U.S. patent application number 13/542895 was filed with the patent office on 2012-11-15 for heterocyclic compound as protein kinase inhibitor.
This patent application is currently assigned to NEOPHARM CO., LTD.. Invention is credited to JungJe JOO, Doyoung KIM, Tae-Seong KIM, Eunkyung LEE, Bu-mahn PARK, Jiyeon PARK.
Application Number | 20120289509 13/542895 |
Document ID | / |
Family ID | 42107002 |
Filed Date | 2012-11-15 |
United States Patent
Application |
20120289509 |
Kind Code |
A1 |
KIM; Tae-Seong ; et
al. |
November 15, 2012 |
HETEROCYCLIC COMPOUND AS PROTEIN KINASE INHIBITOR
Abstract
Provided are novel heterocyclic compounds useful as anti-cancer
drugs by suppressing protein kinase activities of growth factor
receptors such as c-Met, pharmaceutical compositions containing the
same, and methods for using the compound.
Inventors: |
KIM; Tae-Seong; (Daejeon,
KR) ; LEE; Eunkyung; (Daejeon, KR) ; KIM;
Doyoung; (Daejeon, KR) ; PARK; Bu-mahn;
(Daejeon, KR) ; PARK; Jiyeon; (Daejeon, KR)
; JOO; JungJe; (Daejeon, KR) |
Assignee: |
NEOPHARM CO., LTD.
Daejeon
KR
|
Family ID: |
42107002 |
Appl. No.: |
13/542895 |
Filed: |
July 6, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12920243 |
Aug 30, 2010 |
|
|
|
13542895 |
|
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|
Current U.S.
Class: |
514/243 ;
514/248; 514/300; 544/183; 544/235; 546/113 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 17/00 20180101; C07D 487/04 20130101; A61P 43/00 20180101;
A61P 35/00 20180101; A61P 29/00 20180101; A61P 17/06 20180101; C07D
471/04 20130101; A61P 37/08 20180101; A61P 19/02 20180101 |
Class at
Publication: |
514/243 ;
544/235; 514/248; 546/113; 514/300; 544/183 |
International
Class: |
C07D 487/04 20060101
C07D487/04; A61P 35/00 20060101 A61P035/00; A61K 31/437 20060101
A61K031/437; A61K 31/53 20060101 A61K031/53; A61K 31/5025 20060101
A61K031/5025; C07D 471/04 20060101 C07D471/04 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 14, 2008 |
KR |
10-2008-0100522 |
Claims
1. A compound represented by Chemical Formula 1, or a
pharmaceutically acceptable salt or a stereoisomer thereof:
##STR00116## wherein R.sup.1 is alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, arylalkyl, substituted
arylalkyl, aryl, substituted aryl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl,
heterocyclyl, substituted heterocyclyl, heteroarylalkyl,
substituted heteroarylalkyl, heterocycloalkyl or substituted
heterocycloalkyl; R.sup.2 is C.sub.1-C.sub.6 alkyl or substituted
C.sub.1-C.sub.6 alkyl; R.sup.3 is alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, arylalkyl, substituted
arylalkyl, aryl, substituted aryl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl,
heterocyclyl, substituted heterocyclyl, heteroarylalkyl,
substituted heteroarylalkyl, heterocycloalkyl or substituted
heterocycloalkyl; X is hydrogen or halogen; Y is CH or N; Z is CH
or N; and Q is selected from structures below: ##STR00117## wherein
the structures above, R.sup.4 is hydrogen, alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted
arylalkyl, halogen, aryl, substituted aryl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, alkylcarbonyl, substituted
alkylcarbonyl, hydroxyalkyl, substituted hydroxyalkyl, saturated or
unsaturated heterocyclyl, substituted saturated or unsaturated
heterocyclyl, saturated or unsaturated heterocyclyl-alkyl, or
substituted saturated or unsaturated heterocyclyl-alkyl; and
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17,
R.sup.18, R.sup.19 and R.sup.20 are independently is hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, --NH(C.sub.1-C.sub.6
alkyl) or --NRR' where R and R' are independently C.sub.1-C.sub.6
alkyl, or a pharmaceutically acceptable salt or a stereoisomer
thereof.
2. The compound according to claim 1, wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl,
O.sub.2--C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7
cycloalkyl, substituted C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7
heterocycloalkyl, C.sub.6-C.sub.10 aryl, substituted
C.sub.6-C.sub.10 aryl, C.sub.5-C.sub.11 monocyclic or bicyclic
heteroaryl, or substituted C.sub.5-C.sub.11 monocyclic or bicyclic
heteroaryl, or a pharmaceutically acceptable salt or a stereoisomer
thereof.
3. The compound according to claim 2, wherein R.sup.1 is phenyl,
substituted phenyl, naphthyl, substituted naphthyl, pyridyl,
azepanyl, pyrazolyl, thiazolyl, indolyl, indazolyl, indenyl,
cyclopropyl, isopropyl, phenylethyl, aminoalkyl, benzyl,
amidoalkyl, morpholinyl or furanylmethyl, or a pharmaceutically
acceptable salt or a stereoisomer thereof.
4. The compound according to claim 3, wherein R.sup.1 is phenyl,
substituted phenyl, naphthyl or substituted naphthyl, or a
pharmaceutically acceptable salt or a stereoisomer thereof.
5. The compound according to claim 1, wherein R.sup.3 is
C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl,
C.sub.6-C.sub.10 aryl or substituted C.sub.6-C.sub.10 aryl, or a
pharmaceutically acceptable salt or a stereoisomer thereof.
6. The compound according to claim 1, wherein X is halogen selected
from the group consisting of F, Cl, Br and I, or a pharmaceutically
acceptable salt or a stereoisomer thereof.
7. The compound according to claim 1, wherein Q is ##STR00118## or
a pharmaceutically acceptable salt or a stereoisomer thereof.
8. The compound according to claim 7, wherein R.sup.4 is hydrogen,
halogen selected from the group consisting of F, Cl, Br and I,
C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7
cycloalkyl, substituted C.sub.3-C.sub.7 cycloalkyl,
C.sub.6-C.sub.10 aryl, substituted C.sub.6-C.sub.10 aryl,
C.sub.1-C.sub.6 alkylcarbonyl, substituted C.sub.1-C.sub.6
alkylcarbonyl, C.sub.1-C.sub.6 hydroxyalkyl, substituted
C.sub.1-C.sub.6 hydroxyalkyl, 3- to 10-membered saturated or
unsaturated heterocyclyl having one or more heteroatom(s) selected
from the group consisting of N, S and O, or substituted 3- to
10-membered saturated or unsaturated heterocyclyl, or a
pharmaceutically acceptable salt or a stereoisomer thereof.
9. The compound according to claim 8, wherein R.sup.4 is hydrogen,
halogen, phenyl, substituted phenyl, naphthyl, substituted
naphthyl, pyridyl, substituted pyridyl, pyrazinyl, pyrimidinyl,
azepanyl, pyrazolyl, thiazolyl, thiophenyl, isoxazolyl, substituted
isoxazolyl, ethyl, acetyl, 1-hydroxyethyl, hydroxypropyl,
cyclopropyl, isopropyl, aminoalkyl, benzyl, amidoalkyl,
morpholinyl, furanylmethyl or piperidinyl, or a pharmaceutically
acceptable salt or a stereoisomer thereof.
10. The compound according to claim 9, wherein R.sup.4 is hydrogen,
halogen, phenyl, substituted phenyl, naphthyl, substituted
naphthyl, pyridyl, substituted pyridyl, pyrazinyl, pyrimidinyl,
thiazolyl, thiophenyl, isoxazolyl, ethyl, acetyl, 1-hydroxyethyl,
hydroxypropyl, substituted isoxazolyl or piperidinyl, or a
pharmaceutically acceptable salt or a stereoisomer thereof.
11. The compound according to claim 10, wherein R.sup.4 is halogen,
phenyl, or phenyl substituted with halogen or alkoxy, or a
pharmaceutically acceptable salt or a stereoisomer thereof.
12. The compound according to claim 7, wherein Q is ##STR00119## or
a pharmaceutically acceptable salt or a stereoisomer thereof.
13. The compound according to claim 12, wherein R.sup.4 is
hydrogen, halogen, phenyl, substituted phenyl, naphthyl,
substituted naphthyl, pyridyl, substituted pyridyl, pyrazinyl,
pyrimidinyl, thiazolyl, thiophenyl, isoxazolyl, substituted
isoxazolyl, ethyl, acetyl, 1-hydroxyethyl, hydroxypropyl, 5- or
6-membered saturated or unsaturated heterocyclyl having one or more
heteroatom(s) selected from a group consisting of N, S and O, or
substituted 5- or 6-membered saturated or unsaturated heterocyclyl,
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
14. The compound according to claim 1, which is selected from the
group consisting of:
N-(4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimethy-
l-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxo)phenyl)-1,5-dimeth-
yl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-(4-fluorophenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-
-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-(3-fluorophenyl)pyrrolo[1,2-b]pyridazin-4-yloxo)phenyl)--
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-(3-methoxyphenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-
-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluoro-
phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluor-
ophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid [3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)-phenyl]-amide;
N-(3-fluoro-4-(pyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-2-(4-fluoroph-
enyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(pyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-1,5-dimethyl--
3-oxy-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
N-(3-fluoro-4-(6-phenylpyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-2-(4--
fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(4-(6-chloropyrrolo[1,2-f][1,2,4]triazin-4-yloxy)-3-fluoro
phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-c-
arboxamide;
N-(4-(6-chloropyrrolo[1,2-f][1,2,4]triazin-4-yloxy)-3-fluoro
phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide-
;
N-(3-fluoro-4-(6-phenylpyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-1,5--
dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,2-dimeth-
yl-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-(pyridin-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2--
(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-(thiophen-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-
-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide-
;
N-(3-fluoro-4-(5-(pyrimidin-5-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-
-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxami-
de;
N-(3-fluoro-4-(5-(thiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-
-2-(4-fluorophenyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamid-
e;
N-(3-fluoro-4-(5-(pyrazin-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamid-
e;
N-(3-fluoro-4-(5-(piperidin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl-
)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxam-
ide;
N-(3-fluoro-4-(5-(pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl-
)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxam-
ide;
N-(3-fluoro-4-(5-(pyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl-
)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxam-
ide;
N-(3-fluoro-4-(5-(thiophen-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)pheny-
l)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxa-
mide;
N-(3-fluoro-4-(5-(3,5-dimethylisoxazol-4-yl)pyrrolo[1,2-b]pyridazin--
4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyraz-
ole-4-carboxamide;
N-(3-fluoro-4-(5-(6-methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)ph-
enyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carb-
oxamide;
N-(3-fluoro-4-(5-(2-methylpyridin-4-yl)pyrrolo[1,2-b]pyridazin-4--
yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazol-
e-4-carboxamide;
N-(3-fluoro-4-(5-(1-hydroxyethyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamid-
e;
N-(4-(5-acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-flu-
orophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(4-(5-acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimeth-
yl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-(1-hydroxyethyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-thiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5-
-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-(pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,-
5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(4-(5-ethylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluoro-
phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-
-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-(pyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,-
5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(4-(5-chloropyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluor-
ophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(4-(5-chloropyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimeth-
yl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
N-(3-fluoro-4-(5-(1-hydroxypropyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-
-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
or a pharmaceutically acceptable salt or a stereoisomer
thereof.
15. A pharmaceutical composition comprising a therapeutically
effective amount of one or more compound(s) according to claim 1 in
admixture with one or more pharmaceutically acceptable
carrier(s).
16. The pharmaceutical composition according to claim 15, which is
for treating cancer, asthma, allergy, atopic skin disease,
psoriasis or rheumatoid arthritis.
17. A method for treating HGF-mediated disorders in a subject in
need thereof, comprising administering a therapeutically effective
amount of the compound according to claim 1 to the subject.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel heterocyclic
compounds which are useful as an anti-cancer drug by suppressing
protein kinase activity of growth factor receptors such as c-Met.
Also, pharmaceutical compositions containing the compound is useful
in treating diseases other than cancer, related to signal
transduction pathways operated through receptors of growth factors
and neo-vascularization, for example, c-Met.
BACKGROUND ART
[0002] Since protein kinases which phosphorylate specific amino
acids of proteins, are closely involved in various signal
transduction in cells and disease mechanisms, inhibition of such
kinases have been an important therapeutic target.
[0003] The protein kinases represent a large group of proteins
playing critical roles in regulating various cellular processes for
maintenance and control of cellular functions. They include abl,
Akt, AXL, bcr-abl, Blk, Brk, Btk, c-kit, c-Met, c-src, c-fms, CDK1,
CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1,
CSFlR, CSK, DDR1, DDR2, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes,
FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, flt-3, flt-4, Fps,
Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR,
PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes and Zap70.
[0004] It is known that some protein kinases are closely related to
uncontrolled vascularization, such asocular neovascularization,
retinopathy (including diabetic retinopathy), age-related macular
degeneration, psoriasis, hemangioblastoma, angioma,
arteriosclerosis, inflammatory diseases, such as a rheumatoid,
rheumatic inflammatory diseases including rheumatoid arthritis, or
other chronic inflammatory diseases such as chronic asthma,
post-transplantation atherosclerosis, endometriosis, and other
neoplastic diseases, including solid tumor and liquid tumor. With
regard to a lot of pathological disorders and diseases during
embryonic development and normal growth, an angiogenic factor known
as vascular endothelial growth factor (VEGF, originally known as
"vascular permeability factor (VPR)") and its receptor play a
critical role in the regulation of growth and differentiation of
the vascular system and its components.
[0005] VEGF is a disulfide-linked, 46-kDa dimeric glycoprotein
related to "platelet-derived growth factor (PDGF)". It is produced
in normal and tumor cells, is an endothelial cell-specific mitogen,
exhibits angiogenic activity in in vivo tests (e.g. in the rabbit
cornea), is chemotactic for endothelial cells and monocytes, and
induces plasminogen activating factor in endothelial cells, which
is involved in degradation of protein in the cellular matrix during
neovascularization of capillary vessels. A number of VEGF isoforms
are known that exhibit biological activity comparable to VEGF but
are secreted from different cells and have different
heparin-binding abilities. Further, "placental growth factor
(PlGF)" and VEGF-C are included in the VEGF family.
[0006] VEGF receptors (VEGFR) are transmembranous receptors of
tyrosine kinase. They are characterized by seven extracellular
immunoglobulin-like domains and an intracellular tyrosine kinase
domain. Several VEGF receptors, such as VEGFR-1 (also known as
flt-1), VEGFR-2 (also known as KDR) and VEGFR-3 are known.
[0007] In a lot of human tumors, especially in glioma and
carcinomas, VEGF and VEGF receptors are expressed in high levels.
This has led to the hypothesis that the VEGF released by tumor
cells stimulates the growth of blood capillaries and proliferation
of tumor endothelium in a paracrine manner and, through the
improved blood supply, accelerates the tumor growth. Increased VEGF
expression could explain the occurrence of cerebral edema in
patients with glioma. A direct evidence of the role of VEGF as a
tumor angiogenesis factor in vivo is shown in studies in which VEGF
expression or VEGF activity was inhibited.
[0008] Angiogenesis is regarded as a necessary requirement for
tumors to grow beyond a diameter of about 1-2 mm. Up to this limit,
oxygen and nutrients may be transported to the tumor cells by
diffusion. Every tumor, regardless of its origin and cause, is thus
dependent on angiogenesis for its growth after it has reached a
certain size.
[0009] Three principal mechanisms are important in the activity of
angiogenesis inhibitors against tumors. They are: 1) inhibition of
the growth of vessels, especially capillary vessels, into avascular
resting tumors, with the result that there is no net tumor growth
because of the balance that is activated between cell death and
proliferation; 2) prevention of the migration of tumor cells owing
to the absence of blood flow to and from tumors; and 3) inhibition
of endothelial cell proliferation, thus avoiding the paracrine
growth-stimulating effect exerted on the surrounding tissue by the
endothelial cells which normally line the blood vessels.
[0010] It is known that VEGFs are the only angiogenic growth
factors contributing vascular hyperpermeability and the formation
of edema. In fact, vascular hyperpermeability and edema appear to
be mediated via VEGF production.
[0011] VEGF-mediated hyperpermeability can significantly contribute
to disorders with excessive matrix deposition, aberrant stromal
proliferation, fibrosis, and so forth. Therefore, regulators of
angiogenesis have become an important therapeutic target.
[0012] Hepatocyte growth factor (HGF) also known as scatter factor
plays an important role in the regeneration of liver cells. HGF is
a mesenchyme-derived cytokine known to induce multiple pleiotropic
responses in normal and neoplastic cells result in proliferation in
both epithelial and endothelial cells, dissociation of epithelial
colonies into individual cells, stimulation of motility
(motogenesis) of epithelial cells, cell survival, induction of
cellular morphogenesis, promotion of invasion, and all critical
processes underlying metastasis It is also reported that HGF
promotes angiogenesis, and that it plays a critical role in tissue
regeneration, wound healing and normal embryonic processes, all of
which are dependent on both cell motility and proliferation.
[0013] Those physiological processes are initiated by HGF through
high-affinity binding to its receptor, c-Met, an identified
proto-oncogene. The ligand binding induces c-Met dimerization that
results in an autophosphorylated activated receptor. Activation of
c-Met promotes signal transduction cascades of transphosphorylation
of key cytoplasmic tyrosine residues responsible for recruiting
multiple effector proteins including the p85 subunit of PI3-kinase,
phospholipase C.gamma., Grb2 and Shc adaptor proteins, the protein
phosphatase SHP2 and Gab1. Activation of other signaling molecules
has been reported in HGF-stimulated cells, most notably Ras, MAP
kinase, STAT, ERK-1, -2 and FAK which are involved in cell
proliferation.
[0014] c-Met, also known as hepatocyte growth factor receptor
(HGFR), is a membrane receptor molecule located in epithelial
cells. It plays a critical role in the regulation of cell motility.
HGF/SF is secreted in the liver, as well as in the lungs, kidneys
and heart, when the organs are damaged. c-Met is expressed
predominantly in epithelial cells but has also been identified in
endothelial cells, myoblasts, hematopoietic cells and motor
neurons. Overexpression of HGF and activation of c-Met have been
associated with the onset and progression of a number of different
tumor types as well as the promotion of metastatic diseases.
[0015] HGF and c-Met are overexpressed in various solid tumors,
liver cancer, breast cancer, pancreatic cancer, lung cancer, renal
cancer, bladder cancer, ovarian cancer, brain tumor, prostate
cancer, gallbladder cancer, myeloma and many other diseases.
Mutations of c-Met have also been identified in ovarian cancer,
childhood HCC, gastric carcinoma, head and neck squamous cell
carcinoma, non-small cell lung carcinoma and colorectal metastasis.
In addition, further evidence supporting the role of c-Met in
cancer is based on the overexpression of HGF and c-Met receptor in
various tumors including thyroid, ovarian and pancreatic
carcinomas. It has also been demonstrated to be amplified in liver
metastasis of colorectal carcinoma. Generally, most human tumors
and tumor cell lines of mesenchymal origin inappropriately express
HGFR and/or HGF.
[0016] Numerous experimental data have demonstrated the role of HGF
and c-Met in tumor invasion, growth, survival and progression
ultimately leading to metastasis. In preclinical studies,
transgenic expression of HGF results in a metastatic phenotype, and
an amplified/overexpression c-Met spontaneously transforms NIH-3T3
cells. In addition, biological agents, such as ribozymes,
antibodies and antisense RNAs targeting either HGF or c-Met have
been shown to inhibit tumorigenesis. In this regard, the contents
of Korean Patent Publication No. 10-2008-0004617 are incorporated
hereto in its entirety by reference.
[0017] Thus, selective, small molecule kinase modulators targeting
c-Met are expected to have therapeutic potential for the treatment
of cancers in which c-Met receptor activation plays a critical role
in the development and progression of primary tumors and secondary
metastases. HGF is also known to regulate angiogenesis, a process
critical in tumor growth and dissemination. Therefore, there is a
potential for this class of modulators to impact
angiogenesis-dependent diseases as well that may include, among
others, diabetic retinopathy, macular degeneration, obesity and
inflammatory disease such as rheumatoid arthritis.
[0018] Considering the role of HGF and/or c-Met, it is important to
substantially suppress or inhibit the biological effect of HGF
and/or its receptor in order to improve the aforesaid diseases or
pathological conditions. Thus, a compound inhibiting HGF will be a
useful compound.
[0019] The compounds presented herein have never been described in
regard to treatment of cancer as angiogenesis inhibitors nor
treatment of cancer as c-Met inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
Technical Problem
[0020] The object of the present invention is to provide novel
heterocyclic compounds which are useful for, but not limited to, an
anti-cancer drug by suppressing protein kinase activities of growth
factor receptors such as c-Met, pharmaceutical compositions
containing the same, and methods for using the compound. Also, the
pharmaceutical compositions containing the compounds are useful in
treating diseases other than cancer, related to signal transduction
pathways operated through receptors of growth factors and
anti-vascularization, for example, c-Met.
Technical Solution
[0021] The object of the present invention could be attained by
novel heterocyclic compounds represented by Chemical Formula 1,
which are useful as an anti-cancer drug by suppressing protein
kinase activity of growth factor receptors such as c-Met.
[0022] The present invention relates to novel heterocyclic
compounds represented by Chemical Formula 1, pharmaceutical
compositions containing the compounds, and methods for using the
compounds.
[0023] The present invention provides novel heterocyclic compounds
represented by Chemical Formula 1, pharmaceutically acceptable
salts thereof, stereoisomers (e.g. enantiomer, diastereomer, etc.)
thereof or solvates thereof:
##STR00001## [0024] wherein [0025] R.sup.1 is alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted
arylalkyl, aryl, substituted aryl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl,
heterocyclyl, substituted heterocyclyl, heteroarylalkyl,
substituted heteroarylalkyl, heterocycloalkyl or substituted
heterocycloalkyl; [0026] R.sup.2 is C.sub.1-C.sub.6 alkyl or
substituted C.sub.1-C.sub.6 alkyl; [0027] R.sup.3 is alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl,
substituted arylalkyl, aryl, substituted aryl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, heteroaryl, substituted
heteroaryl, heterocyclyl, substituted heterocyclyl,
heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl or
substituted heterocycloalkyl; [0028] Q is unsaturated heterocyclyl
fused from nitrogen-containing 5-membered unsaturated heterocyclyl
and nitrogen-containing 6-membered unsaturated heterocyclyl; [0029]
[29] X is hydrogen or halogen; [0030] [30] Y is CH or N; and [0031]
[31] Z is CH or N.
[0032] The present invention further provides pharmaceutical
compositions comprising therapeutically effective amounts of the
compounds represented by Chemical Formula 1, pharmaceutically
acceptable salts thereof, stereoisomers (e.g. enantiomer,
diastereomer, etc.) thereof or solvates thereof in admixture with
pharmaceutically acceptable carriers. The present invention further
provides methods for treating cancer in a subject in need thereof,
comprising administering pharmaceutically effective amounts of the
compounds represented by Chemical Formula 1, pharmaceutically
acceptable salts thereof, stereoisomers (e.g. enantiomer,
diastereomer, etc.) thereof or solvates thereof to the subject and,
optionally, administering one or more additional anti-cancer
drug(s) to the subject.
ADVANTAGEOUS EFFECTS
[0033] According to the present invention, there is provided a
novel nitrogen-containing heterocyclic compound which is useful as
an anti-cancer drug by suppressing protein kinase activity of
growth factor receptors such as c-Met. A pharmaceutical composition
containing the compound and a method for using the compound are
useful in treating cancer. Also, they may useful in treating
diseases related to signal transduction pathways operated through a
receptor of growth factor and anti-vascularization, for example,
c-Met.
BEST MODE FOR CARRYING OUT THE INVENTION
[0034] The present invention provides the novel heterocyclic
compound represented by Chemical Formula 1 defined above, a
pharmaceutical composition containing the compound, a method for
preparing the compound and a method for using the compound.
[0035] The novel heterocyclic compound of the present invention
includes a compound represented by Chemical Formula 1, a
pharmaceutically acceptable salt thereof, a stereoisomer (e.g.
enantiomer, diastereomer, etc.) thereof and a solvate thereof:
##STR00002## [0036] wherein [0037] R.sup.1 is alkyl, substituted
alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted
arylalkyl, aryl, substituted aryl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, heteroaryl, substituted heteroaryl,
heterocyclyl, substituted heterocyclyl, heteroarylalkyl,
substituted heteroarylalkyl, heterocycloalkyl or substituted
heterocycloalkyl; [0038] R.sup.2 is C.sub.1-C.sub.6 alkyl or
substituted C.sub.1-C.sub.6 alkyl; [0039] R.sup.3 is alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl,
substituted arylalkyl, aryl, substituted aryl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, heteroaryl, substituted
heteroaryl, heterocyclyl, substituted heterocyclyl,
heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl or
substituted heterocycloalkyl; [0040] Q is unsaturated heterocyclyl
fused from nitrogen-containing 5-membered unsaturated heterocyclyl
and nitrogen-containing 6-membered unsaturated, heterocyclyl;
[0041] X is hydrogen or halogen; [0042] Y is CH or N; and [0043] Z
is CH or N.
[0044] The present invention includes the compounds represented by
Chemical Formula 1, pharmaceutically acceptable salts thereof,
stereoisomers (e.g. enantiomer, diastereomer, etc.) thereof,
solvates thereof, prodrugs thereof, or the like.
[0045] In an embodiment of the present invention, Q is a radical
represented by:
##STR00003## [0046] wherein [0047] R.sup.4 is hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl,
substituted arylalkyl, halogen, aryl, substituted aryl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, alkylcarbonyl,
substituted alkylcarbonyl, hydroxyalkyl, substituted hydroxyalkyl,
saturated or unsaturated heterocyclyl, substituted saturated or
unsaturated heterocyclyl, saturated or unsaturated
heterocyclyl-alkyl, or substituted saturated or unsaturated
heterocyclyl-alkyl; and [0048] R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19 and
R.sup.20 are independently hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, --NH(C.sub.1-C.sub.6 alkyl) or --NRR'
(where R and R' are independently C.sub.1-C.sub.6 alkyl).
[0049] In an embodiment of the present invention, R.sup.1 is
C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7
cycloalkyl, substituted C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7
heterocycloalkyl, C.sub.6-C.sub.10 aryl, substituted
C.sub.6-C.sub.10 aryl, C.sub.5-C.sub.11 monocyclic or bicyclic
heteroaryl, or substituted C.sub.5-C.sub.11 monocyclic or bicyclic
heteroaryl. Specifically, in an embodiment of the present
invention, R.sup.1 is phenyl, substituted phenyl, naphthyl,
substituted naphthyl, pyridyl, azepanyl, pyrazolyl, thiazolyl,
indolyl, indazolyl, indenyl, cyclopropyl, isopropyl, phenylethyl,
aminoalkyl, benzyl, amidoalkyl, morpholinyl or furanylmethyl.
[0050] More specifically, in an embodiment of the present
invention, R.sup.1 is phenyl, substituted phenyl, naphthyl, or
substituted naphthyl, but is not limited thereto.
[0051] In another embodiment of the present invention, R.sup.3 is
C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl,
C.sub.6-C.sub.10 aryl or substituted C.sub.6-C.sub.10 aryl, but is
not limited thereto.
[0052] In another embodiment of the present invention, X is halogen
selected from the group consisting of F, Cl, Brand I, but is not
limited thereto.
[0053] In another embodiment of the present invention, Q is
##STR00004##
but is not limited thereto.
[0054] In an embodiment of the present invention, R.sup.4 is
hydrogen, halogen selected from the group consisting of F, Cl, Br
and I, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7
cycloalkyl, substituted C.sub.3-C.sub.7 cycloalkyl,
C.sub.6-C.sub.10 aryl, substituted C.sub.6-C.sub.10 aryl,
C.sub.1-C.sub.6 alkylcarbonyl, substituted C.sub.1-C.sub.6
alkylcarbonyl, C.sub.1-C.sub.6 hydroxyalkyl, substituted
C.sub.1-C.sub.6 hydroxyalkyl, 3- to 10-membered saturated or
unsaturated heterocyclyl having one or more heteroatom(s) selected
from the group consisting of N, S and O, or substituted 3- to
10-membered saturated or unsaturated heterocyclyl, but is not
limited thereto.
[0055] Specifically, in an embodiment of the present invention,
R.sup.4 is hydrogen, halogen, phenyl, substituted phenyl, naphthyl,
substituted naphthyl, pyridyl, substituted pyridyl, pyrazinyl,
pyrimidinyl, azepanyl, pyrazolyl, thiazolyl, thiophenyl,
isoxazolyl, substituted isoxazolyl, ethyl, acetyl, 1-hydroxyethyl,
hydroxypropyl, cyclopropyl, isopropyl, aminoalkyl, benzyl,
amidoalkyl, morpholinyl, furanylmethyl or piperidinyl, but is not
limited thereto.
[0056] More specifically, in an embodiment of the present
invention, R.sup.4 is hydrogen, halogen, phenyl, substituted
phenyl, naphthyl, substituted naphthyl, pyridyl, substituted
pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thiophenyl, isoxazolyl,
ethyl, acetyl, 1-hydroxyethyl, hydroxypropyl, substituted
isoxazolyl or piperidinyl, but is not limited thereto.
[0057] In an embodiment of the present invention, R.sup.4 is
halogen, phenyl, or phenyl substituted with halogen or alkoxy, but
is not limited thereto.
[0058] In another embodiment of the present invention, Q is
##STR00005##
R.sup.4 is independently selected from hydrogen, halogen, phenyl,
substituted phenyl, naphthyl, substituted naphthyl, pyridyl,
substituted pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thiophenyl,
isoxazolyl, substituted isoxazolyl, ethyl, acetyl, 1-hydroxyethyl,
hydroxypropyl, 5- or 6-membered saturated or unsaturated
heterocyclyl having one or more heteroatom(s) selected from the
group consisting of N, S and O, or substituted 5- or 6-membered
saturated or unsaturated heterocyclyl, but is not limited
thereto.
[0059] In an embodiment of the present invention, Q is
##STR00006##
Herein, R.sup.4 may be hydrogen, halogen, phenyl, substituted
phenyl, naphthyl, substituted naphthyl or thiophenyl, but is not
limited thereto.
[0060] In an embodiment of the present invention, Q is
##STR00007##
Herein, R.sup.4 may be hydrogen, halogen, phenyl, substituted
phenyl, naphthyl or substituted naphthyl, but is not limited
thereto.
[0061] The present invention also relates to a compound selected
from the following compounds, a pharmaceutically acceptable salt
thereof, a stereoisomer (e.g. enantiomer, diastereomer, etc.)
thereof and a solvate thereof: [0062]
N-(4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimethy-
l-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; [0063]
N-(3-fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxo)phenyl)-1,5-dimeth-
yl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; [0064]
N-(3-fluoro-4-(5-(4-fluorophenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0065]
N-(3-fluoro-4-(5-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-
-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0066]
N-(3-fluoro-4-(5-(3-fluorophenyl)pyrrolo[1,2-b]pyridazin-4-yloxo)
phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide-
; [0067]
N-(3-fluoro-4-(5-(3-methoxyphenyl)pyrrolo[1,2-b]pyridazin-4-yloxy-
)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide-
; [0068]
N-(4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(-
4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0069]
N-(3-fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(-
4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0070]
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid [3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)-phenyl]-amide;
[0071]
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid [0072]
[3-fluoro-4-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenyl]-am-
ide; [0073]
2-(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxyl-
ic acid [0074]
[3-fluoro-4-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenyl]-amide;
[0075]
2-(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-c-
arboxylic acid [0076]
[3-fluoro-4-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenyl]-amide;
[0077]
N-(3-fluoro-4-(pyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-2-(4-f-
luorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0078]
N-(3-fluoro-4-(pyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-1,5-di-
methyl-3-oxy-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; [0079]
N-(3-fluoro-4-(6-phenylpyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-2-(4--
fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0080]
N-(4-(6-chloropyrrolo[1,2-f][1,2,4]triazin-4-yloxy)-3-fluorophenyl-
)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxam-
ide; [0081]
N-(4-(6-chloropyrrolo[1,2-f][1,2,4]triazin-4-yloxy)-3-fluorophenyl)-1,5-d-
imethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0082]
N-(3-fluoro-4-(6-phenylpyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-1,5-d-
imethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0083]
N-(3-fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,2-dimeth-
yl-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; [0084]
N-(3-fluoro-4-(5-(pyridin-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2--
(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1-pyrazole-4-carboxamide;
[0085]
N-(3-fluoro-4-(5-(thiophen-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)ph-
enyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carb-
oxamide; [0086]
N-(3-fluoro-4-(5-(pyrimidin-5-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamid-
e; [0087]
N-(3-fluoro-4-(5-(thiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)p-
henyl)-2-(4-fluorophenyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carb-
oxamide; [0088]
N-(3-fluoro-4-(5-(pyrazin-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2--
(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0089]
N-(3-fluoro-4-(5-(piperidin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)p-
henyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-car-
boxamide; [0090]
N-(3-fluoro-4-(5-(pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-Yloxy)phenyl)-2--
(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0091]
N-(3-fluoro-4-(5-(pyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phe-
nyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carbo-
xamide; [0092]
N-(3-fluoro-4-(5-(thiophen-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-
-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide-
; [0093]
N-(3-fluoro-4-(5-(3,5-dimethylisoxazol-4-yl)pyrrolo[1,2-b]pyridaz-
in-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-py-
razole-4-carboxamide; [0094]
N-(3-fluoro-4-(5-(6-methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)ph-
enyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carb-
oxamide; [0095]
N-(3-fluoro-4-(5-(2-methylpyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)ph-
enyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carb-
oxamide; [0096]
N-(3-fluoro-4-(5-(1-hydroxyethyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamid-
e; [0097]
N-(4-(5-acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-
-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide-
; [0098]
N-(4-(5-acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,-
5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0099]
N-(3-fluoro-4-(5-(1-hydroxyethyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0100]
N-(3-fluoro-4-(5-thiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5-
-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0101]
N-(3-fluoro-4-(5-(pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,-
5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0102]
N-(4-(5-ethylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluoro-
phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0103]
N-(3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-
-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide [0104]
N-(3-fluoro-4-(5-(pyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,-
5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0105]
N-(4-(5-chloropyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluor-
ophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0106]
N-(4-(5-chloropyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimeth-
yl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; [0107]
N-(3-fluoro-4-(5-(1-hydroxypropyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-
-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0108]
N-(3-fluoro-4-(2-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl)-
-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxami-
de; [0109]
N-(3-fluoro-4-(2-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylo-
xy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-
-carboxamide; [0110]
N-(3-fluoro-4-(2-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)pheny-
l)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxa-
mide; [0111]
N-(3-fluoro-4-(2-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)pheny-
l)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
[0112]
N-(3-fluoro-4-(2-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-
phenyl-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide;
and [0113]
N-(3-fluoro-4-(2-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl)-
-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide.
[0114] The various substituents used to describe the compound of
the present invention are defined as follows. The definition
applies to the present invention individually or as part of larger
groups (unless specified otherwise).
[0115] The term "alkyl" used herein alone or as a suffix or prefix
as in "alkoxy", "arylalkyl", "haloalkyl" and "alkylamino" includes,
unless defined otherwise, a linear or branched radical having 1 to
12 carbon atoms. A more preferred alkyl radical is a "lower alkyl"
radical having 1 to 6 carbon atom(s). The alkyl group may be
substituted at any possible sites and may be a substituted linear,
branched or cyclic saturated hydrocarbon group. An alkyl group
substituted with another alkyl group is referred to as "branched
alkyl". Typical alkyl groups include methyl, ethyl, propyl,
isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl,
heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl,
decyl, undecyl, dodecyl, etc. Typical substituents of the alkyl
group include the followings, but are not limited thereto: alkyl,
aryl, halo (e.g. F, Cl, Br, I), haloalkyl (e.g. CCl.sub.3 or
CF.sub.3), alkoxy, alkylthio, hydroxy, carboxy (--COOH),
alkyloxycarbonyl (--C(O)OR), alkylcarbonyl (--C(O)R),
alkylcarbonyloxy (--OCOR), amino (--NH.sub.2), carbamoyl
(--NHCOOR-- or --OCONHR--), urea (--NHCONHR--) and thiol
(--SH).
[0116] The term "alkenyl" used herein alone or as a suffix or
prefix refers to a linear, branched or cyclic hydrocarbon radical
having 2 to 12 carbon atoms and one or more carbon-carbon double
bond(s). A more preferred alkenyl radical is a "lower alkenyl"
radical having 2 to 6 carbon atoms. The most preferred lower
alkenyl radical is one having 2 to 4 carbon atoms. The alkenyl
group may be substituted at any possible sites. Examples of the
alkenyl radical include ethenyl, propenyl, allyl, propenyl, butenyl
and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl"
embrace radicals having "cis" and "trans" configurations, or
alternatively, "E" and "Z" configurations. Typical substituents of
the alkenyl group are the aforesaid alkyl groups. They may be
further substituted with, for example, amino, oxo, hydroxyl,
etc.
[0117] The term "alkynyl" used herein alone or as a suffix or
prefix refers to a linear, branched or cyclic hydrocarbon radical
having 2 to 12 carbon atoms and one or more carbon-carbon triple
bond(s). A more preferred alkynyl radical is a "lower alkynyl"
radical having 2 to 6 carbon atoms. The most preferred one is a
lower alkynyl radical having 2 to 4 carbon atoms. Examples of the
radical include propargyl, butynyl, etc. The alkynyl group may be
substituted at any possible sites. Typical substituents of the
alkynyl group are the aforesaid alkyl groups as well as amino,
alkylamino, etc.
[0118] The subscript number following the symbol "C" refers to the
number of carbon atoms that the particular group may have. For
instance, "C.sub.1-C.sub.6 alkyl" or "C.sub.1-C.sub.6 alkyl" refers
to a linear or branched saturated carbon chain having 1 to 6 carbon
atom(s), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,
sec-butyl, isobutyl, t-butyl, n-pentyl, sec-pentyl, isopentyl and
n-hexyl. Depending on the context, "C.sub.1-C.sub.6 alkyl" may
refer only to C.sub.1-C.sub.6 alkylene with two bridged groups, for
example, propane-1,3-diyl, butane-1,4-diyl,
2-methyl-butane-1,4-diyl, etc. "C.sub.2-C.sub.6 alkenyl" refers to
a linear or branched carbon chain having one or more carbon-carbon
double bond(s) and 2 to 6 carbon atoms, for example, ethenyl,
propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and hexenyl.
Depending on the context, "C.sub.2-C.sub.6 alkenyl" may refer only
to C.sub.2-C.sub.6 alkenediyl with two bridged groups, for example,
ethylene-1,2-diyl (vinylene), 2-methyl-2-butene-1,4-diyl,
2-hexene-1,6-diyl, etc. "C.sub.2-C.sub.6 alkynyl" refers to a
linear or branched carbon chain having one or more carbon-carbon
triple bond(s) and 2 to 6 carbon atoms, for example, ethynyl,
propynyl, butynyl and hexynyl.
[0119] The term "alkoxy" or "alkylthio" used herein alone or as a
suffix or prefix respectively refers to an alkyl group linked by
oxygen (--O--) or sulfur (--S--).
[0120] The term "alkoxycarbonyl" used herein alone or as a suffix
or prefix refers to an alkoxy group linked by a carbonyl group. The
alkoxycarbonyl radical is represented by --C(O)OR (where R is
linear or branched C.sub.1-C.sub.6 alkyl, cycloalkyl, aryl or
heteroaryl).
[0121] The term "alkylcarbonyl" used herein alone or as a suffix or
prefix refers to an alkyl group linked by a carbonyl, i.e.,
--C(O)R.
[0122] The term "hydroxyalkyl" used herein alone or as a suffix or
prefix refers to an alkyl group linked by a hydroxy group, i.e.,
--COH.
[0123] The term "alkylcarbonyloxy" used herein alone or as a suffix
or prefix refers to an alkylcarbonyl linked by oxygen.
[0124] The term "arylalkyl (or aralkyl)" used herein alone or as a
suffix or prefix refers to an aromatic ring linked by an alkyl
group, i.e., an aryl-substituted alkyl radical. A preferred
arylalkyl radical is a "lower arylalkyl" radical with an aryl
radical attached to an alkyl radical having 1 to 6 carbon atom(s).
More preferred is "phenylalkylenyl" attached to an alkyl moiety
having 1 to 3 carbon atom(s). Examples of the radical include
benzyl, biphenylmethyl and phenylethyl. The aryl of the arylalkyl
may be further substituted with halo, alkyl, alkoxy, haloalkyl or
haloalkoxy.
[0125] The term "aryl" used herein alone or as a suffix or prefix
refers to a monocyclic or bicyclic aromatic ring, for example,
phenyl, substituted phenyl, etc., as well as a fused ring, for
example, naphthyl, phenanthrenyl, indenyl, tetrahydronaphthyl,
indanyl, etc. Thus, the aryl group may have one or more ring(s)
having 6 or more atoms and 5 or less rings having 22 or less atoms.
Alternating (conjugated) double bonds may be present between
neighboring carbon atoms or adequate heteroatom(s). The aryl group
may be substituted with one or more group(s) including, halogen,
e.g. F, Br, Cl or I, alkyl, e.g. methyl, ethyl or propyl, alkoxy,
e.g. methoxy or ethoxy, hydroxy, carboxy, carbamoyl,
alkyloxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino,
cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O).sub.m (where m=O, 1
or 2) or thiol, but not limited thereto. A preferred aryl group is
substituted phenyl.
[0126] The term "heterocyclyl" includes a saturated, partially
saturated or unsaturated heteroatom-containing ring radical,
wherein the heteroatom may be one or more selected from nitrogen,
sulfur and oxygen. The "heterocyclyl" group may be a 3- to
10-membered heterocyclyl group. The "heterocyclyl" group may be
substituted with 1 to 3 hydroxyl, Boc, halo, haloalkyl, cyano,
lower alkyl, lower aralkyl, oxo, lower alkoxy, amino or lower
alkylamino substituent(s).
[0127] Examples of the saturated heterocyclyl group include: a
saturated 3- to 6-membered heterocyclyl group containing 1 to 4
nitrogen atom(s) (e.g. pyrrolidinyl, imidazolinyl, piperidinyl,
pyrrolinyl or piperazinyl); a saturated 3- to 6-membered
heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3
nitrogen atom(s) (e.g. morpholinyl); and a saturated 3- to
6-membered heteromonocyclic group containing 1 or 2 sulfur atom(s)
and 1 to 3 nitrogen atom(s) (e.g. thiazolidinyl). Examples of the
partially saturated heterocyclyl radical include dihydrothienyl,
dihydropyranyl, dihydrofuryl and dihydrothiazolyl.
[0128] Examples of the unsaturated heterocyclyl group include: an
unsaturated 5- or 6-membered heteromonocyclic group containing 1 to
4 nitrogen atom(s), e.g. pyrrolyl, imidazolyl, pyrazolyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl
or triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl or
2H-1,2,3-triazolyl); an unsaturated 5- or 6-membered
heteromonocyclic group containing one oxygen atom, e.g. pyranyl,
2-furyl, 3-furyl, etc.; an unsaturated 5- or 6-membered
heteromonocyclic group containing one sulfur atom, e.g. 2-thienyl,
3-thienyl, thiophenyl, etc.; an unsaturated 5- or 6-membered
heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3
nitrogen atom(s), e.g. oxazolyl, isoxazolyl or oxadiazolyl (e.g.
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl); and an
unsaturated 5- or 6-membered heteromonocyclic group containing 1 or
2 sulfur atom(s) and 1 to 3 nitrogen atom(s), e.g. thiazolyl,
thiadiazolyl (e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl).
[0129] The term "heterocyclyl" also embraces a heterocyclic radical
fused/condensed with an aryl radical. For example, an unsaturated
condensed heterocyclic group containing 1 to 5 nitrogen atom(s),
e.g. indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,
isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.
tetrazolo[1,5-b]pyridazinyl); an unsaturated condensed heterocyclic
group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s),
e.g. benzoxazolyl or benzoxadiazolyl; an unsaturated condensed
heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3
nitrogen atom(s), e.g. benzothiazolyl or benzothiadiazolyl; and a
saturated, partially saturated or unsaturated condensed
heterocyclic group containing 1 or 2 oxygen atom(s) or sulfur
atom(s), e.g. benzofuryl, benzothienyl,
2,3-dihydro-benzo[1,4]dioxynyl or dihydrobenzofuryl, are included.
A preferred heterocyclic radical includes a fused or unfused
radical consisting of 5 to 10 atoms. More preferred examples of the
heteroaryl radical include quinolyl, isoquinolyl, imidazolyl,
pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl. Another
preferred heteroaryl radical is 5- or 6-membered heteroaryl
containing 1 or 2 heteroatom(s) selected from sulfur, nitrogen and
oxygen, and may be selected form thienyl, furyl, pyrrolyl,
indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl,
isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.
[0130] Specific examples of a non-nitrogen-containing heteroaryl
include pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
benzofuryl, benzothienyl, etc.
[0131] Specific examples of partially saturated or saturated
heterocyclyl include pyrrolidinyl, imidazolinyl, piperidinyl,
pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, dihydrothienyl,
2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl,
dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl,
1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,
1,2,3,4-tetrahydro-quinolyl,
2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,
5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,
3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,
2,3-dihydro-1H--I-'-benzo[d]isothiazol-6-yl, dihydropyranyl,
dihydrofuryl, dihydrothiazolyl, etc.
[0132] The term "amino" used herein alone or as a suffix or prefix
refers to --NH.sub.2. The "amino" group may be substituted with 1
or 2 identical or different substituent(s), e.g. alkyl, aryl,
arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl,
cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl,
cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl,
carbonyl or carboxyl. These substituents may be further substituted
with a carboxylic, alkyl or aryl substituent. In some embodiments,
the amino group is substituted with carboxyl or carbonyl to form an
N-acyl or N-carbamoyl derivative.
[0133] The term "cycloalkyl" used herein alone or as a suffix or
prefix refers to a completely saturated or partially saturated
hydrocarbon ring having 3 to 9, preferably 3 to 7 carbon atoms. The
cycloalkyl group may be substituted. A substituted cycloalkyl ring
may have 1, 2 or 3 substituent(s) selected from the group
consisting of halo, alkyl, substituted alkyl, alkenyl, alkynyl,
nitro, cyano, oxo (.dbd.O), hydroxy, alkoxy, thioalkyl,
--CO.sub.2H, --C(.dbd.O)H, CO.sub.2-alkyl, --C(.dbd.O) alkyl, keto,
.dbd.N--OH, .dbd.N--O-alkyl, aryl, heteroaryl, heterocyclyl, 5- or
6-membered ketal (e.g. 1,3-dioxolane or 1,3-dioxane), --NR'R'',
--C(.dbd.O)NR'R'', --CO.sub.2NR'R'', --NR'CO.sub.2R'',
--NR'C(.dbd.O)R'', --SO.sub.2NR'R'' and --NR'SO.sub.2R'' (where
each R' and R'' is independently selected from hydrogen, alkyl,
substituted alkyl and cycloalkyl, or R' and R'' together forms a
heterocyclo or heteroaryl ring).
[0134] The term "heteroaryl" used herein alone or as a suffix or
prefix refers to a substituted or unsubstituted aromatic 5- or
6-membered monocyclic group, 9- or 10-membered bicyclic group or
11- to 14-membered tricyclic group containing one or more
heteroatom(s) (O, S or N) in one or more ring(s). Each ring of the
heteroaryl group containing the heteroatom(s) may contain 1 or 2
oxygen or sulfur atom(s) and/or 1 to 4 nitrogen atom(s), with the
proviso that each ring contains 4 or less heteroatom(s) and has 1
or more carbon atom(s). The fused rings that constitute a bicyclic
or tricyclic group may contain carbon atoms only, and may be
saturated, partially saturated or unsaturated. The nitrogen or
sulfur atom may be oxidized, and the nitrogen atom may be
quaternized. The bicyclic or tricyclic heteroaryl group should have
one or more complete aromatic ring(s), but other fused rings may be
aromatic or non-aromatic. The heteroaryl may be substituted at
nitrogen or carbon atom of any possible sites. The heteroaryl ring
may have 0, 1, 2 or 3 substituent(s) selected from the group
consisting of halo, alkyl, substituted alkyl, alkenyl, alkynyl,
aryl, nitro, cyano, hydroxy, alkoxy, thioalkyl, --CO.sub.2H,
--C(.dbd.O)H, --CO.sub.2-alkyl, --C(.dbd.O) alkyl, phenyl, benzyl,
phenylethyl, phenyloxy, phenylthio, cycloalkyl, substituted
cycloalkyl, heterocyclyl, heteroaryl, --NR'R'', --C(.dbd.O)NR'R'',
--CO.sub.2NR'R'', --NR'CO.sub.2R'', --NR'C(.dbd.O)R'',
--SO.sub.2NR'R'' and --NR'SO.sub.2R'' (where each R' and R'' is
independently selected from hydrogen, alkyl, substituted alkyl and
cycloalkyl, or R' and R'' together forms a heterocyclo or
heteroaryl ring).
[0135] Typical monocyclic heteroaryl groups include pyrrolyl,
pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, diazolyl, isoxazolyl,
thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl,
oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl, etc.
[0136] Typical bicyclic heteroaryl groups include indolyl,
benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl,
quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl,
benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,
furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, etc.
[0137] Typical tricyclic heteroaryl groups include carbazolyl,
benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl,
etc.
[0138] The term "heterocycloalkyl" used herein alone or as a suffix
or prefix refers to cycloalkyl (non-aromatic) one carbon atom of
which is replaced by a heteroatom selected from O, S and N and 3 or
less additional carbon atom(s) of which may be replaced by the
heteroatom(s). The term "heterocycloalkyl" used herein alone or as
a suffix or prefix refers to a stable, 5- to 7-membered saturated
or partially saturated monocyclic ring containing carbon atoms and
heteroatom(s) selected from nitrogen, sulfur and oxygen. The
heterocyclic ring may be a 5-, 6- or 7-membered monocyclic ring and
may contain 1, 2 or 3 heteroatom(s) selected from nitrogen, sulfur
and oxygen. The heterocyclic ring may be substituted at one or more
possible site(s) with one or more substituent(s) selected from
alkyl (preferably lower alkyl), heterocycloalkyl, heteroaryl,
alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably
lower alkylamino), dialkylamino (preferably di[lower]alkylamino),
cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl,
aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl,
alkylamido (preferably lower alkylamido), alkoxyalkyl (preferably
lower alkoxy[lower]alkyl), alkoxycarbonyl (preferably lower
alkoxycarbonyl), alkylcarbonyloxy (preferably lower
alkylcarbonyloxy) and aryl (preferably phenyl) (the aryl may be
substituted with halo, lower alkyl or lower alkoxy). Examples of
the heterocycloalkyl group include piperazinyl, piperidinyl,
morpholinyl, homomorpholinyl, thiomorpholinyl, pyrrolidinyl and
azetidinyl.
[0139] Also, the heteroaryl or heterocycloalkyl group may be a 8-
to 11-membered bicyclic ring containing carbon atoms and 1, 2 or 3
heteroatom(s) selected from nitrogen, sulfur and oxygen. Some
preferred bicyclic rings include benzodioxolyl, quinoxalinyl,
indolyl and quinolinyl. The phrase that heteroaryl or
heterocycloalkyl "may be substituted" means that the heteroaryl or
heterocycloalkyl group may be substituted at one or more possible
site(s) with one or more substituent(s) selected from alkyl
(preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro,
monoalkylamino (preferably lower alkylamino), dialkylamino
(preferably di[lower]alkylamino), cyano, halo, haloalkyl
(preferably trifluoromethyl), alkanoyl, aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl, alkylamido
(preferably lower alkylamido), alkoxyalkyl (preferably lower
alkoxy[lower]alkyl), alkoxycarbonyl (preferably lower
alkoxycarbonyl), alkylcarbonyloxy (preferably lower
alkylcarbonyloxy) and aryl (preferably phenyl) (the aryl may be
substituted with halo, lower alkyl or lower alkoxy).
[0140] The term "heteroatom" refers to O, S or N. It is to be noted
that a heteroatom having unsatisfied valence has hydrogen atom(s)
to satisfy the valence requirement.
[0141] The term "halogen" or "halo" refers to chlorine, bromine,
fluorine or iodine.
[0142] The term "sulfonyl" used herein alone or with other terms
such as alkylsulfonyl refer to the divalent radical
--SO.sub.2--.
[0143] The terms "sulfamyl", "aminosulfonyl" and "sulfonamidyl"
refer to a sulfonyl radical substituted with an amine radical,
forming sulfonamide (--SO.sub.2NH.sub.2).
[0144] The term "alkylaminosulfonyl" embraces
"N-alkylaminosulfonyl" with a sulfamyl radical substituted with 1
or 2 alkyl radical(s). A more preferred alkylaminosulfonyl radical
is a "lower alkylaminosulfonyl" radical having to 6 carbon atom(s).
Further more preferred is a lower alkylaminosulfonyl radical having
1 to 3 carbon atom(s). Examples of the lower alkylaminosulfonyl
radical include N-methylaminosulfonyl and N-ethylaminosulfonyl.
[0145] The term "carboxy" or "carboxyl" used herein alone or with
other terms such as "carboxyalkyl" refers to --CO.sub.2H.
[0146] The term "carbonyl" used herein alone or with other terms
such as "aminocarbonyl" refers to --(C.dbd.O)--.
[0147] The term "aminocarbonyl" refers to an amide group
represented by --C(.dbd.O)NH.sub.2--.
[0148] The terms "N-alkylaminocarbonyl" and
"N,N-dialkylaminocarbonyl" respectively refer to an aminocarbonyl
radical substituted with 1 or 2 alkyl radical(s). More preferred is
"lower alkylaminocarbonyl" with a lower alkyl radical attached to
the aminocarbonyl radical.
[0149] The terms "N-arylaminocarbonyl" and
"N-alkyl-N-arylaminocarbonyl" respectively refer to an
aminocarbonyl radical substituted with one aryl radical or with one
alkyl and one aryl radicals.
[0150] The terms "heterocyclylalkylenyl" and "heterocyclylalkyl"
embrace a heterocyclic-substituted alkyl radical. A more preferred
heterocyclylalkyl radical is a "5- or 6-membered heteroarylalkyl"
radical having a C.sub.1-C.sub.6' alkyl moiety and a 5- or
6-membered heteroaryl radical. Further more preferred is a lower
heteroarylalkylenyl radical having a C.sub.1-C.sub.3 alkyl moiety.
Examples include pyridinylmethyl and thienylmethyl.
[0151] The term "alkylthio" embraces a radical having a
C.sub.1-C.sub.10 linear or branched alkyl radical attached to a
divalent sulfur atom. More preferred is a lower alkylthio radical
having 1 to 3 carbon atom(s). Examples of "alkylthio" include
methylthio (CH.sub.3S--).
[0152] The term "haloalkylthio" embraces a radical having a
C.sub.1-C.sub.10 haloalkyl radical attached to a divalent sulfur
atom. More preferred is a lower haloalkylthio radical having 1 to 3
carbon atom(s). Examples of "haloalkylthio" include
trifluoromethylthio.
[0153] The term "alkylamino" embraces "N-alkylamino" and
"N,N-dialkylamino", wherein the amino group may be substituted with
one or two alkyl radical(s).
[0154] A more preferred alkylamino radical is a "lower alkylamino"
radical with one or two C.sub.1-C.sub.6 alkyl radical(s) attached
to the nitrogen atom. Further more preferred is a lower alkylamino
radical having 1 to 3 carbon atom(s). A suitable alkylamino radical
may be mono- or dialkylamino such as N-methylamino, N-ethylamino,
N,N-dimethylamino, N,N-diethylamino, etc.
[0155] The term "arylamino" refers to an amino group substituted
with one or two aryl radical(s) such as N-phenylamino. The aryl
ring moiety of the arylamino radical may be further
substituted.
[0156] The term "heteroarylamino" refers to an amino group
substituted with one or two heteroaryl radical(s) such as
N-thienylamino. The heteroaryl ring moiety of the "heteroarylamino"
radical may be further substituted.
[0157] The term "aralkylamino" refers to an amino group substituted
with one or two aralkyl radical(s). More preferred is a
phenyl-C.sub.1-C.sub.3 alkylamino radical such as N-benzylamino.
The aryl ring moiety of the aralkylamino radical may be further
substituted.
[0158] The terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino"
respectively refer to an amino group substituted with one aralkyl
and one alkyl radicals, or with one aryl and one alkyl
radicals.
[0159] The term "aminoalkyl" embraces a linear or branched alkyl
radical having 1 to 10 carbon atom(s) one of which may be
substituted with one or more amino radical(s). A more preferred
aminoalkyl radical is a "lower aminoalkyl" radical having 1 to 6
carbon atom(s) and one or more amino radical(s). Examples of the
radical include aminomethyl, aminoethyl, aminopropyl, aminobutyl
and aminohexyl. More preferred is a lower aminoalkyl radical having
1 to 3 carbon atom(s).
[0160] The term "alkylaminoalkyl" embraces an alkyl radical
substituted with an alkylamino radical. A more preferred
alkylaminoalkyl radical is a "lower alkylaminoalkyl" radical having
1 to 6 carbon atom(s). Further more preferred is a lower alkyl
aminoalkyl radical having a C.sub.1-C.sub.3 alkyl radical. A
suitable alkylaminoalkyl radical may be mono- or
dialkyl-substituted such as N-methylaminomethyl,
N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl, and the like.
[0161] The term "alkylaminoalkoxy" embraces an alkoxy radical
substituted with an alkylamino radical. A more preferred
alkylaminoalkoxy radical is a "lower alkylaminoalkoxy" radical
having a C.sub.1-C.sub.6 alkoxy radical. Further more preferred is
a lower alkylaminoalkoxy radical having a C.sub.1-C.sub.3 alkyl
radical. A suitable alkylaminoalkoxy radical may be mono- or
dialkyl-substituted such as N-methylaminoethoxy,
N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy, and the like.
[0162] The term "alkylaminoalkoxyalkoxy" embraces an alkoxy radical
substituted with an alkylaminoalkoxy radical. A more preferred
alkylaminoalkoxyalkoxy radical is a "lower alkylaminoalkoxyalkoxy"
radical having a C.sub.1-C.sub.6 alkoxy radical. Further more
preferred is a lower alkylaminoalkoxyalkoxy radical having a
C.sub.1-C.sub.3 alkyl radical. A suitable alkylaminoalkoxyalkoxy
radical may be mono- or dialkyl-substituted such as
N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy,
N,N-dimethylaminoethoxyethoxy, N,N-diethylaminomethoxymethoxy, and
the like.
[0163] The term "carboxyalkyl" embraces a linear or branched alkyl
radical having 1 to 10 carbon atom(s) one of which may be
substituted with one or more carboxy radical(s). A more preferred
carboxyalkyl radical is a "lower carboxyalkyl" radical having 1 to
6 carbon atom(s) and a carboxy radical. Examples of the radical
include carboxylmethyl, carboxypropyl, and the like.
[0164] Further more preferred is a lower carboxyalkyl radical
having 1 to 3 CH.sub.2 group(s).
[0165] The term "halosulfonyl" embraces a sulfonyl radical
substituted with a halogen radical. Examples of the halosulfonyl
radical include chlorosulfonyl and fluorosulfonyl.
[0166] The term "arylthio" embraces a C.sub.6-C.sub.10 aryl radical
attached to a divalent sulfur atom. Examples of "arylthio" include
phenylthio.
[0167] The term "aralkylthio" embraces an aralkyl radical attached
to a divalent sulfur atom. More preferred is a
phenyl-C.sub.1-C.sub.3 alkylthio radical. Examples of "aralkylthio"
include benzylthio.
[0168] The term "aryloxy" embraces an aryl radical, which may be
substituted, attached to an oxygen atom. Examples of the radical
include phenoxy.
[0169] The term "aralkoxy" embraces an oxy-containing aralkyl
radical attached to another radical via an oxygen atom.
[0170] A more preferred aralkoxy radical is a "lower aralkoxy"
radical having a lower alkoxy radical with a phenyl radical, which
may be substituted, attached thereto.
[0171] The term "heteroaryloxy" embraces a heteroaryl radical,
which may be substituted, attached to an oxygen atom.
[0172] The term "heteroarylalkoxy" embraces an oxy-containing
heteroarylalkyl radical attached to another radical via an oxygen
atom. A more preferred heteroarylalkoxy radical is a "lower
heteroarylalkoxy" radical having a lower alkoxy radical with a
heteroaryl radical, which may be substituted, attached thereto.
[0173] The term "cycloalkylalkyl" embraces a cycloalkyl-substituted
alkyl radical. A preferred cycloalkylalkyl radical is a "lower
cycloalkylalkyl" radical with a cycloalkyl radical attached to a
C.sub.1-C.sub.6 alkyl radical. Further more preferred is "5- or
6-membered cycloalkylalkyl" attached to a C.sub.1-C.sub.3 alkyl
moiety. Examples of the radical include cyclohexylmethyl. The
cycloalkyl of the radical may be further substituted with halo,
alkyl, alkoxy or hydroxy.
[0174] The term "cycloalkenyl" embraces a carbocyclic group having
one or more carbon-carbon double bond(s), including
"cycloalkyldienyl". A preferred cycloalkenyl group has a
C.sub.3-C.sub.6 ring. More preferred are cyclopentenyl,
cyclopentadienyl, cyclohexenyl and cycloheptadienyl.
[0175] The term "include", "embrace" or "comprise" is to be
understood to include the listed elements but not exclude
others.
[0176] The term "Chemical Formula 1" is to be understood to include
any subformulae.
[0177] Medical Use
[0178] The compound of the present invention is effective in
preventing or treating angiogenesis-related diseases although not
limited thereto. The compound of the present invention has
inhibitory activity against kinases such as VEGFR/KDR and/or c-Met.
The compound of the present invention is useful in treating tumors
or minimizing harmful effects of VEGF and/or HGF.
[0179] The present invention provides pharmaceutical compositions
comprising therapeutically effective amounts of one or more
compound(s) represented by Chemical Formula 1 and a
pharmaceutically acceptable carrier.
[0180] The pharmaceutical composition of the present invention is
useful in treating HGF-mediated diseases.
[0181] The pharmaceutical composition of the present invention is
also useful in treating cancer, asthma, allergy, atopic skin
disease, psoriasis or rheumatoid arthritis. Thus, the present
invention provides a pharmaceutical composition useful in treating
non-small cell lung cancer, colorectal cancer, glioblastoma, head
and neck cancer, stomach cancer, bladder cancer, liver cancer,
ovarian cancer, and etc.
[0182] The pharmaceutical composition of the present invention may
further comprise one or more selected from the group consisting of
antibiotics, alkylating agents, antimetabolites, hormone drugs,
immunological agents, interferon agents and other anti-cancer
drugs.
[0183] The present invention also provides methods for treating an
HGF-mediated disease in a subject in need thereof, comprising
administering therapeutically effective amounts of the compound
represented by Chemical Formula 1 to the subject.
[0184] The present invention also provides methods for treating
cancer in a subject in need thereof, comprising administering a
therapeutically effective amount of the compound represented by
Chemical Formula 1 to the subject.
[0185] In the above treating methods, one or more selected from the
group consisting of antibiotic, alkylating agent, antimetabolite,
hormone drug, immunological agent, interferon agent and other
anti-cancer drug may be further administered to the subject.
[0186] However, the medical use and treating methods using the
compound of the present invention represented by Chemical Formula 1
are not limited to those afore-described. In addition, the drugs
that may be used in combination therewith are not limited to those
afore-described.
[0187] Hereinafter, the medical use and treating method using the
compound of the present invention represented by Chemical Formula 1
will be described in detail.
[0188] The compound of the present invention is useful in treating
tumors, including the following cancers and metastatic tumors,
without being limited thereto: cancers, e.g. bladder cancer, breast
cancer, colon cancer, renal cancer, liver cancer, lung cancer
(including small cell lung cancer), esophageal cancer, gallbladder
cancer, ovarian cancer, pancreatic cancer; stomach cancer, cervical
cancer, thyroid cancer, prostate cancer and skin cancer (including
squamous cell carcinoma); lymphatic hematopoietic tumors (including
leukemia, acute lymphoblastic leukemia, acute lymphoblastic
leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma,
non-Hodgkin lymphoma, hairy cell lymphoma and Burkitt's lymphoma);
myelogenous hematopoietic tumors (including acute and chronic
myelogenous leukemia, myelodysplastic syndrome and promyelocytic
leukemia); mesenchymally-derived tumors (fibrosarcoma,
rhabdomyosarcoma and other sarcoma of, e.g., soft tissue and bone);
tumors of the central and peripheral nervous systems (including
astrocytoma, neuroblastoma, glioma and neurilemmoma); and other
tumors (including melanoma, seminoma, teratocarcinoma,
osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular
thyroid carcinoma and Kaposi's sarcoma).
[0189] Preferably, the compound of the present invention is useful
in treating tumors selected from lung cancer, colon cancer and
breast cancer.
[0190] The compound of the present invention may also be useful in
treating ophthalmological symptoms, e.g. corneal graft rejection,
ocular neovascularization, retinal neovascularization including
neovascularization following damage or infection, diabetic
retinopathy, retrolental fibroplasia and neovascular glaucoma,
retinal ischemia and vitreous hemorrhage; ulcer diseases, e.g.
gastric ulcer; pathological but nonmalignant symptoms, e.g. angioma
including infantile hemangioma, nasopharyngeal angiofibroma and
avascular bone necrosis; and women's reproductive disorders, e.g.
endometriosis. The compound of the present invention is also useful
in treating edema and vascular hyperpermeability.
[0191] The compound of the present invention is useful in treating
proliferative diseases. The compound may be used to treat
inflammatory or rheumatoid diseases, particularly clinical symptoms
of locomotive organs, e.g. various rheumatoid inflammatory
diseases, especially rheumatoid arthritis, juvenile arthritis or
chronic multiple arthritis including psoriatic arthropathy;
psoriatic arthropathy, tumor-induced inflammatory disease, opacity,
extravasation or collagenosis, e.g. systemic lupus erythematosus,
multiple myositis, dermatomyositis, systemic scleroderma or mixed
collagenosis; post-infection arthritis (In this case, living
pathogenic organisms cannot be found in the infected site.) or
seronegative spondylarthritis, e.g. ankylosing spondylitis;
vasculitis, sarcoidosis or arthropathy; or complications thereof.
Examples of inflammatory diseases include synovial inflammation,
e.g. synovitis of particular undetermined/non-induced type,
especially bursal synovitis and purulent synovitis. The synovial
inflammation may be caused by or related with diseases, for
example, osteoarthritis, rheumatoid arthritis or arthritis
deformans. The present invention is further applicable to treatment
of inflammation, e.g. inflammatory disease or condition at the
musculotendinous junction or tendon sheath or systemic inflammation
of joints or locomotive organs. The inflammation may be caused by
or related with, for example, diseases or conditions including
myofascial syndrome and tendomyositis or surgical treatments. The
present invention is further applicable to treatment of
inflammatory diseases or conditions of connective tissues, e.g.
dermatomyositis and myositis.
[0192] The compound of the present invention may be used as an
active ingredient for disease conditions such as arthritis,
atherosclerosis, psoriasis, angioma, myocardial angiogenesis,
coronary and cerebral angiogenesis, ischemic leg vascularization,
wound healing, peptic ulcer, Helicobacter-related disease, bone
fracture, cat scratch fever, rubeosis, neovascular glaucoma,
retinopathy, e.g. diabetic retinopathy, and macular
degeneration-related diseases. Further, some of the compounds may
be used as an active ingredient for solid tumors, malignant
ascites, hematopoietic cancers and hyperproliferative diseases,
e.g. hyperthyroidism (especially Grave's disease) and cystoma [e.g.
hypervascularity of the ovarian stroma characteristic of polycystic
ovarian syndrome (Stein-Leventhal syndrome)], since these diseases
require proliferation of blood vessel cells for growth and/or
metastasis.
[0193] Also, some of these compounds may be used as an active
ingredient for burns, chronic pulmonary diseases, seizure, polyps,
hypersensitivity, chronic and allergic inflammations, ovarian
hyperstimulation syndrome, brain tumor-related cerebral edema,
high-grade trauma- or hypoxia-induced cerebral or pulmonary edema,
intraocular and mascular edema, ascitic and vascular
hyperpermeability, extravasation, exudation, protein extravasation
or other diseases accompanying edema. These compounds are useful in
treating the diseases that induce deposition of fibrin in the
extracellular matrix by protein extravasation and accelerate matrix
expansion (e.g. fibrosis, cirrhosis and carpal tunnel
syndrome).
[0194] The compound of the present invention is also useful in
treating ulcers including bacterial ulcer, fungal ulcer, Mooren's
ulcer and ulcerative colitis.
[0195] The compound of the present invention is also useful in
treating unwanted angiogenesis, edema or matrix deposition in viral
or protozoan infections, e.g. herpes simplex, shingles, AIDS,
Kaposi's sarcoma and toxoplasmosis, following trauma, radiation,
seizure, endometriosis, ovarian hyperstimulation syndrome, systemic
lupus, sarcoidosis, synovitis, Crohn's disease, sickle cell anemia,
Lyme disease, pemphigoid, Paget's disease, hyperviscosity syndrome,
Osler-Weber-Rendu disease, chronic inflammation, chronic
obstructive pulmonary disease, asthma, inflammatory rheumatoid or
rheumatoid diseases.
[0196] These compounds are also useful in reducing subcutaneous fat
or treating obesity.
[0197] The compound of the present invention is also useful in
treating ophthalmological conditions other than retinopathy and
macular degeneration, such as intraocular and macular edema, ocular
neovascularization disease, sclerotitis, uveitis, vitritis, myopia,
optical pits, chronic retinal detachment, complications following
radial keratotomy or laser surgery, glaucoma, conjunctivitis,
Stargardt disease and Eales disease.
[0198] The compound of the present invention is also useful in
treating cardiovascular conditions, e.g. atherosclerosis,
restenosis, arteriosclerosis, occlusion and carotid artery
occlusive disease.
[0199] The compound of the present invention is also useful in
treating cancer-related symptoms, e.g. solid tumor, sarcoma
(especially Ewing's sarcoma and osteosarcoma), retinoblastoma,
rhabdomyosarcoma, neuroblastoma, hematopoietic tumors including
leukemia, lymphoma, tumor-induced pleural or pericardial
extravasation, and malignant ascites.
[0200] The compound of the present invention is also useful in
treating diabetic symptoms, e.g. diabetic retinopathy and
microangiopathy. The compound of the present invention is also
useful in reducing blood flow to tumors in a patient. The compound
of the present invention is also useful in reducing metastasis of
tumors in a patient. The compound of the present invention may act
as an inhibitor against other protein kinases, e.g. tie-2, lck,
src, fgf, c-Met, ron, ckit and ret, and thus may be useful in
treating other protein kinase-related diseases.
[0201] In addition to treatment of human, the compound of the
present invention is also useful for veterinary treatment of
mammals, companion animals including rodents, exotic animals and
farm animals. More preferred animals include horse, dog and
cat.
[0202] As used herein, the compound of the present invention
includes pharmaceutically acceptable derivatives thereof. In the
specification, the plural form of the compound, salt, or the like,
is understood to include a sing compound, salt, or the like.
[0203] The compound of the present invention may be administered
alone as an active ingredient. However, one or more of the compound
of the present invention may also be used optionally in combination
with other agent. When used in combination, the treatment drug may
be formulated into individual compositions to be administered at
once or at different times, or into a single composition.
[0204] The term "cotherapy" or "combination-therapy", in defining
the use of the compound of the present invention or other
pharmaceutical agents, embraces the administration of each agent in
a sequential manner in a regimen that will provide beneficial
effects of the drug combination, and is intended as well to embrace
co-administration of these agents in a substantially simultaneous
manner, such as in a single capsule having a fixed ratio of these
active agents or in multiple, separate capsules for each agent.
[0205] Specifically, the administration of the compound of the
present invention may be accompanied by an additional therapy known
to those skilled in the art with regard to the prevention or
treatment of tumors, such as radiotherapy or administration of an
inhibitor of cell proliferation or a cytotoxic agent.
[0206] When formulated for a fixed administration dose, the
combination drug may comprise the compound of the present invention
within an allowed administration range. If combination with other
agent is inadequate, the compound represented by Chemical Formula 1
may be administered sequentially with a known anti-cancer drug or
cytotoxic agent. The order of administration is not particularly
limited. That is to say, the compound of the present invention may
be administered before, after or simultaneously with the known
anti-cancer drug or cytotoxic agent.
[0207] At present, the standard treatment of primary tumors
consists of surgical operation followed by radiation or
chemotherapy via IV injection. Commonly, a chemotherapic regimen
comprises a DNA alkylating agent, a DNA insertion agent, a CDK
inhibitor or a microtubular toxin. The chemotherapic administration
dose is below the maximum allowable dose. In general, the
dose-limiting toxicities include nausea, vomiting, diarrhea,
depilation, neutropenia, or the like.
[0208] A lot of antitumor agents selected for the treatment of
tumors via combination drug chemotherapy for commercial purpose,
clinical evaluation and pre-clinical development may be used. The
antitumor agent may be classified into several major categories,
i.e., antibiotic agents, alkylating agents, antimetabolic agents,
hormone agents, immunological agents, interferon agents, or the
like.
[0209] A first class of antitumor agents that may be used in
combination with the compound of the present invention consists of
antimetabolic/thymidylate synthase-inhibiting antitumor agents.
Suitable antimetabolic antitumor agents may be selected from the
group consisting of 5-FU-fibrinogen, acanthifolic acid,
aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694,
cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine
conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine,
dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,
doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,
floxuridine, fludarabine phosphate, 5-fluorouracil,
N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl
pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,
methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI
NSC-264880, NSC-39661, NCI NSC-612567, Warner-Lambert PALA,
pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda
TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate,
tyrosine kinase inhibitors, Taiho UFT and uricytin, but are not
limited thereto.
[0210] A second class of antitumor agents which may be used in
combination with the compound of the present invention consists of
alkylating-type antitumor agents.
[0211] Suitable alkylating-type antitumor agents may be selected
from the group consisting of Shionogi 254-S, aldo-phosphamide
analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207,
bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine,
Chinoin-139, Chinoin-153, chlorambucil, cisplatin,
cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233,
cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenyl
spiromustine, diplatinum cytostatic, Erba distamycin derivatives,
Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517,
estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin
GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine,
mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI
NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter
PTT-119, ranimustine, semustine, SmithKline SK&F-101772, Yakult
Honsha SN-22, spiromustine, Tanabe Seiyaku TA-077, tauromustine,
temozolomide, teroxirone, tetraplatin and trimelamol, but are not
limited thereto.
[0212] A third class of antitumor agents that may be used in
combination with the compound of the present invention consists of
antibiotic-type antitumor agents. Suitable antibiotic-type
antitumor agents may be selected from known antibiotic-type
antitumor agents.
[0213] A fourth class of antitumor agents that may be used in
combination with the compound of the present invention consists of
tubulin-interacting agents, topoisomerase II inhibitor,
topoisomerase I inhibitor, hormone agents and other antitumor
agents, but are not limited thereto.
[0214] Alternatively, the compound of the present invention may be
used in combination with the following other antitumor agents:
acemannann, aclarubicin, aldesleukin, alemtuzumab, alitretinoin,
altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine,
anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic
trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine,
capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole,
cytarabine ocfosfate, DA 3030 (Dong-A), daclizximab, denileukin
diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol,
doxercalciferol, doxifluridine, doxorubicin, bromocriptine, [0215]
carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon
alfa, daunorubicinalfa, doxorubicin, tretinoin, edelfosine,
edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta,
etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim,
finasteride, fludarabine phosphate, formestane, fotemustine,
gallium nitrate, gemcitabine, gemtuzumab zogamicin,
gimeracil/oteracil/tegafur combination, glycopine, goserelin,
heptaplatin, human chorionic gonadotropin, human fetal alpha
fetoprotein, ibandronic acid, idarubicin, imiquimod,
interferonalfa, interferon alfa, natural, interferon alfa-2,
interferon alfa-2a, interferon alfa-2b, interferon alfa-N1,
interferon alfa-n3, interferon alfacon-1, interferon alfa, natural,
interferon beta, interferon beta-1a, interferon beta-1b, interferon
gamma, natural, interferon gamma-1a, interferon gamma-1b,
interleukin-1 beta, iobenguane, irinotecan, irsogladine,
lanreotide, LC 9018 (Yakult), lefiunomide, lenograstim, lentinan
sulfate, letrozole, leukocyte alpha interferon, leuprorelin,
levamisole+fluorouracil, liarozole, lobaplatin, lonidamine,
lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone,
miltefosine, mirimostim, mismatched double stranded RNA,
mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin,
naloxone+pentazocine, nartograstim, nedaplatin, nilutamide,
noscapine, novel erythropoiesis stimulating protein, NSC 631570
octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel,
pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan
polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit
antithymocyte polyclonal antibody, polyethylene glycol interferon
alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburicase,
rhenium (.sup.186Re) etidronate, RII retinamide, rituximab,
romurtide, samarium (.sup.153Sm) lexidronam, sargramostim,
sizofuran, sobuzoxane, sonermin, strontium-89 chloride, suramin,
tasonermin, tazarotene, tegafur, temoporfin, temozolomide,
teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin,
thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131,
trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate,
triptorelin, tumor necrosis factor alpha, natural, ubenimex,
bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine,
valrubicin, verteporfin, vinorelbine, virulizin, zinostatin
stimalamer, zoledronic acid, abarelix, AE 941 (Aeterna),
ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015
(Dendreon), cetuximab, decitabine, dexaminoglutethimide,
diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil,
etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant,
galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical),
granulocyte macrophage colony stimulating factor, histamine
dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),
interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim,
lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical
Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC
Technology), idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb
(Techniclone), polymorphic epithelial mucin-yttrium 90 MAb
(Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium,
MX 6 (Galderma), nelarabine, nolatrexed, p30 protein, pegvisomant,
pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan,
satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172
(SRPharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate,
thaliblastine, thrombopoietin, tin ethyl etiopurpurin,
tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York
University), melanoma vaccine (Sloan Kettering Institute), melanoma
oncolysate vaccine (New York Medical College), viral melanoma cell
lysate vaccine (Royal Newcastle Hospital) oor valspodar.
[0216] Alternatively, the compound of the present invention may
also be used in combination therapies with known VEGFR inhibitors.
Other compounds described in various patents and patent
applications can be used in combination therapies.
[0217] In some embodiments, the combination comprises the
composition of the present invention with one or more
anti-angiogenic agent(s). These agents are inclusive of, but not
limited to, chemical compositions synthesized in vitro, antibodies,
antigen binding regions, radionuclides and combinations and
conjugates thereof. The agent can be agonist, antagonist,
allosteric modulator, toxin or, more generally, may act to inhibit
or stimulate its target (e.g. receptor or enzyme), and thereby
promote cell death or arrest cell growth.
[0218] Exemplary antitumor agents include HERCEPTIN.TM.
(trastuzumab), which may be used to treat breast cancer and other
forms of cancer, and RITUXAN.TM. (rituximab), ZEVALIN.TM.
(ibritumomab tiuxetan) and LYMPHOCIDE.TM. (epratuzumab), which may
be used to treat non-Hodgkin lymphoma and other forms of cancer,
GLEEVAC.TM. which may be used to treat chronic myelogenous leukemia
and gastrointestinal stromal tumors, and BEXXAR.TM. (iodine 131
tositumomab) which may be used to treat non-Hodgkin lymphoma.
[0219] Exemplary anti-angiogenic agents include ERBITUX.TM.
(IMC-C225), KDR (kinase domain receptor) inhibitors (e.g.
antibodies and antigen binding regions that specifically bind to
the kinase domain receptor), anti-VEGF agents (e.g. antibodies and
antigen binding regions that specifically bind to VEGF, soluble
VEGF receptors or a ligand binding region thereof) such as
AVASTIN.TM. or VEGF-TRAP.TM., anti-VEGF receptor agents (e.g.
antibodies and antigen binding regions that specifically bind
thereto), EGFR inhibitors (e.g. antibodies and antigen binding
regions that specifically bind thereto) such as ABX-EGF
(panitumumab), IRESSA.TM. (gefitinib) and TARCEVA.TM. (erlotinib),
anti-Ang1 and anti-Ang2 agents (e.g. antibodies and antigen binding
regions that specifically bind thereto or to their receptors, e.g.
Tie2/Tek) and anti-Tie2 kinase inhibitors (e.g. antibodies and
antigen binding regions that specifically bind thereto). The
pharmaceutical composition of the present invention can also
include one or more agent(s) (e.g. antibodies, antigen binding
regions or soluble receptors) that specifically bind to and inhibit
the activity of growth factors, such as antagonists of hepatocyte
growth factor (HGF, also known as scatter factor), and antibodies
and antigen binding regions that specifically bind to its receptor
"c-Met".
[0220] Other anti-angiogenic agents include Campath, IL-8, B-FGF,
Tek antagonists, anti-TWEAK agents (e.g. antibodies and antigen
binding regions that specifically bind thereto or soluble TWEAK
receptor antagonists), ADAM disintegrin domain that antagonizes the
binding of integrin to its ligand, anti-eph receptor and/or
anti-ephrin antibodies or antigen binding regions that specifically
bind thereto, and anti-PDGF-BB antagonists (e.g. antibodies and
antigen binding regions that specifically bind thereto), as well as
antibodies and antigen binding regions that specifically bind to
PDGF-BB ligands, and PDGFR kinase inhibitors (e.g. antibodies and
antigen binding regions that specifically bind thereto).
[0221] Alternatively, the compound of the present invention may
also be used in combination therapies with other antitumor agents,
such as VEGF antagonists, other kinase inhibitors including p38
inhibitors KDR inhibitors, EGF inhibitors and CDK inhibitors, TNF
inhibitors, matrix metalloprotease inhibitors (MMP), COX-2
inhibitors including celecoxib, NSAID's or
.alpha..sub.v.beta..sub.3 inhibitors.
[0222] A pharmaceutical composition containing the compound of the
present invention may be in a form adequate for oral
administration, for example, tablet, buccal tablet, lozenge,
aqueous or oily suspension, dispensable powder, granule, emulsion,
hard or soft capsule, syrup or elixir. The composition intended for
oral administration may be prepared according to any method known
in the art. Such compositions may typically contain one or more
agent(s) selected from the group consisting of sweetener, flavoring
agent, coloring agent and preservative in order to provide
pharmaceutically elegant and palatable preparations. The tablet may
contain an adequate, nontoxic, pharmaceutically acceptable
excipient as well as the active ingredient. The excipient may be,
for example, inert diluents such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate,
granulating and disintegrating agents such as microcrystalline
cellulose, sodium crosscarmellose, corn starch or alginic acid,
binders such as starch, gelatin, polyvinylpyrrolidone or gum
acacia, and lubricants such as magnesium stearate, stearic acid or
talc. The tablet may be un-coated or coated by known techniques to
mask the taste of the drug or delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a water-soluble taste
masking material such as hydroxypropyl methylcellulose or
hydroxypropylcellulose, or a time delay material such as ethyl
cellulose or cellulose acetate butyrate may be employed.
Formulations for oral use may be presented as hard gelatin capsules
wherein the active ingredient is mixed with an inert solid diluent,
for example, calcium carbonate, calcium phosphate or kaolin, or as
soft gelatin capsules wherein the active ingredient is mixed with a
water-soluble carrier such as polyethylene glycol or an oil medium,
for example, peanut oil, liquid paraffin or olive oil.
[0223] An aqueous suspension contains the active ingredient in
admixture with an excipient suitable for the preparation of aqueous
suspensions. The excipient may be suspending agents, for example,
sodium carboxymethylcellulose, methylcellulose, hydroxypropyl
methylcellulose, sodium alginate, polyvinylpyrrolidone, gum
tragacanth and gum acacia, dispersing or wetting agents such as a
naturally-occurring phosphatide, e.g. lecithin, condensation
products of alkylene oxide with fatty acid, e.g. polyoxyethylene
stearate, condensation products of ethylene oxide with long chain
aliphatic alcohol, e.g. heptadecaethyleneoxycetanol, condensation
products of ethylene oxide with partial ester derived from fatty
acid and hexitol, e.g. polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial ester derived
from fatty acid and hexitol anhydride, e.g. polyethylene sorbitan
monooleate. The aqueous suspension may also contain one or more
preservative(s), e.g. ethyl or n-propyl p-hydroxybenzoate, one or
more coloring agent(s), one or more flavoring agent(s) and one or
more sweetener(s), e.g. sucrose, saccharin or aspartame.
[0224] An oily suspension may be formulated by suspending the
active ingredient in a vegetable oil, for example, arachis oil,
olive oil, sesame oil or coconut oil, or in a mineral oil such as
liquid paraffin. The oily suspension may contain a thickening
agent, for example, beeswax, hard paraffin or cetyl alcohol. A
sweetener such as those set forth above and a flavoring agent may
be added to provide a palatable oral preparation. These
compositions may be preserved by adding an antioxidant such as
butylated hydroxyanisole or alpha-tocopherol.
[0225] Dispensable powder and granule suitable for preparation of
an aqueous suspension by adding water provide the aqueous
suspension comprising the active ingredient in admixture with a
dispersing agent, a wetting agent, a suspending agent and one or
more preservative(s). A suitable dispersing agent, wetting agent or
suspending agent are exemplified by those already mentioned above.
Additional excipients, for example, sweetener, flavoring agent and
coloring agent may also be present. These compositions may be
preserved by adding an antioxidant such as ascorbic acid. The
pharmaceutical composition of the present invention may also be in
the form of an oil-in-water emulsion. The oily phase may be a
vegetable oil, for example, olive oil or arachis oil, or a mineral
oil, for example, liquid paraffin, or a mixture thereof. A suitable
emulsifier may be naturally-occurring phosphatides, e.g. soybean
lecithin, and esters or partial esters derived from fatty acid and
hexitol anhydride, e.g. sorbitan monooleate, and condensation
products of the aforesaid partial ester with ethylene oxide, e.g.
polyoxyethylene sorbitan monooleate.
[0226] The emulsion may also contain a sweetener, a flavoring
agent, a preservative or an antioxidant.
[0227] The syrup and elixir may be formulated using a sweetener,
for example, glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative, a
flavoring agent, a coloring agent or an antioxidant. The
pharmaceutical composition may also be a sterile injectable aqueous
solution. Among the acceptable vehicles and solvents that may be
employed are water, Ringer's solution and isotonic sodium chloride
solution.
[0228] The sterile injectable preparation may also be a sterile
injectable oil-in-water microemulsion where the active ingredient
is dissolved in an oily phase. For example, the active ingredient
may be first dissolved in a mixture of soybean oil and lecithin.
The oil solution is then introduced into a mixture of water and
glycerol and processed to form a microemulsion. The injectable
solution or microemulsion may be introduced into a patient's
bloodstream by local bolus injection.
[0229] Alternatively, it may be advantageous to administer the
solution or microemulsion in such a way as to maintain a constant
circulating concentration of the compound of the present invention.
In order to maintain such a constant concentration, a continuous
intravenous delivery device may be utilized. An example of such a
device is the Deltec CADD-PLUS.TM. model 5400 intravenous pump.
[0230] The pharmaceutical composition of the present invention may
be in the form of a sterile injectable aqueous or oleaginous
suspension for intramuscular or subcutaneous administration. This
suspension may be formulated according to the known art using those
suitable dispersing agents, wetting agents or suspending agents
which have been mentioned above. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example,
as a solution in 1,3-butanediol. In addition, a sterile fixed oil
may be commonly employed as a solvent or suspending medium. For
this purpose, any bland fixed oil may be employed including
synthetic mono- or diglyceride. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0231] The compound of the present invention represented by
Chemical Formula 1 may also be administered in the form of a
suppository for rectal administration of the drug. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient which is solid at ordinary temperatures
but liquid at the rectal temperature and will therefore melt in the
rectum to release the drug. Such materials include cocoa butter,
glycerinated gelatin, hydrogenated vegetable oils, mixtures of
polyethylene glycols of various molecular weights and fatty acid
esters of polyethylene glycol.
[0232] For topical use, creams, ointments, jellies, solutions,
suspensions, and the like containing the compound represented by
Chemical Formula 1 can be used (As used herein, topical application
can include mouth washes and gargles).
[0233] The compound of the present invention can be administered in
intranasal form via topical use of suitable intranasal vehicles and
delivery devices, or via transdermal routes, using those forms of
transdermal skin patches well known to those of ordinary skill in
the art. To be administered in the form of a transdermal delivery
system, the administration dosage will, of course, be continuous
rather than intermittent throughout the dosage regimen. The
compound of the present invention may be administered in the form
of a suppository using, for example, cocoa butter, glycerinated
gelatin, hydrogenated vegetable oils, mixtures of polyethylene
glycols of various molecular weights or fatty acid esters of
polyethylene glycol.
[0234] When the compound according to the present invention is
administered into a human subject, the daily dosage will normally
be determined by the prescribing physician with the dosage
generally varying according to the age, weight, sex and response of
the individual patient, as well as the severity of the patient's
symptoms. Such combination products if formulated as a fixed dose
employ the compound of the present invention within the dose range
described above as well as other pharmaceutically active agent
within its approved dose range. In case the combination preparation
of the compound represented by Chemical Formula 1 is inappropriate,
it may be administered sequentially with a known anti-cancer drug
or cytotoxic agent. The sequence of the administration is not
limited in the present invention. That is to say, the compound
represented by Chemical Formula 1 may be administered before or
after the administration of the known anti-cancer drug or cytotoxic
agent.
[0235] The terms used in this specification are defined as
follows.
[0236] The term "angiogenesis" refers to the change in existing
blood vessels favoring tissue perfusion or the formation of new
vasculature. It embraces sprouting of new blood vessels from
existing ones by producing endothelial cells, as well as
modification of existing blood vessels for improving tissue
perfusion through change in size, development, direction or
fluidity.
[0237] As used herein, the term "HGF" refers to hepatocyte growth
factor/scatter factor. It embraces purified hepatocyte growth
factor/scatter factor, fragments of hepatocyte growth
factor/scatter factor, fragments of chemically synthesized
hepatocyte growth factor/scatter factor, derivatives or mutation
variants of hepatocyte growth factor/scatter factor, and fused
protein comprising hepatocyte growth factor/scatter factor and
other protein. The term "HGF" as used herein also embraces
hepatocyte growth factor/scatter factor isolated from species other
than human.
[0238] As used herein, the term "c-Met" refers to an HGF receptor.
It embraces a purified receptor, fragments of the receptor,
fragments of a chemically synthesized receptor, derivatives or
mutation variants of the receptor, and fused protein comprising the
receptor and other protein. The term "c-Met" also embraces an HGF
receptor isolated from species other than human.
[0239] As used herein, the term "HGF" refers to hepatocyte growth
factor/scatter factor. It embraces purified hepatocyte growth
factor/scatter factor, fragments of hepatocyte growth
factor/scatter factor, fragments of chemically synthesized
hepatocyte growth factor/scatter factor, derivatives or mutation
variants of hepatocyte growth factor/scatter factor, and fused
protein comprising hepatocyte growth factor/scatter factor and
other protein. The term "HGF" as used herein also embraces
hepatocyte growth factor/scatter factor isolated from species other
than human.
[0240] As used herein, the term "c-Met" refers to an HGF receptor.
It embraces a purified receptor, fragments of the receptor,
fragments of a chemically synthesized receptor, derivatives or
mutation variants of the receptor, and fused protein comprising the
receptor and other protein. The term "c-Met" also embraces an HGF
receptor isolated from species other than human.
[0241] As used herein, the terms "hepatocyte growth factor" and
"HGF" generally refer to a growth factor having 6 domains (finger,
Kringle 1, Kringle 2, Kringle 3, Kringle 4' and serine protease
domains). A fragment of HGF has a smaller number of domains, and a
variant of HGF may have some HGF domains in plural numbers. Both
are allowed as long as the ability to bind to the HGF receptor is
retained. The terms "hepatocyte growth factor" and "HGF" embrace a
hepatocyte growth factor derived from human ("huHGF") and non-human
mammals, especially rat. As used herein, the terms embrace mature,
pre, pre-pro and pro forms purified from a naturally occurring
source, synthesized chemically, or produced by recombination. Human
HGF is encoded by the cDNA sequence recorded by Miyazawa et al. or
Nakamura et al. The sequences recorded by them differ in 14 amino
acids. The reason for the differences is not entirely clear.
Polymorphism or cloning artifacts are among the possibilities.
[0242] Both sequences are specifically encompassed by the foregoing
terms. It will be understood that natural allelic variations exist
and can occur among individuals, as demonstrated by one or more
difference(s) in the amino acid sequence of each individual. The
terms "hepatocyte growth factor" and "HGF" specifically include
delta 5 huHGF.
[0243] The terms "HGF receptor" and "c-Met" as used herein refer to
a cellular receptor for HGF, which typically includes an
extracellular domain, a transmembrane domain and an intracellular
domain, as well as variants and fragments thereof which retain the
ability to bind to HGF. The terms "HGF receptor" and "c-Met"
include the polypeptide molecule that comprises the full-length,
native amino acid sequence encoded by the gene variously known as
p190.sup.MET. This definition specifically encompasses soluble
forms of HGF receptor and HGF receptors from natural sources,
synthetically produced in vitro or obtained by genetic manipulation
including methods of recombinant DNA technology. The HGF receptor
variants or fragments preferably share at least about 65% sequence
homology, and more preferably about 75% sequence homology with any
domain of the human c-Met amino acid sequence.
[0244] The terms "agonist" and "agonistic" as used herein refer to
or describe a molecule which is capable of, directly or indirectly,
substantially inducing, promoting or enhancing biological activity
of HGF or activation of HGF receptor.
[0245] The terms "cancer", "cancerous" and "malignant" refer to or
describe the physiological condition in mammals that is typically
characterized by unregulated cell growth. Examples of cancer
include but are not limited to carcinoma, lymphoma, sarcoma,
blastoma and leukemia. More particular examples of such cancers
include squamous cell carcinoma, lung cancer, pancreatic cancer,
cervical cancer, bladder cancer, liver cancer, breast cancer, colon
cancer and head and neck cancer. Although the term "cancer" used
herein is not limited to particular types of diseases, the method
according to the present invention seems to be particularly
effective for cancers in mammals that are known to be accompanied
by increased level of HGF or c-Met expression.
[0246] The terms "treating", "treatment" and "therapy" as used
herein refer to curative therapy, prophylactic therapy and
preventive therapy.
[0247] The term "mammal" as herein refers to any mammal classified
as a mammal, including human, cow, horse, dog and cat. In a
preferred embodiment of the present invention, the mammal is a
human.
[0248] When increased levels of c-Met and HGF are observed in
hypertension, arteriosclerosis, myocardial infarction and
rheumatoid arthritis, the compound of the present invention is
effective for treating the diseases.
[0249] The term "treatment" embraces therapeutic measures as well
as prophylactic measures (inhibition of onset of disorders or
retardation of onset of pre-clinically explicit disorders in
individuals).
[0250] The term "pharmaceutically acceptable derivative" refers to
a salt or ester of the compound of the present invention, other
compound that may provide the compound of the present invention
(directly or indirectly) or otherwise inhibit angiogenesis when
administered to a patient, a metabolite thereof, or a residue
thereof.
[0251] The phrase "therapeutically effective amount" is meant to
refer to an amount of each agent that will accomplish the
improvement of the severity or occurrence of the disease while
avoiding undesired adverse reactions. For example, a
therapeutically effective amount of an antitumor agent will provide
the effect of prolonging the survival period of a patient,
suppressing proliferation of tumors or leading to degeneration of
tumors.
[0252] The present invention also provides a method for preparing
the compound represented by Chemical Formula 1. And, the compound
represented by Chemical Formula I includes a pharmaceutically
acceptable salt thereof. The term "pharmaceutically acceptable
salt" includes a salt commonly used to form an alkali metal salt
and an addition salt of free acid or free base. Although the
properties of the salt are not particularly important, it should be
pharmaceutically acceptable. A pharmaceutically acceptable acid
addition salt of the compound represented by Chemical Formula 1 may
be prepared form an inorganic acid or an organic acid. Examples of
the inorganic acid include hydrochloric acid, hydrobromic acid,
hydriodic acid, nitric acid, carbonic acid, sulfuric acid and
phosphoric acid. Suitable organic acids may be selected from
aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic,
carboxylic and sulfonic organic acids. Examples include formic
acid, acetic acid, adipic acid, butyric acid, propionic acid,
succinic acid, glycolic acid, gluconic acid, lactic acid, malic
acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid,
maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic
acid, benzoic acid, anthranilic acid, mesylic acid,
4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic
acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid,
ethanedisulfonic acid, benzenesulfonic acid, pantothenic acid,
2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfanilic
acid, cyclohexylaminosulfonic acid, camphoric acid, camphorsulfonic
acid, digluconic acid, cyclopentanepropionic acid, dodecylsulfonic
acid, glucoheptanoic acid, glycerophosphonic acid, heptanoic acid,
hexanoic acid, 2-hydroxy-ethanesulfonic acid, nicotinic acid,
2-naphthalenesulfonic acid, oxalic acid, palmoic acid, pectinic
acid, persulfuric acid, 2-phenylpropionic acid, picric acid,
pyvalic acid, propionic acid, succinic acid, tartaric acid,
thiocyanic acid, undecanoic acid, stearic acid, alginic acid,
.beta.-hydroxybutyric acid, salicylic acid, galactaric acid and
galacturonic acid. Examples of the pharmaceutically acceptable base
addition salt of the compound represented by Chemical Formula 1
include metal salts such as aluminum, calcium, lithium, magnesium,
potassium, sodium and zinc salts, organic base including primary,
secondary or amine and substituted amine such as cyclic amine, e.g.
caffeine, arginine, diethylamine, N-ethylpiperidine, aistidine,
glucamine, isopropylamine, lysine, morpholine, N-ethylmorpholine,
piperazine, piperidine, triethylamine and trimethylamine. All of
these salts may be prepared by conventional methods from the
corresponding compound of the present invention by reacting, for
example, the appropriate acid or base with the compound represented
by Chemical Formula 1. When a base group and an acid group are
present in the same molecule, the compound represented by Chemical
Formula 1 may also form an internal salt.
[0253] Synthesis Process
[0254] Specific compounds of the present invention, which are
represented by Chemical Formula 1, may be prepared according to the
following reaction schemes. The compounds are easily synthesized
using the synthesis methods known to those skilled in the art.
Tautomers and solvates (e.g. hydrate) of the compound represented
by Chemical Formula 1 are also included in the scope of the present
invention. Solvation techniques are known in the art. Accordingly,
the compound of the present invention may be in free or hydrated
form, and may be obtained from the methods exemplified by the
following reaction schemes. In the following reaction schemes, the
substituents are the same as defined in Chemical Formula 1 unless
specified otherwise.
[0255] Abbreviations used in the specification are as follows.
[0256] HBTU: O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0257] HATU:
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0258] PyBop:
benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium
hexafluorophosphate [0259] Pd.sub.2(dba).sub.3:
bis(dibenzylideneacetone)palladium [0260] BINAP:
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [0261] TEAC:
bis(tetraethylammonium)carbonate [0262] Et.sub.2O: diethyl ether
[0263] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL: [0264]
diisobutylaluminum hydride [0265] DIAD: diisopropyl
azodicarboxylate [0266] DIEA: diisopropylethylamine [0267] DMF:
dimethylformamide [0268] DMAP: 4-dimethylaminopyridine [0269] DMSO:
dimethyl sulfoxide [0270] EDC, EDCl:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [0271]
DPPA: diphenylphosphoryl azide [0272] EtOAc: ethyl acetate [0273]
FBS: fetal bovine serum [0274] HOBt: 1-hydroxybenzotriazole hydrate
[0275] LiHMDS: lithium bis(trimethylsilyl)amide [0276] LDA: lithium
diisopropylamide [0277] MCPBA: meta-chloroperbenzoic acid [0278]
CH.sub.2Cl.sub.2, DCM: methylene chloride [0279] NMP:
N-methylpyrrolidone [0280] Pd/C: palladium on carbon [0281]
Pd(OAc).sub.2: palladium(II) acetate [0282] Pd(OH).sub.2: palladium
hydroxide [0283] Pd(PPh.sub.3).sub.4:
tetrakis(triphenylphosphine)palladium [0284] Pd(dppf)Cl.sub.2:
1,1-bis(diphenylphosphino)ferrocene palladium chloride [0285] PBS:
phosphate buffered saline [0286] RT: room temperature [0287] SEM:
2-(trimethylsilyl)ethoxymethyl [0288] TBTU:
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
[0289] THF: tetrahydrofuran [0290] Et3N, TEA: triethylamine [0291]
TFA: trifluoroacetic acid [0292] P(t-Bu).sub.3:
tri(tert-butyl)phosphine
[0293] In general, the target heterocyclic compound represented by
Chemical Formula 1 may be prepared according to Reaction Schemes 1
to 3.
##STR00008##
[0294] In Reaction Scheme 1, Q, X, Y, Z, R.sup.1, R.sup.2 and
R.sup.3 are the same as defined in Chemical Formula 1.
[0295] Specifically, a compound with Y.dbd.Z.dbd.CH and Q=
##STR00009##
may be prepared according to Reaction Scheme 2.
##STR00010## ##STR00011##
[0296] According to Reaction Scheme 2, Compound 10
(pyrrolo[1,2-b]pyridazin-4(1H)-one) is silylated to obtain compound
11. After sequentially adding water, a 3-X-4-fluoronitrobenzene
derivative and 1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU) to a
solution of compound 11 in dimethyl sulfoxide, reaction is carried
out to obtain Compound 12. Compound 12 is brominated to obtain
compound 13. The nitro group of compound 13 is reduced to an amino
group using zinc powder and ammonium chloride to obtain compound
14. Compound 14 and a pyrazole-4-carboxylic acid derivative
(Compound 15) are dissolved in DMF. After sequentially adding HATU
and triethylamine are sequentially added, the reaction is carried
out to obtain compound 16. Compound 16 and an R.sup.4-containing
boronic acid [R.sup.4--B(OH).sub.2] are dissolved in dioxane. After
sequentially adding potassium carbonate aqueous solution and
Pd(PPh.sub.3).sub.4, reaction is carried out to obtain compound
17.
[0297] Specifically, a compound with Y.dbd.Z.dbd.CH and Q=
##STR00012##
may be prepared according to Reaction Scheme 3.
##STR00013##
[0298] According to Reaction Scheme
3,4-chloro-1H-pyrrolo[2,3-b]pyridine (compound 18) is dissolved in
tetrahydrofuran under nitrogen atmosphere and then cooled to
0.degree. C. After adding 40% NaH and stirring, SEM-Cl is added. By
heating to 80.degree. C., compound 19 is obtained as an
intermediate. Compound 19 is iodinated under nitrogen atmosphere to
obtain compound 20. Compound 20 and an R.sup.4-containing boronic
acid [R.sup.4--B(OH).sub.2] are dissolved in dioxane. After
sequentially adding Pd(PPh.sub.3).sub.4 and potassium carbonate
aqueous solution, the reaction is carried out by stirring at
80.degree. C. to obtain compound 21. Compound 21 and
(3-X-4-hydroxy-phenyl)-carbamic acid t-butyl ester (compound 22)
are dissolved in anhydrous toluene under nitrogen atmosphere. After
adding dicyclohexyl-phosphino-2',4',6'-triisopropylbiphenyl
(XPHOS), Pd.sub.2dba.sub.3 and potassium carbonate, reaction is
carried out to obtain Compound 23. 1:1 solution of hydrochloric
acid and methanol is added to a solution of compound 23 in
methanol. Reaction is carried out by stirring at room temperature
to obtain compound 24. Compound 24,
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid (compound 25) and HATU are dissolved in dimethylformamide.
After adding triethylamine, reaction is carried out by heating at
50.degree. C. to obtain compound 26.
[0299] If necessary, the starting materials in the above reaction
schemes may have their functional groups protected and/or may have
salt-forming groups. They may also be present in salt forms if
reactions are possible in those forms.
[0300] Depending on purposes, one or more compound(s) represented
by Chemical Formula 1 may be converted to another compound
represented by Chemical Formula 1 or an N-oxide thereof. The
compound represented by Chemical Formula 1 may also be converted to
a salt. A salt of the compound represented by Chemical Formula 1
may be converted to a free compound or another salt. Further, a
mixture of isomer compounds represented by Chemical Formula 1 may
be separated into individual isomers.
[0301] An N-oxide may be obtained by reacting the compound
represented by Chemical Formula 1 with hydrogen peroxide, Oxone or
a peracid (e.g. mCPBA) at about -10 to 35.degree. C., for example,
at about 0.degree. C. to room temperature, in a mixture of an inert
solvent (e.g. CH.sub.2Cl.sub.2), water and alcohol (e.g. MeOH or
EtOH).
[0302] If there are one or more different functional groups, e.g.
carboxy, hydroxy, amino or mercapto, or the compound represented by
Chemical Formula 1 has a functional group that needs to be
protected, they may be protected using a protecting group commonly
used in the synthesis of peptide compounds, cephalosporin and
penicillin, as well as nucleic acid derivatives and sugars.
[0303] The protecting group may be already present in a precursor
and is intended to protect the functional group in question from
undesired secondary reactions, e.g. acylation, etherification,
esterification, oxidation, solvolysis and other similar reactions.
The protecting group can be removed easily, i.e. without undesired
secondary reactions taking place, for example by solvolysis,
reduction or photolysis, and also enzymatically, for example, under
physiological conditions, and does not exist in the end product.
Those skilled in the art will know or easily select the protecting
groups that are appropriate for the above and following
reactions.
[0304] In the following processes, the functional groups of the
staring materials that did not participate in the reaction as
desired may be present as unprotected or protected by one or more
protecting group(s). Later, all or some of the protecting groups
are removed according to the aforesaid method.
[0305] A salt of a compound represented by Chemical Formula 1
having a salt-forming group may be prepared according to a known
method. An acid addition salt of the compound represented by
Chemical Formula 1 may be prepared by treating with an acid or a
suitable anion exchange reagent. A salt with two acid molecules
(for example, a dihalogenide of the compound represented by
Chemical Formula 1) may also be converted into a salt with one acid
molecule per compound (for example, a monohalogenide). This may be
done by heating to a melt or, for example, by heating as a solid
under a high vacuum at elevated temperature, for example from 130
to 170.degree. C., so that one acid molecule is expelled per
molecule of the compound represented by Chemical Formula 1.
[0306] A salt can usually be converted to a free compound, for
example, by treating with a suitable basic compound, e.g. alkali
metal carbonate, alkali metal hydrogen carbonate or alkali metal
hydroxide, typically potassium carbonate or sodium hydroxide.
[0307] All the processes described herein may be performed under a
known reaction condition, preferably under a specified condition,
in the absence of or usually in the presence of a solvents or
diluents that, preferably such as are inert to the reagents used
and able to dissolve these, in the absence or presence of
catalysts, condensing agents or neutralizing agents, for example
ion exchangers, typically cation exchangers (e.g. in the H.sup.+
form), depending on the type of reaction and/or reactants, at
reduced, normal or elevated temperature, for example in the range
from about -100.degree. C. to about 190.degree. C., preferably from
about -80.degree. C. to about 150.degree. C., for example, from
about -80.degree. C. to about 60.degree. C., at room temperature,
from about -20.degree. C. to about 40.degree. C. or at the boiling
point of the solvent used, under atmospheric pressure or in a
closed vessel, where appropriate, under pressure and/or in an inert
atmosphere, for example, under argon or nitrogen atmosphere.
[0308] Salts may be present in all starting materials and
intermediates, if these contain salt-forming groups. Salts may also
be present during the reaction of such compounds, provided the
reaction is not disturbed thereby.
[0309] Under certain circumstance, typically in hydrogenation, a
stereoseletive reaction may be achieved, for example, to allow
easier obtainment of individual isomers.
[0310] Solvents that may be used in the reactions may be selected
from the followings: water, ester, typically lower alkyl-lower
alkanoate (e.g. EtOAc), ether, typically aliphatic ether (e.g.
Et.sub.2O) or cyclic ether (e.g. THF), liquid aromatic hydrocarbon,
typically benzene or toluene, alcohol, typically MeOH, EtOH,
1-propanol or IPOH, nitrile, typically CH.sub.3CN, halogenated
hydrocarbon, typically CH.sub.2Cl.sub.2, acid amide, typically DMF,
base, typically heterocyclic nitrogenous base (e.g. pyridine),
carboxylic acid, typically lower alkanecarboxylic acid (e.g. AcOH),
carboxylic acid anhydride, typically lower alkanoic anhydride (e.g.
acetic anhydride), cyclic, linear or branched hydrocarbon,
typically cyclohexane, hexane or isopentane, and mixtures of these
solvent (e.g. aqueous solution). Such solvent mixtures may also be
employed in such processes as chromatography.
[0311] In accordance with the present invention, a specific
material may be prepared from a compound that may be obtained
transiently at any step. An omitted step may be performed and the
process may be stopped at any step. Also, the starting material may
be formed under the reaction condition, or the starting material
may be used in the form of a reactive derivative or salt. Or, a
compound that may be obtained according to the method of the
present invention may be prepared to be used in the other process.
In a preferred embodiment, a material is prepared from the starting
material that gives rise to the material.
[0312] The compound represented by Chemical Formula 1 includes a
salt thereof and may be obtained in a hydrated form. Crystals of
the compounds may include, for example, the solvent (existing as
solvate) used for crystallization.
[0313] Not only the novel starting material and/or intermediate,
but also the preparation method thereof is a subject matter of the
present invention. In a preferred embodiment, a reaction condition
is selected so that the desired compound can be obtained from the
starting material.
[0314] The starting material of the present invention may be known
or commercially available or may be synthesized according to a
method known in the art.
[0315] When preparing the starting material, the functional groups
that do not participate in the reaction may be needed to be
protected.
[0316] Preferred protecting groups, and introduction and removal
thereof are described in the foregoing description or in the
following examples.
[0317] All the starting materials are previously known, may be
prepared according to known methods, or are commercially available.
Especially, they may be prepared according to the description of
the examples.
[0318] In general, the compound of the present invention may have
one or more asymmetric carbon atom(s). Therefore, the compound of
the present invention may be present as optical isomers, racemates
or non-racemic mixtures thereof. The optical isomers can be
obtained by resolving the racemic mixture according to a common
method, for example by treating with an optically active acid or
base, thereby forming diastereomeric salts. Examples of suitable
acids include tartaric acid, diacetyltartaric acid,
dibenzoyltartaric acid, ditoloyltartaric acid and camphorsulfonic
acid. Then, the diastereomeric mixture is separated by
crystallization followed by freeing of the optically active base
from the salt. Another method for the separation of optical isomers
is to use a chiral chromatographic column optimally selected to
maximize the separation of enantiomers. Another available method is
to react the compound of the present invention with an activated,
optically pure acid or optically pure isocyanate to synthesize a
covalently bonded diastereomer molecule. The synthesized
diastereomer is separated by a common method such as
chromatography, distillation, crystallization or sublimation, and
then hydrolyzed to obtain an enantiomerically pure. compound.
Optically active compounds of the present invention may be prepared
from optically active starting materials. These isomers may be in
the form of free acids, free bases, esters or salts.
[0319] Since the compound of the present invention has one or more
asymmetric center(s), it may be present as racemate, racemic
mixture, scalemic mixture, enantiomer, individual diastereomers and
diastereomeric mixture. All of these isomers are explicitly
encompassed in the present invention. The present invention also
explicitly encompasses all tautomer forms of the compounds
described herein. The compound may also be in cis-, trans-, E- or
Z-isomer form. All of these isomer forms are also explicitly
encompassed in the present invention. And, all crystal forms of the
compounds described herein are explicitly encompassed in the
present invention.
[0320] A cyclic substituent (e.g. phenyl, thienyl, and the like)
may be attached to a specific atom. This means that the substituent
may or may not be fixed at specific atom.
[0321] The compound of the present invention may include a
heterocyclic ring attached to another ring. The heterocyclic ring
may be attached via a carbon atom or a heteroatom of the ring
system.
[0322] Any of the compounds with the chemical formulae described
herein may be synthesized by the methods disclosed herein.
[0323] In the preparation methods described in this specification,
the steps may be performed sequentially and, if necessary, further
protecting/deprotecting step may precede or follow. Additional
inert solvent, reagent, for example base (e.g. LDA, DIEA, pyridine,
K.sub.2CO.sub.3, and the like), catalyst, or salts thereof may be
used under suitable reaction conditions. An intermediate may be
isolated or subjected to the next step with or without a
purification process. The purification may be performed according
to methods known in the art. They include, for example,
crystallization, chromatography (liquid-phase, gas-phase),
extraction, distillation, pulverization, reversed-phase HPLC, or
the like. Reaction conditions such as temperature, period, pressure
and atmosphere (e.g., inert gas or ambient atmosphere) are known in
the art and may be adjusted appropriately depending on the
particular reactions.
[0324] As will be recognized by those skilled in the art, the
foregoing synthesis reaction schemes are not intended to
comprehensively include all the possible means of synthesizing the
compounds of the present invention. Those skilled in the art will
also appreciate other additional methods. In the foregoing reaction
schemes, various synthesis steps may be performed alternatingly or
sequentially to obtain the desired compounds.
[0325] The compound of the present invention may be modified by
attaching an adequate functional group to selectively enhance its
biological features. Such modification is known in the art and
includes those enhancing biological infiltration into a given
biological system (e.g. cardiovascular system, lymphatic system,
CNS), increasing oral availability, increasing solubility to allow
administration by injection, altering metabolism and changing
secretion rate.
[0326] The foregoing detailed description is given to describe
examples of the general synthesis procedure which is included in
the scope of the present invention. The detailed description is
provided for illustrative purposes only and is not intended to
limit the scope of the present invention.
[0327] Hereunder is given examples and preparations according to
the present invention. The following examples are only exemplary
and the present invention is not limited thereby. It is to be
understood that there may exist other embodiments that are included
in the intent and scope of the present invention.
EXAMPLES
[0328] Unless specified otherwise, all materials were acquired from
ordinary suppliers and were used without further purification.
[0329] For analysis of compounds, all the .sup.1H-NMR spectra were
measured using Varian's Unity Inova 400 Series and all the mass
spectra were measured using Shimadzu's LCMS-2010EV Series.
[0330] LCMS analysis was performed using Shimadzu's LCMS-2010 EV
under the following conditions: [0331] Degasser: DGU-20A [0332]
Pump: LC-20AD [0333] Autosampler: SIL-20A [0334] UV/Vis detector:
SPD-20A [0335] Column oven: CTO-20A [0336] Solvent: 90% CAN (0.1%
TFA) in H.sub.2O [0337] Wavelength: 254 nm [0338] Injection volume:
5 .mu.L [0339] Column: XDB C18 5 m, 4.5.times.150 mm (Agilent)
Preparation Example 1
1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid
##STR00014##
[0341]
1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid, which is one of the intermediate compounds used in the
synthesis of the compound of the present invention, was prepared as
follows:
##STR00015##
[0342] To a mixture of
1-benzyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxaldehyde
(1 g, 4.624 mmol) in butyl alcohol were added to NaClO.sub.2 (1.254
g, 13.873 mmol) in an aqueous solution and potassium phosphate
monobasic monohydrate (3.146 g, 23.12 mmol) in an aqueous solution
slowly at 0.degree. C. The resulting reaction mixture was slowly
heated to room temperature and stirred for 10 hours. NaClO.sub.3 (1
g) was further added while monitoring the reaction. Following the
addition of sodium chlorite, the reaction mixture was stirred and
then extracted with ethyl acetate. The organic layer was washed
with, dried with Na.sub.2SO.sub.4 and then filtered. The filtrate
was concentrated under reduced pressure. The resulting residue was
washed with 20% ethyl acetate solution in small amount of hexane.
The target compound was obtained as a white solid (808 mg, 3.48
mmol, 75% yield).
[0343] .sup.1H NMR (400 MHz, DMSO): 12.22 (br s, 1H), 7.61-7.42 (m,
5H), 3.36 (s, 3H), 2.59 (s, 3H).
Preparation Example 2
2-(4-Fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic
acid
##STR00016##
[0344]
2-(4-Fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-car-
boxylic acid, which is one of the common intermediates used in the
synthesis of compounds of the present invention, was prepared as
follows:
##STR00017##
(Step 1) 2-(4-fluorophenyl)-5-methyl-1H-pyrazol-3(2H)-one
##STR00018##
[0346] (4-Fluorophenyl)hydrazine hydrochloride (20.0 g, 0.123 mol)
was added to a solution of triethylamine (20.5 mL) in methanol (350
mL). Then, a solution of ethyl acetoacetate (16.0 g, 0.123 mol) in
methanol (50 mL) was added. The resulting reaction mixture was
stirred for 4 hours under reflux and extracted with dichloromethane
and sodium chloride aqueous solution. The aqueous layer was
extracted again with dichloromethane. All the organic layers were
collected, dried with Na.sub.2SO.sub.4 and then filtered. The
filtrate was concentrated. The resulting residue was purified by
silica gel chromatography (ethyl acetate:hexane=1:2). The target
compound was yielded (21.0 g, 89% yield).
[0347] MS (ESI pos. ion) m/z: 193 (MH.sup.+). Calc'd exact mass for
C.sub.10H.sub.9FN.sub.2O: 192.07.
[0348] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.84-7.81 (m, 2H),
7.09-7.05 (m, 2H), 3.43 (s, 1H), 3.07 (br s, 1H), 2.19 (s, 3H).
(Step 2)
benzyl-2-(4-fluorophenyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazole--
4-carboxylate
##STR00019##
[0350] 2-(4-Fluorophenyl)-5-methyl-1H-pyrazol-3(2H)-one (20.3 g,
0.105 mol) and calcium hydroxide (17.2 g, 0.232 mol) were suspended
in anhydrous 1,4-dioxane (200 mL). The resulting suspension was
heated at 50.degree. C. for 20 minutes. The heated suspension was
cooled to 10.degree. C. and a solution of benzyl chloroformate
(14.9 mL, 0.105 mol) in dioxane (10 mL) was added. The resulting
reaction mixture was heated at 90.degree. C. for 3 hours. Upon
completion of the reaction, the reaction mixture was slowly cooled
to 0.degree. C. After adding 1 M hydrochloric acid, the mixture was
stirred at room temperature overnight. Then, the produced solid was
collected by filtration, washed with cold ethanol and ether, and
dried in vacuum to give the target compound (22.88 g, 66%
yield).
[0351] MS (ESI pos. ion) m/z: 327 (MH.sup.+). Calc'd exact mass for
C.sub.18H.sub.15FN.sub.2O.sub.3: 326.11.
[0352] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.82-7.79 (m, 2H),
7.40-7.29 (m, 5H), 7.09-7.04 (m, 2H), 5.30 (s, 1H), 5.19 (s, 1H),
2.38 (s, 3H).
(Step 3)
benzyl2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazo-
le-4-carboxylate
##STR00020##
[0354] To a solution of benzyl
2-(4-fluorophenyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate
(8.0 g, 0.024 mol) in dichloromethane (80 mL), methyl
trifluoromethanesulfonate (4.8 g, 0.029 mol) was added and stirred
at room temperature for 29 hours. The resulting mixture was
extracted with dichloromethane and saturated baryta water. After
phase separation, the aqueous layer was extracted again with
dichloromethane. All the organic layers were collected, dried with
Na.sub.2SO.sub.4 and then filtered. The filtrate was concentrated
under reduced pressure. The resulting residue was purified by
silica gel chromatography (ethyl acetate:hexane=4:1) to give the
target compound (2.69 g, 32% yield).
[0355] MS (ESI pos. ion) m/z: 341 (MH.sup.+). Calc'd exact mass for
C.sub.19H.sub.17FN.sub.2O.sub.3: 340.12.
[0356] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.51-7.48 (m, 2H),
7.35-7.26 (m, 5H), 7.19-7.15 (m, 2H), 5.33 (s, 1H), 3.28 (s, 3H),
2.62 (s, 3H).
(Step 4)
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-c-
arboxylic acid
##STR00021##
[0358] To a solution of benzyl
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxyla-
te (2.6 g, 7.64 mmol) in methanol (25 mL), Pd/C (0.5 g) was added.
While blowing in hydrogen gas, the mixture was stirred for 8 hours.
The resulting reaction mixture was filtered by passing through a
celite pad. The filtrate was concentrated under reduced pressure.
The target compound was yielded (1.8 g, 94% yield).
[0359] MS (ESI pos. ion) m/z: 251 (MH.sup.+). Calc'd exact mass for
C.sub.12H.sub.11FN.sub.2O.sub.3: 250.08.
[0360] .sup.1H NMR (400 MHz, CDCl.sub.3): 11.94 (br s, 1H),
7.36-7.32 (m, 2H), 7.27-7.22 (m, 2H), 3.36 (s, 3H), 2.69 (s,
3H).
Example 1
N-(4-(5-Bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimethyl-
-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00022##
[0362] The target compound was prepared as follows:
##STR00023## ##STR00024##
(Step 1) N-aminophthalimide
##STR00025##
[0364] Phthalimide powder was added to a solution of hydrazine
monohydrate (28.9 mL, 462.4 mmol) in ethanol (415 mL). The
resulting solution was stirred at room temperature for 2 minutes
and then stirred under reflux for 8 minutes. The resulting mixture
was added to icy water to precipitate solid. The resulting solid
was filtered, collected, washed with a small volume of water, and
then dried in vacuum. The target compound was yielded as white
solid (29.5 g, 182.1 mmol, 42% yield).
[0365] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.88-7.86 (m, 2H),
7.76-7.73 (m, 2H), 4.14 (br s, 2H).
(Step 2) 1-phthalimidopyrrole
##STR00026##
[0367] A solution of N-aminophthalimide (29.0 g, 178.8 mmol) and
2,5-dimethoxytetrahydrofuran (24.2 mL, 187.8 mmol) in anhydrous
dioxane (290 mL) was stirred under reflux. While heating so that
the resulting solution remained yellow, 5 N hydrochloric acid
solution was cautiously added. The resulting mixture was allowed to
cool to room temperature. The produced solid was filtered and
washed with a 1:3 solution of dioxane and water. The target
compound was yielded as a white solid (34.9 g, 164.5 mmol, 92%
yield).
[0368] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.02-7.96 (m, 2H),
7.88-7.83 (m, 2H), 6.75-6.74 (m, 2H), 6.37-6.35 (m, 2H).
(Step 3) N-aminopyrrole
##STR00027##
[0370] Hydrazine monohydrate (8.8 ml, 144.8 mmol) was added to a
solution of 1-phthalimidopyrrole (25.6 g, 120.6 mmol) in methanol
(500 mL) and stirred for 1 hour under reflux. The resulting
reaction mixture was cooled to room temperature and stirred for 15
minutes under reflux after cautiously adding acetic acid. The
resulting solution was filtered and methanol was removed by
distillation. The resulting residue was extracted with
dichloromethane after adding 40% sodium hydroxide aqueous solution.
Then, the extract was concentrated and the remaining residue was
purified by vacuum distillation. The target compound was yielded
(6.5 g, 79.2 mmol, 66% yield).
[0371] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.70-6.68 (m, 2H),
6.05-6.03 (m, 2H), 4.84 (br s, 2H).
(Step 4) ethyl
4-oxo-1,4-dihydropyrrole[1,2-b]pyridazin-3-carboxylate
##STR00028##
[0373] A mixture of N-aminopyrrole (6.2 g, 75.5 mmol) and diethyl
ethoxymethylenemalonate (18.2 mL, 90.6 mmol) was heated at
125.degree. C. for 2 hours to give diethyl
2-((1H-pyrrol-1-ylamino)methylene)malonate as an intermediate and
then diphenyl ether (22 mL) was added thereto. The resulting
reaction mixture was heated under nitrogen atmosphere at
220.degree. C. for 2 hours and ethanol produced during the reaction
was removed by distillation. The reaction mixture with ethanol
removed was cooled to room temperature and purified by silica gel
chromatography. The target compound was yielded as a yellow solid
(11.0 g, 53.3 mmol, 71% yield).
[0374] .sup.1H NMR (400 MHz, CDCl.sub.3): 12.34 (br s, 1H), 8.29
(s, 1H), 7.44 (dd, J=2.8 Hz, 1.6 Hz, 1H), 6.97 (dd, J=4.4 Hz, 1.6
Hz, 1H), 6.78-6.76 (m, 1H).
(Step 5) 4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylic
acid
##STR00029##
[0376] 2 M sodium hydroxide aqueous solution was added to a
suspension of ethyl
4-oxo-1,4-dihydropyrrolo[1,2,b]pyridazin-3-carboxylate in ethanol
(165 mL) and stirred overnight at 100.degree. C. The resulting
reaction mixture was cooled to room temperature, distilled under
reduced pressure, and concentrated. Then, concentrated hydrochloric
acid was added until pH decreased to 2. Thereafter, the solid was
filtered, washed with water and dried in vacuum. The target
compound obtained was subjected to the next step without further
purification.
(Step 6) pyrrolo[1,2-b]pyridazin-4(1H)-one
##STR00030##
[0378] 4-Oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylic acid
was dissolved in dimethyl sulfoxide (110 mL) and heated at
150.degree. C. for 1 hour. After removing the solvent by
distillation under reduced pressure, the resulting residue was
purified by silica gel chromatography (5% ethyl acetate in
dichloromethane) to give the target compound (5.3 g, 39.5 mmol, 74%
yield).
[0379] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.88 (d, J=5.2 Hz, 1H),
7.74-7.72 (m, 1H), 6.78-6.75 (m, 1H), 6.65-6.63 (m, 1H), 5.99 (d,
J=5.2 Hz, 1H).
(Step 7) 4-(t-butyldimethylsilyloxy)pyrrolo[1,2-b]pyridazine
##STR00031##
[0381] Pyrrolo[1,2-b]pyridazin-4(1H)-one (2.0 g, 14.9 mmol) and
t-butyldimethylsilyl chloride (2.7 g, 17.9 mmol) were dissolved in
anhydrous toluene under nitrogen atmosphere. After adding
triethylamine (3.1 mL, 22.4 mmol), the mixture was stirred for 1
hour under reflux. Upon completion of the reaction, the produced
solid was filtered and washed with a small volume of toluene. The
filtrate was concentrated by distillation under reduced pressure.
The resulting residue was subjected to the next step without
further purification.
(Step 8) 4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-b]pyridazine
##STR00032##
[0383] Water (0.05 mL, 2.68 mmol), 3,4-difluoronitrobenzene (1.65
mL, 14.9 mmol) and 1,8-diazabicyclo[5,4,0]-undec-7-ene (0.27 mL,
1.79 mmol) were sequentially added to a solution of
4-(t-butyldimethylsilyloxy)pyrrolo[1,2-b]pyridazines in dimethyl
sulfoxide (55 mL). The resulting mixture was heated to 80.degree.
C. and stirred until 3,4-difluoronitrobenzene disappeared. Upon
completion of the reaction, the mixture was extracted with
dichloromethane and sodium chloride aqueous solution. The organic
layer was separated, dried with anhydrous magnesium sulfate, and
then filtered. The filtrate was concentrated by distillation under
reduced pressure. The resulting residue was purified by silica gel
chromatography (10% ethyl acetate in n-hexane) to give the target
compound as a yellow solid (2.65 g, 9.70 mmol, 65% yield).
[0384] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.19-8.11 (m, 2H), 7.92
(d, J=5.2 Hz, 1H), 7.82 (dd, J=2.8 Hz, 1.6 Hz, 1H), 7.39 (dd, J=8.8
Hz, 7.6 Hz, 1H), 6.85 (dd, J=4.4 Hz, 2.4 Hz, 1H), 6.67 (dd, J=4.4
Hz, 1.6 Hz, 1H), 5.83 (d, J=5.2 Hz, 1H).
(Step 9)
5-bromo-4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-b]pyridazine
##STR00033##
[0386] N-Bromosuccinimide (1.49 g, 8.42 mmol) was added to a
solution of 4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-b]pyridazine
(2.30 g, 8.42 mmol) in anhydrous chloroform (70 mL) at 0.degree. C.
and stirred for 4 hours. Upon completion of the reaction, the
resulting mixture was washed by adding water thereto. The organic
layer was separated, dried with magnesium sulfate, and then
filtered. The filtrate was concentrated by distillation under
reduced pressure. The resulting residue was purified by silica gel
chromatography (10% ethyl acetate in n-hexane) to give the target
compound as a yellow solid (840 mg, 2.39 mmol, 28% yield).
[0387] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.19-8.12 (m, 8H), 7.89
(d, J=5.2 Hz, 1H), 7.74 (d, J=5.2 Hz, 1H), 7.35 (dd, J=8.8 Hz, 7.6
Hz, 1H), 6.86 (dd, J=3.2 Hz, 0.4 Hz, 1H), 5.84 (dd, J=5.2 Hz, 0.8
Hz, 1H).
(Step 10)
4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluoroaniline
##STR00034##
[0389] Methanol (1.2 mL), zinc powder (300 mg, 4.57 mmol) and
ammonium chloride (130 mg, 2.47 mmol) were sequentially added to a
solution of
5-bromo-4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-b]pyridazine (67 mg,
0.19 mmol) in tetrahydrofuran (4.7 mL) and heated at 70.degree. C.
for 1.5 hours. Upon completion of the reaction, the resulting
reaction mixture was cooled to room temperature and filtered by
passing through a celite pad. The filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (1-6% ethyl acetate in dichloromethane) to give the
target compound (57 mg, 0.178 mmol, 93% yield).
[0390] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.77 (d, J=5.2 Hz, 1H),
7.65 (d, J=2.8 Hz, 1H), 7.05 (t, J=8.8 Hz, 1H), 6.79 (dd, J=2.8 Hz,
0.4 Hz, 1H), 6.56-6.46 (m, 2H), 5.66 (dd, J=5.2 Hz, 1.2 Hz, 1H),
3.81 (br s, 2H).
(Step 11)
N-(4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,-
5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00035##
[0392] To a solution of
4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluoroaniline (57 mg,
0.178 mmol) and
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxyli- c
acid (124 mg, 0.534 mmol) prepared in Preparation Example 1 in
dimethylformamide (2 mL), HATU (270 mg, 0.711 mmol) and
triethylamine (0.1 mL, 0.711 mmol) were sequentially added and
stirred at 50.degree. C. overnight. The resulting reaction mixture
was concentrated under reduced pressure and the resulting residue
was extracted with dichloromethane and water. The organic layer was
separated, dried with magnesium sulfate, and then filtered. The
filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (10% ethyl
acetate in dichloromethane) to give the target compound as a white
solid (60 mg, 0.111 mmol, 63% yield).
[0393] MS (ESI pos. ion) m/z: 536, 538 (MH.sup.+). Calc'd exact
mass for C.sub.25FN.sub.19Br.sub.79FN.sub.5O.sub.3: 535, Calc'd
exact mass for C.sub.25H.sub.19Br.sub.81FN.sub.5O.sub.3: 537.
[0394] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.89 (br s, 1H), 7.91
(dd, J=12.4 Hz, 2.4 Hz, 1H), 7.78 (d, J=5.6 Hz, 1H), 7.65 (d, J=2.8
Hz, 1H), 7.59-7.54 (m, 2H), 7.52-7.46 (m, 1H), 7.38-7.35 (m, 2H),
7.31-7.28 (m, 1H), 7.19 (t, J=8.8 Hz, 1H), 6.80 (d, J=2.8 Hz, 1H),
5.67 (dd, J=5.6 Hz, 1.2 Hz, 1H), 3.38 (s, 3H), 2.80 (s, 3H).
Example 2
N-(3-Fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxo)phenyl)-1,5-dimethy-
l-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00036##
[0396] To a solution of
N-(4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimethy-
l-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (50 mg,
6.093 mmol) prepared in Example 1 and phenylboronic acid (45 mg,
0.373 mmol) dissolved in dioxane (0.8 mL), 1 M potassium carbonate
aqueous solution (0.4 mL, 0.373 mmol) and Pd(PPh.sub.3).sub.4 (11
mg, 0.009 mmol) were sequentially added. The resulting reaction
mixture was stirred at 80.degree. C. for 2 hours. The resulting
mixture was extracted with dichloromethane and water. The organic
layer was separated, dried with magnesium sulfate, and then
filtered. The filtrate was concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography (10%
ethyl acetate in dichloromethane) to give the target compound as a
yellow solid (36 mg, 0.067 mmol, 72% yield).
[0397] MS (ESI pos. ion) m/z: 534 (MH.sup.+). Calc'd exact mass for
C.sub.31H.sub.24FN.sub.5O.sub.3: 533.
[0398] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.84 (br s, 1H), 7.87
(dd, J=12.8 Hz, 2.4 Hz, 1H), 8.83-7.79 (m, 2H), 7.66-7.44 (m, 5H),
7.37-7.32 (m, 4H), 7.24-7.20 (m, 2H), 7.07 (t, J=8.8 Hz, 1H), 6.88
(d, J=2.8 Hz, 1H), 5.68 (d, J=5.2 Hz, 1H), 3.37 (s, 3H), 2.79 (s,
3H).
Example 3
N-(3-Fluoro-4-(5-(4-fluorophenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1-
,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00037##
[0400] The target compound
N-(3-fluoro-4-(5-(4-fluorophenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 2, except for using
4-fluorophenylboronic acid (0.373 mmol) instead of phenylboronic
acid.
[0401] MS (ESI pos. ion) m/z: 552 (MH.sup.+). Calc'd exact mass for
C.sub.31H.sub.23F.sub.2N.sub.5O.sub.3: 551.
[0402] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.85 (br s, 1H), 7.88
(dd, J=12.4 Hz, 2.4 Hz, 1H), 7.81 (dd, J=5.2 Hz, 0.4 Hz, 1H), 7.79
(d, J=2.8 Hz, 1H), 7.61-7.52 (m, 4H), 7.50-7.45 (m, 1H), 7.37-7.35
(m, 2H), 7.25-7.21 (m, 1H), 7.08-7.00 (m, 3H), 6.84 (dd, J=2.4 Hz,
0.4 Hz, 1H), 5.68 (dd, J=5.2 Hz, 1.2 Hz, 1H), 3.71 (s, 3H), 2.79
(s, 3H).
Example 4
N-(3-Fluoro-4-(5-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00038##
[0404] The target compound
N-(3-fluoro-4-(5-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-
-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 2, except for using
4-methoxyphenylboronic acid (0.373 mmol) instead of phenylboronic
acid.
[0405] MS (ESI pos. ion) m/z: 564 (MH.sup.+). Calc'd exact mass for
C.sub.32H.sub.26FN.sub.5O.sub.4: 563.
[0406] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.84 (br s, 1H), 7.87
(dd, J=12.4 Hz, 2.8 Hz, 1H), 7.79 (d, J=5.2 Hz, 1H), 7.77 (d, J=2.8
Hz, 1H), 7.59-7.53 (m, 4H), 7.50-7.44 (m, 1H), 7.38-7.34 (m, 2H),
7.26-7.21 (m, 1H), 7.07 (t, J=8.8 Hz, 1H), 6.91-6.88 (m, 2H), 6.83
(d, J=2.4 Hz, 1H), 5.65 (dd, J=5.2 Hz, 1.2 Hz, 1H), 3.81 (s, 3H),
3.37 (s, 3H), 2.79 (s, 3H).
Example 5
N-(3-Fluoro-4-(5-(3-fluorophenyl)pyrrolo[1,2-b]pyridazin-4-yloxo)phenyl)-1-
,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00039##
[0408] The target compound
N-(3-fluoro-4-(5-(4-fluorophenyl)pyrrolo[1,2-b]Pyridazin-4-yloxy)phenyl)--
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 2, except for using
3-fluorophenylboronic acid (0.373 mmol) instead of phenylboronic
acid.
[0409] MS (ESI pos. ion) m/z: 552 (MH.sup.+). Calc'd exact mass for
C.sub.31H.sub.23F.sub.2N.sub.5O.sub.3: 551.
[0410] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.85 (br s, 1H), 7.88
(dd, J=12:4 Hz, 2.4 Hz, 1H), 7.84 (d, J=5.6 Hz, 1H), 7.80 (d, J=2.8
Hz, 1H), 7.59-7.54 (m, 2H), 7.50-7.46 (m, 1H), 7.43-7.40 (m, 1H),
7.37-7.22 (m, 5H), 7.08 (t, J=8.8 Hz, 1H), 6.94-6.87 (m, 1H), 6.88
(d, J=3.2 Hz, 1H), 5.72 (dd, J=5.6 Hz, 1.2 Hz, 1H), 3.37 (s, 3H),
2.79 (s, 3H).
Example 6
N-(3-Fluoro-4-(5-(3-methoxyphenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00040##
[0412] The target compound
N-(3-fluoro-4-(5-(4-methoxyphenyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-
-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 2, except for using
3-methoxyphenylboronic acid (0.373 mmol) instead of phenylboronic
acid.
[0413] MS (ESI pos. ion) m/z: 564 (MH.sup.+). Calc'd exact mass for
C.sub.32H.sub.26FN.sub.5O.sub.4: 563.
[0414] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.85 (br s, 1H), 7.89
(dd, J=12.4 Hz, 2.4 Hz, 1H), 7.82 (d, J=5.6 Hz, 1H), 7.79 (d, J=2.8
Hz, 1H), 7.58-7.54 (m, 2H), 7.50-7.47 (m, 1H), 7.37-7.34 (m, 2H),
7.26-7.21 (m, 4H), 7.07 (t, J=8.8 Hz, 1H), 6.90 (d, J=2.8 Hz, 1H),
6.81-6.78 (m, 1H), 5.68 (dd, J=5.2 Hz, 1.2 Hz, 1H), 3.78 (s, 3H),
3.72 (s, 3H), 2.79 (s, 3H).
Example 7
N-(4-(5-Bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluorop-
henyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00041##
[0416] The target compound
N-(4-(5-bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluoro-
phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 1, except for using
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxyli-
c acid prepared in Preparation Example 2 instead of
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic in
Step 11 of Example 1.
[0417] MS (ESI pos. ion) m/z: 554 (MH.sup.+). Calc'd exact mass for
C.sub.25H.sub.18BrF.sub.2N.sub.5O.sub.3: 553.
[0418] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.81 (br s, 1H), 7.91
(dd, J=12.4 Hz, 2.4 Hz, 1H), 7.78 (d, J=5.2 Hz, 1H), 7.65 (d, J=3.2
Hz, 1H), 7.37-7.33 (m, 2H), 7.31-7.17 (m, 4H), 6.80 (d, J=3.2 Hz,
1H), 5.67 (dd, J=5.2 Hz, 1.2 Hz, 1H), 3.36 (s, 3H), 2.80 (s,
3H).
Example 8
N-(3-Fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluoro-
phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00042##
[0420] The target compound
N-(3-fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluor-
ophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 2.
[0421] MS (ESI pos. ion) m/z: 552 (MH.sup.+). Calc'd exact mass for
C.sub.nH.sub.23F.sub.2N.sub.5O.sub.3: 551.
[0422] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.77 (br s, 1H), 7.86
(dd, J=12.4 Hz, 2.4 Hz, 1H), 8.83-7.79 (m, 2H), 7.75-7.72 (m, 1H),
7.66-7.63 (m, 2H), 7.43-7.32 (m, 5H), 7.28-7.20 (m, 2H), 7.06 (t,
J=8.8 Hz, 1H), 6.89 (d, J=2.8 Hz, 1H), 5.68 (dd, J=5.2 Hz, 0.8 Hz,
1H), 3.35 (s, 3H), 2.79 (s, 3H).
Example 9
1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid
[3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)-phenyl]-amide
##STR00043##
[0424] To a solution of
3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)-phenylamine (50 mg,
0.206 mmol) and
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxyli- c
acid (32 mg, 0.137 mmol) dissolved in dimethylformamide (3 mL),
HATU (78 mg, 0.206 mmol) and triethylamine (0.05 mL, 0.343 mmol)
were sequentially added and heated at 50.degree. C. for 7 hours.
The resulting mixture was concentrated and the resulting residue
was extracted with dichloromethane and water. After phase
separation, the organic layer was washed with sodium chloride
aqueous solution, dried with magnesium sulfate, and then filtered.
The filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (ethyl
acetate:hexane=1:3) to give the target compound as a white solid
(16 mg, 0.04 mmol, 25% yield).
[0425] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.88 (br S, 1H) 7.90
(dd, J=12.8 Hz, 2.4 Hz, 1H), 7.83 (d, J=5.6 Hz, 1H), 7.74 (dd,
J=2.4 Hz, 1.6 Hz, 1H), 7.59-7.36 (m, 5H), 7.29 (m, J=8.8 Hz, 2.4
Hz, 1.2 Hz, 1H), 7.17 (t, J=8.8 Hz, 1H), 6.81 (dd, J=4.4 Hz, 2.4
Hz, 1H), 5.69 (d, J=5.2 Hz, 1H), 3.38 (s, 3H), 2.80 (s, 3H). MS
(ESI pos. ion) m/z: 458 (MH.sup.+), Calc'd exact mass for
C.sub.25H.sub.20FN.sub.5O.sub.3: 457.16.
Example 10
1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid
[3-fluoro-4-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenyl]-amide
##STR00044##
[0427] The target compound was prepared as follows:
##STR00045##
(Step 1)
4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]py-
ridine
##STR00046##
[0429] 4-Chloro-1H-pyrrolo[2,3-b]pyridine (170 mg, 1.114 mmol) was
dissolved in tetrahydrofuran (2 mL) under nitrogen atmosphere.
After cooling to 0.degree. C., 40% NaH (30 mg, 1.224 mmol) was
added. The resulting reaction mixture was stirred for 15 minutes
and then heated at 80.degree. C. for 3 hours after adding SEM-Cl
(185 mg, 1.114 mmol). The heated reaction mixture was cooled to
room temperature and then extracted with dichloromethane and water.
The organic layer was separated and washed with sodium chloride
aqueous solution. The organic layer was dried with magnesium
sulfate and then filtered. The filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (ethyl acetate:hexane=1:1) to give the target
compound as a yellow oil (235 mg, 0.83 mmol, 74% yield).
[0430] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.22 (d, J=5.2 Hz, 1H),
7.38 (d, J=3.6 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 6.6 (d, J=3.6 Hz,
1H), 5.67 (s, 2H), 3.53 (t, J=8 Hz, 2H), 0.90 (t, J=8 Hz, 2H),
-0.07 (s, 9H).
(Step 2)
4-chloro-2-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,-
3-b]pyridine
##STR00047##
[0432]
4-Chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyrid-
ine (235 mg, 0.831 mmol) was dissolved in tetrahydrofuran (3 mL)
under nitrogen atmosphere. After cooling to -78.degree. C.,
n-butyllithium (0.675 mL, 1.080 mmol, 1.6 M hexane solution) was
slowly added dropwise. The resulting mixture was stirred for 1
hour. After adding a solution of iodine (253 mg, 0.997 mmol) in
tetrahydrofuran (2 mL), the mixture was slowly heated to room
temperature. One hour later, the mixture was extracted with
dichloromethane and water and the organic layer was washed with
sodium chloride aqueous solution. The organic layer was dried with
magnesium sulfate and then filtered. The filtrate was concentrated
under reduced pressure. The resulting residue was purified by
silica gel chromatography (hexane:ethyl acetate=9:1) to give the
target compound as a yellow oil (339 mg, 0.83 mmol, 97% yield).
(Step 3)
4-chloro-2-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[-
2,3-b]pyridine
##STR00048##
[0434]
4-Chloro-2-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3--
b]pyridine (329 mg, 0.805 mmol) and phenylboronic acid (118 mg,
0.966 mmol) were dissolved in dioxane and then Pd(PPh.sub.3).sub.4
(46 mg, 0.04 mmol) was added. After adding 1 M potassium carbonate
aqueous solution (1.61 mL), the resulting reaction mixture was
stirred at 80.degree. C. for 2 hours. The reaction mixture was
extracted with dichloromethane and water. The organic layer was
washed with sodium chloride aqueous solution, dried with magnesium
sulfate, and then filtered. The filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=9:1) to give the target
compound as a yellow oil (182 mg, 0.51 mmol, 63% yield).
[0435] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.22 (d, J=4.8 Hz, 1H),
7.80-7.43 (m, 5H), 7.14 (d, J=4.8 Hz, 1H), 6.69 (s, 1H), 5.66 (s,
2H), 3.72 (t, J=8.4 Hz, 2H), 0.95 (t, J=8.4 Hz, 2H), 0.04 (s,
9H).
(Step 4)
3-fluoro-4-[2-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrro-
lo[2,3-b]pyridin-4-yloxy]-phenyl-carbamic acid t-butyl ester
##STR00049##
[0437]
4-Chloro-2-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,-
3-b]pyridine (312 mg, 0.87 mmol) and
(3-fluoro-4-hydroxy-phenyl)-carbamic acid t-butyl ester (336 mg,
1.48 mmol) were dissolved in anhydrous toluene (5 mL) under
nitrogen atmosphere. After adding
dicyclohexyl-phosphino-2,4,6-triisopropylbiphenyl (41 mg, 0.087
mmol), Pd.sub.2 dba.sub.3 (40 mg, 0.044 mmol) and potassium
carbonate, the mixture was heated at 110.degree. C. The resulting
reaction mixture was cooled to room temperature and filtered by
passing through a celite pad. The filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (hexane:ethyl acetate=9:1) to give the target
compound as a white solid (404 mg, 0.73 mmol, 84% yield).
[0438] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.16 (d, J=5.6 Hz, 1H),
7.77-7.741 (m, 6H), 7.16 (t, J=8.8 Hz, 1H), 7.04-7.01 (m, 1H), 6.57
(s, 1H), 6.53 (br s, 1H), 6.43 (dd, J=4.8, 1H), 5.66 (s, 2H), 3.73
(t, J=8.4 Hz, 2H), 1.54 (s, 9H), 0.96 (t, J=8.4 Hz, 2H), -0.04 (s,
9H).
(Step 5)
3-fluoro-4-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenylamin-
e
##STR00050##
[0440] To a solution of
3-fluoro-4-[2-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b-
]pyridin-4-yloxy]-phenyl-carbamic acid t-butyl ester in methanol, a
1:1 solution (10 mL) of hydrochloric acid and methanol was added.
The mixture was stirred at room temperature for 4 hours. The
resulting reaction mixture was concentrated under reduced pressure
and ether was added to the resulting residue. After stirring for 2
hours, the produced solid was collected by filtering. Thus obtained
hydrochloride was dissolved in water and neutralized to about pH 8
by adding 1M sodium hydroxide aqueous solution. The resulting
mixture was extracted with ethyl acetate. The organic layer was
separated and washed with sodium chloride aqueous solution. The
organic layer was dried with Na.sub.2SO.sub.4 and then filtered.
The filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (hexane:ethyl
acetate=1:1) to give the target compound as a white solid (81 mg,
0.25 mmol, 40% yield).
[0441] .sup.1H NMR (400 MHz, DMSO): 12.21 (br s, 1H), 8.04 (d,
J=5.6 Hz, 1H), 7.93-7.32 (m, 5H), 7.05 (t, J=8.8 Hz, 1H), 6.85 (d,
J=2.0 Hz, 1H), 6.54 (dd, J=13.2 Hz, 2.4 Hz, 1H), 6.45 (m, J=10 Hz,
1.6 Hz, 0.8 Hz, 1H), 6.25 (m, 1H), 5.45. (s, 2H).
(Step 6)
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid
[3-fluoro-4-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenyl]-amid-
e
##STR00051##
[0443]
3-Fluoro-4-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenylamine
(80 mg, 0.25 mmol),
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid (72 mg, 0.31 mmol) and HATU (190 mg, 0.5 mmol) were dissolved
in dimethylformamide (3 mL). After adding triethylamine (0.04 mL,
0.5 mmol), the mixture was heated at 50.degree. C. for 7 hours. The
resulting reaction mixture was extracted with dichloromethane and
water. The organic layer was washed with sodium chloride aqueous
solution, dried with magnesium sulfate, and then filtered. The
filtrate was concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (hexane:ethyl
acetate=1:1) to give the target compound as a white solid (12 mg,
0.02 mmol, 9% yield).
[0444] .sup.1H NMR (400 MHz, DMSO): 12.29 (br s, 1H), 10.95 (br s,
1H), 8.08 (d, J=5.6 Hz, 1H), 7.98 (d, J=2.4, 1H), 7.94 (m, 2H),
7.60 (m, 2H), 7.52 (m, 1H), 7.46 (m, 4H), 7.33 (m, 3H), 6.89 (d,
J=2.0 Hz, 1H), 6.35 (d, J=5.6, 1H), 3.38 (s, 3H), 2.71 (s, 3H). MS
(ESI pos. ion) m/z: 534, Calc'd exact mass for
C.sub.31H.sub.24FN.sub.5O.sub.3: 533.55.
Example 11
2-(4-Fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxyli-
c acid
[3-fluoro-4-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenyl]-amide
##STR00052##
[0446] The target compound was prepared in the same manner as
Example 10, except for using
1,5-dimethyl-3-oxo-2-3-fluorophenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid (0.31 mmol) instead of
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid (0.31 mmol) in Step 6 of Example 10.
[0447] MS (ESI pos. ion) m/z: 552 (MH.sup.+). Calc'd exact mass for
C.sub.31H.sub.23F.sub.2N.sub.5O.sub.3: 551.
[0448] .sup.1H NMR (400 MHz, DMSO): 10.90 (s, 1H), 8.16 (d, J=5.6
Hz, 1H), 7.93 (dd, J=13.2 Hz, 2.4 Hz, 1H), 7.71 (s, 1H), 7.68-7.65
(m, 2H), 7.53-7.49 (m, 2H), 7.46-7.42 (m, 2H), 7.38-7.32 (m, 3H),
7.29-7.27 (m, 1H), 7.25-7.21 (m, 1H), 6.37 (d, J=5.6 Hz, 1H), 5.67
(s, 1H), 3.36 (s, 3H), 2.69 (s, 3H).
Example 12
2-(4-Fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxyli-
c acid
[3-fluoro-4-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenyl]-ami-
de
##STR00053##
[0450] The target compound was prepared in the same manner as
Example 10.
[0451] MS (ESI pos. ion) m/z: 552 (MH.sup.+), Calc'd exact mass for
C.sub.31H.sub.23F.sub.2N.sub.5O.sub.3: 551.
[0452] .sup.1H NMR (400 MHz, DMSO): 12.29 (br s, 1H), 10.92 (br s,
1H), 8.08 (d, J=5.6 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.94-7.92 (m,
2H), 7.54-7.30 (m, 9H), 6.89 (s, 1H), 6.35 (d, J=5.6 Hz, 1H), 3.37
(s, 3H), 2.70 (s, 3H).
Example 13
N-(3-Fluoro-4-(pyrrolo[1,2-f][1, 2,
4]triazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihyd-
ro-1H-pyrazole-4-carboxamide
##STR00054##
[0454] The target compound was prepared as follows:
##STR00055##
(Step 1) methyl-amino-1H-pyrrolo-2-carboxylate
##STR00056##
[0456] To a mixture of NaH (60%, 4.1 g, 102.2 mmol) suspended in
dimethylformamide (120 mL) at 0.degree. C. under nitrogen
atmosphere, methyl pyrrolo-1-H-2-carboxylate (8.0 g, 63.9 mmol) was
slowly added over minutes. After stirring for 1 hour, a solution of
2,4-dinitrophenolamine (19.1 g, 95.9 mmol) in dimethylformamide (30
mL) was added dropwise for 30 minutes. The resulting reaction
mixture was stirred at 0.degree. C. for 2.5 hours. The reaction was
completed by slowly adding saturated sodium thiosulfate aqueous
solution. The resulting mixture was extracted with ethyl acetate.
The organic layer was washed with 10% lithium chloride aqueous
solution, dried with sodium sulfate, and then filtered. The
filtrate was concentrated. The resulting brown residue was purified
by silica gel chromatography (10% ethyl acetate in hexane) to give
the target compound as an oil (7.5 g, 53.5 mmol, 84% yield).
[0457] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.96 (t, J=2.4 Hz, 1H),
6.83 (dd, J=4.4 Hz, 2.0 Hz, 1H), 6.02 (dd, J=4.4 Hz, 2.8 Hz, 1H)
5.54 (br s, 2H), 3.83 (s, 3H).
(Step 2) pyrrolo[1,2-f]1,2,4]triazin-4(3H)-one
##STR00057##
[0459] Methyl 1H-pyrrole-2-carboxylate (7.5 g, 53.5 mmol) was
dissolved in formamide (30 mL). After heating at 170.degree. C. for
1 hour, the mixture was further heated at 190.degree. C. for 2
hours. The resulting reaction mixture was cooled to room
temperature. The produced solid was recrystallized with ethyl
acetate to give the target compound as a white solid (5.0 g, 37.0
mmol, 69% yield).
[0460] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.57 (s, 1H), 7.47 (dd,
J=2.8 Hz, 1.6 Hz, 1H), 7.10 (dd, J=4.4 Hz, 1.6 Hz, 1H), 7.47 (dd,
J=4.4 Hz, 2.8 Hz, 1H).
(Step 3) 4-chloropyrrolo[1,2-f][1,2,4]triazine
##STR00058##
[0462] Diisopropylethylamine (3.5 mL, 20.3 mmol) was added to a
solution of pyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (2.5 g, 18.5
mmol) dissolved in toluene (37.5 mL) under nitrogen atmosphere.
Subsequently, after adding phosphorus oxychloride (5.1 mL, 55.7
mmol), the mixture was heated for 20 hours at 100.degree. C. The
resulting reaction mixture was cooled to 0.degree. C. and, after
slowly adding sodium bicarbonate aqueous solution, stirred at room
temperature for 30 minutes. The resulting aqueous layer was
extracted with ethyl acetate, dried with magnesium sulfate, and
then filtered. The filtrate was concentrated in vacuum. The
resulting yellow solid product was subjected to the next step
without purification (2.31 g, 15.0 mmol, 81% yield).
[0463] .sup.1H NMR (400 MHz, CDCl.sub.3): (s, 1H), 7.87 (dd, J=2.4
Hz, 1.6 Hz, 1H), 7.00-6.97 (m, 2H).
(Step 4)
4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-f][1,2,4]triazine
##STR00059##
[0465] A solution of 4-chloropyrrolo[1,2-f][1,2,4]triazine (4.30 g,
28.0 mmol), 2-fluoro-4-nitrophenol (5.28 g, 33.6 mmol) and
potassium carbonate (7.74 g, 56.0 mmol) added to anhydrous
N-dimethylformamide (60 mL) under nitrogen atmosphere was heated at
60.degree. C. for 1 hour and 20 minutes. The resulting mixture was
allowed to cool to room temperature and then extracted with ethyl
acetate. The resulting extract was concentrated and purified by
silica gel chromatography (25% ethyl acetate inn-hexane) to give
the target compound as a white solid (5.50 g, 20.0 mmol, 72%
yield).
[0466] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.21-8.14 (m, 2H), 7.97
(s, 1H), 7.86 (dd, J=2.8 Hz, 1.2 Hz, 1H) 7.54 (t, J=8.0 Hz, 1H),
7.07 (dd, J=4.4 Hz, 1.2 Hz, 1H), 6.93 (dd, J=4.4 Hz, 2.8 Hz,
1H).
(Step 5)
3-fluoro-4-(pyrrolo[1,2-f][1,2,4]triazin-4-yloxy)aniline
##STR00060##
[0468] 4-(2-Fluoro-4-nitrophenoxy)pyrrolo[1,2-f][1, 2, 4]triazine
(50 mg, 0.18 mmol), zinc powder (280 mg, 4.37 mmol) and ammonium
chloride (130 mg, 2.37 mmol) were added to tetrahydrofuran (3.3 mL)
and methanol (0.8 mL) and stirred for 1.5 hours at 70.degree. C.
under reflux. The resulting mixture was allowed to cool to room
temperature and filtered with celite. Purification by silica gel
chromatography (1-6% ethyl acetate in dichloromethane) yielded the
target compound as an ivory solid (44 mg, 0.18 mmol, 99%
yield).
[0469] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.92 (s, 1H), 7.70 (dd,
J=2.5 Hz, 1.6 Hz, 1H) 6.98 (t, J=8.5 Hz, 1H), 6.92 (dd, J=4.4 Hz,
1.4 Hz, 1H), 6.77 (m, 1H), 6.42 (m, 2H), 3.71 (br s, 2H).
(Step 6)
N-(3-fluoro-4-(pyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-2-(4--
fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00061##
[0471] To a solution of
3-fluoro-4-(pyrrolo[1,2-f][1,2,4]triazin-4-yloxy)aniline (44 mg,
0.18 mmol) and
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-
-carboxylic acid (90 mg, 0.36 mmol) in dimethylformamide (1.7 mL),
HATU (200 mg, 0.54 mmol) and triethylamine (0.08 mL, 0.55 mmol)
were sequentially added and stirred at 50.degree. C. overnight. The
resulting reaction mixture was concentrated under reduced pressure
and the resulting residue was extracted with ethyl acetate and
water. The organic layer was separated from the reaction mixture,
dried with magnesium sulfate, and then filtered. The filtrate was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (10% ethyl acetate in
dichloromethane) to give the target compound as a white solid (85
mg, 0.18 mmol, 99% yield).
[0472] MS (ESI pos. ion) m/z: 477 (MH.sup.+). Calc'd exact mass for
C.sub.24H.sub.18F.sub.2N.sub.6O.sub.3: 476. .sup.1H NMR (400 MHz,
CDCl.sub.3): 10.79 (br s, 1H), 7.98 (s, 1H), 7.90 (dd, J=4.0 Hz,
1.6 Hz, 1H), 7.78 (dd, J=1.6 Hz, 0.8 Hz, 1H), 7.37-7.34 (m, 2H),
7.31-7.24 (m, 3H), 7.20 (t, J=5.6 Hz, 1H), 7.00 (dd, J=2.8 Hz, 0.4
Hz, 1H), 6.85 (dd, J=2:8 Hz, 2.0 Hz, 1H), 3.35 (s, 3H), 2.79 (s,
3H).
Example 14
N-(3-Fluoro-4-(pyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-1,5-dimethyl-3-
-oxy-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00062##
[0474] The target compound
N-(3-fluoro-4-(pyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-1,5-dimethyl--
3-oxy-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide was prepared
in the same manner as Example 13.
[0475] MS (ESI neg. ion) m/z: 457 (MH.sup.-). Calc'd exact mass for
C.sub.24H.sub.19FN.sub.6O.sub.3: 458.
[0476] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.87 (br s, 1H), 7.99
(s, 1H), 7.92 (dd, J=12.0 Hz, 1.8 Hz, 1H), 7.78 (dd, J=2.4 Hz, 1.2
Hz, 1H), 7.58-7.55 (m, 2H), 7.49-7.46 (m, 1H), 7.37-7.36 (m, 2H),
7.32-7.30 (m, 1H), 7.20 (t, J=8.4 Hz, 1H), 7.00 (dd, J=4.2 Hz, 1.2
Hz, 1H), 6.85 (dd, J=4.2 Hz, 2.4 Hz, 1H), 3.37 (s, 3H), 2.80 (s,
3H).
Example 15
N-(3-fluoro-4-(6-phenylpyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-2-(4-f-
luorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00063##
[0478] The target compound was prepared as follows:
##STR00064## ##STR00065##
(Step 1) methyl-amino-4-chloro-1H-pyrrolo-2-carboxylate
##STR00066##
[0480] Methyl 4-chloro-1-H-pyrrole-2-carboxylate (1.0 g, 6.27 mmol)
was slowly added over 30 minutes to a mixture of NaH (60%, 0.4 g,
10.03 mmol) suspended in dimethylformamide (12 mL) at 0.degree. C.
under nitrogen atmosphere. After stirring at 0.degree. C. for 1
hour, a solution of 4-2,4-dinitrophenolamine (1.87 g, 9.40 mmol) in
dimethylformamide (6 mL) was added dropwise for 30 minutes. The
resulting reaction mixture was stirred at 0.degree. C. for 2.5
hours and the reaction was terminated by slowly adding saturated
sodium thiosulfate aqueous solution. The resulting mixture was
extracted with ethyl acetate. The organic layer was washed with 10%
lithium chloride aqueous solution, dried with sodium sulfate, and
then filtered. The filtrate was concentrated. The resulting brown
residue was purified by silica gel chromatography (10% ethyl
acetate in hexane) to give the target compound as an oil (930 mg,
5.33 mmol, 85% yield).
[0481] .sup.1H NMR (400 MHz, CDCl.sub.3): 6.91 (d, J=2.4 Hz, 1H),
6.73 (d, J=2.4 Hz, 1H), 5.54 (br s, 2H), 3.83 (s, 3H).
(Step 2) 6-chloropyrrolo[1,2-f][1,2,4]triazin-4(3H)-one
##STR00067##
[0483] Methyl-amino-4-chloro-1H-pyrrolo-2-carboxylate (900 mg, 5.15
mmol) was dissolved in formamide (3.6 mL) and heated at 170.degree.
C. for 1 hour and then at 190.degree. C. for 2 hours. The resulting
reaction mixture was cooled to room temperature. The produced solid
was recrystallized with ethyl acetate to give the target compound
as a white solid (500 mg, 2.95 mmol, 57% yield).
[0484] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.54 (s, 1H), 7.41 (d,
J=1.6 Hz, 1H), 7.01 (d, J=1.6 Hz, 1H).
(Step 3) 4,6-dichloropyrrolo[1,2-f][1,2,4]triazine
##STR00068##
[0486] Diisopropylethylamine (0.56 mL, 3.25 mmol) was added to a
solution of 6-chloropyrrolo[1,2-f][1,2,4]triazin-4(3H)-one (500 mg,
2.95 mmol) dissolved in toluene (7.5 mL) under nitrogen atmosphere.
Subsequently, after adding phosphorus oxychloride (0.8 mL, 8.87
mmol), the mixture was heated for 20 hours at 100.degree. C. The
resulting reaction mixture was cooled to 0.degree. C. After slowly
adding sodium bicarbonate aqueous solution, the mixture was stirred
at room temperature for 30 minutes. The resulting aqueous layer was
extracted with ethyl acetate, dried with magnesium sulfate, and
then filtered. The filtrate was concentrated in vacuum. The
resulting yellow solid product was subjected to the next step
without purification (510 mg, 2.71 mmol, 92% yield).
[0487] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.25 (s, 1H), 7.84 (d,
J=1.6 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H).
(Step 4)
6-chloro-4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-f][1,2,4]triazine
##STR00069##
[0489] 4,6-Dimethylpyrrolo[1,2-f][1,2,4]triazine (150 mg, 0.798
mmol), 2-fluoro-4-nitrophenol (150 mg, 0.957 mmol) and potassium
carbonate (220 mg, 1.59 mmol) were added to anhydrous
N-dimethylformamide (3.6 mL). The resulting solution was heated at
60.degree. C. for 1 hour and 20 minutes under nitrogen atmosphere.
The resulting mixture was allowed to cool to room temperature and
then extracted with ethyl acetate. The extract was concentrated and
purified by silica gel chromatography (25% ethyl acetate in
n-hexane) to give the target compound as a white solid. (203 mg,
0.658 mmol, 83% yield)
[0490] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.20-8.15 (m, 2H), 7.98
(s, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.54-7.51 (m, 1H), 7.00 (d, J=1.8
Hz, 1H).
(Step 5)
4-(6-chloropyrrolo[1,2-f][1,2,4]triazin-4-yloxy)-3-fluoroaniline
##STR00070##
[0492]
6-Chloro-4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-f][1,2,4]triazine
(0.2 g, 0.648 mmol), zinc powder (1.02 g, 15.6 mmol) and ammonium
chloride (0.45 g, 8.42 mmol) were added to tetrahydrofuran (13.3
mL) and methanol (3.3 mL) and stirred for 1 hour and 10 minutes at
70.degree. C. under reflux. The resulting mixture was allowed to
cool to room temperature, filtered with celite, concentrated and
then purified by silica gel chromatography to give the target
compound as an ivory solid (153 mg, 0.549 mmol, 85% yield).
[0493] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.01 (s, 1H), 7.73 (d,
J=1.8 Hz, 1H), 7.03 (t, J=2.4 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H),
6.54-6.47 (m, 2H), 3.80 (br s, 2H).
(Step 6)
3-fluoro-4-(6-phenylpyrrolo[1,2-f][1,2,4]triazin-4-yloxy)aniline
##STR00071##
[0495] t-Butanol (0.5 mL) was added under nitrogen atmosphere to a
flask containing palladium acetate (4 mg, 0.018 mmol), X-Phos
ligand (21 mg, 0.045 mmol),
4-(6-chloropyrrolo[1,2-f][1,2,4]triazin-4-yloxy)-3-fluoroaniline
(50 mg, 0.018 mmol), phenylboronic acid (44 mg, 0.036 mmol) and
potassium phosphate (65 mg, 0.054 mmol). After stirring, the
resulting mixture was heated at 80.degree. C. for 10 hours. Upon
completion of the reaction, the resulting reaction mixture was
cooled to room temperature and filtered through celite while
washing with dichloromethane. The filtrate was concentrated and
extracted with ethyl acetate and water. The organic layer was dried
with magnesium sulfate and then filtered. The filtrate was
concentrated under reduced pressure. The resulting residue was
purified by silica gel chromatography (n-hexane:ethyl acetate=5:1)
to give the target compound as a pale yellow solid (32 mg, 0.1
mmol, 56% yield).
[0496] MS (ESI pos. ion) m/z: 321 (MH.sup.+). Calc'd exact mass for
C.sub.18H.sub.13FN.sub.4O: 320.11.
[0497] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.06 (s, 1H), 8.00 (s,
3H), 7.68 (d, J=8.4 Hz, 2H), 7.44 (t, J=7.2 Hz, 2H), 7.32 (t, J=7.2
Hz, 1H), 7.25 (s, 1H), 7.07 (t, J=8.4 Hz, 1H), 6.56-6.49 (m, 2H),
3.80 (s, 2H).
(Step 7)
N-(3-fluoro-4-(6-phenylpyrrolo[1,2-f][1,2,4]triazin-4-yloxy)pheny-
l)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxa-
mide
##STR00072##
[0499] To a solution of
3-fluoro-4-(6-phenylpyrrolo[1,2-f][1,2,4]triazin-4-yloxy)aniline
(27 mg, 0.084 mmol) and
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxyli-
c acid (42 mg, 0.017 mmol) in dimethylformamide (0.5 mL), HATU (96
mg, 0.25 mmol) and triethylamine (0.035 mL, 0.25 mmol) were
sequentially added and then stirred at 50.degree. C. overnight. The
resulting reaction mixture was concentrated under reduced pressure
and the produced residue was extracted with ethyl acetate and
water. The organic layer was separated, dried with magnesium
sulfate, and then filtered. The filtrate was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (50% ethyl acetate in n-hexane) to give the target
compound as a white solid (38 mg, 0.069 mmol, 83% yield).
[0500] MS (ESI pos. ion) m/z: 553 (MH.sup.+). Calc'd exact mass for
C.sub.30H.sub.22F.sub.2N.sub.6O.sub.3: 552.17.
[0501] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.80 (br s, 1H), 8.07
(d, J=1.6 Hz, 1H), 7.99 (s, 1H), 7.92 (dd, J=12.4, 2.4 Hz, 1H),
7.69 (d, J=7.6, 2H), 7.44 (t, J=7.6, 2H), 7.38-7.23 (m, 8H), 3.56
(s, 3H), 2.80 (s, 3H).
Example 16
N-(4-(6-Chloropyrrolo[1,2-f][1,2,4]triazin-4-yloxy)-3-fluorophenyl)-2-(4-f-
luorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00073##
[0503] The target compound
N-(4-(6-chloropyrrolo[1,2-f][1,2,4]triazin-4-yloxy)-3-fluorophenyl)-1,5-d-
imethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide was
prepared in the same manner as Example 15.
[0504] MS (ESI pos. ion) m/z: 511 (MH.sup.+). Calc'd exact mass for
C.sub.24H.sub.17ClF.sub.2N.sub.6O.sub.3: 510.10.
[0505] .sup.1H NMR (400 MHz, CDCl.sub.3 in DMSO-d.sub.6 2 drops):
10.84 (br s, 1H), 8.00 (s, 1H), 7.91 (m, 1H), 7.75 (s, 1H),
7.39-7.17 (m, 6H), 6.94 (s, 1H), 3.37 (s, 3H), 2.80 (s, 3H).
Example 17
N-(4-(6-Chloropyrrolo[1,2-f][1,2,4]triazin-4-yloxy)-3-fluorophenyl)-1,5-di-
methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00074##
[0507] The target compound
N-(4-(6-chloropyrrolo[1,2-f][1,2,4]triazin-4-yloxy)-3-fluorophenyl)-1,5-d-
imethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide was
prepared in the same manner as Example 15.
[0508] MS (ESI pos. ion) m/z: 493 (MH.sup.+). Calc'd exact mass for
C.sub.24H.sub.18ClFN.sub.6O.sub.3: 492.11.
[0509] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.88 (br s, 1H), 7.92
(dd, J=12.2, 2.2 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.58-7.29 (m,
6H), 7.18 (t, J=8.6 Hz, 1H), 6.95 (d, J=1.6 Hz, 1H), 3.37 (s, 3H),
2.80 (s, 3H).
Example 18
N-(3-Fluoro-4-(6-phenylpyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-1,5-di-
methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00075##
[0511] The target compound
N-(3-fluoro-4-(6-phenylpyrrolo[1,2-f][1,2,4]triazin-4-yloxy)phenyl)-1,5-d-
imethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide was
prepared in the same manner as Example 15.
[0512] MS (ESI pos. ion) m/z: 535 (MH.sup.+). Calc'd exact mass for
C.sub.30H.sub.23FN.sub.6O.sub.3: 534.18.
[0513] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.88 (br s, 1H), 8.07
(d, J=1.6 Hz, 1H), 8.00 (s, 1H), 7.92 (dd, J=12.2, 2.2 Hz, 1H),
7.69 (d, J=7.2, 2H), 7.57 (t, J=2H), 7.50-7.42 (m, 3H), 7.38-7.20
(m, 5H), 3.37 (s, 3H), 2.80 (s, 3H).
Example 19
N-(3-Fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,2-dimethy-
l-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00076##
[0515] The target compound was prepared as follows:
##STR00077##
(Step 1) 1,2-dimethyl-5-phenyl-1H-pyrazol-3(2H)-one
##STR00078##
[0517] 1,2-Dimethylhydrazine 2-dihydrochloride (2.77 g, 20.8 mmol)
was added to an aqueous solution of sodium hydroxide (1.66 g, 41.6
mmol) in water (32 mL). After stirring for 10 minutes, ethyl
benzoylacetate (2.0 g, 10.4 mmol) and glacial acetic acid (0.89 mL,
15.6 mmol) were added and the mixture was stirred at 115.degree. C.
overnight under reflux. The resulting reaction mixture was cooled
to room temperature and extracted with ethyl acetate, 10:1
dichloromethane/methanol, and then with ethyl acetate. The organic
layer was collected, dried with sodium sulfate, and then filtered.
The filtrate was concentrated. The resulting residue was separated
by silica gel chromatography (DCM:MeOH=95:5) to give the target
compound (420 mg, 2.23 mmol, 21% yield).
[0518] MS (ESI pos. ion) m/z: 189 (MH.sup.+). Calc'd exact mass for
C.sub.11H.sub.12N.sub.2O: 188.23.
[0519] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.49-7.41 (m, 5H), 5.66
(s, 1H), 3.43 (s, 3H), 3.16 (s, 3H).
(Step 2)
1,2-dimethyl-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyd-
e
##STR00079##
[0521] N,N-Dimethylformamide (3.4 mL, 43.6 mmol) was added to a
flask under nitrogen atmosphere. After cooling to 0.degree. C.,
phosphorus oxychloride (1.4 mL, 15.2 mmol) was added. The resulting
reaction mixture was stirred at room temperature for 50 minutes.
The resulting reaction mixture was transferred to a reaction flask
containing a solution of 1,2-dimethyl-5-phenyl-1H-pyrazol-3(2H)-one
(820 mg, 4.36 mmol) in DMF (4.9 mL). The reaction flask was
immersed in a preheated oil bath (120.degree. C.) and, after
stirring for 12 minutes, cooled to room temperature. 5 N NaOH (15
mL) was added to the cooled reaction mixture. After diluting with
icy water, the mixture was extracted with chloroform. The organic
layer was dried with sodium sulfate and then filtered. The filtrate
was concentrated. After diluting DMF remaining in the resulting
residue again with chloroform and then washing with water, the
aqueous layer was extracted again with chloroform. The organic
layer was collected, dried with sodium sulfate, and then filtered.
The filtrate was concentrated. The concentrated residue was
subjected to the next step without further purification.
(Step 3)
1,2-dimethyl-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid
##STR00080##
[0523]
1,2-Dimethyl-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde
was dissolved in t-butyl alcohol (23.5 mL) and 2-methyl-2-butene
(8.3 mL, 78.5 mmol) was added at 0.degree. C. After adding an
aqueous solution of sodium chlorite (80% tech, 0.95 g, 8.7 mmol) in
water (10 mL) and a suspension of potassium phosphite monobasic
(3.44 g, 25.3 mmol) in water (23.5 mL) to the resulting reaction
mixture, the mixture was stirred at room temperature for 10 hours.
After adding water to the stirred reaction mixture, the aqueous
layer was extracted with ethyl acetate, dichloromethane and 10:1
dichloromethane/methanol. The organic layer was collected, dried
with sodium sulfate, and then filtered. The filtrate was
concentrated. The resulting residue was washed with a small volume
of ethyl acetate to give the target compound as a white solid (350
mg, 1.5 mmol, 35% yield).
[0524] MS (ESI pos. ion) m/z: 233 (MH.sup.+). Calc'd exact mass for
C.sub.12H.sub.12N.sub.2O.sub.3: 232.24.
[0525] .sup.1H NMR (400 MHz, DMSO): 12.46 (br s, 1H), 7.58-7.47 (m,
5H), 3.62 (s, 3H), 3.48 (s, 3H).
(Step 4)
N-(3-fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,-
2-dimethyl-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00081##
[0527] The target compound
N-(3-fluoro-4-(5-phenylpyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,2-dimeth-
yl-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide was
prepared in the same manner as Example 1, except for using
1,2-dimethyl-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid (0.534 mmol) prepared in Step 3 of Example 19 instead of
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid (0.534 mmol), in Step 11 of Example 1.
[0528] MS (ESI pos. ion) m/z: 534 (MH.sup.+). Calc'd exact mass for
C.sub.31H.sub.24FN.sub.5O.sub.3: 533.55.
[0529] .sup.1H NMR (400 MHz, CDCl.sub.3): 11.01 (br s, 1H),
7.85-7.78 (m, 2H), 7.65-7.45 (m, 8H), 7.33 (t, J=7.6 Hz, 2H),
7.25-7.21 (m, 2H), 7.03 (t, J=8.6 Hz, 1H), 6.88 (d, J=2.8 Hz, 1H),
5.64 (dd, J=5.6 Hz, 0.8 Hz, 1H), 3.61 (s, 3H), 3.40 (s, 3H).
Example 20
[0530]
N-(3-Fluoro-4-(5-(pyridin-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)ph-
enyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1-pyrazole-4-carbo-
xamide
##STR00082##
[0531]
N-(4-(5-Bromopyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4--
fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
(70 mg, 0.126 mmol) and Pd(PPh.sub.3).sub.4 (11 mg, 0.009 mmol)
were suspended in anhydrous toluene (1.4 mL) under nitrogen
atmosphere. After adding 2-(tributylstannyl)pyridine, the mixture
was stirred for 7 hours under reflux. The resulting reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then filtered with celite. The filtrate was concentrated and
the resulting residue was purified by silica gel chromatography
(50% ethyl acetate in dichloromethane) to give the target compound
as a white solid (33 mg, 0.060 mmol, 48% yield).
[0532] MS (ESI pos. ion) m/z: 553 (MH.sup.+) Calc'd exact mass for
C.sub.30H.sub.22F.sub.2N.sub.6O.sub.3: 552.53.
[0533] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.80 (br s, 1H),
8.64-8.62 (m, 1H), 7.91-7.80 (m, 4H), 7.64-7.60 (m, 1H), 7.37-7.34
(m, 2H), 7.28-7.23 (m, 4H), 7.12-7.08 (m, 2H), 5.77 (d, J=2.8 Hz,
1H), 3.56 (s, 3H), 2.79 (s, 3H).
Example 21
N-(3-Fluoro-4-(5-(thiophen-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2--
(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00083##
[0535] The target compound
N-(3-fluoro-4-(5-(thiophen-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-
-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 2.
[0536] MS (ESI pos. ion) m/z: 558 (MH.sup.+). Calc'd exact mass for
C.sub.29H.sub.21F.sub.2N.sub.5O.sub.3S: 557.57.
[0537] .sup.1H NMR (600 MHz, CDCl.sub.3): 10.81 (br s, 1H), 7.90
(dd, J=12.6 Hz, 1.6 Hz, 1H), 7.81 (d, J=5.4 Hz, 1H), 7.75 (d, J=3.0
Hz, 1H), 7.37-7.14 (m, 8H), 7.02-7.00 (m, 1H), 6.95 (d, J=3.0 Hz,
1H), 5.70 (d, J=5.4 Hz, 1H), 3.36 (s, 3H), 2.80 (s, 3H).
Example 22
N-(3-Fluoro-4-(5-(pyrimidin-5-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-
-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00084##
[0539] The target compound
N-(3-fluoro-4-(5-(pyrimidin-5-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamid-
e was prepared in the same manner as Example 2.
[0540] MS (ESI pos. ion) m/z: 554 (MH.sup.+). Calc'd exact mass for
C.sub.29H.sub.21F.sub.2N.sub.7O.sub.3: 553.52.
[0541] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.82 (br s, 1H), 9.06
(s, 1H), 8.99 (s, 2H), 7.92-7.86 (m, 3H), 7.37-7.09 (m, 6H), 6.93
(d, J=2.8 Hz, 1H), 5.79 (dd, J=5.6 Hz, 0.8 Hz, 1H), 3.36 (s, 3H),
2.79 (s, 3H).
Example 23
N-(3-Fluoro-4-(5-(thiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(-
4-fluorophenyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00085##
[0543] The target compound was prepared in the same manner as
Example 20.
[0544] MS (ESI pos. ion) m/z: 559 (MH.sup.+). Calc'd exact mass for
C.sub.28H.sub.20F.sub.2N.sub.6O.sub.3S: 558.56.
[0545] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.84 (br s, 1H), 7.93
(dd, J=12.6 Hz, 2.4 Hz, 1H), 7.87 (d, J=5.2 Hz, 1H), 7.80-7.77 (m,
2H), 7.48 (d, J=2.8 Hz, 1H), 7.38-7.19 (m, 7H), 5.83 (d, J=4.0 Hz,
1H), 3.37 (s, 3H), 2.80 (s, 3H).
Example 24
N-(3-Fluoro-4-(5-(pyrazin-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(-
4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00086##
[0547] The target compound was prepared in the same manner as
Example 20.
[0548] MS (ESI pos. ion) m/z: 554 (MH.sup.+). Calc'd exact mass for
C.sub.29H.sub.21F.sub.2N.sub.7O.sub.3: 553.52.
[0549] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.83 (br s, 1H), 9.10
(s, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 7.92-7.87 (m, 3H), 7.36-7.25
(m, 6H), 7.13 (t, J=8.7 Hz, 1H), 5.84 (d, J=5.4 Hz, 1H), 3.36 (s,
3H), 2.79 (s, 3H).
Example 25
N-(3-Fluoro-4-(5-(piperidin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-
-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00087##
[0551] The target compound
N-(3-fluoro-4-(5-(piperidin-4-yl)pyrrolo[1,2-b]Pyridazin-4-yloxy)phenyl)--
2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamid-
e was prepared in the same manner as Example 2.
[0552] MS (ESI pos. ion) m/z: 559 (MH.sup.+). Calc'd exact mass for
C.sub.30H.sub.28F.sub.2N.sub.6O.sub.3: 558.58.
[0553] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.83 (br s, 1H),
7.92-7.89 (m, 1H), 7.74-7.72 (m, 1H), 7.67 (t, J=2.4 Hz, 1H),
7.38-7.24 (m, 5H), 7.16 (t, J=8.8 Hz, 1H), 6.72 (dd, J=8.0 Hz, 2.8
Hz, 1H), 5.57 (t, J=5.8 Hz, 1H), 3.37 (s, 3H), 2.80 (s, 3H),
2.21-1.82 (m, 4H), 1.39-1.08 (m, 2H), 0.95-0.81 (m, 2H).
Example 26
N-(3-Fluoro-4-(5-(pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(-
4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00088##
[0555] The target compound
N-(3-fluoro-4-(5-(pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2--
(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 2.
[0556] MS (ESI pos. ion) m/z: 553 (MH.sup.+). Calc'd exact mass for
C.sub.30H.sub.22F.sub.2N.sub.6O.sub.3: 552.53.
[0557] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.80 (br s, 1H), 8.88
(d, J=2.4 Hz, 1H), 8.46 (dd, J=4.8 Hz, 1.8 Hz, 1H), 7.95 (d, J=7.8
Hz, 1H), 7.90-7.84 (m, 3H), 7.36-7.08 (m, 7H), 6.91 (d, J=3.0 Hz,
1H), 5.73 (d, J=4.8 Hz, 1H), 3.36 (s, 3H), 2.79 (s, 3H).
Example 27
N-(3-Fluoro-4-(5-(pyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(-
4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00089##
[0559] The target compound
N-(3-fluoro-4-(5-(pyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2--
(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 2.
[0560] MS (ESI pos. ion) m/z: 553 (MH.sup.+). Calc'd exact mass for
C.sub.30H.sub.22F.sub.2N.sub.6O.sub.3: 552.53.
[0561] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.82 (br s, 1H), 8.55
(dd, J=4.6 Hz, 1.4 Hz, 2H), 7.94-7.88 (m, 2H), 7.83 (d, J=3.2 Hz,
1H), 7.57 (dd, J=4.4 Hz, 1.6 Hz, 2H), 7.37-7.09 (m, 6H), 6.96 (d,
J=3.2 Hz, 1H), 5.78 (d, J=4.4 Hz, 1H) 3.36 (s, 3H), 2.79 (s,
3H).
Example 28
N-(3-Fluoro-4-(5-(thiophen-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2--
(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00090##
[0563] The target compound
N-(3-fluoro-4-(5-(thiophen-3-yl)pyrrolo[1,2-b]pyridazin-4-Yloxy)phenyl)-2-
-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 2.
[0564] MS (ESI pos. ion) m/z: 558 (MH.sup.+). Calc'd exact mass for
C.sub.29H.sub.21F.sub.2N.sub.5O.sub.3S: 557.57.
[0565] .sup.1H NMR (600 MHz, CDCl.sub.3): 10.81 (br s, 1H), 7.91
(dd, J=12.6 Hz, 2.4 Hz, 1H), 7.80 (d, J=5.4 Hz, 1H), 7.77 (d, J=2.4
Hz, 1H), 7.45-7.25 (m, 8H), 7.13 (t, J=8.7 Hz, 1H), 6.92 (d, J=3.0
Hz, 1H), 5.68 (d, J=5.4 Hz, 1H), 3.37 (s, 3H), 2.80 (s, 3H).
Example 29
N-(3-Fluoro-4-(5-(3,5-dimethylisoxazol-4-yl)pyrrolo[1,2-b]pyridazin-4-ylox-
y)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4--
carboxamide
##STR00091##
[0567] The target compound
N-(3-fluoro-4-(5-(3,5-dimethylisoxazol-4-yl)pyrrolo[1,2-b]pyridazin-4-ylo-
xy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-
-carboxamide was prepared in the same manner as Example 2.
[0568] MS (ESI pos. ion) m/z: 571 (MH.sup.+). Calc'd exact mass for
C.sub.30H.sub.24F.sub.2N.sub.6O.sub.4: 570.55.
[0569] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.80 (br s, 1H),
7.89-7.79 (m, 3H), 7.37-7.21 (m, 5H), 7.00 (t, J=8.8 Hz, 1H), 6.66
(d, J=2.8 Hz, 1H), 5.65 (d, J=5.2 Hz, 1H), 3.36 (s, 3H), 2.79 (s,
3H), 2.35 (s, 3H), 2.23 (s, 3H).
Example 30
N-(3-Fluoro-4-(5-(6-methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phe-
nyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1-H-pyrazole-4-carb-
oxamide
##STR00092##
[0571] The target compound
N-(3-fluoro-4-(5-(6-methylpyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)ph-
enyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carb-
oxamide was prepared in the same manner as Example 2.
[0572] MS (ESI pos. ion) m/z: 567 (MH.sup.+). Calc'd exact mass for
C.sub.31H.sub.24F.sub.2N.sub.6O.sub.3: 566.56.
[0573] .sup.1H NMR (600 MHz, CDCl.sub.3): 10.79 (br s, 1H), 8.76
(d, J=1.8 Hz, 1H), 7.88 (dd, J=12.0 Hz, 2.4 Hz, 1H), 7.85-7.82 (m,
3H), 7.36-7.22 (m, 5H), 7.14 (d, J=7.8 Hz, 1H), 7.08 (t, J=8.4 Hz,
1H), 6.88 (d, J=3.0 Hz, 1H), 5.70 (d, J=5.4 Hz, 1H), 3.36 (s, 3H),
2.79 (s, 3H), 2.55 (s, 3H).
Example 31
N-(3-Fluoro-4-(5-(2-methylpyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phe-
nyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carbo-
xamide
##STR00093##
[0575] The target compound
N-(3-fluoro-4-(5-(2-methylpyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)ph-
enyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxy-2,3-dihydro-1H-pyrazole-4-carb-
oxamide was prepared in the same manner as Example 2.
[0576] MS (ESI pos. ion) m/z: 567 (MH.sup.+). Calc'd exact mass for
C.sub.31H.sub.24F.sub.2N.sub.6O.sub.3: 566.56.
[0577] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.81 (br s, 1H), 8.43
(d, J=5.2 Hz, 1H), 7.94-7.82 (m, 3H), 7.46 (s, 1H), 7.39-7.24 (m,
6H), 7.09 (t, J=8.4 Hz, 1H), 6.95 (d, J=2.8 Hz, 1H), 5.78 (d, J=5.2
Hz, 1H), 3.36 (s, 3H), 2.79 (s, 3H) 2.55 (s, 3H).
Example 32
N-(3-Fluoro-4-(5-(1-hydroxyethyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-
-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00094##
[0579] The target compound was prepared as follows:
##STR00095##
(Step 1)
1-(4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-b]pyridazin-5-yl)ethan-
one
##STR00096##
[0581] AlCl.sub.3 (1.46 g, 10.98 mmol) was added to a solution of
4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-b]pyridazine (600 mg, 2.19
mmol) in dichloroethane (60 mL). After stirring at room temperature
for 1 hour and adding acetyl chloride (0.17 mL, 2.42 mmol), the
mixture was further stirred for 3 hours. The resulting reaction
mixture was neutralized with saturated sodium bicarbonate aqueous
solution. The resulting mixture was filtered through celite. After
phase separation of the filtrate, the organic layer was dried with
magnesium sulfate and then filtered. The filtrate was concentrated
and then purified by silica gel chromatography (1-6% ethyl acetate
in dichloromethane) to give the target compound as a white solid
(640 mg, 2.03 mmol, 93% yield).
[0582] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.24-8.16 (m, 3H), 7.58
(d, J=4.8 Hz, 1H), 7.45 (dd, J=8.8 Hz, 7.2 Hz, 1H), 6.81 (d, J=4.8
Hz, 1H), 6.06 (dd, J=5.6 Hz, 1.2 Hz, 1H) 2.75 (s, 3H).
(Step 2)
1-(4-(2-fluoro-4-aminophenoxy)pyrrolo[1,2-b]pyridazin-5-yl)ethano-
ne
##STR00097##
[0584] The target compound
1-(4-(2-fluoro-4-aminophenoxy)pyrrolo[1,2-b]pyridazin-5-yl)ethanone
was prepared in the same manner as Step 5 of Example 13.
(Step 3)
N-(4-(5-acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2--
(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00098##
[0586] The target compound
N-(4-(5-acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluor-
ophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Step 6 of Example 13 using the
compound of Step 2 of this example.
(Step 4) [710]
N-(3-fluoro-4-(5-(1-hydroxyethyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)--
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamid-
e
##STR00099##
[0588] NaBH.sub.4 (11 mg, 0.288 mmol) was added to a suspension of
N-(4-(5-acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluor-
ophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
(50 mg, 0.0.96 mmol) in tetrahydrofuran (2.5 mL) and methanol (3
mL) under nitrogen atmosphere. After stirring at room temperature
for 30 minutes, saturated ammonium chloride aqueous solution was
added to the resulting reaction mixture. After extraction with
dichloromethane, the organic layer was dried with sodium sulfate
and then filtered. The filtrate was concentrated. The resulting
residue was purified by silica gel chromatography (10% ethyl
acetate in dichloromethane) to give the target compound as a white
solid (16 mg, 0.029 mmol, 32% yield).
[0589] MS (ESI pos. ion) m/z: 542 (MNa.sup.+). Calc'd exact mass
for C.sub.27H.sub.23F.sub.2N.sub.5O.sub.4: 519.5.
[0590] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.81 (br s, 1H),
7.91-7.88 (m, 2H) 7.38-7.24 (m, 6H), 7.17 (t, J=8.4 Hz, 1H),
6.73-6.71 (m, 2H), 5.73 (d, J=5.2 Hz, 1H), 5.39 (m, 1H), 3.96 (br
s, 3H), 3.36 (s, 3H), 2.80 (s, 3H). 1.73 (d, J=6.8 Hz, 1H).
Example 33
N-(4-(5-Acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluoro-
phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00100##
[0592] The target compound
N-(4-(5-acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluor-
ophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 32.
[0593] MS (ESI pos. ion) m/z: 518 (MH.sup.+). Calc'd exact mass for
C.sub.27H.sub.21F.sub.2N.sub.5O.sub.4: 517.48.
[0594] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.84 (br s, 1H), 8.16
(d, J=5.2 Hz, 1H), 7.92 (dd, J=12.4 Hz, 2.4 Hz, 1H), 7.54 (d, J=5.2
Hz, 1H), 7.38-7.24 (m, 5H), 7.18 (t, J=8.8 Hz, 1H), 6.85 (d, J=5.2
Hz, 1H), 5.98 (d, J=5.2 Hz, 1H), 3.37 (s, 3H), 2.80 (s, 3H), 2.73
(s, 3H).
Example 34
N-(4-(5-Acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimethy-
l-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00101##
[0596] The target compound
N-(4-(5-acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimeth-
yl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide was
prepared in the same manner as Example 32.
[0597] MS (ESI pos. ion) m/z: 500 (MH.sup.+) Calc'd exact mass for
C.sub.27H.sub.22FN.sub.5O.sub.4: 499.49.
[0598] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.91 (br s, 1H), 8.16
(d, J=5.6 Hz, 1H), 7.93 (dd, J=12.8 Hz, 2.4 Hz, 1H), 7.59-7.49 (m,
4H), 7.37-7.29 (m, 3H), 7.18 (t, J=8.4 Hz, 1H), 6.85 (d, J=4.8 Hz,
1H), 5.99 (d, J=4.8 Hz, 1H), 3.39 (s, 3H), 2.80 (s, 3H), 2.73 (s,
3H).
Example 35
N-(3-Fluoro-4-(5-(1-hydroxyethyl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1-
,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00102##
[0600] The target compound
N-(4-(5-acetylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluor-
ophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 32.
[0601] MS (ESI pos. ion) m/z: 524 (MNa.sup.+). Calc'd exact mass
for C.sub.27H.sub.24FN.sub.5O.sub.4: 501.51.
[0602] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.88 (br s, 1H),
7.92-7.88 (m, 2H) 7.59-7.46 (m, 3H), 7.38-7.27 (m, 3H), 7.16 (t,
J=8.8 Hz, 1H), 6.73-6.70 (m, 2H), 5.73 (dd, J=5.2 Hz, 0.8 Hz, 1H),
5.40 (m, 1H), 3.96 (d, J=3.2 Hz, 1H), 3.38 (s, 3H), 2.80 (s, 3H).
1.73 (d, J=6.4 Hz, 1H).
Example 36
N-(3-Fluoro-4-(5-thiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5--
dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00103##
[0604] The target compound was prepared in the same manner as
Example 20.
[0605] MS (ESI pos. ion) m/z: 541 (MH.sup.+). Calc'd exact mass for
C.sub.28H.sub.21FN.sub.6O.sub.3S: 540.57.
[0606] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.91 (br s, 1H), 7.94
(dd, J=12.4 Hz, 2.8 Hz, 1H), 7.87 (d, J=5.2 Hz, 1H), 7.78 (dd,
J=3.6 Hz, 2.8 Hz, 1H), 7.69-7.64 (m, 2H), 7.59-7.44 (m, 4H),
7.38-7.29 (m, 2H), 7.24-7.1.9 (m, 2H), 5.83 (dd, J=5.2 Hz, 0.8 Hz,
1H), 3.38 (s, 3H), 2.80 (s, 3H).
Example 37
N-(3-Fluoro-4-(5-(pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5-
-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00104##
[0608] The target compound
N-(3-fluoro-4-(5-(pyridin-3-yl)pyrrolo[1,2-b]Pyridazin-4-yloxy)phenyl)-1,-
5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide was
prepared in the same manner as Example 2.
[0609] MS (ESI pos. ion) m/z: 535 (MH.sup.+). Calc'd exact mass for
C.sub.30H.sub.23FN.sub.6O.sub.3: 534.54.
[0610] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.87 (br s, 1H), 8.87
(d, J=2.0 Hz, 1H), 8.46 (dd, J=4.8 Hz, 1.6 Hz, 1H), 7.97-7.83 (m,
4H), 7.58-7.46 (m, 3H), 7.37-7.22 (m, 4H), 7.04 (t, J=8.4 Hz, 1H),
6.90 (d, J=2.8 Hz, 1H), 5.74 (d, J=5.2 Hz, 1H), 3.38 (s, 3H), 2.80
(s, 3H).
Example 38
N-(4-(5-ethylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluorop-
henyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00105##
[0612] The target compound
N-(4-(5-ethylpyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluoro-
phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 2.
[0613] MS (ESI pos. ion) m/z: 504 (MH.sup.+). Calc'd exact mass for
C.sub.27H.sub.23F.sub.2N.sub.5O.sub.3: 503.50.
[0614] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.81 (br s, 1H), 7.90
(dd, J=12.4 Hz, 2.4 Hz, 1H), 7.70 (d, J=5.2 Hz, 1H), 7.65 (d, J=2.8
Hz, 1H), 7.38-7.34 (m, 2H), 7.28-7.24 (m, 3H), 7.17 (t, J=8.4 Hz,
1H), 6.64 (d, J=2.8 Hz, 1H), 5.52 (d, J=5.2 Hz, 1H), 3.36 (s, 3H),
3.02 (q, J=7.6 Hz, 2H), 2.80 (s, 3H), 1.31 (t, J=7.6 Hz, 3H).
Example 39
N-(3-Fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)--
1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00106##
[0616] The target compound
N-(3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-2-(4-fluorophenyl)-
-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide was
prepared in the same manner as Example 9.
[0617] MS (ESI pos. ion) m/z: 476 (MH.sup.+). Calc'd exact mass for
C.sub.25H.sub.19F.sub.2N.sub.5O.sub.3: 475.45.
[0618] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.81 (br s, 1H), 7.89
(dd, J=12.4 Hz, 2.4 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 7.74 (dd,
J=2.4 Hz, 1.6 Hz, 1H), 7.38-7.34 (m, 2H), 7.29-7.24 (m, 2H), 7.17
(t, J=8.8 Hz, 1H), 6.81 (dd, J=4.4 Hz, 2.4 Hz, 1H), 6.75 (dd, J=4.4
Hz, 1.6 Hz, 1H), 5.68 (dd, J=5.2 Hz, 0.8 Hz, 1H), 3.36 (s, 3H),
2.99 (s, 3H).
Example 40
N-(3-Fluoro-4-(5-(pyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,5-
-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00107##
[0620] The target compound
N-(3-fluoro-4-(5-(pyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yloxy)phenyl)-1,-
5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide was
prepared in the same manner as Example 2.
[0621] MS (ESI pos. ion) m/z: 535 (MH.sup.+). Calc'd exact mass for
C.sub.30H.sub.23FN.sub.6O.sub.3: 534.54.
[0622] .sup.1H NMR (400 MHz, CDCl.sub.3): 10.89 (br s, 1H),
8.56-8.53 (m, 2H), 7.92 (dd, J=12.4 Hz, 2.4 Hz, 1H), 7.89 (d, J=5.2
Hz, 1H), 7.83 (d, J=2.8 Hz, 1H), 7.59-7.46 (m, 5H), 7.37-7.35 (m,
2H), 7.27-7.24 (m, 1H), 7.08 (t, J=8.4 Hz, 1H), 6.96 (d, J=2.8 Hz,
1H), 5.79 (d, J=5.2 Hz, 1H), 3.38 (s, 3H), 2.80 (s, 3H).
Example 41
N-(4-(5-Chloropyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluoro-
phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00108##
[0624] The target compound
N-(4-(5-chloropyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-2-(4-fluor-
ophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 1.
[0625] MS (ESI pos. ion) m/z: 509 (MH.sup.+). Calc'd exact mass for
C.sub.25H.sub.18ClF.sub.2N.sub.5O.sub.3: 509.89.
[0626] .sup.1H NMR (600 MHz, CDCl.sub.3): 10.81 (br s, 1H), 7.90
(dd, J=6.6, 2.4 Hz, 1H), 7.76 (d, J=4.8 Hz, 1H), 7.63 (d, J=3.0,
1H), 7.37-7.25 (m, 5H), 7.20 (t, J=2.7, 1H), 6.72 (d, J=2.4, 1H),
5.63 (d, J=5.4, 1H), 3.36 (s, 3H), 2.80 (s, 3H).
Example 42
N-(4-(5-Chloropyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimethy-
l-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00109##
[0628] The target compound
N-(4-(5-chloropyrrolo[1,2-b]pyridazin-4-yloxy)-3-fluorophenyl)-1,5-dimeth-
yl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide was
prepared in the same manner as Example 1.
[0629] MS (ESI pos. ion) m/z: 492 (MH.sup.+). Calc'd exact mass for
C.sub.25H.sub.19ClFN.sub.5O.sub.3: 491.90.
[0630] .sup.1H NMR (600 MHz, CDCl.sub.3): 10.89 (br s, 1H), 7.91
(dd, J=12.3, 2.1 Hz, 1H), 7.76 (d, J=7.2, 1H), 7.63 (d, J=3.0 Hz,
1H), 7.57 (t, J=7.8, 2H), 7.49 (t, J=7.5, 1H), 7.36 (d, J=8.4, 2H),
7.29 (d, J=7.8, 1H), 7.19 (t, J=8.7, 1H), 6.72 (d, J=2.4, 1H), 5.64
(d, J=5.4, 1H), 3.38 (s, 3H), 2.80 (s, 3H).
Example 43
N-(3-Fluoro-4-(2-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl)--
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamid-
e
##STR00110##
[0632] The target compound
N-(3-fluoro-4-(2-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl)-
-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxami-
de was prepared in the same manner as Example 10.
[0633] MS (ESI pos. ion) m/z: 558 (MH.sup.+). Calc'd exact mass for
C.sub.29H.sub.21F.sub.2N.sub.5O.sub.3S: 557.57.
Example 44
N-(3-Fluoro-4-(2-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl)--
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamid-
e
##STR00111##
[0635] The target compound
N-(3-fluoro-4-(2-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl)-
-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxami-
de was prepared in the same manner as Example 10.
[0636] MS (ESI pos. ion) m/z: 558 (MH.sup.+). Calc'd exact mass for
C.sub.29H.sub.21F.sub.2N.sub.5O.sub.3S: 557.57.
Example 45
N-(3-Fluoro-4-(2-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl-
)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxam-
ide
##STR00112##
[0638] The target compound
N-(3-fluoro-4-(2-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)pheny-
l)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxa-
mide was prepared in the same manner as Example 10.
[0639] MS (ESI pos. ion) m/z: 584 (MH.sup.+). Calc'd exact mass for
C.sub.32H.sub.27F.sub.2N.sub.5O.sub.4: 583.58.
Example 46
N-(3-Fluoro-4-(2-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl-
)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00113##
[0641] The target compound
N-(3-fluoro-4-(2-(4-methoxyphenyl)-1H-pyrrolo[2,3-b]Pyridin-4-yloxy)pheny-
l)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 10.
[0642] MS (ESI pos. ion) m/z: 566 (MH.sup.+). Calc'd exact mass for
C.sub.32H.sub.28FN.sub.5O.sub.4: 565.59.
Example 47
N-(3-Fluoro-4-(2-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl-1-
,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00114##
[0644] The target compound
N-(3-fluoro-4-(2-(thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl--
1,5-dimethyl-3-oxo-2-phenyl-2,37-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 10.
[0645] MS (ESI pos. ion) m/z: 540 (MH.sup.+). Calc'd exact mass for
C.sub.29H.sub.22FN.sub.5O.sub.3S: 539.58.
Example 48
N-(3-Fluoro-4-(2-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl)--
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
##STR00115##
[0647] The target compound
N-(3-fluoro-4-(2-(thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl)-
-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
was prepared in the same manner as Example 10.
[0648] MS (ESI pos. ion) m/z: 540 (MH.sup.+). Calc'd exact mass for
C.sub.29H.sub.22FN.sub.5O.sub.3S: 539.58.
[0649] Activity Analysis
[0650] The pharmacological characteristics of the compound of the
present invention may be confirmed through many pharmacological
analyses. The following typical pharmacological assays were
performed for the compounds according to the present invention
and/or pharmaceutically acceptable salts thereof.
Elk Luciferase Assay
[0651] In order to evaluate the effect of the compounds of the
present invention on the signal transduction system of the HGF
receptor, c-Met, the PathDetect trans-reporting system (Stratagene
Cloning Systems Inc.) was employed. After infecting Chinese hamster
ovary (CHO) cells with pFR-Luc and pFA2-Elk1 plasmids (Stratagene),
the cells growing in a medium containing G418 were selected to
obtain stable pool. Clones responding well to the HGF signal
transduction were selected using the Luciferase Assay System
(Promega Corp.). The selected CHO clone was maintained in
Dulbecco's modified Eagle's medium (DMEM, Invitrogen) containing
200 .mu.g/mL G418.
[0652] Luciferase assay was carried out as follows. First, the
cells were detached using PBS containing 0.5 mM EDT. The cells were
added to F12 medium containing 0.1% BSA. The cells were transferred
to a 96-well plate treated with poly-D-lysine, at about 45000 cells
per well. After culturing the cells for about 16 hours, followed by
treating with HGF (Cell Signal) diluted in F12-BSA medium, 10 mL
each well, the cells were further cultured for about 4 to 6 hours.
In order to measure luciferase activity, Bright-Glo (60 mL,
Promega) was added and then luminescence was measured using Victor2
(Perkin Elmer). For testing of the efficiency of the compounds, HGF
was used at a final concentration of 50 ng/mL. After adding the
compound diluted in F12-BSA medium, 10 .mu.L each well, and waiting
for 10 minutes, 350 ng/mL HGF (10 .mu.L) was added. After culturing
for 4 to 6 hours, luciferase activity was measured according to the
same procedure. For result analysis, plotting was carried out using
the Prism software (GraphPad Software, Inc.) and IC.sub.50 was
measured.
[0653] The compounds of the present invention have IC.sub.50 values
for c-Met kinase of 0.001 to 2 .mu.M. More preferred compounds have
an IC.sub.50 value less than 1.0 .mu.M, more preferably less than
about 0.5 .mu.M. Table 1 shows the activity analysis result for
some compounds of the present invention.
[0654] cMet ELISA Assay
[0655] To measure the potency of compounds to inhibit HGF signaling
through cMet in cells expressing human cMet endogenously, sandwich
ELISA was used to detect phosphorylated cMet. A549 cells or other
cells were plated in 96 well plate at 50,000 cells per well in 100
ul volume of growth media (DMEM containing 10% FBS). After
overnight growth, the medium was replaced with assay media (F-12
containing 0.1% BSA). The next day, compounds were serially diluted
in assay media, and added to the wells for 10 minutes. Then cells
were activated with HGF at 500 ug/ml final concentration for 15
minutes. After a brief wash, cells were lysed with lysis buffer
containing protease and phosphatase inhibitor (Cell Signal) and
extract was harvested.
[0656] Then, the cell extract was added to an ELISA plate that had
been coated with anti-cMET antibody (Cell Signal). After washing
and reacting with anti-phospho-cMET antibody (Cell Signal), the
cell extract was further incubated using HRP-labeled secondary
antibody. The degree of phosphorylation of cMET was detected by
adding LumiGlo (KPL).
[0657] The ELISA assay result for some compounds of the present
invention is also shown in Table 1'.
TABLE-US-00001 TABLE 1 Example Number Luciferase, IC.sub.50 (-M)
ELISA, IC.sub.50 (-M) 1 0.679 0.929 2 0.099 0.522 3 0.492 0.159 4
0.055 0.369 5 0.354 2.653 6 0.236 0.256 7 0.410 0.513 8 0.030 0.119
9 0.205 0.320 10 0.016 0.232 11 0.008 0.311 12 0.008 0.225 13 0.242
14 4.288 3.022 15 0.373 16 1.743 3.508 17 2.297 8.443 18 2.000 19
2.045 0.510 20 0.096 0.070 21 0.186 0.264 22 0.069 0.074 23 0.055
0.062 24 0.036 0.041 25 0.738 0.264 26 0.050 0.058 27 0.042 0.048
28 0.035 0.239 29 0.144 0.137 30 0.061 0.081 31 0.074 0.081 32
1.842 33 1.426 34 2.259 35 2.438 36 0.089 0.126 37 0.008 0.148 38
0.393 0.358 39 0.345 0.248 40 0.040 0.118 41 0.518 42 1.048 43
0.036 0.203 44 0.027 0.138 45 0.052 0.711 46 0.041 0.288 47 0.056
0.203 48 0.228 0.249
[0658] The foregoing examples are for illustrative purposes only
and are not intended to limit the present invention to the
compounds described therein. Modifications and changes obvious to
those skilled in the art are also within the scope of the present
invention as set forth in the appended claims.
[0659] Those skilled in the art will easily understand the
essential features of the present invention from the foregoing
description and may make various changes and modifications of the
present invention to meet various applications and conditions
without departing from the spirit and scope of the present
invention.
[0660] As long as the compound of the present invention is
administered according to the present invention, no forbidden toxic
effect is expected.
[0661] All the cited references, patents, patent applications and
patent publications are incorporated herein by reference.
* * * * *