, 1-phenyl-1H-pyrrolyl,
phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl,
phenanthridinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,
pyrazolo[3,4-d]pyrimidinyl, pyridinyl (pyridyl),
pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,
pyrimidinyl, pyridazinyl (pyridazyl), pyrrolyl, pyrrolopyrimidinyl,
pyrrolopyridazinyl, pyrrolopyrazinyl,
2H-pyrido[3,2-b][1,4]oxazinonyl, 1H-pyrido[2,3-b][1,4]oxazinonyl,
pyrrolopyridinyl such as 1H-pyrrolo[2,3-b]pyridinyl, quinazolinyl,
quinoxalinyl, quinolinyl, quinuclidinyl, tetrahydroquinolinyl,
5,6,7,8-tetrahydroquinazolinyl, 2,3,4,5-tetrahydrobenzo[b]oxepinyl,
6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridinyl,
6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepinyl,
5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl,
thiadiazolyl, triazolyl, tetrazolyl,
1,2,3,4-tetrahydroisoquinolin-7-yl, triazinyl,
thieno[2,3-d]pyrimidinyl, thienopyrimidinyl (e.g.,
thieno[3,2-d]pyrimidinyl), thieno[2,3-c]pyridinyl,
thienopyridazinyl, thienopyrazinyl, and thiophenyl (thienyl).
[0087] "Optionally substituted heteroaryl" refers to a heteroaryl
radical, as defined above, which is optionally substituted by one
or more substituents selected from the group consisting of alkyl,
alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.21--OR.sup.20,
--R.sup.21--OC(O)--R.sup.20, --R.sup.21--N(R.sup.20).sub.2,
--R.sup.21--C(O)R.sup.20, --R.sup.21--C(O)OR.sup.20,
--R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.20,
--R.sup.21--N(R.sup.20)C(O)R.sup.20,
--R.sup.21--N(R.sup.20)S(O).sub.2R.sup.202,
--R.sup.21--C(.dbd.NR.sup.20)N(R.sup.20).sub.2,
--R.sup.21--S(o).sub.tOR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--R.sup.21--S(O).sub.2N(R.sup.20).sub.2, where each R.sup.20 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.20's, together with the common nitrogen to which they
are both attached, form an optionally substituted N-heterocyclyl or
an optionally substituted N-heteroaryl, and each R.sup.21 is
independently a direct bond or a straight or branched alkylene or
alkenylene chain.
[0088] "N-heteroaryl" refers to a heteroaryl radical as defined
above containing at least one nitrogen and where the point of
attachment of the N-heteroaryl radical to the rest of the molecule
may be through a nitrogen atom in the N-heteroaryl radical or
through a carbon atom in the N-heteroaryl radical.
[0089] "Optionally substituted N-heteroaryl" refers to an
N-heteroaryl, as defined above, which is optionally substituted by
one or more substituents as defined above for optionally
substituted heteroaryl.
[0090] "Polycyclic heteroaryl containing more than 14 ring atoms"
refers to a 15- to 20-membered ring system radical comprising
hydrogen atoms, one to fourteen carbon atoms, one to eight
heteroatoms selected from the group consisting of nitrogen, oxygen
and sulfur, and at least one aromatic ring. A "polycyclic
heteroaryl containing more than 14 ring atoms" radical is commonly,
but not necessarily, attached to the parent molecule via an
aromatic ring of the "polycyclic heteroaryl containing more than 14
ring atoms" radical. For purposes of this invention, the
"polycyclic heteroaryl containing more than 14 ring atoms" radical
may be a bicyclic, tricyclic or tetracyclic ring system, which may
include fused or spiro ring systems; and the nitrogen, carbon or
sulfur atoms in the "polycyclic heteroaryl containing more than 14
ring atoms" radical may be optionally oxidized and the nitrogen
atom may also be optionally quaternized. For purposes of this
invention, the aromatic ring of the "polycyclic heteroaryl
containing more than 14 ring atoms" radical need not contain a
heteroatom, as long as one ring of the "polycyclic heteroaryl
containing more than 14 ring atoms" radical contains a heteroatom.
Examples of "polycyclic heteroaryl containing more than 14 ring
atoms" radicals include, but are not limited to,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxolane]-3--
yl,
5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1,3]dioxolane]-3-yl,
5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl,
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,
5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl
and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl.
[0091] "Optionally substituted polycyclic heteroaryl containing
more than 14 ring atoms" is meant to include "polycyclic heteroaryl
containing more than 14 ring atoms" radicals, as defined above,
which are optionally substituted by one or more substituents
selected from the group consisting of alkyl, alkenyl, alkynyl,
halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, optionally substituted heteroarylalkynyl,
--R.sup.21--OR.sup.20, --R.sup.21--OC(O)--R.sup.20,
--R.sup.21--N(R.sup.20).sub.2, --R.sup.21--C(O)R.sup.20,
--R.sup.21--C(O)OR.sup.20, --R.sup.21--C(O)N(R.sup.20).sub.2,
--R.sup.21--N(R.sup.20)C(O)OR.sup.20,
--R.sup.21--N(R.sup.20)C(O)R.sup.20,
--R.sup.21--N(R.sup.20)S(O).sub.tR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.tOR.sup.20 (where t is 1 or 2),
--R.sup.21--S(O).sub.pR.sup.20 (where p is 0, 1 or 2), and
--R.sup.21--S(O).sub.tN(R.sup.20).sub.2 (where t is 1 or 2), where
each R.sup.20 is independently selected from the group consisting
of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.20's, together with the common nitrogen to which they
are both attached, may optionally form an optionally substituted
N-heterocyclyl or an optionally substituted N-heteroaryl, and each
R.sup.21 is independently a direct bond or a straight or branched
alkylene or alkenylene chain.
[0092] "Heteroarylalkyl" refers to a radical of the formula
--R.sub.bR.sub.i where R.sub.b is an alkylene chain as defined
above and R.sub.i is a heteroaryl radical as defined above, and
when the heteroaryl is a nitrogen-containing heteroaryl, the
heteroaryl may be attached to the alkylene chain at the nitrogen
atom.
[0093] "Optionally substituted heteroarylalkyl" refers to a
heteroarylalkyl radical, as defined above, wherein the alkylene
chain of the heteroarylalkyl radical is an optionally substituted
alkylene chain, as defined above, and the heteroaryl radical of the
heteroarylalkyl radical is an optionally substituted heteroaryl
radical, as defined above.
[0094] "Heteroarylalkenyl" refers to a radical of the formula
--R.sub.dR.sub.i where R.sub.d is an alkenylene chain as defined
above and R.sub.i is a heteroaryl radical as defined above, and
when the heteroaryl is a nitrogen-containing heteroaryl, the
heteroaryl may be attached to the alkenylene chain at the nitrogen
atom.
[0095] "Optionally substituted heteroarylalkenyl" refers to a
heteroarylalkenyl radical, as defined above, wherein the alkenylene
chain of the heteroarylalkenyl radical is an optionally substituted
alkenylene chain, as defined above, and the heteroaryl radical of
the heteroarylalkenyl radical is an optionally substituted
heteroaryl radical, as defined above.
[0096] "Heteroarylalkynyl" refers to a radical of the formula
--R.sub.eR.sub.i where R.sub.e is an alkynylene chain as defined
above and R.sub.i is a heteroaryl radical as defined above, and
when the heteroaryl is a nitrogen-containing heteroaryl, the
heteroaryl may be attached to the alkynylene chain at the nitrogen
atom.
[0097] "Optionally substituted heteroarylalkynyl" refers to a
heteroarylalkynyl radical, as defined above, wherein the alkynylene
chain of the heteroarylalkynyl radical is an optionally substituted
alkynylene chain, as defined above, and the heteroaryl radical of
the heteroarylalkynyl radical is an optionally substituted
heteroaryl radical, as defined above.
[0098] "Hydroxyalkyl" refers to an alkyl radical as defined above
which is substituted by one or more hydroxy radicals (--OH).
[0099] Certain chemical groups named herein may be preceded by a
shorthand notation indicating the total number of carbon atoms that
are to be found in the indicated chemical group. For example;
C.sub.7-C.sub.12alkyl describes an alkyl group, as defined below,
having a total of 7 to 12 carbon atoms, and
C.sub.4-C.sub.12cycloalkylalkyl describes a cycloalkylalkyl group,
as defined below, having a total of 4 to 12 carbon atoms. The total
number of carbons in the shorthand notation does not include
carbons that may exist in substituents of the group described.
[0100] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0101] "Patient" means a mammal who has been diagnosed as having
cancer and/or metastatic cancer, or who is predisposed to having
metastatic cancer due to having cancer.
[0102] "Mammal" means any vertebrate of the class Mammalia. Humans
and domestic animals, such as cats, dogs, swine, cattle, sheep,
goats, horses, rabbits, and the like are a particular focus.
Preferably, for purposes of this invention, the mammal is a primate
(e.g., monkey, baboon, chimpanzee and human), and more preferably,
the mammal is a human.
[0103] "Optional" or "optionally" means that the subsequently
described event or circumstances may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted aryl" means that the aryl radical may or may not be
substituted and that the description includes both substituted aryl
radicals and aryl radicals having no substitution. However, when a
first functional group is described as "optionally substituted,"
and in turn, substituents on the first functional group are also
"optionally substituted" and so forth, for the purposes of this
invention, such iterations for a radical to be optionally
substituted are limited to three. Thus, groups described as
substituents on the third iteration are not themselves optionally
substituted. For example, if an R group herein is defined as being
"optionally substituted aryl" (the first iteration) and the
optional substituents for the "optionally substituted aryl" include
"optionally substituted heteroaryl" (the second iteration) and the
optional substituents for the "optionally substituted heteroaryl"
include "optionally substituted cycloalkyl" (the third iteration),
the optional substituents on the cycloalkyl can not be optionally
substituted.
[0104] "Pharmaceutically acceptable excipient" includes without
limitation any adjuvant, carrier, excipient, glidant, sweetening
agent, diluent, preservative, dye/colorant, flavor enhancer,
surfactant, wetting agent, dispersing agent, suspending agent,
stabilizer, isotonic agent, solvent, or emulsifier which has been
approved by the United States Food and Drug Administration as being
acceptable for use in humans or domestic animals.
[0105] "Pharmaceutically acceptable salt" includes both acid and
base addition salts.
[0106] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as, but not limited to, hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid and the like, and
organic acids such as, but not limited to, acetic acid,
2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid,
aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,
capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic
acid, citric acid, cyclamic acid, dodecylsulfonic acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic
acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric
acid, lactic acid, lactobionic acid, lauric acid, maleic acid,
malic acid, malonic acid, mandelic acid, methanesulfonic acid,
mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic
acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid,
orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic
acid, pyroglutamic acid, pyruvic acid, salicylic acid,
4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,
tartaric acid, thiocyanic acid, p-toluenesulfonic acid,
trifluoroacetic acid, undecylenic acid, and the like.
[0107] "Pharmaceutically acceptable base addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free acids, which are not biologically or
otherwise undesirable. These salts are prepared from addition of an
inorganic base or an organic base to the free acid. Salts derived
from inorganic bases include, but are not limited to, the sodium,
potassium, lithium, ammonium, calcium, magnesium, iron, zinc,
copper, manganese, aluminum salts and the like. Preferred inorganic
salts are the ammonium, sodium, potassium, calcium, and magnesium
salts. Salts derived from organic bases include, but are not
limited to, salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins, such as
ammonia, isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, diethanolamine, ethanolamine,
2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,
lysine, arginine, histidine, caffeine, procaine, hydrabamine,
choline, betaine, benethamine, benzathine, ethylenediamine,
glucosamine, methylglucamine, theobromine, triethanolamine,
tromethamine, purines, piperazine, piperidine, N-ethylpiperidine,
polyamine resins and the like. Particularly preferred organic bases
are isopropylamine, diethylamine, ethanolamine, trimethylamine,
dicyclohexylamine, choline and caffeine.
[0108] A "pharmaceutical composition" refers to a formulation of a
compound of formula (I) or a formulation of a chemotherapeutic
agent described herein and a medium generally accepted in the art
for the delivery of the biologically active compound to mammals,
for example, humans. Such a medium includes all pharmaceutically
acceptable carriers, diluents or excipients therefor.
[0109] "Therapeutically effective amount" refers to that amount of
the therapeutic agent sufficient to destroy, modify, control or
remove mestastatic cancer tissue. A therapeutically effective
amount may refer to the amount of therapeutic agents sufficient to
delay or minimize the spread of metastatic cancer. A
therapeutically effective amount may also refer to the amount of
the therapeutic agent that provides a therapeutic benefit in the
treatment or management of metastatic cancer. Further, a
therapeutically effective amount with respect to an Axl inhibitor
of the combination therapies of the invention means that amount of
an Axl inhibitor in combination with one or more chemotherapeutic
agents that provides a therapeutic benefit in the treatment or
management of metastatic cancer, including the amelioration of
symptoms associated with metastatic cancer. Used in connection with
an amount of an Axl inhibito, the term can encompass an amount that
improves overall therapy, reduces or avoids unwanted effects, or
enhances the therapeutic efficacy of or synergizes with the one or
more chemotherapeutic agents utilized in the combination therapies
of the invention.
[0110] "Prophylactically effective amount" refers to that amount of
the prophylactic agent sufficient to result in the prevention of
metastatic cancer. A prophylactically effective amount may refer to
the amount of prophylactic agent sufficient to prevent metastatic
cancer in a patient, including, but not limited to, those patients
who are predisposed to cancer or previously exposed to carcinogens.
A prophylactically effective amount may also refer to the amount of
the prophylactic agent that provides a prophylactic benefit in the
prevention of metastatic cancer. Further, a prophylactically
effective amount with respect to with respect to an Axl inhibitor
of the combination therapies of the invention means that amount of
an Axl inhibitor in combination with other chemotherapeutic agents,
that provides a prophylactic benefit in the prevention of
metastatic cancer. Used in connection with an amount of an Axl
inhibitor, the term can encompass an amount that improves overall
prophylaxis or enhances the prophylactic efficacy of or synergizes
with another prophylactic or therapeutic agent.
[0111] As used herein, the terms "manage", "managing" and
"management" refer to the beneficial effects that a patient derives
from a combination therapy of the invention, which does not result
in a cure of the metastatic cancer. In certain embodiments, a
combination therapy of the invention "manages" metastatic cancer so
as to prevent the progression or worsening of the metastatic
cancer.
[0112] As used herein, the terms "prevent", preventing" and
"prevention" refer to the prevention of the spread or onset of
metastatic cancer in a patient.
[0113] As used herein, the terms "treat", "treating" and
"treatment" refer to the eradication, removal, modification or
control of metastatic cancer that results from the combination
therapy of the invention. In certain embodiments, such terms refer
to the minimizing or delay of the spread of metastatic cancer.
[0114] The compounds of formula (I), or their pharmaceutically
acceptable salts, may contain one or more asymmetric centers and
may thus give rise to enantiomers, diastereomers, and other
stereoisomeric forms that may be defined, in terms of absolute
stereochemistry, as (R)- or (S)- or, as (D)- or (L)-for amino
acids. The present invention is meant to include all such possible
isomers, as well as their racemic and optically pure forms.
Optically active (+) and (-), (R)- and (S)-, or (D)- and
(L)-isomers may be prepared using chiral synthons or chiral
reagents, or resolved using conventional techniques, such as HPLC
using a chiral column. When the compounds described herein contain
olefinic double bonds or other centers of geometric asymmetry, and
unless specified otherwise, it is intended that the compounds
include both E and Z geometric isomers. Likewise, all tautomeric
forms are also intended to be included.
[0115] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present invention contemplates various stereoisomers and mixtures
thereof and includes "enantiomers", which refers to two
stereoisomers whose molecules are nonsuperimposeable mirror images
of one another.
[0116] A "tautomer" refers to a proton shift from one atom of a
molecule to another atom of the same molecule. The present
invention includes tautomers of any said compounds.
[0117] "Atropisomers" are stereoisomers resulting from hindered
rotation about single bonds where the barrier to rotation is high
enough to allow for the isolation of the conformers (Eliel, E. L.;
Wilen, S. H. Stereochemistry of Organic Compounds; Wiley &
Sons: New York, 1994; Chapter 14). Atropisomerism is significant
because it introduces an element of chirality in the absence of
stereogenic atoms. The invention is meant to encompass
atropisomers, for example in cases of limited rotation around the
single bonds emanating from the core triazole structure,
atropisomers are also possible and are also specifically included
in the compounds of the invention.
[0118] The chemical naming protocol and structure diagrams used
herein are a modified form of the I.U.P.A.C. nomenclature system
wherein the compounds of formula (I) are named herein as
derivatives of the central core structure, i.e., the triazole
structure. For complex chemical names employed herein, a
substituent group is named before the group to which it attaches.
For example, cyclopropylethyl comprises an ethyl backbone with
cyclopropyl substituent. In chemical structure diagrams, all bonds
are identified, except for some carbon atoms, which are assumed to
be bonded to sufficient hydrogen atoms to complete the valency.
[0119] For purposes of this invention, the depiction of the bond
attaching the R.sup.3 substituent to the parent triazole moiety in
formula (I), as shown below:
##STR00002##
is intended to include only the two regioisomers shown below, i.e.,
compounds of formula (Ia) and (Ib):
##STR00003##
[0120] The numbering system of the ring atoms in compounds of
formula (Ia) is shown below:
##STR00004##
[0121] For example, a compound of formula (Ia) wherein R.sup.1,
R.sup.4 and R.sup.5 are each hydrogen, R.sup.2 is
4-(2-(pyrrolidin-1-yl)ethoxy)phenyl and R.sup.3 is
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl; i.e., a
compound of the following formula:
##STR00005##
is named herein as
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.
[0122] The numbering system of the ring atoms in compounds of
formula (Ib) is shown below:
##STR00006##
Compounds of formula (Ib) are similarly named herein.
Embodiments of the Invention
[0123] Of the various aspects of the invention, as set forth
herein, certain embodiments are preferred.
[0124] In one embodiment of the methods of preventing, treating or
managing cancer in a patient comprising administering to the
patient in need thereof a therapeutically or prophylactically
effective amount of an Axl inhibitor in combination with the
administration of a therapeutically or prophylactically effective
amount of one or more chemotherapeutic agents, the Axl inhibitor is
a compound of formula (I), as set forth above in the Summary of the
Invention, as an isolated stereoisomer or mixture thereof or as a
tautomer or mixture thereof, or a pharmaceutically acceptable salt
or N-oxide thereof.
[0125] Of this embodiment, one preferred embodiment is wherein the
compound of formula (I) is a compound of formula (Ia):
##STR00007##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as
described in the Summary of the Invention for compounds of formula
(I), as an isolated stereoisomer or mixture thereof or as a
tautomer or mixture thereof, or a pharmaceutically acceptable salt
or N-oxide thereof.
[0126] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above, R.sup.2 and R.sup.3 are each
independently a polycyclic heteroaryl containing more than 14 ring
atoms optionally substituted by one or more substituents selected
from the group consisting of oxo, thioxo, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--CN, --R.sup.9--O--R.sup.10--C(O)OR.sup.8,
--R.sup.9--O--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--O--R--S(O).sub.pR.sup.8 (where p is 0, 1 or 2),
--R.sup.9--O--R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--C(NR.sup.11)N(R.sup.11)H,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
R.sup.1, R.sup.4, R.sup.5, each R.sup.6, each R.sup.7, each
R.sup.8, each R.sup.9, each R.sup.10, each R.sup.11 and R.sup.12
are as described above for compounds of formula (Ia).
[0127] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0128] R.sup.1, R.sup.4 and
R.sup.5 are each hydrogen; [0129] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.10--OR.sup.8, --R.sup.10--CN,
--R.sup.10--NO.sub.2, --R.sup.10--N(R.sup.8).sub.2,
--R.sup.10--C(O)OR.sup.8 and --R.sup.10--C(O)N(R.sup.8).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0130] each R.sup.8 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, and optionally substituted heteroarylalkyl; [0131] each
R.sup.9 is independently selected from the group consisting of a
direct bond and an optionally substituted straight or branched
alkylene chain; [0132] each R.sup.10 is an optionally substituted
straight or branched alkylene chain; and [0133] each R.sup.11 is
independently selected from the group consisting of hydrogen,
alkyl, cyano, nitro and --OR.sup.8.
[0134] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0135] R.sup.2 and R.sup.3 are
each independently a polycyclic heteroaryl containing more than 14
ring atoms selected from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxolane]-3--
yl,
5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1,3]dioxolane]-3-yl,
5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl,
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,
5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl
and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2).
[0136] Another embodiment is the method wherein the compound of
formula (Ia) is
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.su-
p.3-(5',5'-dimethyl-6,
8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl)--
1H-1,2,4-triazole-3,5-diamine.
[0137] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above, R.sup.2 is a polycyclic heteroaryl
containing more than 14 ring atoms optionally substituted by one or
more substituents selected from the group consisting of oxo,
thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted heteroaryl, optionally substituted
heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--CN, --R.sup.9--O--R.sup.10--C(O)OR.sup.8,
--R.sup.9--O--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--S(O).sub.pR.sup.8 (where p is 0, 1 or 2),
--R.sup.9--O--R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--C(NR.sup.11)N(R.sup.11)H,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); R.sup.3
is selected from the group consisting of aryl and heteroaryl, where
the aryl and the heteroaryl are each independently optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); and
R.sup.1, R.sup.4, R.sup.5, each R.sup.6, each R.sup.7, each
R.sup.8, each R.sup.9, each R.sup.10, each R.sup.11, each R.sup.12,
each R.sup.13 and each R.sup.14 are as described above for
compounds of formula (Ia).
[0138] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0139] R.sup.1, R.sup.4 and
R.sup.5 are each hydrogen; [0140] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.10--OR.sup.8, --R.sup.10--CN,
--R.sup.10--NO.sub.2, --R.sup.10--N(R.sup.8).sub.2,
--R.sup.10--C(O)OR.sup.8 and --R.sup.10--C(O)N(R.sup.8).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0141] each R.sup.8 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, and optionally substituted heteroarylalkyl; [0142] each
R.sup.9 is independently selected from the group consisting of a
direct bond and an optionally substituted straight or branched
alkylene chain; [0143] each R.sup.10 is an optionally substituted
straight or branched alkylene chain; [0144] each R.sup.11 is
independently selected from the group consisting of hydrogen,
alkyl, cyano, nitro and --OR.sup.8; [0145] each R.sup.12 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.12's, together with the common nitrogen to which they
are both attached, form an optionally substituted N-heterocyclyl or
an optionally substituted N-heteroaryl; [0146] each R.sup.13 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and each R.sup.14 is an optionally substituted straight or branched
alkylene chain.
[0147] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0148] R.sup.1, R.sup.4 and
R.sup.5 are each hydrogen; [0149] R.sup.2 is a polycyclic
heteroaryl containing more than 14 ring atoms selected from the
group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxolane]-3--
yl,
5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1,3]dioxolane]-3-yl,
5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl,
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,
5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl
and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); [0150]
each R.sup.6 and R.sup.7 is independently selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.10--OR.sup.8,
--R.sup.10--CN, --R.sup.10--NO.sub.2, --R.sup.10--N(R.sup.8).sub.2,
--R.sup.10--C(O)OR.sup.8 and --R.sup.10--C(O)N(R.sup.8).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0151] each R.sup.8 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, and optionally substituted heteroarylalkyl; [0152] each
R.sup.9 is independently selected from the group consisting of a
direct bond and an optionally substituted straight or branched
alkylene chain; [0153] each R.sup.10 is an optionally substituted
straight or branched alkylene chain; [0154] each R.sup.12 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.12's, together with the common nitrogen to which they
are both attached, form an optionally substituted N-heterocyclyl or
an optionally substituted N-heteroaryl; [0155] each R.sup.13 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0156] each R.sup.14 is an optionally substituted straight or
branched alkylene chain.
[0157] Another embodiment is a method where, in the compound of
formula (Ia) as set forth above: [0158] R.sup.2 is a polycyclic
heteroaryl containing more than 14 ring atoms selected from the
group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxolane]-3--
yl,
5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1,3]dioxolane]-3-yl,
5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl,
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,
5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl
and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
[0159] R.sup.3 is heteroaryl selected from the group consisting of
pyridinyl, pyrimidinyl,
4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-8-yl, benzo[d]imidazolyl,
6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl,
6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl,
5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl,
5,6,7,8-tetrahydroquinolin-3-yl,
1,2,3,4-tetrahydroisoquinolin-7-yl,
2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,
3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, benzo[d]oxazol-5-yl,
3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, benzo[b]thiophenyl,
thieno[3,2-d]pyrimidinyl and
6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2).
[0160] Another embodiment is a method wherein the compound of
formula (Ia), as set forth above, is selected from the group
consisting of: [0161]
1-(6,7-dimethoxy-quinazolin-4-yl)-N.sup.3-(5,7,8,9-tetrahydrospiro-
[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl)-1H-1,2,4-triazole-3,5-di-
amine; [0162]
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(5,7,8,9-tetrahy-
drospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl)-1H-1,2,4-triazol-
e-3,5-diamine; [0163]
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(5,6,8,9-tetrahy-
drospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl)-1H-1,2,4-triazol-
e-3,5-diamine; and [0164]
1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N.sup.3-(5',5'-dimethyl--
6,8,9,10-9tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl-
)-1H-1,2,4-triazole-3,5-diamine.
[0165] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above, R.sup.2 is selected from the group
consisting of aryl and heteroaryl, where the aryl and the
heteroaryl are each independently optionally substituted by one or
more substitutents selected from the group consisting of alkyl,
alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2);
R.sup.3 is a polycyclic heteroaryl containing more than 14 ring
atoms optionally substituted by one or more substituents selected
from the group consisting of oxo, thioxo, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--CN, --R.sup.9--O--R.sup.10--C(O)OR.sup.8,
--R.sup.9--O--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--S(O).sub.pR.sup.8 (where p is 0, 1 or 2),
--R.sup.9--O--R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--C(NR.sup.11)N(R.sup.11)H,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
R.sup.1, R.sup.4, R.sup.5, each R.sup.6, each R.sup.7, each
R.sup.8, each R.sup.9, each R.sup.10, each R.sup.11, each R.sup.12,
each R.sup.13 and each R.sup.14 are as described above for
compounds of formula (I).
[0166] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0167] R.sup.1, R.sup.4 and
R.sup.5 are each independently hydrogen; [0168] each R.sup.6 and
R.sup.7 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.10--OR.sup.8,
--R.sup.10--CN, --R.sup.10--NO.sub.2, --R.sup.10--N(R.sup.8).sub.2,
--R.sup.10--C(O)OR.sup.8 and --R.sup.10--C(O)N(R.sup.8).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0169] each R.sup.8 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, and optionally substituted heteroarylalkyl;
[0170] each R.sup.9 is independently selected from the group
consisting of a direct bond and an optionally substituted straight
or branched alkylene chain; [0171] each R.sup.10 is an optionally
substituted straight or branched alkylene chain; [0172] each
R.sup.11 is independently selected from the group consisting of
hydrogen, alkyl, cyano, nitro and --OR.sup.8; [0173] each R.sup.12
is independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.10--OR.sup.8, --R.sup.10--CN, --R.sup.10--NO.sub.2,
--R.sup.10--N(R.sup.8).sub.2, --R.sup.10--C(O)OR.sup.8 and
--R.sup.10--C(O)N(R.sup.8).sub.2, or two R.sup.12's, together with
the common nitrogen to which they are both attached, form an
optionally substituted N-heterocyclyl or an optionally substituted
N-heteroaryl; [0174] each R.sup.13 is independently selected from
the group consisting of a direct bond and an optionally substituted
straight or branched alkylene chain; and [0175] each R.sup.14 is an
optionally substituted straight or branched alkylene chain.
[0176] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0177] R.sup.2 is aryl optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2).
[0178] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0179] R.sup.2 is aryl selected
from the group consisting of phenyl and
6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.2,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); and
[0180] R.sup.3 is a polycyclic heteroaryl containing more than 14
ring atoms selected from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxolane]-3--
yl,
5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1,3]dioxolane]-3-yl,
5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl,
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,
5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl
and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2).
[0181] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0182] R.sup.2 is phenyl
optionally substituted by one or more substitutents selected from
the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2).
[0183] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0184] R.sup.2 is phenyl
optionally substituted by one or more substitutents selected from
the group consisting of alkyl, halo, haloalkyl, cyano, and
optionally substituted heterocyclyl where the optionally
substituted heterocyclyl is selected from the group consisting of
piperidinyl, piperazinyl, pyrrolidinyl, azepanyl,
decahydropyrazino[1,2-a]azepinyl, octahydropyrrolo[3,4-c]pyrrolyl,
azabicyclo[3.2.1]octyl, octahydropyrrolo[3,4-b]pyrrolyl,
octahydropyrrolo[3,2-c]pyridinyl, 2,7-diazaspiro[4.4]nonanyl and
azetidinyl; each independently optionally substituted by one or two
substituents selected from the group consisting of
--R.sup.9--OR.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)OR.sup.6, --R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.7, alkyl, halo, haloalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
and optionally substituted heteroarylalkyl; [0185] R.sup.3 is
selected from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl,
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl and
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-3-yl, each
optionally substituted by one or more substituents selected from
the group consisting of alkyl, aryl, halo and
--R.sup.9--OR.sup.8.
[0186] Another embodiment is the method where the compound of
formula (Ia), as set forth above, is selected from the group
consisting of: [0187]
N.sup.3-(4-(4-cyclohexanylpiperazin-1-yl)phenyl)-1-(6,7-dihydro-5H-
-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine;
[0188]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)-1H-1,2,4-triazole-3,5-d-
iamine; [0189]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-methyl-3-phenylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0190]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-(4-(4-piperidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-di-
amine; [0191]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-(indolin-2-on-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-
-diamine; [0192]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-(morpholin-4-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-di-
amine; [0193]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
4-cyclopentyl-2-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine-
; [0194]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.su-
p.3-(4-(3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0195]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(4-(4-(pyrrolidin-1-yl)piperidin-1-yl)-3-cyanophenyl)-1H-1,2,4-triazole-
-3,5-diamine; [0196]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(3-(diethylamino)pyrrolidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0197]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5--
diamine; [0198]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0199]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-(diethylamino)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diam-
ine; [0200]
1-(6,7-dihydro-5H-9-methoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triaz-
ole-3,5-diamine; [0201]
1-(6,7-dihydro-5H-10-fluorobenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triaz-
ole-3,5-diamine; [0202]
1-(6,7-dihydro-5H-10-fluorobenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(3-fluoro-4-(4-(cyclohexyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3-
,5-diamine; [0203]
1-(6,7-dihydro-5H-9-methoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(3-fluoro-4-(4-(cyclohexyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3-
,5-diamine; [0204]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazol-
e-3,5-diamine; [0205]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-(4-methylpiperidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazol-
e-3,5-diamine; [0206]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-dimethylaminopiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diami-
ne; [0207]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.-
sup.3-(3-chloro-4-(4-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triaz-
ole-3,5-diamine; [0208]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-t-
rifluoromethyl-4-(4-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazo-
le-3,5-diamine; [0209]
1-(6,7-dihydro-5H-9,10-dimethoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl-
)-N.sup.3-(3-fluoro-4-(4-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-t-
riazole-3,5-diamine; [0210]
1-(6,7-dihydro-5H-9,10,11-trimethoxybenzo[6,7]cyclohepta[1,2-c]pyridazin--
3-yl)-N.sup.3-(3-fluoro-4-(4-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2-
,4-triazole-3,5-diamine; [0211]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(5-methyloctahydropyrrolo[3,4-c]pyrrolyl)phenyl)-1H-1,2,4-triazole-
-3,5-diamine; [0212]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(3-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-di-
amine; [0213]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(3-pyrrolidin-1-yl-azepan-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diami-
ne; [0214]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.-
sup.3-(3-fluoro-4-(4-N-methylpiperidin-4-yl-piperidin-1-yl)phenyl)-1H-1,2,-
4-triazole-3,5-diamine; [0215]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N.sup.3-(3-f-
luoro-4-(4-(pyrrolidinyl)piperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine-
; [0216]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.su-
p.3-(3-fluoro-4-(5-propyloctahydropyrrolo[3,4-c]pyrrolyl)phenyl)-1H-1,2,4--
triazole-3,5-diamine; [0217]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(decahydropyrazino[1,2-a]azepin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-
-diamine; [0218]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(5-cyclopentyloctahydropyrrolo[3,4-c]pyrrolyl)phenyl)-1H-1,2,4-tri-
azole-3,5-diamine; [0219]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(3-(pyrrolidin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)phenyl)-1H-1,2,4--
triazole-3,5-diamine; [0220]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-pyrrolidin-1-yl-azepan-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diami-
ne; [0221]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.-
sup.3-(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2-
,4-triazole-3,5-diamine; [0222]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-(4-isopropylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-tria-
zole-3,5-diamine; [0223]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(1-methyloctahydropyrrolo[3,4-b]pyrrol-5-yl)phenyl)-1H-1,2,4-triaz-
ole-3,5-diamine; [0224]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-(N-methylcyclopentylamino)piperidinyl)phenyl)-1H-1,2,4-triazole-
-3,5-diamine; [0225]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-(dipropylamino)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0226]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(1-propyloctahydro-1H-pyrrolo[3,2-c]pyridine-5-yl)phenyl)-1H-1,2,4-
-triazole-3,5-diamine; [0227]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N.sup.3-(3-f-
luoro-4-(4-(N-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazol-
e-3,5-diamine; [0228]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-(tert-butyloxycarbonylamino)piperidin-1-yl)phenyl)-1H-1,2,4-tri-
azole-3,5-diamine; [0229]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-aminopiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0230]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(3-fluoro-4-(4-(5-cyclohexyloctahydropyrrolo[3,4-c]pyrrolyl)piperidin-1-
-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine; [0231]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
methylpiperidin-4-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine; [0232]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0233]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamin-
e; [0234]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(3-methyl-4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3-
,5-diamine; [0235]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-cyclopentylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0236]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(3-fluoro-4-(4-N-methylpiperidin-4-ylpiperazinyl)phenyl)-1H-1,2,4-triaz-
ole-3,5-diamine; [0237]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)-1H-1,2,4-triazole--
3,5-diamine; [0238]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(N-isopropylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0239]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(3-fluoro-4-(3-pyrrolidin-1-ylazetidinyl)phenyl)-1H-1,2,4-triazole-3,5--
diamine; [0240]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-m-
ethyl-4-(4-(N-methylpiperazin-4-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazol-
e-3,5-diamine; [0241]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-((S)-3-(pyrrolidin-1-ylmethyl)pyrrolidinyl)phenyl)-1H-1,2,4-triazo-
le-3,5-diamine; [0242]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-(pyrrolidinylmethyl)piperidinyl)phenyl)-1H-1,2,4-triazole-3,5-d-
iamine; [0243]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-((4aR,8aS)-decahydroisoquinolin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-
-diamine; [0244]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(octahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)-1H-1,2,4-triazole--
3,5-diamine; [0245]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-(4-(3-pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5--
diamine; [0246]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-(5-methyloctahydropyrrolo[3,4-c]pyrrolyl)piperidin-1-yl)phenyl)-
-1H-1,2,4-triazole-3,5-diamine; [0247]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(octahydropyrrolo[3,4-c]pyrrolyl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0248]
1-(6,7-dihydro-9-chloro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazol-
e-3,5-diamine; [0249]
1-(6,7-dihydro-9-chloro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(3-fluoro-4-(4-(N-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,-
4-triazole-3,5-diamine; [0250]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-i-
odophenyl)-1H-1,2,4-triazole-3,5-diamine; [0251]
1-(spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl)-N.sup.3-(3-fl-
uoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-
-3,5-diamine; [0252]
1-(spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl)-N.sup.3-(3-fl-
uoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-di-
amine; [0253]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0254]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N.sup.3-(3-f-
luoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0255]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazol-
e-3,5-diamine; [0256]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-f-
luoro-4-(3-(3R)-dimethylaminopyrrolidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-
-diamine; [0257]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N.sup.3-(3-m-
ethyl-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0258]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N.sup.3-(3-f-
luoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0259]
1-(4-phenyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl)-N.sup-
.3-(3-fluoro-4-(4-cyclohexylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-d-
iamine; [0260]
1-(4-phenyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl)-N.sup-
.3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0261]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diami-
ne; [0262]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.-
sup.3-(4-(1-bicyclo[2.2.1]heptan-2-yl)-piperidin-4-ylphenyl)-1H-1,2,4-tria-
zole-3,5-diamine; [0263]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
1-cyclopropylmethylpiperidin-4-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0264]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(3-fluoro-4-(4-cyclopropylmethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazol-
e-3,5-diamine; [0265]
1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N.sup.3-(4-(1--
bicyclo[2.2.1]heptan-2-yl)-piperidin-4-ylphenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0266]
1-(4-phenyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl)-N.sup-
.3-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole--
3,5-diamine, and [0267]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazol-
e-3,5-diamine.
[0268] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0269] R.sup.2 is phenyl
optionally substituted by one or more substitutents selected from
the group consisting of halo, alkyl, heterocyclylalkenyl,
--R.sup.13--OR.sup.12, --R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)N(R.sup.12).sub.2, and
--R.sup.13--N(R.sup.12)C(O)R.sup.12; [0270] R.sup.3 is selected
from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl and
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-3-yl, each
optionally substituted by one or more substituents selected from
the group consisting of alkyl, aryl, halo and
--R.sup.9--OR.sup.8.
[0271] Another embodiment is the method where the compound of
formula (Ia), as set forth above, is selected from the group
consisting of: [0272]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0273]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(4-(4-(cyclopentyl)piperazin-1-ylcarbonyl)phenyl)-1H-1,2,4-triazole-3,5-
-diamine; [0274]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
(2-pyrrolidin-1-ylethyl)amino
carbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine; [0275]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
2,2,6,6-tetramethylpiperidin-1-yl)ethoxyphenyl)-1H-1,2,4-triazole-3,5-diam-
ine; [0276]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
(2-(dimethylamino)ethyl)aminocarbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamin-
e; [0277]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(4-((2-(methoxy)ethyl)aminocarbonyl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0278]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
(2-(pyrrolidin-1-yl)ethyl)aminocarbonyl)phenyl)-1H-1,2,4-triazole-3,5-diam-
ine; [0279]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
(4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)phenyl)-1H-1,2,4-triazole-3,5--
diamine; [0280]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3-c-
hloro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0281]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-di-
amine; [0282]
1-(6,7-dihydro-5H-10-fluorobenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5--
diamine; [0283]
1-(6,7-dihydro-5H-9-methoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5--
diamine; [0284]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
2-(N-methylcyclopentylamino)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0285]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(3-fluoro-4-(N-methylpiperidin-4-yl-N-methylamino)phenyl)-1H-1,2,4-tria-
zole-3,5-diamine; [0286]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
(N-butyl-N-acetoamino)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0287]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
4-(4-methylpiperazin-1-yl)piperidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triaz-
ole-3,5-diamine; [0288]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
4-(piperidin-1-yl)piperidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5--
diamine; [0289]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
piperidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0290]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
pyrrolidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0291]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
3-dimethylaminopyrrolidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-di-
amine; [0292]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
3-diethylaminopyrrolidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0293]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
4-pyrrolidin-1-ylpiperidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-d-
iamine; [0294]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
4-methylpiperazin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0295]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(4-(4-isopropylpiperazin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5--
diamine; [0296]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
4-cyclopentylpiperazin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diami-
ne; [0297]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.-
sup.3-(4-(morpholin-4-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
and [0298]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
1-methylpiperidin-3-yl-oxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.
[0299] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0300] R.sup.2 is phenyl
optionally substituted by one or more substitutents selected from
the group consisting of alkyl, halo, haloalkyl, cyano, and
optionally substituted heterocyclyl where the optionally
substituted heterocyclyl is selected from the group consisting of
piperidinyl, piperazinyl, pyrrolidinyl, azepanyl,
decahydropyrazino[1,2-a]azepinyl, octahydropyrrolo[3,4-c]pyrrolyl,
azabicyclo[3.2.1]octyl, octahydropyrrolo[3,4-b]pyrrolyl,
octahydropyrrolo[3,2-c]pyridinyl, 2,7-diazaspiro[4.4]nonanyl and
azetidinyl; each independently optionally substituted by one or two
substituents selected from the group consisting of
--R.sup.9--OR.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)OR.sup.6, --R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.7, alkyl, halo, haloalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
and optionally substituted heteroarylalkyl; and [0301] R.sup.3 is
selected from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl and
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of alkyl, aryl, halo and
--R.sup.9--OR.sup.8.
[0302] Another embodiment is the method where the compound of
formula (Ia), as set forth above, is selected from the group
consisting of: [0303]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)-N.sup-
.3-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazo-
le-3,5-diamine; [0304]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)-N.sup.3-(3-f-
luoro-4-(4-(diethylamino)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diam-
ine; [0305]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-N.sup.3-(4-(-
N-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0306]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-N.sup.3-(3-f-
luoro-4-(4-cyclohexylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
and [0307]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-N.sup.3-(4-(-
4-(2S)-bicyclo[2.2.1]heptan-2-yl)-piperazinylphenyl)-1H-1,2,4-triazole-3,5-
-diamine.
[0308] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0309] R.sup.2 is phenyl
optionally substituted by one or more substitutents selected from
the group consisting of halo, alkyl, heterocyclylalkenyl,
--R.sup.13--OR.sup.12, --R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)N(R.sup.12).sub.2, and
--R.sup.13--N(R.sup.12)C(O)R.sup.2; and [0310] R.sup.3 is selected
from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl and
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of alkyl, aryl, halo and
--R.sup.9--OR.sup.8.
[0311] Another embodiment is the method where the compound of
formula (Ia), as set forth above, is selected from the group
consisting of: [0312]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-N.sup-
.3-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-di-
amine; and [0313]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)-N.sup.3-(4-(-
2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.
[0314] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0315] R.sup.2 is phenyl
optionally substituted by one or more substitutents selected from
the group consisting of alkyl, halo, haloalkyl, cyano, and
optionally substituted heterocyclyl where the optionally
substituted heterocyclyl is selected from the group consisting of
piperidinyl, piperazinyl, pyrrolidinyl, azepanyl,
decahydropyrazino[1,2-a]azepinyl, octahydropyrrolo[3,4-c]pyrrolyl,
azabicyclo[3.2.1]octyl, octahydropyrrolo[3,4-b]pyrrolyl,
octahydropyrrolo[3,2-c]pyridinyl, 2,7-diazaspiro[4.4]nonanyl and
azetidinyl; each independently optionally substituted by one or two
substituents selected from the group consisting of
--R.sup.9--OR.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)OR.sup.6, --R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.7, alkyl, halo, haloalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
and optionally substituted heteroarylalkyl; and [0316] R.sup.3 is
selected from the group consisting of
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl, and
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl, each
optionally substituted by one or more substituents selected from
the group consisting of alkyl, aryl, halo and
--R.sup.9--OR.sup.8.
[0317] Another embodiment is the method where the compound of
formula (Ia), as set forth above, is selected from the group
consisting of: [0318]
1-(7-methyl-6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl)-
-N.sup.3-(4-(N-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0319]
1-(7-methyl-6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl)-
-N.sup.3-(3-fluoro-4-(4-cyclohexylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,-
5-diamine; [0320]
1-((Z)-dibenzo[b,f][1,4]thiazepin-11-yl)-N.sup.3-(4-(4-N-methylpiperaziny-
l)phenyl)-1H-1,2,4-triazole-3,5-diamine; [0321]
1-((Z)-dibenzo[b,f][1,4]thiazepin-11-yl)-N.sup.3-(3-fluoro-4-(4-diethylam-
inopiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine; [0322]
1-(6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl)-N.sup.3-(4-(4-p-
yrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0323]
1-(6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl)-N.sup.3-(3-fluo-
ro-4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0324]
1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N.sup.3-
-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-d-
iamine; [0325]
1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N.sup.3-(4-(4--
pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0326]
1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N.sup.3-(3-flu-
oro-4-(4-(pyrrolidinylmethyl)piperidinyl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0327]
1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N.sup.3-(3-flu-
oro-4-((4aR,8aS)-decahydroisoquinolin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-d-
iamine; and [0328]
1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N.sup.3-(3-flu-
oro-4-(octahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)-1H-1,2,4-triazole-3,-
5-diamine.
[0329] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0330] R.sup.2 is phenyl
optionally substituted by one or more substitutents selected from
the group consisting of halo, alkyl, heterocyclylalkenyl,
--R.sup.13--OR.sup.12, --R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)N(R.sup.12).sub.2, and
--R.sup.13--N(R.sup.12)C(O)R.sup.12; and [0331] R.sup.3 is selected
from the group consisting of
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl, and
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2).
[0332] Another embodiment is the method where the compound of
formula (Ia), as set forth above, is selected from the group
consisting of: [0333]
1-(7-methyl-6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl)-
-N.sup.3-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole--
3,5-diamine; and [0334]
1-((Z)-dibenzo[b,f][1,4]thiazepin-11-yl)-N.sup.3-(4-(2-(pyrrolidin-1-yl)e-
thoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.
[0335] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0336] R.sup.2 is phenyl
optionally substituted by a substitutent selected from the group
consisting of optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl;
[0337] R.sup.3 is selected from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl and
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2) [0338]
each R.sup.6 and R.sup.7 is independently selected from the group
consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,
hydroxyalkyl, optionally substituted aryl, optionally substituted
aralkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.10--OR.sup.8,
--R.sup.10--CN, --R.sup.10--NO.sub.2, --R.sup.10--N(R.sup.8).sub.2,
--R.sup.10--C(O)OR.sup.8 and --R.sup.10--C(O)N(R.sup.8).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0339] each R.sup.8 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, and optionally substituted heteroarylalkyl;
[0340] each R.sup.9 is independently selected from the group
consisting of a direct bond and an optionally substituted straight
or branched alkylene chain; [0341] each R.sup.10 is an optionally
substituted straight or branched alkylene chain; and [0342]
R.sup.12 is independently selected from the group consisting of
hydrogen, alkyl, haloalkyl, alkenyl, optionally substituted
cycloalkyl, optionally substituted cycloalkylalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl and optionally substituted
heteroarylalkyl.
[0343] Another embodiment is the method where the compound of
formula (Ia), as set forth above, is selected from the group
consisting of: [0344]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamin-
e; [0345]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(4-((5-fluoroindolin-2-on-3-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-d-
iamine; [0346]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
(4-pyrrolidin-1-ylpiperidinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine-
; [0347]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.su-
p.3-(4-((4-cyclopentylpiperazinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0348]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(4-(-
(4-isopropylpiperazinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
and [0349]
1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N.sup.3-
-(3-fluoro-4-(isoindolin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.
[0350] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0351] R.sup.1, R.sup.4 and
R.sup.5 are each independently hydrogen; [0352] R.sup.2 is
6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl optionally substituted
by one or more substitutents selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.3--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); and
[0353] R.sup.3 is a polycyclic heteroaryl containing more than 14
ring atoms selected from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxolane]-3--
yl,
5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1,3]dioxolane]-3-yl,
5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl,
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,
5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl
and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
each R.sup.6, each R.sup.7, each R.sup.8, each R.sup.9, each
R.sup.12, each R.sup.13 and each R.sup.14 are as described above
for compounds of formula (Ia).
[0354] Another embodiment is the method where the compound of
formula (Ia), as set forth above, is selected from the group
consisting of: [0355]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,-
2,4-triazole-3,5-diamine; [0356]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(bicyclo[2.2.1]heptan-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine; [0357]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(bicyclo[2.2.1]heptan-2-yl)(methyl)amino)
6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamin-
e; [0358]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-((7-piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1-
,2,4-triazole-3,5-diamine; [0359]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triaz-
ole-3,5-diamine; [0360]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-
-triazole-3,5-diamine; [0361]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-d-
iethylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-
-3,5-diamine; [0362]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-c-
yclopentylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-tria-
zole-3,5-diamine; [0363]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-
-triazole-3,5-diamine; [0364]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
(2-(S)-methyloxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]an-
nulene-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0365]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
(2-(S)-carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine; [0366]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(8-d-
iethylaminoethyl-9hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine; [0367]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
3-(S)-fluoropyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine; [0368]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
2-(S)-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine; [0369]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
3-(R)-hydroxypyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-
-1H-1,2,4-triazole-3,5-diamine; [0370]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
2-(R)-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine; [0371]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
3-(S)-hydroxypyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-
-1H-1,2,4-triazole-3,5-diamine; [0372]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
3-(R)-fluoropyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine; [0373]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-o-
xo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diam-
ine; [0374]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-c-
yclohexylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triaz-
ole-3,5-diamine; [0375]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-c-
yclopropylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-tria-
zole-3,5-diamine; [0376]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-h-
ydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5--
diamine; [0377]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,-
2,4-triazole-3,5-diamine; [0378]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
tetrahydrofuran-2-ylmethyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine; [0379]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-c-
yclobutylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triaz-
ole-3,5-diamine; [0380]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
cyclopropylmethyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,-
2,4-triazole-3,5-diamine; [0381]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
2-(diethylamino)ethyl)methylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine; [0382]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-pyrrolidin-ylpiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl-
)-1H-1,2,4-triazole-3,5-diamine; [0383]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(piperidin-ylmethyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0384]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-a-
mino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-di-
amine; [0385]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
2-(dimethylamino)ethyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine; [0386]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
carboxymethyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine; [0387]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine; [0388]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole--
3,5-diamine; [0389]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]ann-
ulene-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0390]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine; [0391]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0392]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine; [0393]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine; [0394]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-
-1,2,4-triazole-3,5-diamine; [0395]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-
-1H-1,2,4-triazole-3,5-diamine; [0396]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annu-
lene-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0397]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine; [0398]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-tri-
azole-3,5-diamine; [0399]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3-
,5-diamine; [0400]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7s-
)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine; [0401]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine; [0402]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine; [0403]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine; [0404]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-t-
riazole-3,5-diamine; [0405]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,-
4-triazole-3,5-diamine; [0406]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2-
,4-triazole-3,5-diamine; [0407]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine; [0408]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine; [0409]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine; [0410]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-
-1H-1,2,4-triazole-3,5-diamine; [0411]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine; [0412]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((5-chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0413]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((2-carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene--
2-yl)-1H-1,2,4-triazole-3,5-diamine; [0414]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine; [0415]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine; [0416]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,-
4-triazole-3,5-diamine; [0417]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine; [0418]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine; [0419]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine; [0420]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl-
)-1H-1,2,4-triazole-3,5-diamine; [0421]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-be-
nzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0422]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benz-
o[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0423]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1-
,2,4-triazole-3,5-diamine; [0424]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine; [0425]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,-
2,4-triazole-3,5-diamine; [0426]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,-
4-triazole-3,5-diamine; [0427]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine; [0428]
1-(6,7-dihydro-5H-pyrido[2,3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
5-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine; [0429]
1-(6,7-dihydro-5H-pyrido[2,3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-tria-
zole-3,5-diamine; [0430]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-
-1,2,4-triazole-3,5-diamine; [0431]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine; [0432]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-
-1,2,4-triazole-3,5-diamine; [0433]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annu-
lene-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0434]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-
-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0435]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine; [0436]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N
.sup.3-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine; [0437]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine; [0438]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-
-1H-1,2,4-triazole-3,5-diamine; and [0439]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine.
[0440] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0441] R.sup.1, R.sup.4 and
R.sup.5 are each independently hydrogen; [0442] R.sup.2 is
heteroaryl optionally substituted by one or more substitutents
selected from the group consisting of alkyl, alkenyl, alkynyl,
halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, optionally substituted heteroarylalkynyl,
--R.sup.13--OR.sup.12, --R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12)--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); [0443]
R.sup.3 is a polycyclic heteroaryl containing more than 14 ring
atoms optionally substituted by one or more substituents selected
from the group consisting of oxo, thioxo, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--CN, --R.sup.9--O--R.sup.10--C(O)OR.sup.8,
--R.sup.9--O--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--O--R--S(O).sub.pR.sup.8 (where p is 0, 1 or 2),
--R.sup.9--O--R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--C(NR.sup.11)N(R.sup.11)H,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
each R.sup.6, each R.sup.7, each R.sup.8, each R.sup.9, each
R.sup.12, each R.sup.13 and each R.sup.14 are as described above
for compounds of formula (Ia); and [0444] each R.sup.6, each
R.sup.7, each R.sup.8, each R.sup.9, each R.sup.10, each R.sup.11,
each R.sup.12, each R.sup.13 and each R.sup.14 are as described
above for compounds of formula (Ia).
[0445] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0446] R.sup.2 is heteroaryl
selected from the group consisting of pyridinyl, pyrimidinyl,
4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-8-yl, benzo[d]imidazolyl,
6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl,
6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl,
5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl,
5,6,7,8-tetrahydroquinolin-3-yl,
1,2,3,4-tetrahydroisoquinolin-7-yl,
2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,
3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, benzo[d]oxazol-5-yl,
3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, benzo[b]thiophenyl, and
6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); and
[0447] R.sup.3 is a polycyclic heteroaryl containing more than 14
ring atoms selected from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxolane]-3--
yl,
5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1,3]dioxolane]-3-yl,
5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl,
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,
5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl
and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2).
[0448] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0449] R.sup.2 is selected from
the group consisting of pyridinyl and pyrimidinyl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2).
[0450] Another embodiment is the method where the compound of
formula (Ia), as set forth above, is selected from the group
consisting of: [0451]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(6-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)pyridin-3-yl)-1H-1,2,4--
triazole-3,5-diamine; [0452]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
4-cyclopentyl-1,4-diazepan-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamin-
e; [0453]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamin-
e; [0454]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.s-
up.3-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine-3-yl)-1H-1,2,4--
triazole-3,5-diamine; [0455]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(pyr-
idin-3-yl)-1H-1,2,4-triazole-3,5-diamine; [0456]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
6-aminopyridin-3-yl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;
[0457]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
3-aminophenyl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine; [0458]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
3-cyanophenyl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine; [0459]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
benzo[d][1,3]dioxole-6-yl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;
[0460]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(6-(3-methylsulfonamidylphenyl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-dia-
mine; [0461]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
2-diethylaminomethyl)pyrrolidin-1-ylpyridin-3-yl)-1H-1,2,4-triazole-3,5-di-
amine; [0462]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
3-diethylaminopyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;
[0463]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(6-(3-(4-(N-methylpiperazin-4-yl)piperidin-1-yl)-(E)-propenyl)pyridin-3-
-yl)-1H-1,2,4-triazole-3,5-diamine; [0464]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
4-(pyrrolidin-1-yl)piperidin-1-yl)-5-methylpyridin-3-yl)-1H-1,2,4-triazole-
-3,5-diamine; [0465]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
3-piperidin-1-yl-(E)-propenyl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;
[0466]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(6-(4-(bicyclo[2.2.1]heptan-2-yl)-1,4-diazepan-1-yl)pyridin-3-yl)-1H-1,-
2,4-triazole-3,5-diamine; [0467]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
3-(4-(pyrrolidin-1-yl)piperidin-1-yl)-(E)-propenyl)pyridin-3-yl)-1H-1,2,4--
triazole-3,5-diamine; [0468]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
3-piperidin-1-yl)-propanylpyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;
[0469]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(6-(3-(4-(piperidin-1-yl)piperidin-1-yl)-(E)-propenyl)pyridin-3-yl)-1H--
1,2,4-triazole-3,5-diamine; [0470]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
3-(4-dimethylaminopiperidin-1-yl)-(E)-propenyl)pyridin-3-yl)-1H-1,2,4-tria-
zole-3,5-diamine; [0471]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(2-(-
4-pyrrolidin-1-ylpiperidin-1-yl)pyrimidin-5-yl)-1H-1,2,4-triazole-3,5-diam-
ine; [0472]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(2-(-
4-(piperidin-1-ylmethyl)piperidin-1-yl)pyrimidin-5-yl)-1H-1,2,4-triazole-3-
,5-diamine; [0473]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
(4-piperidin-1-ylpiperidin-1-yl)carbonyl)pyridin-3-yl)-1H-1,2,4-triazole-3-
,5-diamine; [0474]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(2-(-
4-cyclopropylmethylpiperazin-1-yl)pyridine-5-yl)-1H-1,2,4-triazole-3,5-dia-
mine; and [0475]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(2-(-
3-(S)-methyl-4-cyclopropylmethylpiperazin-1-yl)pyridine-5-yl)-1H-1,2,4-tri-
azole-3,5-diamine.
[0476] Another embodiment is the method where, in the compound of
formula (Ia) as set forth above: [0477] R.sup.1, R.sup.4 and
R.sup.5 are each independently hydrogen; [0478] R.sup.2 is selected
from the group consisting of
4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-8-yl, benzo[d]imidazolyl,
6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl,
6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl,
5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl,
5,6,7,8-tetrahydroquinolin-3-yl,
1,2,3,4-tetrahydroisoquinolin-7-yl,
2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,
3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, benzo[d]oxazol-5-yl,
3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, benzo[b]thiophenyl, and
6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); and
[0479] R.sup.3 is a polycyclic heteroaryl containing more than 14
ring atoms selected from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxolane]-3--
yl,
5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1,3]dioxolane]-3-yl,
5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl,
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,
5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl
and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2).
[0480] Another embodiment is the method where the compound of
formula (Ia), as set forth above, is selected from the group
consisting of: [0481]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-8-yl)-1H-1,2,4-triazole-3,5-dia-
mine; [0482]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(2-(-
dimethylaminomethyl)-1H-benzo[d]imidazol-5-yl)-1H-1,2,4-triazole-3,5-diami-
ne; [0483]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.-
sup.3-(7-cyclopentyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl)-1H-1,-
2,4-triazole-3,5-diamine; [0484]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-m-
ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-1H-1,2,4-triazole-3,5-diam-
ine; [0485]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine-3-yl)-1H-1,2,4-triazole--
3,5-diamine; [0486]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
4-methylpiperazin-1-yl)carbonyl-5,6,7,
8-tetrahydroquinolin-3-yl)-1H-1,2,4-triazole-3,5-diamine, compound
#31, 1H-1,2,4-triazole-3,5-diamine; [0487]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(2,3-
,4,5-tetrahydrobenzo[b]oxepin-7-yl)-1H-1,2,4-triazole-3,5-diamine;
[0488]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(3,4-
-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1H-1,2,4-triazole-3,5-diamine;
[0489]
1-(6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl)-N.sup.3--
(2-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-5-yl)-1H-1,2,4-triazole-3,5-diami-
ne; [0490]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.-
sup.3-(4-(2-dimethylaminoethyl)-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl))-
-1H-1,2,4-triazole-3,5-diamine; [0491]
1-(6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl)-N.sup.3-(4-(2-d-
imethylaminoethyl)-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl))-1H-1,2,4-tri-
azole-3,5-diamine; [0492]
1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N.sup.3-(2-(1--
(4-(2-(dimethylamino)ethyl)piperazin-1-yl)oxomethyl)benzo[b]thiophen-5-yl)-
-1H-1,2,4-triazole-3,5-diamine; [0493]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-c-
yclopentyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)-1H-1,2,4-triazo-
le-3,5-diamine; [0494]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-yl)-1H-1,2,-
4-triazole-3,5-diamine; [0495]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3
(2-cyclopentyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5--
diamine; [0496]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-(-
pyrrolidin-1-yl)-5,6,7,8-tetrahydroquinolin-3-yl)-1H-1,2,4-triazole-3,5-di-
amine; [0497]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(6-c-
yclopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-1H-1,2,4-triazole-3,-
5-diamine; [0498]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((S)-
-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-yl)-1H--
1,2,4-triazole-3,5-diamine; [0499]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(1,2-
,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine;
[0500]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(2-(-
1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triaz-
ole-3,5-diamine; and [0501]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(2-(-
cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3-
,5-diamine.
[0502] Another embodiment is the method where the compound of
formula (Ia), as set forth above, is a compound of formula
(Ia1):
##STR00008##
wherein: [0503] A is .dbd.C(H)-- or .dbd.N--; [0504] each R.sup.2a
is independently selected from the group consisting of
--N(R.sup.12a).sub.2 and --N(R.sup.12a)C(O)R.sup.12a, [0505] or
R.sup.2a is an N-heterocyclyl optionally substituted by one or more
substituents selected from the group consisting of halo and
--R.sup.21--C(O)OR.sup.20, [0506] each R.sup.12a is independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heteroaryl and optionally substituted heteroarylalkyl; [0507]
R.sup.20 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heteroaryl and optionally
substituted heteroarylalkyl; and [0508] R.sup.21 is independently
selected from the group consisting of a direct bond or an
optionally substituted straight or branched alkylene chain; [0509]
as an isolated stereoisomer or mixture thereof, or a
pharmaceutically acceptable salt thereof.
[0510] Of the embodiment of utilizing a compound of formula (I), as
set forth above in the Summary of the Invention, in the methods of
the invention, another embodiment is wherein the compound of
formula (I) is a compound of formula (Ib):
##STR00009##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as
described above in the Summary of the Invention for compounds of
formula (I), as an isolated stereoisomer or mixture thereof or as a
tautomer or mixture thereof, or a pharmaceutically acceptable salt
or N-oxide thereof.
[0511] Another embodiment is the method where, in the compound of
formula (Ib) as set forth above, R.sup.2 and R.sup.3 are each
independently a polycyclic heteroaryl containing more than 14 ring
atoms optionally substituted by one or more substituents selected
from the group consisting of oxo, thioxo, cyano, nitro, halo,
haloalkyl, alkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--CN, --R.sup.9--O--R.sup.10--C(O)OR.sup.8,
--R.sup.9--O--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--O--R--S(O).sub.pR.sup.8 (where p is 0, 1 or 2),
--R.sup.9--O--R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--C(NR.sup.11)N(R.sup.11)H,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2); and
R.sup.1, R.sup.4, R.sup.5, each R.sup.6, each R.sup.7, each
R.sup.8, each R.sup.9, each R.sup.10, each R.sup.11 and R.sup.12
are as described above in the Summary of the Invention.
[0512] Another embodiment is the method where, in the compound of
formula (Ib) as set forth above: [0513] R.sup.1, R.sup.4 and
R.sup.5 are each hydrogen; [0514] each R.sup.6 and R.sup.7 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.10--OR.sup.8, --R.sup.10--CN,
--R.sup.10--NO.sub.2, --R.sup.10--N(R.sup.8).sub.2,
--R.sup.10--C(O)OR.sup.8 and --R.sup.10--C(O)N(R.sup.8).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0515] each R.sup.8 is
independently selected from the group consisting of hydrogen,
alkyl, haloalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted cycloalkyl, optionally
substituted cycloalkylalkyl, optionally substituted heterocyclyl,
optionally substituted heterocyclylalkyl, optionally substituted
heteroaryl, and optionally substituted heteroarylalkyl; [0516] each
R.sup.9 is independently selected from the group consisting of a
direct bond and an optionally substituted straight or branched
alkylene chain; [0517] each R.sup.10 is an optionally substituted
straight or branched alkylene chain; and [0518] each R.sup.11 is
independently selected from the group consisting of hydrogen,
alkyl, cyano, nitro and --OR.sup.8.
[0519] Another embodiment is the method where, in the compound of
formula (Ib) as set forth above: [0520] R.sup.2 and R.sup.3 are
each independently a polycyclic heteroaryl containing more than 14
ring atoms selected from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxolane]-3--
yl,
5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1,3]dioxolane]-3-yl,
5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl,
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,
5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl
and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2)
[0521] Another embodiment is the method where the compound of
formula (Ib), as set forth above, is
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(5,7-
,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'[1,3]dioxolane]-3-yl)-1H-1,-
2,4-triazole-3,5-diamine.
[0522] Another embodiment is the method where, in the compound of
formula (Ib) as set forth above: [0523] R.sup.2 is selected from
the group consisting of aryl and heteroaryl, where the aryl and the
heteroaryl are each independently optionally substituted by one or
more substitutents selected from the group consisting of alkyl,
alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heterocyclylalkenyl,
optionally substituted heterocyclylalkynyl, optionally substituted
heteroaryl, optionally substituted heteroarylalkyl, optionally
substituted heteroarylalkenyl, optionally substituted
heteroarylalkynyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); and
[0524] R.sup.3 is a polycyclic heteroaryl containing more than 14
ring atoms optionally substituted by one or more substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heteroaryl, optionally substituted heterocyclyl,
--R.sup.9--OR.sup.8, --R.sup.9--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--CN, --R.sup.9--O--R.sup.10--C(O)OR.sup.8,
--R.sup.9--O--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--S(O).sub.pR.sup.8 (where p is 0, 1 or 2),
--R.sup.9--O--R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--C(NR.sup.11)N(R.sup.11)H,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2).
[0525] Another embodiment is the method where, in the compound of
formula (Ib) as set forth above: [0526] R.sup.1, R.sup.4 and
R.sup.5 are each independently hydrogen; [0527] each R.sup.6 and
R.sup.7 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,
optionally substituted aryl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.10--OR.sup.8,
--R.sup.10--CN, --R.sup.10--NO.sub.2, --R.sup.10--N(R.sup.8).sub.2,
--R.sup.10--C(O)OR.sup.8 and --R.sup.10--C(O)N(R.sup.8).sub.2, or
any R.sup.6 and R.sup.7, together with the common nitrogen to which
they are both attached, form an optionally substituted N-heteroaryl
or an optionally substituted N-heterocyclyl; [0528] each R.sup.8 is
independently selected from the group consisting of hydrogen,
alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, and optionally substituted heteroarylalkyl;
[0529] each R.sup.9 is independently selected from the group
consisting of a direct bond and an optionally substituted straight
or branched alkylene chain; [0530] each R.sup.10 is an optionally
substituted straight or branched alkylene chain; [0531] each
R.sup.11 is independently selected from the group consisting of
hydrogen, alkyl, cyano, nitro and --OR.sup.8; [0532] each R.sup.12
is independently selected from the group consisting of hydrogen,
alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl and optionally substituted heteroarylalkyl,
or two R.sup.12's, together with the common nitrogen to which they
are both attached, form an optionally substituted N-heterocyclyl or
an optionally substituted N-heteroaryl; [0533] each R.sup.13 is
independently selected from the group consisting of a direct bond
and an optionally substituted straight or branched alkylene chain;
and [0534] each R.sup.14 is an optionally substituted straight or
branched alkylene chain.
[0535] Another embodiment is the method where, in the compound of
formula (Ib) as set forth above: [0536] R.sup.2 is aryl optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); and
[0537] R.sup.3 is a polycyclic heteroaryl containing more than 14
ring atoms optionally substituted by one or more substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heteroaryl, optionally substituted heterocyclyl,
--R.sup.9--OR.sup.8, --R.sup.9--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--CN, --R.sup.9--O--R.sup.10--C(O)OR.sup.8,
--R.sup.9--O--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--O--R--S(O).sub.pR.sup.8 (where p is 0, 1 or 2),
--R.sup.9--O--R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--C(NR.sup.11)N(R.sup.11)H,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2);
[0538] Another embodiment is the method where, in the compound of
formula (Ib) as set forth above: [0539] R.sup.1, R.sup.4 and
R.sup.5 are each independently hydrogen; [0540] R.sup.2 is aryl
selected from the group consisting of phenyl and
6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
cycloalkylalkynyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heterocyclylalkynyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, optionally substituted heteroarylalkenyl,
optionally substituted heteroarylalkynyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); and
[0541] R.sup.3 is a polycyclic heteroaryl containing more than 14
ring atoms selected from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxolane]-3--
yl,
5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1,3]dioxolane]-3-yl,
5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl,
6,7-dihydro-5H-benzo [2,3]thiepino[4,5-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,
5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl
and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2).
[0542] Another embodiment is the method where, in the compound of
formula (Ib) as set forth above: [0543] R.sup.2 is phenyl
optionally substituted by one or more substitutents selected from
the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2).
[0544] Another embodiment is the method where the compound of
formula (Ib), as set forth above, is selected from the group
consisting of: [0545]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.5-(3-fluoro-4-(4-(indolin-2-on-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triaz-
ole-3,5-diamine; [0546]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(3-fluoro--
4-(4-(morpholin-4-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0547]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.5-(4-(3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0548]
1-(7-methyl-6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl)-
-N.sup.5-(4-(N-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0549]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.5-(4-((5-fluoroindolin-2-on-3-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0550]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(4-(-
4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0551]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(4-(-
(4-pyrrolidin-1-ylpiperidinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine-
; [0552]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.su-
p.5-(4-((4-cyclopentylpiperazinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-dia-
mine; [0553]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(4-(-
(4-isopropylpiperazinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0554]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.5-(3-fluoro-4-(4-N-methylpiperid-4-ylpiperazinyl)phenyl)-1H-1,2,4-triazol-
e-3,5-diamine; [0555]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(3-f-
luoro-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)-1H-1,2,4-triazole--
3,5-diamine; [0556]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(3-f-
luoro-4-(3-pyrrolidin-1-ylazetidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine-
; [0557]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(3-
-methyl-4-(4-(N-methylpiperazin-4-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triaz-
ole-3,5-diamine; [0558]
1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N.sup.5-(4-(4--
pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0559]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(3-fluoro--
(4-(3-pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamin-
e; [0560]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(-
3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
and [0561]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(3-f-
luoro-4-(4-cyclopropylmethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-d-
iamine.
[0562] Another embodiment is the method where, in the compound of
formula (Ib) as set forth above: [0563] R.sup.1, R.sup.4 and
R.sup.5 are each independently hydrogen; [0564] R.sup.2 is
6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl optionally substituted
by one or more substitutents selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl,
oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted cycloalkyl, optionally substituted cycloalkylalkyl,
optionally substituted cycloalkylalkenyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); and
[0565] R.sup.3 is a polycyclic heteroaryl containing more than 14
ring atoms selected from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxolane]-3--
yl,
5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1,3]dioxolane]-3-yl,
5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl,
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,
5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl
and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2).
[0566] Another embodiment is the method where the compound of
formula (Ib), as set forth above, is selected from the group
consisting of: [0567]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7--
(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-tr-
iazole-3,5-diamine; [0568]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-((7S)-7-(t-
-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,-
4-triazole-3,5-diamine; [0569]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(7-(-
(bicyclo[2.2.1]heptan-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]an-
nulene-2-yl)-1H-1,2,4-triazole-3,5-diamine; and [0570]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(7-(-
S)-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-t-
riazole-3,5-diamine.
[0571] Another embodiment is the method where, in the compound of
formula (Ib) as set forth above: [0572] R.sup.1, R.sup.4 and
R.sup.5 are each independently hydrogen; [0573] R.sup.2 is
heteroaryl optionally substituted by one or more substitutents
selected from the group consisting of alkyl, alkenyl, alkynyl,
halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted cycloalkylalkenyl,
optionally substituted cycloalkylalkynyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heterocyclylalkenyl, optionally substituted
heterocyclylalkynyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, optionally substituted heteroarylalkynyl,
--R.sup.13--OR.sup.12, --R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.2 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.2).sub.2 (where t is 1 or 2); and
[0574] R.sup.3 is a polycyclic heteroaryl containing more than 14
ring atoms optionally substituted by one or more substituents
selected from the group consisting of oxo, thioxo, cyano, nitro,
halo, haloalkyl, alkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
heteroaryl, optionally substituted heterocyclyl,
--R.sup.9--OR.sup.8, --R.sup.9--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--O--R.sup.10--OR.sup.8,
--R.sup.9--O--R.sup.10--CN, --R.sup.9--O--R.sup.10--C(O)OR.sup.8,
--R.sup.9--O--R.sup.10--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--O--R--S(O).sub.pR.sup.8 (where p is 0, 1 or 2),
--R.sup.9--O--R.sup.10--N(R.sup.6)R.sup.7,
--R.sup.9--O--R.sup.10--C(NR.sup.11)N(R.sup.11)H,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2);
[0575] Another embodiment is the method where, in the compound of
formula (Ib) as set forth above: [0576] R.sup.2 is heteroaryl
selected from the group consisting of pyridinyl, pyrimidinyl,
4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-8-yl, benzo[d]imidazolyl,
6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl,
6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl,
5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl,
5,6,7,8-tetrahydroquinolin-3-yl,
1,2,3,4-tetrahydroisoquinolin-7-yl,
2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,
3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, benzo[d]oxazol-5-yl,
3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, benzo[b]thiophenyl, and
6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl, each optionally
substituted by one or more substitutents selected from the group
consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
cycloalkylalkenyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted
heterocyclylalkenyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, optionally substituted
heteroarylalkenyl, --R.sup.13--OR.sup.12,
--R.sup.13--OC(O)--R.sup.12,
--R.sup.13--O--R.sup.14--N(R.sup.12).sub.2,
--R.sup.13--N(R.sup.12).sub.2, --R.sup.13--C(O)R.sup.12,
--R.sup.13--C(O)OR.sup.12, --R.sup.13--C(O)N(R.sup.12).sub.2,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--N(R.sup.12)R.sup.13,
--R.sup.13--C(O)N(R.sup.12)--R.sup.14--OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)OR.sup.12,
--R.sup.13--N(R.sup.12)C(O)R.sup.12,
--R.sup.13--N(R.sup.12)S(O).sub.tR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.tOR.sup.12 (where t is 1 or 2),
--R.sup.13--S(O).sub.pR.sup.12 (where p is 0, 1 or 2), and
--R.sup.13--S(O).sub.tN(R.sup.12).sub.2 (where t is 1 or 2); and
[0577] R.sup.3 is a polycyclic heteroaryl containing more than 14
ring atoms selected from the group consisting of
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,
6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,
(Z)-dibenzo[b,f][1,4]thiazepin-1 l-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,
6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,
spiro[chromeno[4,3-c]pyridazine-5,1'-cyclopentane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxolane]-3--
yl,
5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2'-[1,3]dioxolane]-3-yl,
5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2'-[1,3]dioxolane]-3-yl,
6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,
5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2'-[1,3]dioxolane]-3-yl,
6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl
and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each
optionally substituted by one or more substituents selected from
the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,
alkyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted heteroaryl, optionally
substituted heterocyclyl, --R.sup.9--OR.sup.8,
--R.sup.9--OC(O)--R.sup.8, --R.sup.9--N(R.sup.6)R.sup.7,
--R.sup.9--C(O)R.sup.8, --R.sup.9--C(O)OR.sup.8,
--R.sup.9--C(O)N(R.sup.6)R.sup.7,
--R.sup.9--N(R.sup.6)C(O)OR.sup.12,
--R.sup.9--N(R.sup.6)C(O)R.sup.8,
--R.sup.9--N(R.sup.6)S(O).sub.tR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.tOR.sup.8 (where t is 1 or 2),
--R.sup.9--S(O).sub.pR.sup.8 (where p is 0, 1 or 2), and
--R.sup.9--S(O).sub.tN(R.sup.6)R.sup.7 (where t is 1 or 2).
[0578] Another embodiment is the method where the compound of
formula (Ib), as set forth above, is selected from the group
consisting of: [0579]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.5-(6-(4-(pyrrolidin-1-yl)piperidin-1-yl)-5-methylpyridin-3-yl)-1H-1,2,4-t-
riazole-3,5-diamine; [0580]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(4-(-
3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;
[0581]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(1,2-
,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine; and
[0582]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(2-(1-meth-
ylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,-
5-diamine.
[0583] Another embodiment is the method where the compound of
formula (Ib), as set forth above, is a compound of formula
(Ib1):
##STR00010##
wherein: [0584] A is .dbd.C(H)-- or .dbd.N--; [0585] each R.sup.2a
is independently selected from the group consisting of
--N(R.sup.12a).sub.2 and --N(R.sup.12a)C(O)R.sup.12a, [0586] or
R.sup.2a is an N-heterocyclyl optionally substituted by one or more
substituents selected from the group consisting of halo and
--R.sup.21--C(O)OR.sup.20, [0587] each R.sup.12a is independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heteroaryl and optionally substituted heteroarylalkyl; [0588]
R.sup.20 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heteroaryl and optionally
substituted heteroarylalkyl; and [0589] R.sup.21 is independently
selected from the group consisting of a direct bond or an
optionally substituted straight or branched alkylene chain; [0590]
as an isolated stereoisomer or mixture thereof, or a
pharmaceutically acceptable salt thereof.
[0591] In one embodiment of the methods of preventing, treating or
managing cancer in a patient comprising administering to the
patient in need thereof a therapeutically or prophylactically
effective amount of an Axl inhibitor in combination with the
administration of a therapeutically or prophylactically effective
amount of one or more chemotherapeutic agents, the one or more
chemotherapeutic agents is selected from the group consisting of
antimetabolites, alkylating agents, coordination compounds,
platinum complexes, DNA cross-linking compounds, inhibitors of
transcription enzymes, tyrosine kinase inhibitors, protein kinase
inhibitors, topoisomerase inhibitors, DNA minor-groove binding
compounds, vinca alkyloids, taxanes, antitumor antibiotics,
hormones, aromatase inhibitors, enzymes, growth factor receptors
antibodies, cytokines, cell surface markers antibodies, HDAC
inhibitors, HSP 90 inhibitors, BCL-2 inhibitors, mTOR inhibitors,
proteasome inhibitors and monoclonal antibodies.
[0592] In another embodiment of methods of preventing, treating or
managing cancer in a patient comprising administering to the
patient in need thereof a therapeutically or prophylactically
effective amount of an Axl inhibitor in combination with the
administration of a therapeutically or prophylactically effective
amount of one or more chemotherapeutic agents, the one or more
chemotherapeutic agents are independently selected from the group
consisting of mechlorothamine, cyclophosphamide, ifosfamide,
melphalan, chlorambucil, ethyleneimines, methylmelamines,
procarbazine, dacarbazine, temozolomide, busulfan, carmustine,
lomustine, methotrexate, fluorouracil, capecitabine, cytarabine,
gemcitabine, cytosine arabinoside, mecaptopurine, fludarabine,
cladribine, thioguanine, azathioprine, vinblastine, vincristine,
paclitaxel, docetaxel, colchicine, actinomycin D, daunorubicin,
bleomycin, L-asparaginase, cisplatin, carboplatin, oxaliplatin,
prednisone, dexamethasone, amino glutethimide, formestane,
anastrozole, hydroxyprogesterone caproate, medroxyprogesterone,
tamoxifen, amsacrine, mitoxantrone, topotecan, irinotecan,
camptothecin, axtinib, bosutinib, cediranib, dasatinib, erlotinib,
gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib,
sunitinib, vandetanib, vatalanib, anti-Her2 antibodies,
interferon-.alpha., interferon-.gamma., interleukin-2, GM-CSF,
anti-CTLA-4 antibodies, rituximab, anti-CD33 antibodies, MGCD0103,
vorinostat, 17-AAG, thalidomide, lenalidomide, rapamycin, CCI-779,
sorafenib, doxorubicine, gemcitabine, melphalan, bortezomib,
NPI052, gemtuzumab, alemtuzumab, ibritumomab tiuxaetan,
tositumomab, iodine-131 tositumomab, trastuzumab, bevacizumab,
rituximab, and anti-TRAIL death receptor antibodies.
[0593] In another embodiment of methods of preventing, treating or
managing cancer in a patient comprising administering to the
patient in need thereof a therapeutically or prophylactically
effective amount of an Axl inhibitor in combination with the
administration of a therapeutically or prophylactically effective
amount of one or more chemotherapeutic agents, the one or more
chemotherapeutic agents are independently selected from the group
consisting of paclitaxel, cyclophosphamide, 5-fluorouracil,
cisplatin, carboplatin, methotrexate and imitanib.
[0594] Preferably, one embodiment of the methods of preventing,
treating or managing cancer, preferably metastatic cancer, in a
patient comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, is the method wherein the Axl inhibitor is
a compound of formula (I) selected from the group consisting of:
[0595]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-tri-
azole-3,5-diamine; [0596]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-
-triazole-3,5-diamine; [0597]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-
-triazole-3,5-diamine; [0598]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazol-
e-3,5-diamine; [0599]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(7-(-
pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-tri-
azole-3,5-diamine; [0600]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(S)-pyr-
rolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazol-
e-3,5-diamine; [0601]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine; [0602]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole--
3,5-diamine; [0603]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]ann-
ulene-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0604]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine; [0605]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0606]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine; [0607]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine; [0608]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-
-1,2,4-triazole-3,5-diamine; [0609]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
(carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-
-1H-1,2,4-triazole-3,5-diamine; [0610]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annu-
lene-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0611]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine; [0612]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-tri-
azole-3,5-diamine; [0613]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3-
,5-diamine; [0614]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7s-
)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine; [0615]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine; [0616]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine; [0617]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine; [0618]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-t-
riazole-3,5-diamine; [0619]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,-
4-triazole-3,5-diamine; [0620]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2-
,4-triazole-3,5-diamine; [0621]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine; [0622]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine; [0623]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine; [0624]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-
-1H-1,2,4-triazole-3, 5-diamine; [0625]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine; [0626]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((5-chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0627]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((2-carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene--
2-yl)-1H-1,2,4-triazole-3,5-diamine; [0628]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine; [0629]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine; [0630]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,-
4-triazole-3,5-diamine; [0631]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4--
triazole-3,5-diamine; [0632]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine; [0633]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine; [0634]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl-
)-1H-1,2,4-triazole-3,5-diamine; [0635]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-be-
nzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0636]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benz-
o[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0637]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1-
,2,4-triazole-3,5-diamine; [0638]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine; [0639]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,-
2,4-triazole-3,5-diamine; [0640]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,-
4-triazole-3,5-diamine; [0641]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine; [0642]
1-(6,7-dihydro-5H-pyrido[2,3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
5-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine; [0643]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-tri-
azole-3,5-diamine; [0644]
1-(6,7-dihydro-5H-pyrido[2,3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine; [0645]
1-(6,7-dihydro-5H-pyrido[2',3:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1-
,2,4-triazole-3,5-diamine; [0646]
1-(6,7-dihydro-5H-pyrido[2',3:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine; [0647]
1-(6,7-dihydro-5H-pyrido[2',3:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annul-
ene-2-yl)-1H-1,2,4-triazole-3,5-diamine; [0648]
1-(6,7-dihydro-5H-pyrido[2',3:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene--
2-yl)-1H-1,2,4-triazole-3,5-diamine; [0649]
1-(6,7-dihydro-5H-pyrido[2',3:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine; [0650]
1-(6,7-dihydro-5H-pyrido[2,3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine; [0651]
1-(6,7-dihydro-5H-pyrido[2,3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl-
)-1H-1,2,4-triazole-3,5-diamine; [0652]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-
-1H-1,2,4-triazole-3,5-diamine; and [0653]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine; and the one or more chemotherapeutic
agents is selected from the group consisting of paclitaxel,
cyclophosphamide, 5-fluorouracil, cisplatin, carboplatin,
methotrexate and imitanib.
[0654] Preferably, one embodiment of the methods of preventing,
treating or managing cancer, preferably metastatic cancer, in a
patient comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, is the method wherein the Axl inhibitor is
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-(7-(-
pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-tri-
azole-3,5-diamine.
[0655] Preferably, another embodiment of the methods of preventing,
treating or managing cancer, preferably metastatic cancer, in a
patient comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, is the method wherein the Axl inhibitor is
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-
-triazole-3,5-diamine.
[0656] Preferably, another embodiment of the methods of preventing,
treating or managing cancer, preferably metastatic cancer, in a
patient comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, is the method wherein the Axl inhibitor is
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-
-triazole-3,5-diamine.
[0657] Preferably, another embodiment of the methods of preventing,
treating or managing cancer, preferably metastatic cancer, in a
patient comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, is the method wherein the Axl inhibitor is
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup-
.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazol-
e-3,5-diamine.
[0658] Preferably, another embodiment of the methods of preventing,
treating or managing cancer, preferably metastatic cancer, in a
patient comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, is the method wherein the Axl inhibitor is
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(7-(-
pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-tri-
azole-3,5-diamine.
[0659] Preferably, another embodiment of the methods of preventing,
treating or managing cancer, preferably metastatic cancer, in a
patient comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, is the method wherein the Axl inhibitor is
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.5-(7-(-
S)-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-t-
riazole-3,5-diamine.
[0660] Preferably, in one embodiment, in any of the above
embodiments of the methods of preventing, treating or managing
cancer, preferably metastatic cancer, in a patient comprising
administering to the patient in need thereof a therapeutically or
prophylactically effective amount of an Axl inhibitor in
combination with the administration of a therapeutically or
prophylactically effective amount of one or more chemotherapeutic
agents, the one or more chemotherapeutic agents is cisplatin.
[0661] Preferably, in another embodiment, in any of the above
embodiments of the methods of preventing, treating or managing
cancer, preferably metastatic cancer, in a patient comprising
administering to the patient in need thereof a therapeutically or
prophylactically effective amount of an Axl inhibitor in
combination with the administration of a therapeutically or
prophylactically effective amount of one or more chemotherapeutic
agents, the one or more chemotherapeutic agents is paclitaxel.
[0662] Preferably, in another embodiment, in any of the above
embodiments of the methods of preventing, treating or managing
cancer, preferably metastatic cancer, in a patient comprising
administering to the patient in need thereof a therapeutically or
prophylactically effective amount of an Axl inhibitor in
combination with the administration of a therapeutically or
prophylactically effective amount of one or more chemotherapeutic
agents, the one or more chemotherapeutic agents is imitanib.
[0663] In one embodiment of the methods of preventing, treating or
managing cancer, preferably metastatic cancer, in a patient
comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, the method prevents metastatic cancer.
[0664] In another embodiment of the methods of preventing, treating
or managing cancer, preferably metastatic cancer, in a patient
comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, the method treats metastatic cancer.
[0665] In another embodiment of the methods of preventing, treating
or managing cancer, preferably metastatic cancer, in a patient
comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, the method manages metastatic cancer.
[0666] In one embodiment of the methods of preventing, treating or
managing cancer, preferably metastatic cancer, in a patient
comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, the Axl inhibitor is administered to the
patient, preferably a human, in an amount of between about 1 mg/kg
and about 100 mg/kg twice a day, preferably between about 5 mg/kg
and about 80 mg/kg twice a day, even more preferably between about
5 mg/kg and about 25 mg/kg twice a day, and the chemotherapeutic
agent is administered to the mammal in an amount of between about
1.0 mg/kg and about 10.0 mg/kg once a week, preferably between
about 1.0 mg/kg and about 5 mg/kg once a week, even more preferably
between about 1.0 mg/kg and 2.0 mg/kg once a week.
[0667] In one embodiment of the methods of preventing, treating or
managing cancer, preferably metastatic cancer, in a patient
comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, the Axl inhibitor is administered to the
patient, preferably a human, at the same time that the one or more
chemotherapeutic agent is administered to the patient.
[0668] In one embodiment of the methods of preventing, treating or
managing cancer, preferably metastatic cancer, in a patient
comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, the Axl inhibitor is administered to the
patient, preferably a human, concurrently with the administration
of the one or more chemotherapeutic agent is administered to the
patient.
[0669] In another embodiment of the methods of preventing, treating
or managing cancer, preferably metastatic cancer, in a patient
comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, the Axl inhibitor is administered to the
patient, preferably a human, prior to the administration of the one
or more chemotherapeutic agent is administered to the patient.
[0670] In another embodiment of the methods of preventing, treating
or managing cancer, preferably metastatic cancer, in a patient
comprising administering to the patient in need thereof a
therapeutically or prophylactically effective amount of an Axl
inhibitor in combination with the administration of a
therapeutically or prophylactically effective amount of one or more
chemotherapeutic agents, the Axl inhibitor is administered to the
patient, preferably a human, sequentially to the administration of
the one or more chemotherapeutic agent is administered to the
patient.
[0671] Specific embodiments of the invention are described in more
detail in the following sections.
Utility and Testing of the Combination Therapies of the
Invention
[0672] In the combination therapies of the invention, an Axl
inhibitor, preferably a compound of formula (I), as set forth in
the Summary of the Invention, is used as an active ingredient in
combination with one or more chemotherapeutic agents in the
prevention, treatment or management of one or more cancers,
preferably metastatic cancers. Preferably, such combination
therapies of the present invention will exert greater than additive
effects, i.e., synergistic effects, as the mechanisms of action
employed for the Axl inhibitor and the one or more chemotherapeutic
agents may be different and each may act independently of one
another. Accordingly, as used herein "combination therapy" refers
to the administration of an Axl inhibitor, preferably a compound of
formula (I) as set forth above in the Summary of the Invention, in
combination with the administration of one or more chemotherapeutic
agents for the prevention, treatment and management of one or more
cancers, preferably metastatic cancer. Unless the context makes
clear otherwise, "combination therapy" may include simultaneous or
sequential administration of the Axl inhibitor and the one or more
chemotherapeutic agents, in any order, such as administering the
Axl inhibitor at the same time as the administration of the one or
more chemotherapeutic agents, before the administration of the one
or more chemotherapeutic agents or after the administration of the
one or more chemotherapeutic agents. Unless the context makes clear
otherwise, "combination therapy" may include the administration of
dosage forms of an Axl inhibitor combined with the dosage forms of
one or more chemotherapeutic agents. Unless the context makes clear
otherwise, "combination therapy" may include different routes of
administration for the Axl inhibitor and for the one or more
chemotherapeutic agent. Dosage forms, routes of administration and
pharmaceutical compositions include, but are not limited to, those
described herein.
[0673] The oncogenic receptor tyrosine kinase, Axl, was recently
identified, using a retroviral-based functional genetic screening
protocol, as a regulator of haptotactic migration, which is a key
event in angiogenesis. Inhibition of Axl by RNAi-mediated silencing
blocked endothelial cell migration, proliferation and in vitro tube
formation. These observations, which were disclosed at the American
Association Cancer Research General Meeting, Apr. 16-20, 2005,
Anaheim, Calif., and The 7th Annual Symposium on Anti-Angiogenic
Agents, Feb. 10-13, 2005, San Diego, Calif.; (Requirement for The
Receptor Tyrosine Kinase Axl in Angiogenesis and Tumor Growth,
Holland, S. J. Powell, M. J., Franci, C., Chan, E., Friera, A. M.,
Atchison, R., Xu, W., McLaughlin, J., Swift, S. E., Pali, E., Yam,
G., Wong, S., Xu, X., Hu, Y., Lasaga, J., Shen, M., Yu, S., Daniel,
R., Hitoshi, Y., Bogenberger, J., Nor, J. E., Payan, D. G and
Lorens, J. B), were substantiated by an in vivo study which
demonstrated that stable, shRNAi-mediated Axl knockdown impaired
formation of functional human blood vessels in a mouse model of
human angiogenesis. These observations were published in a peer
reviewed journal (Holland S J, Powell M J, Franci C, Chan E W,
Friera A M, Atchison R E, McLaughlin J, Swift S E, Pali E S, Yam G,
Wong S, Lasaga J, Shen M R, Yu S, Xu W, Hitoshi Y, Bogenberger J,
Nor J E, Payan D G, Lorens J B. "Multiple roles for the receptor
tyrosine kinase axl in tumor formation", Cancer Res. (2005) Vol.
65, pp 9294-303. These observations are also disclosed in U.S.
Published Patent Application 2005/0118604 and European Patent
Application 1 563 094, the disclosures of which are incorporated in
full by reference. Axl signaling, therefore, impacts multiple
functions required for neovascularization in vitro, and regulates
angiogenesis in vivo. Regulation of these pro-angiogenic processes
required the catalytic activity of Axl. Thus, Axl-mediated
angiogenic stimulation would be amenable to modulation by a small
molecule inhibitor of Axl catalytic activity.
[0674] Accordingly, Axl inhibitors contemplated for use in the
combination therapies of the invention are disclosed in U.S.
Published Patent Application No. 20070213375, U.S. Published Patent
Application No. 20080153815, U.S. Published Patent Application No.
20080188454, U.S. Published Patent Application No. 20080176847,
U.S. Published Patent Application No. 20080188455, U.S. Published
Patent Application No. 20080182862, U.S. Published Patent
Application No. 20080188474, U.S. Published Patent Application No.
20080117789, U.S. Published Patent Application No. 20090111816, PCT
Published Patent Application No. WO 2007/0030680, PCT Published
Patent Application No. WO 2008/045978, PCT Published Patent
Application No. WO 2008/083353, PCT Published Patent Application
No. WO 2008/0083357, PCT Published Patent Application No. WO
2008/083367, PCT Published Patent Application No. WO 2008/083354,
PCT Published Patent Application No. WO 2008/083356, PCT Published
Patent Application No. WO 2008/080134, and PCT Published Patent
Application No. WO 2009/054864, the disclosures of which are
incorporated in full by reference herein in their entireties. The
Axl inhibitors disclosed in PCT Published Patent Application No. WO
2008/083367 are particularly preferred for use in the combination
therapies of the invention.
[0675] The compounds of formula (I), as set forth above in the
Summary of the Invention, are small molecule inhibitors of Axl
catalytic activity, and are therefore useful in treating diseases
and conditions which are associated with Axl catalytic activity,
including those diseases and conditions which are characterized by
angiogenesis and/or cell proliferation. In particular, the
compounds of formula (I) are useful in treating diseases and
conditions which are alleviated by the modulation of Axl activity.
Diseases and conditions which are alleviated by the "modulation of
Axl activity" includes diseases and conditions which are alleviated
by a decrease in Axl activity and diseases and conditions which are
alleviated by an increase in Axl activity. Preferably such diseases
and conditions are alleviated by a decrease in Axl activity (i.e.,
inhibition of Axl activity). Diseases and conditions which are
alleviated by the modulation of Axl activity include, but are not
limited to, solid cancer tumors, including, but not limited to,
breast, renal, endometrial, ovarian, thyroid, and non-small cell
lung carcinoma, melanoma, prostate carcinoma, sarcoma, gastric
cancer and uveal melanoma; liquid tumors, including but not limited
to, leukemias (particularly myeloid leukemias) and lymphomas;
endometriosis, vascular disease/injury (including but not limited
to restenosis, atherosclerosis and thrombosis), psoriasis; visual
impairment due to macular degeneration; diabetic retinopathy and
retinopathy of prematurity; kidney disease (including but not
limited to glomerulonephritis, diabetic nephropathy and renal
transplant rejection), rheumatoid arthritis; osteoarthritis,
osteoporosis and cataracts.
[0676] In addition to the foregoing, the compounds of formula (I)
are useful in treating diseases and conditions which are affected
by the following biological processes: Invasion, migration,
metastasis, or drug resistance as manifested in cancer; stem cell
biology as manifested in cancer; invasion, migration, adhesion, or
angiogenesis as manifested in endometriosis; vascular remodeling as
manifested in cardiovascular disease, hypertension or vascular
injury; bone homeostatasis as manifested in osteoporosis or
osteoarthritis; viral infection as manifested, for example, in
ebola virus infection; or differentiation as manifested in obesity.
The compounds of formula (I) may also be used to modulate
inflammatory processes by treating sepsis, acting as vaccine
adjuvants, and/or potentiating the immune response in
immuno-compromised patients.
[0677] In a preferred embodiment, the compounds of formula (I) are
useful in preventing, treating and managing cancers, preferably
metastatic cancers.
[0678] The chemotherapeutic agents utilized in the combination
therapies of the invention may be general cytotoxic agents or may
target a specific cellular molecule. Preferably, the
chemotherapeutic agents utilized in the combination therapies of
the invention are useful in the prevention, treatment and
management of one or more cancers, preferably metastatic cancers.
Various classes of chemotherapeutic agents for the treatment of
cancer include, among others, antimetabolites, agents that react
with DNA (e.g., alkylating agents, coordination compounds, platinum
complexes, DNA cross-linking compounds, etc.), inhibitors of
transcription enzymes, tyrosine kinase inhibitors, topoisomerase
inhibitors, DNA minor-groove binding compounds, antimitotic agents
(e.g., vinca alkyloids and taxanes), antitumor antibiotics,
hormones, and enzymes. Exemplary DNA cross-linking drugs and
alkylating agents include, by way of example and not limitation,
mechlorothamine, cyclophosphamide, ifosfamide, melphalan,
chlorambucil, ethyleneimines, methylmelamines, procarbazine,
dacarbazine, temozolomide, alkyl sulfonates (e.g., busulfan),
carmustine and lomustine. Exemplary antimetabolites include, by way
of example and not limitation, folate antagonists, e.g.,
methotrexate; pyrimidine antagonists, e.g., fluorouracil,
capecitabine, cytarabine, gemcitabine and cytosine arabinoside; and
purine analogs, e.g., mecaptopurine, fludarabine, cladribine,
thioguanine and azathioprine. Exemplary taxanes and vinca alkyloids
include, by way of example and not limitation, vinblastine,
vincristine, paclitaxel, docetaxel and colchicine. Exemplary
antitumor antibiotics include, by way of example and not
limitation, actinomycin D, daunorubicin, and bleomycin. An
exemplary enzyme effective as an anti-neoplastic agent is
L-asparaginase. Exemplary platinum complexes and coordination
compounds include, by way of example and not limitation, cisplatin
(cis-diamminedichloridoplatinum(II) (CDDP)), carboplatin and
oxaliplatin. Exemplary hormones and hormone-related compounds
include, by way of example and not limitation,
adrenocorticosteroids, e.g., prednisone and dexamethasone;
aromatase inhibitors, e.g., amino glutethimide, formestane, and
anastrozole; progestin compounds, e.g., hydroxyprogesterone
caproate and medroxyprogesterone; and anti-estrogen compounds,
e.g., tamoxifen. Exemplary topoisomerase inhibitors include, by way
of example and not limitation, amsacrine (m-AMSA), mitoxantrone,
topotecan, irinotecan, and camptothecin. Exemplary tyrosine kinase
inhibitors include, by way of example and not limitation, axtinib,
bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib,
lapatinib, lestaurtinib, nilotinib, semaxanib, sunitinib,
vandetanib and vatalanib. Various derivative anti-neoplastic agents
that combine more than one anticancer activity may also be used in
the combination therapies of the invention. For instance, NSC290205
is a combination therapy compound incorporating d-lactam derivative
of androsterone and an alkylating agent based on
N,N-bis(2-chloroethyl)aniline (Trafalis et al., 2005, Br. J.
Haematol. 128(3):343-50).
[0679] Other chemotherapeutics useful in the combination therapies
of the invention include, by way of example and not limitation,
antibodies directed against growth factor receptors (e.g.,
anti-Her2); cytokines such as interferon-ca and interferon-.gamma.,
interleukin-2, and GM-CSF; and antibodies for cell surface markers
(e.g., anti-CTLA-4. anti-CD20 (rituximab); anti-CD33). When
antibodies against cell surface markers are used, a
chemotherapeutic agent can be conjugated to it for specific
targeting to the tumor cell. Suitable conjugates include
radioactive compounds (e.g., radioactive metal bound to an antibody
conjugated chelator), cytotoxic compounds, and drug activating
enzymes (e.g., allinase, peptidases, esterases, catalytic
antibodies, etc.) (see, e.g., Arditti et al., 2005, Mol. Cancer
Therap. 4(2):325-331, and U.S. Pat. No. 6,258,360, the disclosures
of which are both incorporated herein in full by reference).
[0680] Additional chemotherapeutic agents useful in the combination
therapies of the invention include, but are not limited to, HDAC
inhibitors (e.g., MGCD0103 and vorinostat), HSP 90 inhibitors
(e.g., 17-AAG), BCL-2 inhibitors, thalidomide, lenalidomide, mTOR
inhibitors (e.g., rapamycin, CCI-779), sorafenib, doxorubicine,
gemcitabine, dexamethasone, melphalan, proteasome inhibitors (e.g.,
bortezomib, NPI052), monoclonal antibodies (e.g., gemtuzumab,
alemtuzumab, ibritumomab tiuxaetan, tositumomab, iodine-131
tositumomab, trastuzumab, bevacizumab, rituximab and anti-TRAIL
death receptor antibodies), and the like.
[0681] These and other chemotherapeutic agents useful in treating
cancer are described in the "Commonly Used Antineoplastic Drugs",
The Merck Manuals Online Medical Library For HealthCare
Professionals at www.mercksource.com and Goodman and Gilmans The
Pharmacological Basis of Therapeutics, 10th Edition, Hardman, J. G.
and Limbird, L. E. eds., pg. 1381-1287, McGraw Hill, (1996), the
disclosures of which both of which are incorporated by reference
herein.
[0682] In some embodiments, a compound of formula (I), or a
pharmaceutically acceptable salt thereof, can be used in the
combination therapies of the invention with a second kinase
inhibitor that targets an oncogenic kinase different from Axl.
Examples include inhibitors of kinases associated with cell
proliferative disorders such as, but not limited to the inhibitors
of the kinases, Aurora-A, AKT, CDK1/cyclinB, CDK2/cyclinA,
CDK3/cyclinE, CDK5/p35, CDK6/cyclinD3, CDK7/cyclinH/MAT1, CHK1,
CHK2, EGFR, c-RAF, RAS, cSRC, Yes, Fyn, Lck, Fes, Lyn, Bmx, FGFR3,
GSK3.alpha., GSK3.beta., P13, IGF-1R, MAPK2, MAPKAP-K2, JNK, MEK1,
p70S6K, PAK2, PDGFR.alpha., PDGFR.beta., PDK1, PKA, PKC.epsilon.,
PKC, PKD2, VEGF, PRAK, PRK2, RET, ROCK-II, Rsk1, Rsk2, Rsk3, and
SGK.
[0683] In some embodiments, the second kinase inhibitor is an
inhibitor of Abl kinase. For example, chronic myelogenous leukemia
is a myeloid neoplasm characterized by malignant proliferation of
leukemic stem cells in the bone marrow. The majority of chronic
myelogenous leukemia is associated with a cytogenetic abnormality
defined by a reciprocal translocation t(9;22)(q34;q11). This
chromosomal aberration results in generation of a BCR/ABL fusion
protein with activated kinase activity. Inhibitors of the fusion
protein kinase activity are effective in treating chronic
myelogenous leukemia although resistant forms may develop upon
continued treatment. Use of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, in combination of Abl
kinase inhibitors may lessen the chances of resistant cells by
targeting a cellular process different than that targeted by the
kinase inhibitor alone. An exemplary Abl kinase inhibitor is
2-phenylaminopyrimidine, also known as imatinib mesylate and
GLEEVEC.RTM.. Thus, in some embodiments, a compound of formula (I),
or a pharmaceutically acceptable salt thereof, can be used in
combination with the Abl kinase inhibitor 2-phenylaminopyrimidine
and its derivatives. In other embodiments, the Abl kinase inhibitor
may be pyridol[2-3-d]pyrimidine and its derivatives, which was
originally identified as inhibitors of Src kinase. In yet further
embodiments, the Abl kinase inhibitor is tyrphostins and its
derivatives (e.g., adaphostin) which affects the association of the
kinase with its substrates. Other Abl kinase inhibitors useful in
the combination therapies of the present invention will be apparent
to the skilled artisan.
[0684] In one embodiment of the combination therapies of the
invention, the Axl inhibitor utilized therein works by the same
mechanism as the one or more chemotherapeutic agents utilized
therein. In another embodiment of the combination therapies of the
invention, the Axl inhibitor utilized therein works by a different
mechanism than the one or more chemotherapeutic agents utilized
therein.
[0685] The combination therapies of the invention are useful in
preventing, treating or managing one or more cancers, preferably
metastatic cancers. When a cancer spreads (metastasizes) from its
original site (primary tumor) to another area of the body, it is
termed "metastatic cancer". Virtually all cancers have the
potential to spread this way. Consequently, the combination
therapies of the invention are useful in preventing, treating or
managing metastatic cancer wherein the primary tumor is one or more
of the following cancers: Leukemias such as but not limited to,
acute leukemia, acute lymphocytic leukemia, acute myelocytic
leukemias such as myeloblastic, promyelocytic, myelomonocytic,
monocytic, erythroleukemia leukemias and myelodysplastic syndrome,
chronic leukemias such as but not limited to, chronic myelocytic
(granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell
leukemia; polycythemia vera; lymphomas such as but not limited to
Hodgkin's disease, non-Hodgkin's disease; multiple myelomas such as
but not limited to smoldering multiple myeloma, nonsecretory
myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary
plasmacytoma and extramedullary plasmacytoma; Waldenstrom's
macroglobulinemia; monoclonal gammopathy of undetermined
significance; benign monoclonal gammopathy; heavy chain disease;
bone and connective tissue sarcomas such as but not limited to bone
sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant
giant cell tumor, fibrosarcoma of bone, chordoma, periosteal
sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma),
fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma,
lymphangiosarcoma, metastatic cancers, neurilemmoma,
rhabdomyosarcoma, synovial sarcoma; brain tumors such as but not
limited to, glioma, astrocytoma, brain stem glioma, ependymoma,
oligodendroglioma, nonglial tumor, acoustic neurinoma,
craniopharyngioma, medulloblastoma, meningioma, pineocytoma,
pineoblastoma, primary brain lymphoma; breast cancer, including,
but not limited to, adenocarcinoma, lobular (small cell) carcinoma,
intraductal carcinoma, medullary breast cancer, mucinous breast
cancer, tubular breast cancer, papillary breast cancer, primary
cancers, Paget's disease, and inflammatory breast cancer; adrenal
cancer such as but not limited to pheochromocytom and
adrenocortical carcinoma; thyroid cancer such as but not limited to
papillary or follicular thyroid cancer, medullary thyroid cancer
and anaplastic thyroid cancer; pancreatic cancer such as but not
limited to, insulinoma, gastrinoma, glucagonoma, vipoma,
somatostatin-secreting tumor, and carcinoid or islet cell tumor;
pituitary cancers such as but limited to Cushing's disease,
prolactin-secreting tumor, acromegaly, and diabetes insipius; eye
cancers such as but not limited to ocular melanoma such as iris
melanoma, choroidal melanoma, and cilliary body melanoma, and
retinoblastoma; vaginal cancers such as squamous cell carcinoma,
adenocarcinoma, and melanoma; vulvar cancer such as squamous cell
carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma,
and Paget's disease; cervical cancers such as but not limited to,
squamous cell carcinoma, and adenocarcinoma; uterine cancers such
as but not limited to endometrial carcinoma and uterine sarcoma;
ovarian cancers such as but not limited to, ovarian epithelial
carcinoma, borderline tumor, germ cell tumor, and stromal tumor;
esophageal cancers such as but not limited to, squamous cancer,
adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma,
adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous
carcinoma, and oat cell (small cell) carcinoma; stomach cancers
such as but not limited to, adenocarcinoma, fungating (polypoid),
ulcerating, superficial spreading, diffusely spreading, malignant
lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon
cancers; rectal cancers; liver cancers such as but not limited to
hepatocellular carcinoma and hepatoblastoma, gallbladder cancers
such as adenocarcinoma; cholangiocarcinomas such as but not limited
to pappillary, nodular, and diffuse; lung cancers such as non-small
cell lung cancer, squamous cell carcinoma (epidermoid carcinoma),
adenocarcinoma, large-cell carcinoma and small-cell lung cancer;
testicular cancers such as but not limited to germinal tumor,
seminoma, anaplastic, classic (typical), spermatocytic,
nonseminoma, embryonal carcinoma, teratoma carcinoma,
choriocarcinoma (yolk-sac tumor), prostate cancers such as but not
limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma;
genital cancers such as penile cancer; oral cancers such as but not
limited to squamous cell carcinoma; basal cancers; salivary gland
cancers such as but not limited to adenocarcinoma, mucoepidermoid
carcinoma, and adenoidcystic carcinoma; pharynx cancers such as but
not limited to squamous cell cancer, and verrucous; skin cancers
such as but not limited to, basal cell carcinoma, squamous cell
carcinoma and melanoma, superficial spreading melanoma, nodular
melanoma, lentigo malignant melanoma, acral lentiginous melanoma;
kidney cancers such as but not limited to renal cell cancer,
adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell
cancer (renal pelvis and/or uterer); Wilms' tumor; bladder cancers
such as but not limited to transitional cell carcinoma, squamous
cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers
include myxosarcoma, osteogenic sarcoma, endotheliosarcoma,
lymphangioendotheliosarcoma, mesothelioma, synovioma,
hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,
bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland
carcinoma, papillary carcinoma and papillary adenocarcinomas.
[0686] Whether metastases develop from a primary tumor depends on
the complex interaction of many tumor cell factors, including the
type of primary tumor, the degree of maturity (differentiation) of
the primary tumor cells, the location of the primary tumor and how
long the primary tumor has been present, as well as other
incompletely understood factors.
[0687] The treatment of metastatic cancer depends on where the
primary tumor is located. When breast cancer spreads to the lungs,
for example, it remains a breast cancer and the treatment is
determined by the metastatic cancer origin within the breast, not
by the fact that it is now in the lung. About 5 percent of the
time, metastatic cancer is discovered but the primary tumor cannot
be identified. The treatment of these metastatic cancers is
dictated by their location rather than their origin. Metastatic
cancers are named by the tissue of the original tumor (if known).
For example, a breast cancer that has spread to the brain is called
metastatic breast cancer to the brain.
[0688] Metastases spread in three ways: by local extension from the
tumor to the surrounding tissues, through the bloodstream to
distant sites or through the lymphatic system to neighboring or
distant lymph nodes. Each kind of cancer may have a typical route
of spread.
[0689] Tissues which are particularly susceptible to metastatic
cancer are the brain, liver, bone and lung, although all tissues of
the body may be affected. Any cancer may spread to the brain,
although the most common to do so are lung and breast cancer. The
most common cancer to metastasize to the liver is colon or other
gastrointestinal cancer. The most common cancers to spread to the
bones are prostate, lung and breast cancer. Metastases to the lung
are common for many types of cancer.
[0690] In a preferred embodiment of the invention, the specific
property of metastasis is targeted using the combination therapies
described herein. In some embodiments, an Axl inhibitor, preferably
a compound of formula (I) as set forth above in the Summary of the
Invention, in combination with one or more chemotherapeutic agents,
can be used to treat metastasis arising from a primary tumor in
various tissues of the body, including, but not limited to, primary
tumors of the bone, breast, respiratory tract, brain, reproductive
organs, digestive tract, urinary tract (e.g., bladder), eye, liver,
skin, head, neck, thyroid, parathyroid, and metastatic forms
thereof. In one embodiment, the metastasis to be treated by the
combination therapies of the invention is lung and/or liver
metastasis arising from a primary tumor of the breast.
[0691] The combination therapies of the invention are also useful
in treating certain cellular proliferative disorders. Such
disorders include, but are not limited to, the following:
[0692] a) proliferative disorders of the breast, which include, but
are not limited to, invasive ductal carcinoma, invasive lobular
carcinoma, ductal carcinoma, lobular carcinoma in situ and
metastatic breast cancer;
[0693] b) proliferative disorders of the skin, which include, but
are not limited to, basal cell carcinoma, squamous cell carcinoma,
malignant melanoma and Karposi's sarcoma;
[0694] c) proliferative disorders of the respiratory tract, which
include, but are not limited to, small cell and non-small cell lung
carcinoma, bronchial adema, pleuropulmonary blastoma and malignant
mesothelioma;
[0695] d) proliferative disorders of the brain, which include, but
are not limited to, brain stem and hyptothalamic glioma, cerebellar
and cerebral astrocytoma, medullablastoma, ependymal tumors,
oligodendroglial, meningiomas and neuroectodermal and pineal
tumors;
[0696] e) proliferative disorders of the male reproductive organs,
which include, but are not limited to, prostate cancer, testicular
cancer and penile cancer;
[0697] f) proliferative disorders of the female reproductive
organs, which include, but are not limited to, uterine cancer
(endometrial), cervical, ovarian, vaginal, vulval cancers, uterine
sarcoma and ovarian germ cell tumor;
[0698] g) proliferative disorders of the digestive tract, which
include, but are not limited to, anal, colon, colorectal,
esophageal, gallbladder, stomach (gastric), pancreatic cancer,
pancreatic cancer-Islet cell, rectal, small-intestine and salivary
gland cancers;
[0699] h) proliferative disorders of the liver, which include, but
are not limited to, hepatocellular carcinoma, cholangiocarcinoma,
mixed hepatocellular cholangiocarcinoma, primary liver cancer and
metastatic liver cancer;
[0700] i) proliferative disorders of the eye, which include, but
are not limited to, intraocular melanoma, retinoblastoma, and
rhabdomyosarcoma;
[0701] j) proliferative disorders of the head and neck, which
include, but are not limited to, laryngeal, hypopharyngeal,
nasopharyngeal, oropharyngeal cancers, and lip and oral cancer,
squamous neck cancer, metastatic paranasal sinus cancer;
[0702] k) proliferative disorders of lymphocytic cells, which
include, but are not limited to, various T cell and B cell
lymphomas, non-Hodgkins lymphoma, cutaneous T cell lymphoma,
Hodgkins disease, and lymphoma of the central nervous system;
[0703] l) leukemias, which include, but are not limited to, acute
myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic
leukemia, chronic myelogenous leukemia, and hairy cell
leukemia,
[0704] m) proliferative disorders of the thyroid, which include,
but are not limited to, thyroid cancer, thymoma, malignant thymoma,
medullary thyroid carcinomas, papillary thyroid carcinomas,
multiple endocrine neoplasia type 2A (MEN2A), pheochromocytoma,
parathyroid adenomas, multiple endocrine neoplasia type 2B (MEN2B),
familial medullary thyroid carcinoma (FMTC) and carcinoids;
[0705] n) proliferative disorders of the urinary tract, which
include, but are not limited to, bladder cancer;
[0706] o) sarcomas, which include, but are not limited to, sarcoma
of the soft tissue, osteosarcoma, malignant fibrous histiocytoma,
lymphosarcoma, and rhabdomyosarcoma;
[0707] p) proliferative disorders of the kidneys, which include,
but are not limited to, renal cell carcinoma, clear cell carcinoma
of the kidney; and renal cell adenocarcinoma;
[0708] q) precursor B-lymphoblastic leukemia/lymphoma (precursor
B-cell acute lymphoblastic leukemia), B-cell chronic lymphocytic
leukemia/small lymphocytic lymphoma, B-cell prolymphocytic
leukemia, lymphoplasmacytic lymphoma, splenic marginal zone B-cell
lymphoma, hairy cell leukemia, plasma cell myeloma/plasmacytoma,
extranodal marginal zone B-cell lymphoma of MALT type, nodal
marginal zone B-cell lymphoma, follicular lymphoma, mantle-cell
lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell
lymphoma, primary effusion lymphoma and Burkitt's lymphoma/Burkitt
cell leukemia
[0709] (r) precursor T-lymphoblastic lymphoma/leukemia (precursor
T-cell acute lymphoblastic leukemia), T-cell prolymphocytic
leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell
leukemia, adult T-cell lymphoma/leukemia (HTLV-1), extranodal
NK/T-cell lymphoma, nasal type, enteropathy-type T-cell lymphoma,
hepatosplenic gamma-delta T-cell lymphoma, subcutaneous
panniculitis-like T-cell lymphoma, mycosis fungoides/Sezary
syndrome, anaplastic large-cell lymphoma, T/null cell, primary
cutaneous type, peripheral T-cell lymphoma, not otherwise
characterized, angioimmunoblastic T-cell lymphoma, anaplastic
large-cell lymphoma, T/null cell, and primary systemic type;
[0710] (s) nodular lymphocyte-predominant Hodgkin's lymphoma,
nodular sclerosis Hodgkin's lymphoma (grades 1 and 2),
lymphocyte-rich classical Hodgkin's lymphoma, mixed cellularity
Hodgkin's lymphoma, and lymphocyte depletion Hodgkin's
lymphoma;
[0711] (t) myelogenous leukemia (e.g., Philadelphia chromosome
positive (t(9;22)(qq34;q11)), multiple myeloma, chronic
neutrophilic leukemia, chronic eosinophilic
leukemia/hypereosinophilic syndrome, chronic idiopathic
myelofibrosis, polycythemia vera, essential thrombocythemia,
chronic myelomonocytic leukemia, atypical chronic myelogenous
leukemia, juvenile myelomonocytic leukemia, refractory anemia with
ringed sideroblasts and without ringed sideroblasts, refractory
cytopenia (myelodysplastic syndrome) with multilineage dysplasia,
refractory anemia (myelodysplastic syndrome) with excess blasts,
5q-syndrome, and myelodysplastic syndrome with
t(9;12)(q22;p12);
[0712] (u) AML with t(8;21)(q22;q22), AML1(CBF-alpha)/ETO, acute
promyelocytic leukemia (AML with t(15;17)(q22;q11-12) and variants,
PML/RAR-alpha), AML with abnormal bone marrow eosinophils
(inv(16)(p13q22) or t(16;16)(p13;q11), CBFb/MYH11X), and AML with
11q23 (MLL) abnormalities, AML minimally differentiated, AML
without maturation, AML with maturation, acute myelomonocytic
leukemia, acute monocytic leukemia, acute erythroid leukemia, acute
megakaryocytic leukemia, acute basophilic leukemia, and acute
panmyelosis with myelofibrosis.
[0713] It is to be understood that the descriptions of
proliferative disorders is not limited to the conditions described
above, but encompasses other disorders characterized by
uncontrolled growth and malignancy. It is further understood that
proliferative disorders include various metastatic forms of the
primary tumor and cancer types described herein. The combination
therapies of the invention may be tested for effectiveness against
these disorders, particularly various metastatic forms of the
primary tumor, and a therapeutically effective regimen established.
Effectiveness, as further described below, includes reduction or
remission of the metastatic tumors, decreases in the rate of cell
proliferation, or cytostatic or cytotoxic effect on metastatic
cancer cell growth.
[0714] The antiproliferative effect of a combination therapy of the
invention may be assessed by administering the active ingredients
of the combination therapy to a cultured tumor cell line. In the
context of an in vitro assay, administration of an active
ingredient may be simply achieved by contacting the cells in
culture with the active ingredient in amounts effective to inhibit
cell proliferation. Alternatively, the antiproliferative effect of
a combination therapy of the invention may be assessed by
administering the active ingredients of the combination therapy to
an animal in an approved in vivo model for cell proliferation.
[0715] Examples of tumor cell lines derived from human tumors and
available for use in the in vivo studies include, but are not
limited to, leukemia cell lines (e.g., CCRF-CEM, HL-60(TB), K-562,
MOLT-4, RPM1-8226, SR, P388 and P388/ADR); non-small cell lung
cancer cell lines (e.g., A549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226,
NCI-H23, NCI-H322M, NCI-H460, NCI-H522 and LXFL 529); small cell
lung cancer cell lines (e.g., DMS 114 and SHP-77); colon cancer
cell lines (e.g., COLO 205, HCC-2998, HCT-116, HCT-15, HT29, KM12,
SW-620, DLD-1 and KM20L2); central nervous system (CNS) cancer cell
lines (e.g., SF-268, SF-295, SF-539, SNB-19, SNB-75, U251, SNB-78
and XF 498); melanoma cell lines (e.g., LOX I MVI, MALME-3M, M14,
SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, UACC-62, RPMI-7951 and
M19-MEL); ovarian cancer cell lines (e.g., IGROV1, OVCAR-3,
OVCAR-4, OVCAR-5, OVCAR-8 and SK-OV-3); renal cancer cell lines
(e.g., 786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, UO-31,
RXF-631 and SN12K1); prostate cancer cell lines (e.g., PC-3 and
DU-145); breast cancer cell lines (e.g., MCF7, NCI/ADR-RES,
MDA-MB-231/ATCC, HS 578T, MDA-MB-435, BT-549, T-47D and
MDA-MB-468); and thyroid cancer cell lines (e.g., SK-N-SH).
[0716] The combination therapies of the invention can be tested for
the treatment of leukemias and lymphomas by testing the combination
therapy in the xenograft in SCID mouse model using human
Axl-expresing cancer cell lines including, but not limited to,
HeLa, MDA-MB-231, SK-OV-3, OVCAR-8, DU145, H1299, ACHN, A498 and
Caki-1. In addition, the combination therapy may be tested for its
use in treating leukemias in the xenograft in SCID or nu/nu mouse
model using human Axl-expressing AML and CML leukemia cell
lines.
[0717] The combination therapies of the invention may be tested for
efficacy in preventing, treating or managing metastatic cancers in
known animal models of metastatic cancer, such as the Mouse 4T1
Breast Tumor Model (see Pulaski, B. A. et al., Current Protocols in
Immunology (2000), 20.2.1-20.2.16), the disclosure of which is
incorporated herein in full in its entirety, or variations
thereof.
Pharmaceutical Compositions, Dosages and Administration of the
Combination Therapies of the Invention
[0718] Pharmaceutical compositions of Axl inhibitors and other
chemotherapeutic agents used in the combination therapies of the
invention are known or can be prepared according to methods known
to one skilled in the art. For example, methods of preparing and
formulating pharmaceutical compositions of the Axl inhibitors of
formula (I), as set forth above in the Summary of the invention,
are disclosed in PCT Published Patent Application No. 2008/083367,
which is incorporated in full herein in its entirety, as well as
methods of administration.
[0719] In general, the amount of an Axl inhibitor, preferably a
compound of formula (I), as set forth in the Summary of the
Invention, or the amount of one or more chemotherapeutic agents
which will be effective in the treatment, prevention or management
of metastatic cancer in the combination therapies of the invention
can be determined by standard research techniques. For example, the
dosage amount of each active ingredient in a combination therapy of
the invention which will be effective in the treatment, prevention
or management of metastatic cancer can be determined by
administering the combination therapy to an animal model such as
the ones described herein or by one known to one skilled in the
art. In addition, in vivo assays may optionally be employed to help
identify optimal dosage ranges of each active ingredient in a
combination therapy of the invention.
[0720] Selection of the preferred prophylactically or
therapeutically effective dose of an active ingredient used in the
combination therapies of the invention can be determined (e.g., by
clinical trials) by a skilled artisan based upon the consideration
of several factors, including the activity of the specific compound
employed; the metabolic stability and length of action of the
compound; the age, body weight, general health, sex, and diet of
the patient; the mode and time of administration; the rate of
excretion; the drug combination; and the severity of the metastatic
cancer.
[0721] The precise dose of either the Axl inhibitor or the one or
more chemotherapeutic agents used in the combination therapies of
the invention will also depend on the route of administration and
the seriousness of the metastatic cancer and should be decided
according to the judgment of the medical practitioner and each
patient's circumstances. Effective doses may be extropolated from
dose-respose curves derived from in vitro or animal model test
systems.
[0722] For example, a therapeutically effective daily dose for an
Axl inhibitor, i.e., a compound of formula (I), as set forth above
in the Summary of the Invention, is (for a 70 kg mammal) from about
0.001 mg/kg (i.e., 0.07 mg) to about 100 mg/kg (i.e., 7.0 gm);
preferably a therapeutically effective dose is (for a 70 kg mammal)
from about 0.01 mg/kg (i.e., 0.7 mg) to about 50 mg/kg (i.e., 3.5
gm); more preferably a therapeutically effective dose is (for a 70
kg mammal) from about 1 mg/kg (i.e., 70 mg) to about 25 mg/kg
(i.e., 1.75 gm).
[0723] Dosages, routes of administration and recommended usage of
the chemotherapeutic agents used in the combination therapies of
the invention are known in the art and often described in such
literature as the Physician's Desk Reference (current edition). In
addition, typical doses of certain known chemotherapeutic agents
are provided in U.S. Pat. No. 7,351,729, the relevant section of
which is incorporated in full by reference herein.
[0724] Preferably, the invention provides for any method of
administering lower doses of the one or more chemotherapeutic
agents used in the combination therapies of the invention than
previously known to be effective for the prevention, treatment and
management of metastatic cancer. Even more preferably, lower doses
of the one or more chemotherapeutic agents are administered in the
combination therapies of the invention with lower doses of the Axl
inhibitor.
[0725] In the combination therapies of the invention, an Axl
inhibitor is administered simultaneously with, prior to, or after
administration of one or more other chemotherapeutic agents, as
described herein, by the same route of administration or by
different routes. Such combination therapy includes administration
of a single pharmaceutical dosage formulation which contains an Axl
inhibitor and one or more additional chemotherapeutic agents, as
well as administration of the Axl inhibitor and each
chemotherapeutic agent in its own separate pharmaceutical dosage
formulation. For example, the Axl inhibitor and the other one or
more chemotherapeutic agents can be administered to the patient
together in a single oral dosage composition such as a tablet or
capsule, or each agent can be administered in separate oral dosage
formulations. Where separate dosage formulations are used, the Axl
inhibitor and the one or more chemotherapeutic agents can be
administered to the patient at essentially the same time, i.e.,
concurrently, or at separately staggered times, i.e., sequentially.
All such combinations of administration are encompassed by the
combination therapies of the invention.
[0726] In certain embodiments of the combination therapies of the
invention, the Axl inhibitor is administered to a patient,
preferably a human, concurrently with one or more chemotherapeutic
agents useful for the treatment of cancer. The term "concurrently"
is not limited to the administration of the active ingredients
(i.e., the Axl inhibitor and the one or more chemotherapeutic
agents) at exactly the same time, but rather it is meant that the
Axl inhibitor and the other chemotherapeutic agent are administered
to a patient in a sequence and within a time interval such that the
Axl inhibitor can act together with the other chemotherapeutic
agent to provide an increased benefit than if they were
administered otherwise. For example, each active ingredient of the
combination therapies of the invention may be administered at the
same time or sequentially in any order at different points in time;
however, if not administered at the same time, they should be
administered sufficiently close in time so as to provide the
desired therapeutic or prophylactic effect. Each active ingredient
can be administered separately, in any appropriate form and by any
suitable route. In various embodiments, the active ingredients are
administered less than 1 hour apart, at about 1 hour apart, at
about 1 hour to about 2 hours apart, at about 2 hours to about 3
hours apart, at about 3 hours to about 4 hours apart, at about 4
hours to about 5 hours apart, at about 5 hours to about 6 hours
apart, at about 6 hours to about 7 hours apart, at about 7 hours to
about 8 hours apart, at about 8 hours to about 9 hours apart, at
about 9 hours to about 10 hours apart, at about 10 hours to about
11 hours apart, at about 11 hours to about 12 hours apart, no more
than 24 hours apart or no more than 48 hours apart. In preferred
embodiments, two or more active ingredients are administered within
the same patient visit.
[0727] In other embodiments, the active ingredients are
administered at about 2 to 4 days apart, at about 4 to 6 days
apart, at about 1 week part, at about 1 to 2 weeks apart, or more
than 2 weeks apart. In preferred embodiments, the active
ingredients are administered in a time frame where both active
ingredients are still prophylactically and therapeutically active.
One skilled in the art would be able to determine such a time frame
by determining the half life of the administered active
ingredients.
[0728] In certain embodiments, the active ingredients of the
invention are cyclically administered to a patient. Cycling therapy
involves the administration of a first active ingredient, such as
the Axl inhibitor, for a period of time, followed by the
administration of the second and/or third active ingredient for a
period of time and repeating this sequential administration.
Cycling therapy can reduce the development of resistance to one or
more of the therapies, avoid or reduce the side effects of one of
the therapies, and/or improves the efficacy of the treatment.
[0729] In certain embodiments, the active ingredients are
administered in a cycle of less than about 3 weeks, about once
every two weeks, about once every 10 days or about once every week.
One cycle can comprise the administration of an active ingredient
by infusion over about 90 minutes every cycle, about 1 hour every
cycle, about 45 minutes every cycle. Each cycle can comprise at
least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of
rest. The number of cycles administered is from about 1 to about 12
cycles, more typically from about 2 to about 10 cycles, and more
typically from about 2 to about 8 cycles.
[0730] In yet other embodiments, the active ingredients of the
combination therapies of the invention are administered in
metronomic dosing regimens, either by continuous infusion or
frequent administration without extended rest periods. Such
metronomic administration can involve dosing at constant intervals
without rest periods. Typically the chemotherapeutic agents, in
particular cytotoxic agents, are used at lower doses. Such dosing
regimens encompass the chronic daily administration of relatively
low doses for extended periods of time. In one embodiment, the use
of lower doses of the chemotherapeutic agent can minimize toxic
side effects and eliminate rest periods. In certain embodiments,
the active ingredients are administered by chronic low-dose or
continuous infusion ranging from about 24 hours to about 2 days, to
about 1 week, to about 2 weeks, to about 3 weeks to about 1 month
to about 2 months, to about 3 months, to about 4 months, to about 5
months, to about 6 months. The scheduling of such dose regimens can
be optimalized by the skilled oncologist.
[0731] In other embodiments, the active ingredients are
administered concurrently to a patient such that doses of the
chemotherapeutic agent are administered separately yet within a
time interval such that the Axl inhibitor can work together with
the chemotherapeutic agent. For example, the chemotherapeutic agent
may be administered one time per week and the Axl inhibitor may be
administered every day. In other words, the dosing regimens for the
active ingredients are carried out concurrently even if the active
ingredients are not administered simultaneously or within the same
patient visit.
[0732] In a preferred embodiment, the Axl inhibitor is administered
every day to the patient and the one or more chemotherapeutic agent
is administered once a week.
Preparation of the Compounds of Formula (I)
[0733] Compounds of formula (I) utilized in the combination
therapies of the invention can be made using organic synthesis
techniques known to those skilled in the art, as well as by the
methods described in PCT Published Patent Application No.
2008/083367, which is incorporated herein by reference in its
entirety. Specific examples of the compounds of formula (I) can be
found in this publication.
[0734] Alternatively, certain compounds of formula (I), as set
forth above in the Summary of the Invention, can be made by the
methods disclosed herein. In particular, the following Reaction
Schemes illustrate methods to make compounds of formula (I) having
the following formula (Ia1):
##STR00011##
wherein: [0735] A is .dbd.C(H)-- or .dbd.N--; [0736] each R.sup.2a
is independently selected from the group consisting of
--N(R.sup.12a).sub.2 and --N(R.sup.12a)C(O)R.sup.12a, [0737] or
R.sup.2a is an N-heterocyclyl optionally substituted by one or more
substituents selected from the group consisting of halo and
--R.sup.21--C(O)OR.sup.20, [0738] each R.sup.12a is independently
selected from the group consisting of hydrogen, alkyl, alkenyl,
optionally substituted aralkyl, optionally substituted cycloalkyl,
optionally substituted cycloalkylalkyl, optionally substituted
heteroaryl and optionally substituted heteroarylalkyl; [0739]
R.sup.20 is independently selected from the group consisting of
hydrogen, alkyl, alkenyl, optionally substituted aralkyl,
optionally substituted cycloalkyl, optionally substituted
cycloalkylalkyl, optionally substituted heteroaryl and optionally
substituted heteroarylalkyl; and [0740] R.sup.21 is independently
selected from the group consisting of a direct bond or an
optionally substituted straight or branched alkylene chain; [0741]
as an isolated stereoisomer or mixture thereof, or a
pharmaceutically acceptable salt thereof.
[0742] It is understood that one of ordinary skill in the art would
be able to make the compounds of formula (Ia1) by methods similar
to the methods described herein or by methods known to one of
ordinary skill in the art. It is also understood that one of
ordinary skill in the art would be able to make in a similar manner
as described below other compounds of formula (Ia1) and the
compounds of formula (Ib1), as set forth above in the Embodiments
section, not specifically illustrated below by using the
appropriate starting components and modifying the parameters of the
synthesis as needed.
[0743] It is also understood that in the following Reaction Schemes
and throughout this description, combinations of substituents
and/or variables of the depicted formulae are permissible only if
such contributions result in stable compounds.
[0744] It will also be appreciated by those skilled in the art that
in the processes described below the functional groups of
intermediate compounds may need to be protected by suitable
protecting groups. Such functional groups include hydroxy, amino,
mercapto and carboxylic acid. Suitable protecting groups for
hydroxy include trialkylsilyl or diarylalkylsilyl (for example,
t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),
tetrahydropyranyl, benzyl, and the like. Suitable protecting groups
for amino, amidino and guanidino include benzyl, t-butoxycarbonyl,
benzyloxycarbonyl, and the like. Suitable protecting groups for
mercapto include --C(O)--R'' (where R'' is alkyl, aryl or
arylalkyl), p-methoxybenzyl, trityl and the like. Suitable
protecting groups for carboxylic acids include alkyl, aryl or
arylalkyl esters.
[0745] Protecting groups may be added or removed in accordance with
standard techniques, which are known to one of ordinary skill in
the art and as described herein.
[0746] The use of protecting groups is described in detail in
Greene, T. W. and P. G. M. Wuts, Greene's Protective Groups in
Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the
art would appreciate, the protecting group may also be a polymer
resin such as, but not limited to, a Wang resin, Rink resin or a
2-chlorotrityl-chloride resin.
[0747] It will also be appreciated by those skilled in the art,
although such protected derivatives of compounds of this invention
may not possess pharmacological activity as such, they may be
administered to a mammal and thereafter metabolized in the body to
form compounds of the invention which are pharmacologically active.
Such derivatives may therefore be described as "prodrugs".
[0748] In general, starting components may be obtained from sources
such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix
Scientific, TCI, and Fluorochem USA, etc. or synthesized according
to sources known to those skilled in the art (see, for example,
Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,
5th edition (Wiley, December 2000)) or prepared as described in
this invention. .sup.1H NMR spectra were recorded in CDCl.sub.3,
DMSO-d.sub.6, CD.sub.3OD, Acetone-d.sub.6 with trimethylsilane
(TMS) as internal reference using Gemini 300 MHz instrument.
Reagents and solvents were purchased from commercial sources and
used without further purification. Flash column chromatography was
conducted using silica gel (230-400 mesh) under a positive pressure
of nitrogen. Waters LCMS instruments were used for recording LCMS
spectra for purity and mass determinations. Deionized water was
used to dilute the reactions and wash the products. Brine used was
prepared by dissolving sodium chloride into deionized water to
saturation point.
[0749] Compounds of formula (Ia1), as described above, are
generally prepared as illustrated below in Reaction Scheme 1 where
A and R.sup.2a are as described above for the compounds of formula
(Ia1) and Ph is a phenyl group:
##STR00012##
[0750] Compounds of formula (A), formula (B) and formula (D) are
commercially available or can be prepared by methods known to one
skilled in the art or by methods disclosed herein.
[0751] In general, compounds of formula (Ia1) are prepared, as set
forth by Reaction Scheme 1, by first treating diphenyl
cyanocarbonimidate (A) (where the phenyl groups therein may be
replaced with other suitable groups or suitably substituted groups
known to one skilled in the art) (1.1 equiv) with an equivalent
amount of an aniline of formula (B) in an polar solvent, including,
but not limited to, isopropyl alcohol, at ambient temperatures
overnight. The diarylisourea product of formula (C) generally
precipitates and isolation can be accomplished via filtration,
washing with an appropriate solvent, and drying. Hydrazine hydrate
of formula (D) (2 equivalents) is added to a slurry of the compound
of formula (C) in an alcohol or other appropriate solvent.
Generally, the ring formation reaction occurs at ambient
temperature and the product triazole of formula (Ia1) can be
isolated by standard isolation techniques.
[0752] Compounds of formula (Ib1), as set forth above in the
Embodiments section, can be prepared using the synthetic route
outlined in Reaction Scheme 1 in varying amounts depending on the
steric and electronic nature of the starting materials as well as
the particular reaction conditions employed. In some instances,
compounds of formula (Ib1) are isolated as minor isomers along with
compounds of formula (Ia1) as major isomers, e.g., during column
chromatography as described herein.
[0753] Compounds of formula (C-1) are compounds of formula (C), as
set forth above in Reaction Scheme 1, where R.sup.2a is
pyrrolidin-1-yl. They can be prepared according to the method
described below in relation to Reaction Scheme 2:
##STR00013##
[0754] Compounds of formula (Ca) and formula (A) are commercially
available or can be prepared according to methods described herein
or known to one skilled in the art. Compounds of formula (Ba) are
compounds of formula (B), as set forth above in Reaction Scheme
1.
[0755] In general, compounds of formula (C-1) are prepared, for
example, as set forth above in Reaction Scheme 2, by nitration of
the benzo[7]annulene of formula (Ca) to form the nitro compound of
formula (Cb). Reductive amination of the keto group in the ketone
of formula (Cb) yields the pyrrolidine-substituted compound of
formula (Cc). Reduction of the nitro group of the
pyrrolidine-substituted compound of formula (Cc), for example, by
catalytic hydrogenation, gives the aniline of formula (Ba).
Reaction of the aniline of formula (Ba) with diphenyl
cyanocarbonimidate of formula (A) yields the compound of formula
(C-1). Compounds of formula (C-1) are enantiomeric. The enantiomers
of compound (C-1), and similar compounds of the invention, can be
isolated, for example, by chiral phase HPLC.
[0756] Stereoselective amination of certain cyclic ketones, such as
the compounds of formula (Cb) as set forth above, can be very
challenging or impossible. Accordingly, the following describes one
method of making compounds of formula (Ia1) and (Ib1) using
transaminases to produce enantiomerically pure primary amines from
cyclic ketones, particularly from cyclic ketones fused to a
substituted aromatic ring.
[0757] Transaminases (also known as amino transferases) are enzymes
that catalyze a transamination reaction between an amino-donor
molecule (such as an amine or amino acid) and an amino-acceptor
molecule (such as a ketone or an .alpha.-keto acid). Specifically,
enzymatic transamination involves removing the amino group from the
amino-donor molecule (leaving behind a carbonyl group) and
transferring the amino group to the amino-acceptor molecule (or
.alpha.-keto acid) by converting the ketone moiety therein to an
amine (or an amino acid). A description of transaminases and their
use in stereo-selective synthesis can be found in "Transminations.
Enzyme Catalysis in Organic Synthesis (2.sup.nd Edition) (2002)",
by J. David Rozzell and Andreas S. Bommarius, pp. 873-893, which is
incorporated in full by reference herein.
[0758] Transaminases are particularly suitable for the enzymatic
synthesis of chiral amines from the corresponding ketone
precursors. Commercially available transaminases can be used to
achieve a chiral enzymatic amination of a desired starting material
in the preparation of the compounds of the invention. In
particular, a ketone of the following formula (i) where n and m are
the same and are 0, 1 or 2 and R is nitro, halo or --C(O)OR.sup.12a
(where R.sup.12a is as described above for the compounds of formula
(Ia1)) can be converted under suitable conditions to the
corresponding (S)-enantiomer and (R)-enantiomer wherein the carbon
to which the amino group is attached is either in the (S) or the
(R) configuration, respectively, by utilizing a (S)-specific
tranasminase and an amino donor molecule, such as L-alanine, or a
(R)-specific transaminase and an amino donor molecule, such as
L-alanine, as shown below:
##STR00014##
[0759] One of ordinary skill in the art would appreciate that the
amino group on the (S)-enantiomer and the (R)-enantiomer can be
further functionalized by standard procedures known to one skilled
in the art. For example, treatment of the above (S)-enantiomer with
1,4-dibromobutane under the appropriate alkylation conditions will
result in the amino group being converted to a 1-pyrrolidinyl group
without racemization of the chiral center. Alternatively, treatment
of the above (S)-enantiomer with an appropriate acylating agent
with result in the amino group being acylated accordingly, and so
forth.
[0760] Utilizing the appropriate transaminase to convert the cyclic
ketone of formula (i) into the appropriate enantiomer, the
appropriate enantiomer can be isolated in greater than 80% ee and
preferably greater than 90% ee.
[0761] The following Reaction 3, where the compound of formula
(Cb-1) is a compound of formula (i) as described above and PG
represents a nitrogen protecting group, illustrates a method of
preparing a chiral compound of formula (Ia1) utilizing a
transaminase as described above:
##STR00015## ##STR00016##
[0762] Compounds of formula (Cb-1) are commercially available, or
can be prepared by methods known to one skilled in the art.
Compounds of formula (D-1) can be prepared according to methods
known to one skilled in the art or by methods disclosed herein. The
(S)-specific transaminase is commercially available from Codexis.
Preferably the (S)-specific transaminase is ATA-103 from
Codexis.
[0763] In general, compounds of formula (Ia1-1) are prepared by the
method disclosed above in Reaction Scheme 3 by first converting the
ketone of formula (Cb-1) into the chiral compound of formula (Cb-2)
wherein the amino group from an amino donor molecule, preferably
L-alanine, is transferred to the ketone of formula (Cb-1) through
an enzymatic transamination reaction under suitable conditions. In
particular, the ketone of formula (Cb-1) is treated with a excess
molar amount of an amino donor molecule in the the presence of a
catalytic amount of a transaminase, preferably a (S)-specific
transaminase, and a stoichiometric or excess stoichiometric amount
of a pyruvate reductase mixture that reduces (deactivates) the
2-keto acid side product, thereby driving the reaction into the
desired direction. Preferably the pyruvate reductase mixture is
PRM-102 from Codexix. The reaction is conducted at ambient
temperature, at a pH of between about 7.5 and about 8.0, and for a
period of time of between about 24 hours and about 6 days,
preferably for about 4 days. The chiral compound of formula (Cb-2)
is isolated from the reaction mixture by standard isolation
techniques known to one skilled in the art.
[0764] Alternatively, the transamination reaction can be driven to
completion by coupling the reaction to a second reaction that
consumes the 2-keto acid by-product in an essentially irreversible
step, as described in more detail in "Transminations. Enzyme
Catalysis in Organic Synthesis (2.sup.nd Edition) (2002)", by J.
David Rozzell and Andreas S. Bommarius, pp. 873-893.
[0765] The amino group of the chiral compound of formula (Cb-2) is
then protected by standard nitrogen protecting procedures to yield
the compound of formula (Cb-3), which is isolated from the reaction
mixture by standard isolation techniques known to one skilled in
the art. The compound of formula (Cb-3) is then treated to standard
reducing conditions, such as treatment with H.sub.2/Pd, to produce
the corresponding aniline compound of formula (Cb-4), which is
isolated from the reaction mixture by standard isolation techniques
known to one skilled in the art. The compound of formula (Cb-4) is
then treated with diphenyl cyanocarbonimidate of formula (A) to
produce the compound of formula (Cb-5), which is isolated from the
reaction mixture by standard isolation techniques known to one
skilled in the art.
[0766] The compound of (Cb-5) is then treated with a compound of
formula (D-1) in the presence of an aprotic solvent, preferably
toluene, at a temperature of between about 80.degree. C. and about
100.degree. C. for a period of time of between about 12 hours and
about 36 hours, preferably for about 24 hours, to yield a compound
of formula (Ia1-1), which is isolated from the reaction mixture by
standard isolation techniques known to one skilled in the art.
Compound of formula (Ia1-1) is a compound of formula (Ia1), as set
forth above.
[0767] The protecting group on the compound of formula (Ia1-1) can
be removed under standard deprotecting conditions known to one
skilled in the art, such as acid hydrolysis, to produce a compound
of formula (Ia1-2), which is isolated from the reaction mixture by
standard isolation techniques known to one skilled in the art. The
compound of formula (Ia1-2) can be further treated with the
appropriate aldehyde or ketone under standard reductive amination
conditions to yield a compound of formula (Ia1-3), which is
isolated from the reaction mixture by standard isolation techniques
known to one skilled in the art.
[0768] Compounds of formula (D-1) utilized in Reaction Scheme 3
above are compounds of formula (D), as shown above in Reaction
Scheme 1, where A is .dbd.C(H)--. Compounds of formula (D-1) can be
prepared according to the method disclosed below in Reaction Scheme
4:
##STR00017##
[0769] Compounds of formula (Da) are commercially available or can
be prepared by methods known to one skilled in the art or by
methods disclosed herein.
[0770] In general, compounds of formula (D-1) are prepared, as set
forth above in Reaction Scheme 3, by first dissolving the compound
of formula (Da) (1.0 equiv) in an anhydrous aprotic polar solvent
or mixture of such solvents, for example, tetrahydrofuran with
hexamethylphosphoramide (HMPA) (1.2 equiv). The resulting solution
is stirred at ambient temperature for about 10 minutes and then
cooled to a temperature of between about -10.degree. C. and about
5.degree. C., preferably at 0.degree. C. A strong base, lithium
bis(trimethylsilyl)amide (Li-HMDS) (1.1 equiv), is then added
dropwise to the stirred mixture over a period of time of between
about 20 minutes and 40 minutes, preferably over 30 minutes, while
maintaining the temperature of the resulting mixture at between
about -10.degree. C. and about 5.degree. C., preferably at
0.degree. C. Ethyl bromoacetate (2.5 equiv) is then added to the
resulting anion of (Da) and the resulting mixture is stirred for
additional period of time of between about 5 minutes and 15
minutes, preferably for about about 10 minutes, and then allowed to
warm to ambient temperature and stirred at ambient temperature for
a period of time of between about 30 minutes and 3 hours,
preferably for about 2 hours. The compound of formula (Db) is then
isolated from the reaction mixture by standard isolation techniques
known to one skilled in the art, such as solvent evaporation and
purification by flash column chromatography.
[0771] The compound of formula (Db) is then treated under basic
hydrolysis conditions to form the compound of formula (Dc), which
is isolated from the reaction mixture by standard isolation
techniques known to one skilled in the art.
[0772] The compound of formula (Dc) (1.0 equiv) is then treated
with hydrazine hydrate (1.25 equiv) in the presence of a polar
protic solvent, such as ethanol, to yield the compound of formula
(Dd), which is isolated from the reaction mixture by standard
isolation techniques known to one skilled in the art.
[0773] A mixture of the compound of formula (Dd) (1.0 equiv) and
anhydrous copper(II) chloride (2.0 equiv) is then refluxed in
acetonitrile to yield the unsaturated compound of formula (De),
which is isolated from the reaction mixture by standard isolation
techniques known to one skilled in the art.
[0774] A mixture of the compound of formula (De) and phosphoryl
chloride, is refluxed for a period of time of between about 1 hour
and 3 hours, preferably for about 2 hours to aromatize and
chlorinate the ring containing the N--N linkage. After cooling to
ambient temperature, the compound of formula (Df) is isolated from
the reaction mixture by standard isolation techniques known to one
skilled in the art.
[0775] A mixture of the compound of formula (Df) (1.0 equiv) and
anhydrous hydrazine (19.8 equiv) in a protic solvent, such as
ethanol, is refluxed for a period time of between about 4 hours and
24 hours, preferably for about 16 hours. After cooling to ambient
temperature, water is added to the mixture and the compound of
formula (D-1) is then isolated from the reaction mixture by
standard isolation techniques known to one skilled in the art.
[0776] All compounds of the invention which exist in free base or
acid form can be converted to their pharmaceutically acceptable
salts by treatment with the appropriate inorganic or organic base
or acid by methods known to one of ordinary skill in the art. Salts
of the compounds of the invention can be converted to their free
base or acid form by standard techniques known to one skilled in
the art.
[0777] The following specific Synthetic Preparations (for
intermediates) and Synthetic Examples (for compounds of formula
(Ia1) and (Ib1)) are provided as a guide to assist in the practice
of the invention, and are not intended as a limitation on the scope
of the invention.
Synthetic Preparation 1
Synthesis of 7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene A
compound of formula (Ca)
##STR00018##
[0779] A. Sodium methoxide (9.4 g, 174.2 mmol) was added to a 250
mL of flask with dry methanol (100 mL) at 0.degree. C. After the
solid was dissolved, the resulting solution was warmed to ambient
temperature and was added to a solution of dimethyl
acetone-1,3-dicarboxylate (15.2 g, 87.1 mmol) and o-xylylene
dibromide, also known as 1,2-bis(bromomethyl)benzene, (20 g, 75.7
mmol) in 100 mL of dry THF at 0.degree. C. dropwise within 30 min.
After the addition, the reaction mixture was warmed to ambient
temperature and stirred overnight. The volatiles were evaporated,
the residue was poured into 40 mL of 10% HCl solution and extracted
with ethyl acetate (EtOAc) (200 mL.times.2). The combined extracts
were washed with water, saturated NaHCO.sub.3 solution and brine.
After evaporation, the residual oil was used for next step
directly.
[0780] B. The crude dimethyl
7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6,8-dicarboxylate was
dissolved in 200 mL of ethanol (EtOH) and then 100 mL of 2 N KOH.
The resulting mixture was refluxed at 85.degree. C. for 17 h. After
cooling to ambient temperature, the volatiles were evaporated. To
the residue was added 120 mL of 2N HCl at 0.degree. C., the crude
product was extracted by EtOAc (200 mL.times.2). The combined
extracts were washed with brine. After being dried (MgSO.sub.4),
filtered, and concentrated, the residue was purified by flash
column chromatography on silica gel (hexanes/EtOAc 8:1) to afford
6.6 g (57%) of 7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene as a
white solid: mp 40-41.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.: 7.21 (m, 4H), 2.94-2.90 (m, 4H), 2.63-2.60 (m, 4H); LC-MS:
161 (M+H).sup.+.
Synthetic Preparation 2
Synthesis of 2-nitro-8,9-dihydro-5H-benzo[7]annulene-7 (6H)-one A
compound of formula (Cb)
##STR00019##
[0782] To a solution of cold (0.degree. C.) concentrated sulfuric
acid (15 mL) was added 70% nitric acid (15 mL) dropwise over 30
min. The addition was controlled to maintain the internal reaction
temperature below 5.degree. C. After the addition, the resulting
solution was transferred into an addition funnel and was added
dropwise to a solution of
7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (14 g, 87.5 mmol) in
nitromethane (80 mL) at 0.degree. C. over a period of 40 min. After
the addition, the reaction mixture was stirred at 0.degree. C. for
2 h. Then ice water (.about.80 mL) was added to the reaction
mixture, and the mixture was stirred for additional 30 min. Then
the mixture was transferred to a separatory funnel where the layers
were separated. The aqueous layer was extracted with ethyl acetate
(3.times.80 mL). The combined layers were washed with cold water,
sat. NaHCO.sub.3 solution and brine. After being dried
(MgSO.sub.4), filtered, and concentrated, the residue was purified
by flash column chromatography on silica gel (hexanes/EtOAc=3:1 to
2:1) to afford the mixture of nitro regioisomers (.about.15 g),
which was then purified by recrystallization from MTBE (tert-butyl
methyl ether, 180 mL) to yield 7.3 g of
2-nitro-8,9-dihydro-5H-benzo[7]annulene-7(6H)-one (40% yield) as a
yellow solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 8.10-8.06
(m, 2H), 7.40-7.37 (m, 1H), 3.04-3.00 (m, 4H), 2.67-2.65 (m, 4H);
LC-MS: 206 (M+H).sup.+.
Synthetic Preparation 3
Synthesis of
1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine
A compound of formula (Cc)
##STR00020##
[0784] Pyrrolidine (0.85 g, 12 mmol) and
2-nitro-7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (2.05 g, 10
mmol) were mixed in 1,2-dchloroethane (35 mL) and then treated with
NaBH(OAc).sub.3 (3.18 g, 15 mmol) and AcOH (0.60 g, 10 mmol). The
mixture was stirred at ambient temperature under a N.sub.2
atmosphere overnight. The reaction mixture was quenched with
saturated NaHCO.sub.3, and the product was extracted with EtOAc
(3.times.30 mL). The organic layers were combined and dried over
NaSO.sub.4. The solvent was evaporated and the residue was purified
by flash column chromatography eluting with
CH.sub.2Cl.sub.2/DMA=1/1 (DMA=CH.sub.2Cl.sub.2/MeOH/30%
NH.sub.3=80/19/1) to afford
1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolid-
ine, a yellow oil (2.2 g, 85%); MS (m/e): 261 (M+H.sup.+).
Synthetic Preparation 4
[0785] Synthesis of
1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine
A compound of formula (Ba)
##STR00021##
[0786] A mixture of
1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine
(2.0 g; 7.69 mmol) and 10% palladium on carbon (0.2 g, .about.50%
water) in methanol (150 mL) was shaken under hydrogen (40 psi) for
1 h. After this time the reaction mixture was filtered through
diatomaceous earth and the filtrate was concentrated under reduced
pressure to afford
1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine
as an oil (quantitative yield); MS (m/e): 231 (M+H.sup.+).
Synthetic Preparation 5
Synthesis of Phenyl
N'-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)carbamimidate A compound of formula (C-1)
##STR00022##
[0788] A mixture of
1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine
(1.7 g; 7.39 mmo) and diphenyl cyanocarboimidate (1.76 g, 7.39
mmol) in 20 mL of isopropanol was stirred at ambient temperature
overnight. The solid was filtered, washed with isopropanol and
ether and dried to give phenyl
N'-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)carbamimidate, as a white solid (2.2 g, 80%). MS (m/e): 375
(M+H.sup.+).
Synthetic Preparation 6
Isolation of Phenyl
(S)--N'-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)carbamimidate and Phenyl
(R)--N'-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)carbamimidate Enantiomers of the Compound of formula
(C-1)
[0789] Phenyl
N'-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)carbamimidate (0.43 g, racemic) was eluted on a chiral column
chromatography mobile phase; ethanol/MeOH/triethyl amine=1/1/0.2%
to afford phenyl
(S)--N'-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)carbamimidate and phenyl
(R)--N'-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)carbamimidate: Chiral column: Chiralcel OJ, 21.2.times.250
mm. 10 .mu.M; packing material: cellulose tris-(4-methylbenzoate)
coated on 10 .mu.m silica gel substrate. Flow rate 9.9 mL/min,
sample solubility 30 mg/mL in methanol. Single enantiomers were
isolated in 170 mg and 190 mg quantities, respectively. Absolute
configuration of each enantiomer was not determined at this
time.
Synthetic Preparation 7
Synthesis of ethyl
2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetate
Compound of formula (Db)
##STR00023##
[0791] To a mixture of 1-benzosuberone (5.0 g, 31.2 mmol, Aldrich)
in dry tetrahydrofuran (THF) (20 mL) was added
hexamethylphosphoramide (6.5 mL, 37.5 mmol) (99%, Aldrich). The
resulting mixture was stirred at ambient temperature for 10 min and
then cooled to 0.degree. C. with a ice-water bath, 1.0 M solution
of lithium bis(trimethylsilyl)-amide in THF (32.7 mL, 32.7 mmol)
was added dropwise in 30 min. After the addition, the reaction
mixture was stirred at 0.degree. C. for 30 min. Ethyl bromoacetate
(8.7 mL, 78.1 mmol) was then added. After stirring for a further 10
min, the reaction mixture was warmed to ambient temperature and
stirred for 2 h. Solvent was evaporated, the residue was diluted
with ethyl acetate (EtOAc) (300 mL), and washed with water and
brine. After being dried (MgSO.sub.4), filtered, and concentrated,
the residue was purified by flash column chromatography eluting
with hexanes-ethyl acetate 6:1.fwdarw.4:1) to afford 6.6 g of the
compound of formula (Db), ethyl
2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetate, as an
orange oil (84%), .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.:
7.69-7.21 (m, 4H), 4.22-4.05 (m, 2H), 3.40-3.30 (m, 1H), 3.12-2.92
(m, 3H), 2.52-2.43 (m, 1H), 2.20-1.58 (m, 4H), 1.28-1.21 (m, 3H);
LC-MS: purity: 91.8%; MS (m/e): 247 (MH.sup.+).
Synthetic Preparation 8
Synthesis of
2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetic acid
Compound of formula (Dc)
##STR00024##
[0793] The compound of formula (Db), ethyl
2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetate, (6.6
g, 26.8 mmol) was dissolved in ethanol (EtOH) (30 mL), then 10%
potassium hydroxide (KOH) aqueous solution (37.5 mL, 67 mmol) was
added and the resulting mixture was refluxed for 2 h. After cooling
to ambient temperature, the EtOH was removed by evaporation. The
residue was extracted with EtOAc twice (15 mL.times.2). The aqueous
layer was then transferred into a flask and cooled with an
ice-water bath, con. HCl was added dropwise to adjust pH to about
2.0. EtOAc (60 mL) was then added, the layers were separated, and
the aqueous layer was extracted with EtOAc. The combined extracts
were washed with brine. After being dried (MgSO.sub.4), filtered,
and concentrated, the compound of formula (Dc),
2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetic acid,
was obtained as an orange oil (5.7 g, 97%); .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.: 7.71-7.68 (m, 1H), 7.41-7.20 (m, 3H),
3.37-3.31 (m, 1H), 3.12-2.91 (m, 3H), 2.57-2.49 (m, 1H), 2.15-1.90
(m, 2H), 1.75-1.62 (m, 2H); LC-MS: purity: 100%; MS (m/e): 219
(MH.sup.+).
Synthetic Preparation 9
Synthesis of
4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3 (4H)-one
Compound of formula (Dd)
##STR00025##
[0795] A. A mixture of the compound of formula (Dc),
2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetic acid,
(5.7 g, 26.1 mmol) and hydrazine hydrate (1.6 mL, 32.7 mmol) in 20
mL of ethanol was refluxed for 2 h, cooled and filtered (washed
with small amount of EtOH) to give the compound of formula (Dd),
4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one,
as a white solid (4.7 g, 84%); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.: 8.61 (bs, 1H), 7.53-7.14 (m, 4H), 2.98-2.75 (m, 3H), 2.58
(dd, J=15.3, 16.8 Hz, 1H), 2.31 (dd, J=12.0, 16.8 Hz, 1H),
1.96-1.59 (m, 4H); LC-MS: purity: 100%; MS (m/e): 215
(MH.sup.+).
[0796] B. Alternatively, a mixture of benzosuberone (10.6 g, 66.2
mmol), glyoxylic acid monohydrate (6.08 g, 66.2 mmol), sodium
hydroxide (10.6 g, 265 mmol), ethanol (40 mL) and water (100 mL)
were stirred overnight at ambient temperature, and then heated
under reflux for 1 h. The mixture was cooled, then diluted with
water and extracted twice with dichloromethane (subsequently
discarded). The aqueous layer was then acidified with 10% aqueous
hydrochloric acid. Ice was added for cooling. The mixture was then
filtered to give a pale yellow solid, 10.5 g (after air drying).
The crude solid was then heated at 100.degree. C. for 1 h with a
mixture of acetic acid (60 mL), water (30 mL) and zinc dust (6 g).
The reaction mixture was cooled to ambient temperature and
filtered. The filtrate was extracted with ethyl acetate. The
organic layer was washed three times with saturated sodium chloride
solution, then dried over anhydrous sodium sulfate and concentrated
under vacuum. The crude residue was heated with ethanol (25 mL) and
hydrazine monohydrate (10 mL) under reflux for 3 h. The solvent was
removed under vacuum and the residue was crystallized from
benzene/ethanol, 1/1, to give
4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one
as a white solid, 2.31 g; .sup.1H NMR (CDCl.sub.3, 300 MHz) 8.66
(s, 1H), 7.52 (d, 1H), 7.24-7.50 (m, 2H), 7.16 (d, 2H), 2.75-3.00
(m, 3H), 2.56 (dd, 1H), 2.31 (dd, 1H), 1.60-1.90 (m, 4H) ppm; MS
(ES) 215 (M+H). This procedure followed that reported by V.
Peesapati and S. C. Venkata, Indian J. Chem., 41B, 839 (2002).
Synthetic Preparation 10
Synthesis of
6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one
Compound of formula (De)
##STR00026##
[0798] A. A mixture of the compound of formula (Dd),
4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one
(4.7 g, 22 mmol) and anhydrous copper(II) chloride (6 g, 44 mmol)
was refluxed in acetonitrile (45 mL) for 2 hours. After cooling to
ambient temperature, the mixture was poured into ice-water (200 g)
and the solid obtained was washed with 10% HCl solution twice
(about 20 mL.times.2) and cold water twice (about 20 mL.times.2).
After freeze-drying, the compound of formula (De),
6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one (4.2
g, 90%) was obtained as a white solid, .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.: 10.80 (bs, 1H), 7.53-7.21 (m, 4H), 6.77 (s,
1H), 2.66 (t, J=6.9 Hz, 2H), 2.45 (t, J=6.9 Hz, 2H), 2.14 (quant,
J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e): 213 (MH.sup.+).
[0799] B. Alternatively, a solution of
4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one
(2.31 g, 10.74 mmol), sodium m-nitrobenzenesulfonate (2.48 g, 11
mmol), sodium hydroxide (1.86 g, 46.5 mmol) in water (80 mL) was
heated under reflux for 1.5 h. The solution was cooled to ambient
temperature, and then acidified with concentrated hydrochloric
acid. The solid which precipitated was filtered off, washed with
water and crystallized from ethanol to give
6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one as
tan crystals, 1.46 g; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 13.04 (s,
1H), 7.25-7.45 (m, 4H), 6.78 (s, 1H), 2.49 (m, 2H), 2.35 (m, 2H),
2.04 (m, 2H) ppm; MS (ES) 213 (M+H).
Synthetic Preparation 11
Synthesis of
3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine
Compound of formula (Df)
##STR00027##
[0801] A. A mixture of the compound of formula (De),
6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one (4.0
g, 19.3 mmol) and POCl.sub.3 (20 mL) was refluxed for 2 h. After
cooling to ambient temperature, the volatiles were evaporated. The
residue was poured into a mixture of ice water and sodium
bicarbonate, CH.sub.2Cl.sub.2 (200 mL) was added to dissolve the
solid. The layers were separated, and the aqueous layer was
extracted with CH.sub.2Cl.sub.2 one more time. The combined organic
layers were washed with brine. After being dried (MgSO.sub.4),
filtered, and concentrated, the compound of formula (Df),
3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine was
obtained as a yellow solid (4.3 g, 99%), .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.: 7.82 (m, 1H), 7.45-7.24 (m, 4H), 2.59-2.51 (m,
4H), 2.27 (quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e): 231
(MH.sup.+).
[0802] B. Alternatively,
6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3 (5H)-one was
heated with 20 mL of phosphorus (III) oxychloride at 100.degree. C.
for 4.75 h. The solvent was removed under vacuum. The residue was
treated with ice and saturated sodium bicarbonate solution. The
solid which formed was filtered off, washed well with water and
air-dried to yield the corresponding
3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6
g); .sup.1H NMR (CDCl.sub.3, 300 MHz) 7.82 (m, 1H), 7.44 (m, 2H),
7.39 (s, 1H), 7.27 (m, 1H), 2.55 (m, 4H), 2.32 (m, 2H) ppm; MS (ES)
231/233 (M+H).
Synthetic Preparation 12
Synthesis of
3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine
Compound of formula (D-1)
##STR00028##
[0804] A. A mixture of the compound of formula (Df),
3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine, (4.3
g, 18.6 mmol) and anhydrous hydrazine (11.7 mL, 370 mmol) in 45 mL
of ethanol was refluxed for 16 h. After cooling to ambient
temperature, 5 mL of water was added and the volatiles were then
evaporated. To the solid residue was added cold water (about 80
mL). After sonication for 10 min, the resulting solid was collected
by filtration and washed with cold water three times. After
freeze-drying, the compound of formula (D-1),
3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine,
(4.14 g, 98%) was obtained as a slight yellow solid, .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta.: 7.59 (m, 1H), 7.39-7.26 (m, 3H),
7.04 (s, 1H), 2.54 (t, J=6.9 Hz, 2H), 2.47 (t, J=6.9 Hz, 2H), 2.18
(quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e): 227
(MH.sup.+).
[0805] B. Alternatively,
3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6
g) was heated with anhydrous hydrazine (4 mL) in ethanol (50 mL) at
100.degree. C. for 4.75 h. The solvent was removed under vacuum.
The residue was partitioned between chloroform and 1M saturated
aqueous potassium carbonate. The organic layer was dried over
anhydrous sodium sulfate and concentrated under vacuum to give
3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine as
a brown solid; .sup.1H NMR (CDCl.sub.3, 300 MHz) 7.74 (m, 1H), 7.30
(m, 2H), 7.17 (m, 1H), 6.92 (s, 1H), 2.49 (m, 2H), 2.39 (m, 2H),
2.12 (m, 2H) ppm; MS (ES) 227 (M+H).
Synthetic Preparation 13
Synthesis of Phenyl
N'-cyano-N-(7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annul-
ene-2-yl)carbamimidate (Cb-5)
[0806] Finely ground
2-Nitro-8,9-dihydro-5H-benzo[7]annulen-7(6H)-one (8.00 g, 39.0
mmol) and L-alanine (34.7 g, 390 mmol) were added to the reaction
buffer (1000 mL, Codexis/BioCatalytics). The mixture was stirred
vigorously for about 20 min in order to obtain a uniform suspension
(bright-yellow in color). The pyruvate reductase mix (40.0 g,
PRM-102, Codexis/BioCatalytics) and the transaminase (0.85 g,
.about.10.6 wt %, ATA-103) were added. The pH of the reaction
mixture was .about.7. Stirring was continued at a slow pace; the pH
was checked once a day and, if necessary, adjusted to pH 7.0-7.5
using 1M NaOH. During the course of the reaction the color of the
mixture changed to a yellow-orange color. After 6 days HPLC
analysis showed 99% conversion. The reaction was worked up by
adding sat. NaHCO.sub.3 solution (200 mL) and CHCl.sub.3 (600 mL).
This mixture was stirred vigorously to ensure complete transfer of
the product into the organic phase. After stirring overnight two
layers had formed and the organic layer contained large amounts of
a gel-like solid. The organic layer was separated and filtered
through a large glass frit (medium) to remove the gel-like solid.
The aqueous phase was extracted three times with DCM. The combined
organic layers were filtered through MgSO.sub.4 and the solvents
were evaporated to give the desired amine,
(7S)-2-nitro-7-amino-7,8,9-trihydro-5H-benzo[7]annulene (7.27 g,
91%, dark-red oil).
[0807] The single enantiomer was then BOC-protected, the nitro
group reduced by treatment with H.sub.2/Pd and the primary aniline
treated with diphenyl cyanocarboimidate (slight excess) in 20 mL of
isopropanol with stirring at ambient temperature overnight. The
solid was filtered, washed with isopropanol and ether and dried to
give phenyl
(7S)--N'-cyano-N-(7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)car-
bamimidate, as a white solid in high yield (from the single
enantiomer via transamination).
Synthetic Example 1
Synthesis of
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine
##STR00029##
[0809] Phenyl
N'-cyano-N-(7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annul-
ene-2-yl)carbamimidate (2.00 g, 4.75 mmol) and
3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine
(1.08 g, 4.75 mmol) were mixed in dry toluene (40 ml). The
suspension was heated to 90.degree. C. and stirred for 24 h. The
clear solution was allowed to cool to ambient temperature and the
toluene was evaporated using a rotavapor. The crude product was
then checked by HPLC and TLC. Column chromatography on silica gel
using CHCl.sub.3 and 5% NH.sub.3 (2M in MeOH) afforded some clean
fractions of product which gave 367 mg (14%) of the desired
product,
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S-
)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine. The impure fractions were further
purified by reverse phase HPLC to yield another 515 mg (20%) of the
desired product, .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.04 (s, 1H,
NH), 7.92 (s, 1H), 7.86 (s, 2H), 7.69 (m, 1H), 7.43 (m, 3H), 7.34
(m, 1H), 7.23 (m, 1H), 6.96 (d, 1H), 6.83 (d, 1H), 3.49 (m, 1H),
2.72-2.39 (m, 8H), 2.22 (m, 2H), 2.07 (s, 1H), 1.92 (m, 2H), 1.38
(s, 9H), 1.17 (m, 2H) ppm; trifluoroacetic acid salt MS (ES) 553.24
(M+H), 551.42 (M-H).
Synthetic Example 2
[0810] The following compounds of the invention were prepared
according to the methods similar to those described herein:
[0811]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-(7-(acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-tri-
azole-3,5-diamine, .sup.1H-NMR (DMSO-d6, 300 MHz) 9.07 (s, 1H),
7.93 (s, 1H), 7.90-7.65 (m, 3H), 7.47-7.31 (m, 3H), 7.24 (s, 1H),
7.00 (d, 1H), 3.89-3.80 (m, 1H), 2.71-2.50 (m, 8H), 2.30-2.19 (m,
2H), 1.96-1.88 (m, 2H), 1.80 (s, 3H), 1.37-1.19 (m, 2H) ppm; MS
(ES) 495.21 (M+H);
[0812]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-(7-((2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo-
[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H-NMR
(CDCl.sub.3, 300 MHz) 8.90-8.78 (m, 1H), 8.48 (bs, 2H), 7.93 (s,
1H), 7.80-7.78 (m, 1H), 7.47-7.41 (m, 2H), 7.38-7.30 (m, 3H),
7.05-7.00 (m, 1H), 3.82 (s, 3H), 3.80-3.64 (m, 2H), 2.94-2.81 (m,
3H), 2.79-2.71 (m, 4H), 2.70-2.67 (m, 3H), 2.38-2.43 (m, 4H),
2.38-2.29 (m, 3H), 1.80-1.60 (m, 2H) ppm; MS (ES) 565.29 (M+H);
[0813]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-(7-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H-NMR (DMSO-d6, 300 MHz)
9.60 (s, 1H), 9.11 (s, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.71-7.68
(m, 1H), 7.51-7.45 (m, 2H), 7.39-7.33 (m, 2H), 7.08 (d, 1H), 3.67
(t, 1H), 3.52 (d, 2H), 3.18 (bs, 2H), 2.84-2.52 (m, 6H), 2.37-2.22
(m, 8H), 1.58-1.41 (m, 3H) ppm; MS (ES) 557.23 (M+H);
[0814]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-(7-((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]-
annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H-NMR (DMSO-d6,
300 MHz) 9.62 (s, 1H), 9.11 (s, 1H), 7.92 (s, 1H), 7.81 (s, 1H),
7.78-7.71 (m, 1H), 7.45-7.41 (m, 2H), 7.38-7.32 (m, 1H), 7.04 (d,
1H), 4.37 (d, 1H), 4.11 (d, 1H), 3.78 (s, 2H), 3.59 (t, 1H),
2.81-2.74 (m, 4H), 2.65-2.57 (m, 7H), 2.31-2.21 (m, 3H), 1.59-1.40
(m, 2H) ppm; MS (ES) 539.21 (M+H);
[0815]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-(7-((2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annul-
ene-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H-NMR (DMSO-d6, 300
MHz) 9.55 (s, 1H), 9.18 (s, 1H), 7.94 (s, 1H), 7.72-7.68 (m, 1H),
7.47-7.40 (m, 2H), 7.38-7.31 (m, 2H), 7.05 (d, 1H), 5.05-4.70 (bs,
3H), 4.55 (q, 1H), 3.64 (t, 1H), 3.52-3.48 (m, 1H), 3.31-3.25 (m,
1H), 2.80-2.70 (m, 3H), 2.62-2.52 (m, 3H), 2.39-2.20 (m, 5H),
2.09-1.78 (m, 4H), 1.49-1.38 (m, 3H) ppm; MS (ES) 551.27 (M+H);
[0816]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-(7-(4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annu-
lene-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H-NMR (DMSO-d6, 300
MHz) 9.11 (s, 1H), 8.97-8.90 (m, 1H), 7.94 (s, 1H), 7.85 (s, 1H),
7.71-7.68 (m, 1H), 7.50-7.40 (m, 2H), 7.38-7.30 (m, 2H), 7.05 (d,
1H), 4.09 (q, 2H), 3.55 (t, 1H), 3.38 (d, 1H), 3.10 (q, 1H),
2.85-2.57 (m, 5H), 2.52-2.42 (m, 6H), 2.29-2.18 (m, 3H), 2.06 (d,
2H), 1.77-1.70 (m, 2H), 1.54-1.36 (m, 3H), 1.29 (t, 3H) ppm; MS
(ES) 593.28 (M+H);
[0817]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-(7-(4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H-NMR (DMSO-d6, 300 MHz)
9.90 (bs, 1H), 9.10 (s, 1H), 7.96 (s, 2H), 7.74-7.69 (m, 1H),
7.50-7.41 (m, 2H), 7.37-7.40 (m, 1H), 7.05 (d, 1H), 4.40-3.83 (m,
5H), 3.53-3.44 (m, 1H), 3.36 (d, 1H), 3.12-2.98 (m, 1H), 2.83-2.71
(m, 2H), 2.62-2.59 (m, 1H), 2.57-2.43 (m, 7H), 2.41-2.36 (m, 1H),
2.29-2.20 (m, 1H), 2.02-1.91 (m, 2H), 1.50-1.38 (m, 1H) ppm; MS
(ES) 565.26 (M+H);
[0818]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-(7-((carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-
-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H-NMR (DMSO-d6, 300
MHz) 9.42 (s, 1H), 9.10 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H),
7.73-7.68 (m, 1H), 7.48-7.41 (m, 2H), 7.39-7.33 (m, 2H), 7.05 (d,
1H), 4.10 (bs, 3H), 3.57 (t, 1H), 2.78 (s, 3H), 2.68-2.45 (m, 9H),
2.3.4-2.22 (m, 3H). 1.55-1.39 (m, 2H) ppm; MS (ES) 525.22
(M+H);
[0819]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-(7-(4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[-
7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H-NMR
(DMSO-d6, 300 MHz) 9.21 (s, 1H), 9.12 (s, 1H), 7.93 (s, 1H), 7.87
(s, 1H), 7.73-7.69 (m, 1H), 7.49-7.41 (m, 3H), 7.38-7.32 (m, 2H),
7.06 (d, 1H), 4.11 (q, 2H), 3.54-3.29 (m, 5H), 3.13-2.97 (m, 4H),
2.80-2.70 (m, 8H), 2.60 (t, 2H), 2.37-2.22 (m, 4H), 1.53-1.39 (m,
2H), 1.26 (t, 3H) ppm; MS (ES) 608.31 (M+H);
[0820]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-(7-(4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annul-
ene-2-yl)-1H-1,2,4-triazole-3,5-diamine, MS (ES) 580.25 (M+H);
[0821]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2-
,4-triazole-3,5-diamine, MS (ES) 507.24 (M+H), 505.33 (M-H);
[0822]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
5-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2-
,4-triazole-3,5-diamine, MS (ES) 507.25 (M+H), 505.28 (M-H);
[0823]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
5-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine, MS (ES) 553.31 (M+H), 551.47
(M-H);
[0824]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-tria-
zole-3,5-diamine, formic acid salt .sup.1H NMR (DMSO-d.sub.6, 300
MHz) 9.11 (s, 1H, NH), 7.93 (s, 1H), 7.65 (m, 3H), 7.72 (d, 1H),
7.47 (m, 2H), 7.38 (s, 1H), 7.27 (s, 1H), 7.03 (d, 1H), 3.32 (s,
1H), 2.71 (m, 4H), 2.65-2.45 (m, 4H), 2.21 (m, 4H), 1.29 (m, 2H)
ppm; MS (ES) 553.65 (M+H), 551.37 (M-H); free base MS (ES) 453.65
(M+H), 451.39 (M-H); trifluoroacetic acid salt MS (ES) 453.14
(M+H), 451.23 (M-H);
[0825]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7s)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annul-
ene-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6,
300 MHz) 9.12 (s, 1H, NH), 7.95 (s, 1H), 7.82 (s, 2H, NH.sub.2),
7.71 (m, 1H), 7.45 (m, 3H), 7.31 (m, 2H), 7.05 (d, 2H), 3.75 (t,
1H), 2.96 (m, 4H), 2.73 (m, 4H), 2.65-2.42 (m, 4H), 2.23 (m, 4H),
1.31 (m, 2H), 1.08 (s br, 2H), 0.61 (d, 4H), 0.29 (d, 4H) ppm; MS
(ES) 561.30 (M+H), 559.42 (M-H);
[0826]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-
-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300
MHz): 9.13 (s, 1H), 8.25 (s br, 2H), 7.81-8.00 (m, 3H), 7.66-7.76
(m, 1H), 7.41-7.53 (m, 3H), 7.27-7.39 (m, 2H), 6.97-7.11 (m, 1H),
3.19-3.47 (m, 1H), 2.66-2.86 (m, 6H), 2.43-2.65 (m, 7H), 2.14-2.37
(m, 4H), 1.82-1.99 (m, 1H), 1.20-1.47 (m, 2H), 0.93 (d, J=6.6 Hz,
6H) ppm; MS (ES) 509.23 (M+H), 507.36 (M-H);
[0827]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300 MHz):
9.06-9.18 (m, 1H), 8.19-8.40 (m, 2H), 7.76-7.99 (m, 3H), 7.23-7.54
(m, 5H), 7.03 (d, 1H), 3.20-3.44 (m, 1H), 2.83-3.00 (m, 2H),
2.66-2.82 (m, 4H), 2.51-2.66 (m, 4H), 2.11-2.34 (m, 4H), 1.46-1.73
(m, 2H), 1.19-1.44 (m, 2H), 0.91 (s, 3H) ppm; MS (ES) 495.24 (M+H),
493.38 (M-H);
[0828]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300 MHz):
9.12 (s, 1H), 8.67-8.85 (m, 1H), 7.77-8.02 (m, 3H), 7.65-7.76 (m,
1H), 7.25-7.56 (m, 5H), 7.05 (d, J=8.3 Hz, 1H), 3.47-3.70 (m, 1H),
2.99-3.18 (m, 2H), 2.83-2.98 (m, 2H), 2.66-2.83 (m, 4H), 2.50-2.66
(m, 5H), 2.10-2.34 (m, 4H), 1.34-1.78 (m, 6H), 0.88 (t, J=7.2 Hz,
5H) ppm; MS (ES) 537.30 (M+H), 535.49 (M-H);
[0829]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1-
,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300 MHz):
9.10 (s, 1H), 7.94 (s, 1H), 7.83 (s br, 2H), 7.67-7.75 (m, 1H),
7.41-7.53 (m, 3H), 7.29-7.41 (m, 2H), 7.05 (d, 1H), 3.52-3.68 (m,
2H), 2.93-3.27 (m, 4H), 2.66-2.85 (m, 4H), 2.50-2.65 (m, 4H),
2.11-2.31 (m, 5H), 1.33-1.60 (m, 2H), 1.09-1.29 (m, 7H) ppm; MS
(ES) 509.23 (M+H), 507.35 (M-H);
[0830]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine, MS (ES) 535.30 (M+H), 533.46
(M-H);
[0831]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)--
1H-1,2,4-triazole-3,5-diamine, MS (ES) 521.28 (M+H), 519.28
(M-H);
[0832]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-((1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)-1H-1,2,4-triazole-3,5-diamine, MS (ES) 563.30 (M+H);
[0833]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300 MHz):
9.09 (s, 1H), 8.32 (s, 1H), 7.94 (s, 1H), 7.84 (s, 2H), 7.63-7.77
(m, 1H), 7.40-7.52 (m, 2H), 7.36 (s br, 1H), 7.28 (s, 1H), 7.01 (d,
1H), 3.16-3.35 (m, 2H), 3.10-3.16 (m, 1H), 2.65-2.80 (m, 4H),
2.56-2.65 (m, 2H), 2.07-2.33 (m, 5H), 1.19-1.40 (m, 2H), 1.16 (d,
J=6.3 Hz, 6H) ppm; MS (ES) 495.26 (M+H), 493.37 (M-H);
[0834]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-((3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annu-
lene-2-yl)-1H-1,2,4-triazole-3,5-diamine, MS (ES) 536.18 (M);
[0835]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-
-2-yl)-1H-1,2,4-triazole-3,5-diamine, MS (ES) 549.28 (M+H), 547.29
(M-H);
[0836]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)-1H-1,2,4-triazole-3,5-diamine, MS (ES) 645.43 (M+H),
643.51 (M-H);
[0837]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-((5-chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]-
annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR
(DMSO-d.sub.6, 300 MHz): 9.12 (s, 1H), 8.86 (s br, 2H), 7.66-7.99
(m, 3H), 7.26-7.53 (m, 4H), 7.17 (d, 2H), 7.04 (d, 1H), 4.43 (s br,
2H), 3.21-3.36 (m, 2H), 2.65-2.86 (m, 7H), 2.13-2.39 (m, 4H),
1.17-1.50 (m, 2H) ppm; MS (ES) 583.15 (M+H), 581.28 (M-H);
[0838]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-((2-carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]ann-
ulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, MS (ES) 587.26
(M+H);
[0839]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annul-
ene-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6,
300 MHz): 9.09 (s, 1H), 8.01 (s, 1H), 7.67-7.96 (m, 6H), 7.27-7.50
(m, 5H), 7.03 (d, 1H), 6.50 (s, 1H), 4.12 (s br, 1H), 3.05-3.20 (m,
3H), 2.65-2.79 (m, 4H), 2.55-2.64 (m, 2H), 2.15-2.37 (m, 4H),
1.17-1.46 (m, 3H) ppm; MS (ES) 623.00 (M+H), 619.06 (M-H);
[0840]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300 MHz):
9.06 (s, 1H), 8.25 (s br, 2H), 7.81-8.01 (m, 3H), 7.65-7.78 (m,
2H), 7.25-7.51 (m, 2H), 6.97-7.08 (m, 1H), 4.86-5.00 (m, 1H),
3.99-4.08 (m, 1H), 2.66-2.85 (m, 2H), 2.52-2.65 (m, 4H), 2.15-2.36
(m, 5H), 1.87-2.12 (m, 5H), 1.12-1.48 (m, 3H) ppm; MS (ES) 481.10
(M+H), 479.13 (M-H);
[0841]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine, MS (ES) 507.15 (M+H), 505.24
(M-H);
[0842]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H--
1,2,4-triazole-3,5-diamine, MS (ES) 523.16 (M+H), 521.27 (M-H);
[0843]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6,
300 MHz): 9.05 (s, 1H), 8.29 (s, 1H), 7.93 (s, 1H), 7.85 (s br,
2H), 7.61-7.75 (m, 1H), 7.32-7.49 (m, 3H), 7.28 (s, 1H), 6.99 (d,
1H), 2.82-2.96 (m, 1H), 2.65-2.78 (m, 3H), 2.56-2.65 (m, 2H),
2.36-2.54 (m, 5H), 2.17-2.33 (m, 2H), 1.99-2.16 (m, 2H), 1.15-1.42
(m, 2H), 0.88 (s, 9H) ppm; MS (ES) 523.16 (M+H), 521.26 (M-H);
[0844]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annul-
ene-2-yl)-1H-1,2,4-triazole-3,5-diamine, MS (ES) 617.28 (M+H),
615.31 (M-H);
[0845]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-
e-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6,
300 MHz): 9.07 (s, 1H), 8.34 (s, 1H), 7.94 (s, 1H), 7.84 (s br,
2H), 7.66-7.75 (m, 1H), 7.33-7.53 (m, 3H), 7.28 (s, 1H), 7.00 (d,
1H), 2.87-3.13 (m, 1H), 2.40-2.84 (m, 10H), 1.92-2.33 (m, 5H),
1.63-1.80 (m, 2H), 1.39-1.63 (m, 4H), 1.05-1.38 (m, 4H) ppm; MS
(ES) 535.18 (M+H), 533.16 (M-H);
[0846]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-
-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, MS (ES)
665.26 (M+H), 663.40 (M-H);
[0847]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5-
H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR
(DMS O-d.sub.6, 300 MHz): 9.03 (s, 1H), 8.32 (s, 1H), 7.92 (s, 1H),
7.83 (s br, 2H), 7.63-7.75 (m, 1H), 7.32-7.55 (m, 3H), 7.27 (s,
1H), 6.99 (d, 1H), 6.08-6.21 (m, 1H), 5.89-6.01 (m, 1H), 2.83-3.03
(m, 2H), 2.65-2.82 (m, 4H), 2.54-2.65 (m, 4H), 2.29-2.44 (m, 4H),
1.93-2.33 (m, 6H), 1.81 (t, 1H), 1.14-1.37 (m, 4H), 0.39-0.60 (m,
1H) ppm; MS (ES) 559.17 (M+H), 557.39 (M-H);
[0848]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl-
)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300
MHz): 9.08 (s, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.86 (s br, 2H),
7.67-7.74 (m, 1H), 7.40-7.51 (m, 3H), 7.33-7.39 (m, 1H), 7.29 (s
br, 1H), 7.01 (d, J=8.3 Hz, 1H), 3.08 (s br, 1H), 2.52-2.87 (m,
10H), 2.07-2.33 (m, 4H), 1.52-1.68 (m, 1H), 1.35-1.48 (m, 2H),
1.17-1.34 (m, 2H), 0.87 (d, J=6.3 Hz, 6H) ppm; MS (ES) 523.20
(M+H), 521.27 (M-H);
[0849]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene--
2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300
MHz): 9.01 (s, 1H), 7.91 (s, 1H), 7.83 (s br, 2H), 7.67-7.74 (m,
1H), 7.39-7.49 (m, 3H), 7.33-7.39 (m, 1H), 7.25-7.31 (m, 1H), 6.99
(d, J=8.3 Hz, 1H), 2.52-2.75 (m, 9H), 2.16-2.38 (m, 7H), 1.86-2.04
(m, 2H), 1.49-1.62 (m, 2H), 1.11-1.28 (m, 5H), 0.83 (d, J=6.6 Hz,
12H) ppm; MS (ES) 593.28 (M+H), 591.33 (M-H);
[0850]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-
-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300
MHz): .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.04 (s, 1H), 8.28 (s,
1H), 7.93 (s, 1H), 7.84 (s br, 2H), 7.66-7.75 (m, 1H), 7.40-7.50
(m, 3H), 7.32-7.40 (m, 1H), 7.29 (s, 1H), 7.01 (d, J=8.3 Hz, 1H),
2.96-3.11 (m, 1H), 2.44-2.82 (m, 13H), 2.06-2.30 (m, 4H), 1.17-1.51
(m, 6H), 0.82 (t, J=7.3 Hz, 6H) ppm; MS (ES) 537.20 (M+H), 535.27
(M-H);
[0851]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1-
H-1,2,4-triazole-3,5-diamine, MS (ES) 507.16 (M+H), 505.11
(M-H);
[0852]
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.-
3-((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene--
2-yl)-1H-1,2,4-triazole-3,5-diamine, MS (ES) 562.16 (M);
[0853]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-
-N-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene--
2-yl)-1H-1,2,4-triazole-3,5-diamine, MS (ES) 554.10 (M+H), 552.22
(M-H);
[0854]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-
-N.sup.3-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-t-
riazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300 MHz): 9.23 (s,
1H), 8.54-8.69 (m, 1H), 8.10 (d, 1H), 7.98 (s, 1H), 7.87 (s br,
2H), 7.31-7.56 (m, 3H), 6.97 (t, 1H), 3.38-3.43 (m, 3H), 2.53-2.80
(m, 6H), 2.18-2.41 (m, 5H), 1.97-2.15 (m, 2H), 1.84-1.97 (m, 3H),
1.42-1.76 (m, 4H) ppm; MS (ES) 541.63 (M+H), 539.45 (M-H);
[0855]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-
-N.sup.3-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2-
,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.04
(s, 1H), 8.59 (d, 1H), 8.21 (s, 1H), 8.06 (d, 1H), 7.99 (s, 1H),
7.84 (s, 1H), 7.62-7.43 (m, 2H), 7.26 (s, 1H), 6.95 (d, 1H) 2.92
(m, 1H), 2.68-2.42 (m, 4H), 2.44 (s, 2H), 2.29 (m, 2H), 2.05 (m,
2H), 1.29 (m, 2H), 1.01 (m, 4H) ppm; MS (ES) 454.37 (M+H);
[0856]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-
-N.sup.3-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300
MHz) 9.03 (s, 1H), 8.53 (d, 1H), 8.25 (s, 1H), 8.11 (d, 1H), 7.95
(s, 1H), 7.88 (s, 1H), 7.51-7.39 (m, 2H), 7.26 (s, 1H), 7.08 (d,
1H), 2.92 (m, 1H), 2.72-2.48 (m, 8H), 2.40 (s, 2H), 2.31 (m, 2H),
2.02 (m, 2H), 1.25 (m, 2H), 1.06 (m, 4H) ppm; MS (ES) 482.08 (M+H),
480.23 (M-H);
[0857]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-
-N.sup.3-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-y-
l)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300
MHz) 9.05 (s, 1H), 8.58 (d, 1H), 8.22 (s, 1H), 8.09 (d, 1H), 7.96
(s, 1H), 7.85 (s, 1H), 7.56-7.38 (m, 2H), 7.28 (s, 1H), 7.03 (d,
1H), 2.98 (m, 1H), 2.79-2.52 (m, 12H), 2.49 (s, 2H), 2.33 (m, 2H),
2.04 (m, 2H), 1.27 (m, 2H), 1.03 (m, 4H) ppm; MS (ES) 510.57
(M+H);
[0858]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-
-N.sup.3-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2--
yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300
MHz) 9.04 (s, 1H), 8.58 (d, 1H), 8.18 (s, 1H), 8.08 (d, 1H), 7.96
(s, 1H), 7.85 (s, 1H), 7.60-7.40 (m, 2H), 7.28 (s, 1H), 6.99 (d,
1H), 2.86-2.56 (m, 10H), 2.41-2.24 (m, 6H), 1.99 (m, 2H), 1.50-1.09
(m, 5H), 0.82 (t, 6H) ppm; MS (ES) 538.15 (M+H), 536.25 (M-H);
[0859]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-
-N.sup.3-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[-
7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) 9.05 (s, 1H), 8.60 (d, 1H), 8.21 (s, 1H),
8.09 (d, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.55-7.39 (m, 2H), 7.26
(s, 1H), 7.00 (d, 1H), 3.10 (t, 2H), 2.77-2.54 (m, 8H), 2.45-2.22
(m, 6H), 2.01 (m, 4H), 1.30-1.09 (m, 2H), 0.84 (m, 2H), 0.43 (d,
3H), 0.10 (d, 2H) ppm; MS (ES) 562.16 (M+H), 560.39 (M-H);
[0860]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-
-N.sup.3-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]an-
nulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) 9.04 (s, 1H), 8.59 (d, 1H), 8.21 (s, 1H),
8.06 (d, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.62-7.43 (m, 2H), 7.26
(s, 1H), 6.95 (d, 1H), 2.83-2.59 (m, 6H), 2.51-2.31 (m, 6H), 2.01
(m, 2H), 1.66-1.38 (m, 5H), 1.24 (m, 6H), 0.88 (d, 6H), 0.83 (d,
6H) ppm; MS (ES) 594.21 (M+H); 592.25 (M-H);
[0861]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-
-N.sup.3-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene--
2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300
MHz) 9.04 (s, 1H), 8.59 (d, 1H), 8.29 (s, 1H), 8.10 (d, 1H), 7.96
(s, 1H), 7.85 (s, 1H), 7.55-7.39 (m, 2H), 7.24 (s, 1H), 6.99 (d,
1H), 2.93-2.53 (m, 8H), 2.31 (m, 4H), 2.11 (m, 2H), 1.96 (m, 2H),
1.80 (m, 2H), 1.62 (m, 2H), 1.32-1.10 (m, 2H) ppm; MS (ES) 508.05
(M+H), 506.13 (M-H);
[0862]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-
-N.sup.3-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene--
2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6, 300
MHz) 9.06 (s, 1H), 8.60 (d, 1H), 8.31 (s, 1H), 8.10 (d, 1H), 7.95
(s, 1H), 7.85 (s, 1H), 7.54-7.39 (m, 2H), 7.27 (s, 1H), 6.97 (d,
1H), 2.89-2.58 (m, 8H), 2.52 (m, 2H), 2.36 (m, 2H), 2.09 (m, 2H),
1.87 (m, 2H), 1.70 (m, 2H), 1.56 (m, 2H), 1.36-1.01 (m, 6H) ppm; MS
(ES) 536.12 (M+H);
[0863]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-
-N.sup.3-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annule-
ne-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6,
300 MHz) 9.04 (s, 1H), 8.57 (d, 1H), 8.32 (s, 1H), 8.09 (d, 1H),
7.94 (s, 1H), 7.84 (s, 1H), 7.57-7.38 (m, 2H), 7.22 (s, 1H), 6.96
(d, 1H), 3.18-3.32 (m, 2H), 3.16-3.12 (m, 1H), 2.80-2.64 (m, 4H),
2.66-2.56 (m, 2H), 2.35-2.07 (m, 5H), 1.41-1.08 (m, 2H), 1.15 (d,
J=6.3 Hz, 6H) ppm; MS (ES) 496.09 (M+H), 494.12 (M-H);
[0864]
1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-yl)-
-N.sup.3-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-
-2-yl)-1H-1,2,4-triazole-3,5-diamine, .sup.1H NMR (DMSO-d.sub.6,
300 MHz) 9.05 (s, 1H), 8.61 (d, 1H), 8.21 (s, 1H), 8.11 (d, 1H),
7.96 (s, 1H), 7.84 (s, 1H), 7.57-7.39 (m, 2H), 7.29 (s, 1H), 6.96
(d, 1H), 3.36 (m, 2H) 2.81-2.52 (m, 8H), 2.45-2.21 (m, 6H), 2.01
(m, 2H), 1.87-1.44 (m, 4H), 1.29 (m, 2H) ppm; MS (ES) 522.12 (M+H),
520.31 (M-H); and
[0865] 1-(6,7-dihydro-5H-pyrido[2',3':6,7]cyclo
hepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7S)-7-(2-butylamino)-6,7,8,9-tetrah-
ydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) 9.06 (s, 1H), 8.60 (d, 1H),
8.27 (s, 1H), 8.07 (d, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.59-7.43
(m, 2H), 7.20 (s, 1H), 7.01 (d, 1H), 3.28 (m, 2H), 2.95-2.63 (m,
8H), 2.19 (m, 5H), 1.75 (m, 2H), 1.41-1.11 (m, 2H), 0.95 (t, 3H)
ppm; MS (ES) 510.09 (M+H), 508.38 (M-H).
BIOLOGICAL EXAMPLES
[0866] The following biological examples are provided by way of
illustration, not limitation. In the following biological examples,
1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N.sup.3-((7--
(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-
-triazole-3,5-diamine, which is a compound of formula (I), as set
forth above in the Summary of the Invention, and which is
designated in the following examples and FIGS. 1-8 as "Compound A"
or "Cpd A" or "Cmpd A", was assayed for its ability to prevent,
treat or manage metastatic cancer, either alone or in combination
with another chemotherapeutic agent.
Biological Example 1
Efficacy of Compound A in Preventing Lung and Liver Metastasis of a
Primary Tumor in Breast Tissue
[0867] Using a variation of the mouse 4T1 breast tumor model, as
described in Current Protocols in Immunology (2000),
20.2.1-20.2.16, Compound A was assayed to determine its ability to
prevent, treat or manage metastatic cancer in BALB/c mice.
Formulations
[0868] Vehicle: 0.5% HPMC/0.1% Tween. [0869] Compound A:
Preformulated dosing solutions in vehicle for 25 mg/kg, 40 mg/kg
and 75 mg/kg for oral administration. [0870] Cisplatin (Reference
Control): Diluted in sterile saline for 1.2 mg/kg, 2.4 mg/kg and 75
mg/kg for intravenous administration. [0871] Zometa: Diluted in
sterile saline as per clinical formulation for subcutaneous
administration.
Protocol
[0872] Eighty-eight BALB/c mice were inoculated with
5.times.10.sup.5 4T1 tumor cells (ATCC) orthotoically into the
third mammary fat pad. On Day 0 of the study (2 days
post-inoculation), 80 mice were randomized into 8 groups (10 mice
per group). Dose administration began on Day 0 and continued for 21
days (3 weeks). Compound A was administered twice a day, Cisplatin
was administered once a week, and Zometa was administered three
times weekly. Tumor measurements were performed three times per
week, starting when tumors were palpable (approximately 3.times.3
mm). Body weight measurements were taken three times per week at
the same time each day. Tumor and body weight measurements fall all
mice were measured prior to dose administration.
[0873] On Day 21 of the treatment, mice were euthanized and the
lungs exposed and the numbers of surface lung metastases were
counted. The size of each metastasis was measured using a caliper
in one dimension and categorized as follows:
[0874] Small: Less than 2 mm
[0875] Medium: Greater or equal to 2 mm
[0876] Large: Greater or equal to 3 mm
[0877] The lungs and livers from all mice were excised and placed
in PLP fixative and stained for micrometastasis quantification.
Results
[0878] The results of this assay with respect to the effect of
Compound A on the total number of macroscopic lung metastases are
shown in FIG. 1.
[0879] The results of this assay with respect to the effect of
Compound A on the number of medium lung metastases are shown in
FIG. 2. The difference between the effect of Compound A at 45 mg/kg
and the vehicle was significant (p<0.05, Mann-Whitney Test). The
difference between the effect of cisplatin at 4 mg/kg and the
vehicle was significant (p<0.001, Mann-Whitney Test).
[0880] The results of this assay with respect to the effect of
Compound A on the number of large lung metastases are shown in FIG.
3. The difference between the effect of Compound A at 25 mg/kg and
the vehicle was significant (p<0.05, Mann-Whitney Test). The
difference between the effect of Cisplatin at 1.2 mg/kg and 2.4
mg/kg and the vehicle was significant (p<0.05, Mann-Whitney
Test).
[0881] The results of this assay with respect to the effect of
Compound A on the incidence of liver micrometastases are shown in
FIG. 4. The difference between the effect of Compound A at 25
mg/kg, 45 mg/kg and 75 mg/kg and the vehicle was significant
(p<0.05, Mann-Whitney Test). The difference between the effect
of Cisplatin at 2.4 mg/kg and 4 mg/kg and the effect of Cisplatin
at 1.2 mg/kg was significant (p<0.05, Mann-Whitney Test). The
difference between the effect of Compound A at 45 mg/kg and 75
mg/kg and the effect of Compound A at 25 mg/kg was significant
(p<0.05, Mann-Whitney Test). The difference between the effect
of Zometa at 0.1 mg/kg and the vehicle was significant (p<0.05,
Mann-Whitney Test).
Biological Example 2
Efficacy of Compound A in Combination with Cisplatin in Preventing
Lung and Liver Metastasis of a Primary Tumor in Breast Tissue
[0882] Using a variation of the mouse 4T1 breast tumor model, as
described in Current Protocols in Immunology (2000),
20.2.1-20.2.16, Compound A in combination with Cisplatin was
assayed to determine the efficacy of the combination therapy to
prevent, treat or manage metastatic cancer in BALB/c mice.
Formulations
[0883] Vehicle: 0.5% HPMC/0.1% Tween. [0884] Compound A:
Preformulated dosing solutions in vehicle for 7 mg/kg and 21 mg/kg
for oral administration. [0885] Cisplatin: Diluted in sterile
saline for 1.2 mg/kg (suboptimal clinical formulation) for
intravenous administration.
Protocol
[0886] Sixty-six BALB/c mice were inoculated with 5.times.10.sup.5
4T1 tumor cells (ATCC) orthotoically into the third mammary fat
pad. On Day 0 of the study (2 days post-inoculation), 60 mice were
randomized into 6 groups (10 mice per group). Dose administration
began on Day 0 and continued for 21 days (3 weeks). Compound A was
administered twice a day, Cisplatin was administered once a week,
and Zometa was administered three times weekly. Tumor measurements
were performed three times per week, starting when tumors were
palpable (approximately 3.times.3 mm). Body weight measurements
were taken three times per week at the same time each day. Tumor
and body weight measurements fall all mice were measured prior to
dose administration.
[0887] On Day 21 of the treatment, mice were euthanized and the
lungs exposed and the number of surface lung metastases were
counted. The size of each metastasis was measured using a caliper
in one dimension and categorized as follows:
[0888] Small: Less than 2 mm
[0889] Medium: Greater or equal to 2 mm
[0890] Large: Greater or equal to 3 mm
[0891] The lungs and livers from all mice were excised and placed
in PLP fixative and stained for micrometastasis quantification.
Results
[0892] The results of this assay with respect to the effect of the
combination therapy of Compound A and Cisplatin on the size of the
primary tumor is shown in FIG. 5.
[0893] The results of this assay with respect to the effect of the
combination therapy of Compound A and Cisplatin on the incidence of
liver micrometastases is shown in FIG. 6. The difference between
the effect of both combination therapies (Compound A at 7 mg/kg or
21 mg/kg and Cisplatin at 1.2 mg/kg) and the effect of the vehicle
alone or the active ingredients (Cisplatin or Compound A) alone was
significant (p<0.05, Mann-Whitney Test).
[0894] The results of this assay with respect to the effect of the
combination therapy of Compound A and Cisplatin on reducing the
number of large lung metastases is shown in FIG. 7. The difference
between the effect of Compound A at 21 mg/kg and 7 mg/kg and
vehicle was significant (p<0.01, Mann-Whitney Test). The
difference between the effect of Cisplatin at 1.2 mg/kg and vehicle
was significant (p<0.05, Mann-Whitney Test).
[0895] The results of this assay with respect to the effect of the
combination therapy of Compound A and Cisplatin on reducing the
incidence of large lung metastases is shown in FIG. 8. The
difference between the effect of both combination therapies
(Compound A at 7 mg/kg or 21 mg/kg and Cisplatin at 1.2 mg/kg) and
the effect of the vehicle alone was significant (p<0.05,
Mann-Whitney Test).
[0896] All of the U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non-patent publications referred to in this
specification and/or listed in the Application Data Sheet are
incorporated herein by reference, in their entireties.
[0897] Although the foregoing invention has been described in some
detail to facilitate understanding, it will be apparent that
certain changes and modifications may be practiced within the scope
of the appended claims. Accordingly, the described embodiments are
to be considered as illustrative and not restrictive, and the
invention is not to be limited to the details given herein, but may
be modified within the scope and equivalents of the appended
claims.
* * * * *
References