U.S. patent application number 12/693975 was filed with the patent office on 2010-10-07 for heterobicyclic pyrazole compounds and methods of use.
This patent application is currently assigned to Array BioPharma Inc.. Invention is credited to James F. Blake, Steven Armen Boyd, Frederick Cohen, Jason De Meese, Kin Chiu Fong, John J. Gaudino, Tomas Kaplan, Allison L. Marlow, Jeongbeob Seo, Allen A. Thomas, Hongqi Tian, Wendy B. Young.
Application Number | 20100256356 12/693975 |
Document ID | / |
Family ID | 38475465 |
Filed Date | 2010-10-07 |
United States Patent
Application |
20100256356 |
Kind Code |
A1 |
Blake; James F. ; et
al. |
October 7, 2010 |
HETEROBICYCLIC PYRAZOLE COMPOUNDS AND METHODS OF USE
Abstract
Compounds of Formulas Ia and Ib, and stereoisomers, geometric
isomers, tautomers, solvates, metabolites and pharmaceutically
acceptable salts thereof, are useful for inhibiting receptor
tyrosine kinases and for treating disorders mediated thereby.
Methods of using compounds of Formula Ia and Ib, and stereoisomers,
geometric isomers, tautomers, solvates and pharmaceutically
acceptable salts thereof, for in vitro, in situ, and in vivo
diagnosis, prevention or treatment of such disorders in mammalian
cells, or associated pathological conditions are disclosed.
##STR00001##
Inventors: |
Blake; James F.; (Longmont,
CO) ; Boyd; Steven Armen; (Longmont, CO) ; De
Meese; Jason; (Firestone, CO) ; Fong; Kin Chiu;
(Boulder, CO) ; Gaudino; John J.; (Longmont,
CO) ; Kaplan; Tomas; (Broomfield, CO) ;
Marlow; Allison L.; (Louisville, CO) ; Seo;
Jeongbeob; (Broomfield, CO) ; Thomas; Allen A.;
(Louisville, CO) ; Tian; Hongqi; (Longmont,
CO) ; Cohen; Frederick; (San Francisco, CA) ;
Young; Wendy B.; (San Mateo, CA) |
Correspondence
Address: |
VIKSNINS HARRIS & PADYS PLLP
P.O. BOX 111098
ST. PAUL
MN
55111-1098
US
|
Assignee: |
Array BioPharma Inc.
Boulder
CO
Genentech, Inc.
South San Francisco
CA
|
Family ID: |
38475465 |
Appl. No.: |
12/693975 |
Filed: |
January 26, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11714342 |
Mar 6, 2007 |
7723330 |
|
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12693975 |
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60779805 |
Mar 7, 2006 |
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60874832 |
Dec 14, 2006 |
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Current U.S.
Class: |
540/524 ;
540/575; 544/127; 544/238; 544/284; 544/316; 544/319; 544/321;
544/357; 544/362; 544/405; 546/119; 546/120 |
Current CPC
Class: |
A61P 37/04 20180101;
A61P 31/12 20180101; A61P 29/00 20180101; A61P 25/28 20180101; A61P
3/10 20180101; A61P 9/00 20180101; A61P 43/00 20180101; A61P 25/00
20180101; A61P 5/00 20180101; A61P 37/08 20180101; A61P 7/02
20180101; A61P 35/00 20180101; A61P 35/02 20180101; A61P 31/00
20180101; A61P 37/06 20180101; A61P 37/00 20180101; A61P 9/10
20180101; A61P 17/06 20180101; A61P 1/16 20180101; A61P 19/08
20180101; C07D 471/04 20130101 |
Class at
Publication: |
540/524 ;
546/119; 544/362; 544/127; 544/238; 544/316; 546/120; 544/319;
544/284; 544/321; 540/575; 544/405; 544/357 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 451/04 20060101 C07D451/04 |
Claims
1. A compound selected from Formulas Ia and Ib: ##STR00273## and
pharmaceutically acceptable salts thereof, wherein: X is O, S or
NR.sup.10; Z.sup.2 and Z.sup.3 are independently selected from
CR.sup.4 and N, wherein zero or one of Z.sup.2 and Z.sup.3 is N;
R.sup.1 is H, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, --C(.dbd.O)NR.sup.10R.sup.11, or
--(CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11, or R.sup.1 is
C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20 heterocyclyl,
C.sub.6-C.sub.20 aryl or C.sub.1-C.sub.20 heteroaryl, wherein said
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and
heteroaryl are optionally substituted with one or more groups
independently selected from F, Cl, Br, I, CN, CF.sub.3, oxo,
--OR.sup.10, SR.sup.10, --C(.dbd.Y)R.sup.10, --C(.dbd.Y)OR.sup.10,
--C(.dbd.Y)NR.sup.10R.sup.11,
--(CR.sup.14R.sup.15).sub.n--NR.sup.10R.sup.11,
--NR.sup.10C(.dbd.Y)R.sup.13, --NR.sup.10C(.dbd.Y)OR.sup.11,
--NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11, --NR.sup.12SO.sub.2R.sup.10,
--OC(.dbd.Y)R.sup.10, --OC(.dbd.Y)OR.sup.10,
--OC(.dbd.Y)NR.sup.10R.sup.11, --OS(O).sub.2(OR.sup.10),
--OP(.dbd.Y)(OR.sup.10)(OR.sup.11), --OP(OR.sup.10)(OR.sup.11),
--S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --S(O)(OR.sup.10),
--S(O).sub.2(OR.sup.10), --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, --SC(.dbd.Y)NR.sup.10R.sup.11,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl, C.sub.1-C.sub.20 heteroaryl,
--(CR.sup.14R.sup.15)--NR.sup.12C(.dbd.O)(CR.sup.14R.sup.15)NR.sup.10R.su-
p.11, and (CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11, or R.sup.1 is
NR.sup.xR.sup.y; R.sup.2 is H, CF.sub.3, CN, --C(.dbd.Y)R.sup.10,
--C(.dbd.Y)OR.sup.10, --C(.dbd.Y)NR.sup.10R.sup.11,
--C(.dbd.O)NR.sup.12(CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11,
--SR.sup.10, --S(O)R.sup.10, --S(O).sub.2R.sup.10,
S(O).sub.2NR.sup.10R.sup.11, --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 carbocyclyl,
C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl, or
C.sub.1-C.sub.20 heteroaryl, wherein said alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally
substituted with one or more groups independently selected from F,
Cl, Br, I, (CH.sub.2).sub.nOR.sup.10,
(CH.sub.2).sub.nNR.sup.10R.sup.11, heteroaryl and heterocyclyl;
R.sup.3 is C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl or C.sub.1-C.sub.20 heteroaryl,
wherein said carbocyclyl, heterocyclyl, aryl and heteroaryl are
optionally substituted with one or more groups independently
selected from F, Cl, Br, I, CN, CF.sub.3, OR.sup.10, SR.sup.10,
--C(.dbd.Y)R.sup.10, --C(.dbd.Y)OR.sup.10,
--C(.dbd.Y)NR.sup.10R.sup.11, --NR.sup.10R.sup.11,
--NR.sup.10C(.dbd.Y)R.sup.13, --NR.sup.10C(.dbd.Y)OR.sup.11,
--NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11,
--NR.sup.12C(.dbd.O)C(.dbd.O)R.sup.10R.sup.11,
--NR.sup.12C(.dbd.O)C(.dbd.O)OR.sup.a, --NR.sup.12SO.sub.2R.sup.10,
--NR.sup.12C(.dbd.Y.sup.1)
(CR.sup.14R.sup.15).sub.nC(.dbd.Y.sup.2)NR.sup.10R.sup.11,
--NR.sup.12C(.dbd.Y.sup.1)NR.sup.10C(.dbd.Y.sup.2)(CR.sup.14R.sup.15).sub-
.nR.sup.11, --NR.sup.12C(.dbd.Y.sup.1)
(CR.sup.14R.sup.15).sub.nC(.dbd.Y.sup.2)(CR.sup.14R.sup.15).sub.mR.sup.10-
, --OC(.dbd.Y)R.sup.10, --OC(.dbd.Y)OR.sup.10,
--OC(.dbd.Y)NR.sup.10R.sup.11, --OS(O).sub.2(OR.sup.10),
--OP(.dbd.Y)(OR.sup.10)(OR.sup.11), --OP(OR.sup.10)(OR.sup.11),
--S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --S(O)(OR.sup.10),
--S(O).sub.2(OR.sup.10), --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, --SC(.dbd.Y)NR.sup.10R.sup.11,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl and C.sub.1-C.sub.20
heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl and heteroaryl are optionally substituted with
one or more groups independently selected from F, Cl, Br, I, OH,
C.sub.1-C.sub.12 alkyl, NR.sup.10R.sup.11, and
(CR.sup.14R.sup.15).sub.n-aryl; R.sup.4 is H, F, Cl, Br, CF.sub.3,
CN, --C(.dbd.Y)R.sup.10, --C(.dbd.Y)OR.sup.10,
--C(.dbd.Y)NR.sup.10R.sup.11, --NR.sup.10R.sup.11,
NR.sup.10C(.dbd.Y)R.sup.10, NR.sup.10C(.dbd.Y)OR.sup.11,
NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11,
--NR.sup.12SO.sub.2NR.sup.10R.sup.11, --OR.sup.10,
--OC(.dbd.Y)R.sup.10, --OC(.dbd.Y)OR.sup.10,
--OC(.dbd.Y)NR.sup.10R.sup.11,
--C(.dbd.O)NR.sup.12(CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11,
--OP(.dbd.Y)(OR.sup.10)(OR.sup.11), --OP(OR.sup.10)(OR.sup.11),
--SR.sup.10, --S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 carbocyclyl,
C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl, or
C.sub.1-C.sub.20 heteroaryl; R.sup.10, R.sup.11 and R.sup.12 are
independently H, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 carbocyclyl,
(CR.sup.14R.sup.15).sub.nC.sub.2-C.sub.20 heterocyclyl,
(CR.sup.14R.sup.15).sub.nC.sub.6-C.sub.20 aryl, or C.sub.1-C.sub.20
heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, and heteroaryl are optionally substituted with
one or more groups independently selected from F, Cl, Br, I,
SO.sub.2R.sup.c, CN, OR.sup.a, NR.sup.aR.sup.b,
C(.dbd.O)NR.sup.aR.sup.b, CR.sup.aC(.dbd.O)R.sup.b,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 carbocyclyl, C.sub.6-C.sub.20 aryl, and
C.sub.1-C.sub.20 heteroaryl, or R.sup.10 and R.sup.11 together with
the nitrogen to which they are attached optionally form a
saturated, partially unsaturated or fully unsaturated
C.sub.3-C.sub.20 heterocyclic ring optionally containing one or
more additional ring atoms selected from N, O or S, wherein said
heterocyclic ring is optionally substituted with one or more groups
independently selected from oxo, (CH.sub.2).sub.nOR.sup.a,
NR.sup.aR.sup.b, CF.sub.3, F, Cl, Br, I, SO.sub.2R.sup.a,
C(.dbd.O)R.sup.a, NR.sup.10C(.dbd.Y)R.sup.11,
C(.dbd.Y)NR.sup.10R.sup.11, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 cycloalkyl,
C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl and
C.sub.1-C.sub.20 heteroaryl, or R.sup.10 and R.sup.12 together with
the atoms to which they are attached form an oxo-substituted
C.sub.3-C.sub.20 heterocyclic ring optionally fused to a benzene
ring; R.sup.13 is H, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl,
(CR.sup.14R.sup.15).sub.n-cycloalkyl,
(CR.sup.14R.sup.15).sub.n-heterocyclyl,
(CR.sup.14R.sup.15).sub.n-aryl,
(CR.sup.14R.sup.15).sub.n-heteroaryl,
(CR.sup.14R.sup.15).sub.n--O--(CR.sup.14R.sup.15).sub.m-aryl,
(CR.sup.14R.sup.15).sub.n--OR.sup.10,
(CR.sup.14R.sup.15).sub.n--NR.sup.10R.sup.11,
(CR.sup.14R.sup.15).sub.n--NR.sup.10C(.dbd.O)R.sup.11, or
(CR.sup.14R.sup.15).sub.n--NR.sup.10(SO.sub.2Me)--R.sup.11, wherein
said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and
heteroaryl portions are optionally substituted with one or more
groups independently selected from F, Cl, Br, I, oxo,
SO.sub.2R.sup.c, CN, OR.sup.a, C(.dbd.O)R.sup.a, C(.dbd.O)OR.sup.a,
NR.sup.aR.sup.b, NR.sup.aC(.dbd.O)R.sup.b, C.sub.1-C.sub.12 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12
cycloalkyl, C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl,
and C.sub.1-C.sub.20 heteroaryl; each R.sup.14 and R.sup.15 is
independently H, C.sub.1-C.sub.12 alkyl, or (CH.sub.2).sub.t-aryl,
or R.sup.14 and R.sup.15 together with the atoms to which they are
attached form a saturated or partially unsaturated C.sub.3-C.sub.12
carbocyclic ring, or R.sup.10 and R.sup.15 together with the atoms
to which they are attached form an oxo-substituted saturated or
partially unsaturated monocyclic or bicyclic C.sub.1-C.sub.20
heterocyclic ring optionally further substituted with one or more
groups independently selected from F, Cl, Br, I, OR.sup.a,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl, or C.sub.1-C.sub.20
heteroaryl, wherein said alkyl and aryl are optionally substituted
with one or more groups independently selected from F, Cl, Br, and
I, or R.sup.14 is null and R.sup.10 and R.sup.15 together with the
atoms to which they are attached form a C.sub.1-C.sub.20 heteroaryl
ring having one or more heteroatoms; R.sup.a and R.sup.b are
independently H, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 carbocyclyl,
C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl, or
C.sub.1-C.sub.20 heteroaryl, wherein said alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally
substituted with one or more alkyl groups; R.sup.c is
C.sub.1-C.sub.12 alkyl or C.sub.6-C.sub.20 aryl, wherein said alkyl
and aryl are optionally substituted with one or more groups
independently selected from F, Cl, Br, I, OR.sup.a and
C(.dbd.O)NR.sup.aR.sup.b; R.sup.x is H or C.sub.1-C.sub.6 alkyl;
R.sup.y is (i) (C.sub.1-C.sub.6 alkyl)NR.sup.jR.sup.k wherein
R.sup.j and R.sup.k are independently H or C.sub.1-C.sub.6 alkyl;
(ii) C.sub.5-C.sub.6 cycloalkyl optionally substituted with OH or
--OC(.dbd.O)CF.sub.3; or (iii) a 5-6 membered heterocyclic ring
having 1 to 2 ring heteroatoms independently selected from N and O
and optionally substituted with a halogen group, C.sub.1-C.sub.6
alkyl, (C.sub.1-C.sub.6 alkyl)OH, (C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), or C.sub.1-C.sub.6 fluoroalkyl; Y,
Y.sup.1 and Y.sup.2 are independently O or S; t is 1, 2, 3, 4, 5 or
6; and n and m are independently 0, 1, 2, 3, 4, 5 or 6.
2-73. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/714,342 filed Mar. 6, 2007 and claims
priority to U.S. Provisional Application Ser. Nos. 60/779,805 filed
Mar. 7, 2006 and 60/874,832 filed Dec. 14, 2006, which are
incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The invention relates to heterobicyclic pyrazole compounds
having protein tyrosine kinase activity. The heterobicyclic
pyrazole compounds may be useful in the treatment of
hyperproliferative disorders, such as cancer, in mammals. The
invention also relates to pharmaceutical compositions and
formulations, methods of synthesis, and methods of use such as
treating hyperproliferative disorders.
BACKGROUND OF THE INVENTION
[0003] Met tyrosine kinase is a high-affinity transmembrane
receptor for the hepatocyte growth factor (HGF, Bottaro et al.
(1991) Science 251:802-804). Met was cloned, named (Cooper et al.
(1984) 311:29-33) and identified as an oncogene (Park et al. (1986)
Cell 45:895-904). When deregulated by overexpression or mutations,
Met receptor tyrosine kinase leads to tumor growth and invasion
(Cristiani et al. (2005) Biochem. 44:14110-14119). Stimulation of
Met by the ligand HGF, also known as Scatter Factor, initiates
numerous physiological processes, including cell proliferation,
scattering, morphogenic differentiation, angiogenesis, wound
healing, tissue regeneration, and embryological development (Parr
et al. (2004) Clin. Cancer Res. 10(1, Pt. 1) 202-211; Comoglio et
al. (2002) J. Clin. Invest. 109:857-862; Maulik et al. (2002)
Cytokine Growth Factor Reviews 13:41-59; Hecht et al. (2004) Cancer
Res. 64(17):6109-6118). Receptor c-Met is rapidly internalized via
clathrin-coated vesicles and traffics through an early endosomal
compartment after hepatocyte growth factor stimulation. c-Met
accumulates progressively in perinuclear compartments, which in
part include the Golgi (Kermorgant et al. (2003) J. of Biol. Chem.
278(31):28921-28929).
[0004] The phenomena of: deregulation or dysregulation of Met
and/or HGF; Met overexpression; and Met mutations are implicated in
uncontrolled cell proliferation and survival, and play a key role
in early-stage tumorigenesis, invasive growth of cancer cells, and
metastasis (Danilkovitch-Miagkova et al. (2002) J. Clin. Invest.
109(7):863-867; Di Renzo et al. (1994) Int. J. Cancer 58:658-662;
Matsumoto et al. (1994) J. Biol. Chem. 269:31807-31813; Tusolino et
al. (1998) J. Cell Biol. 142:1145-1156; Jeffers et al. (1996) Mol.
Cell. Biol. 16:1115-1125; Wong et al. (2004) Exper. Cell Res.
299(1):248-256; Konda et al. (2004) J. Urology 171(6), Pt.
1:2166-2170; Heideman et al. (2004) J. Gene Med. 6(3):317-327; Ma
et al. (2003) Cancer Res. 63(19):6272-6281; Maulik et al. (2002)
Clin. Cancer Res. 8:620-627), making Met an important target for
anticancer drug development (Cohen, P. (2002) Nat. Rev. Drug
Discovery 1:309-315). Overexpression of Met and HGF is associated
with poor prognosis.
[0005] Recent data demonstrating the suppression of cancer cell
proliferation, survival, and invasion upon inhibition of Met
binding to HGF and Met receptor dimerization (Furge et al. (2001)
Proc. Natl. Acad. Sci. USA 98:10722-10727; Michieli et al. (2004)
Cancer Cell 6:61-73) confirm the relevance of Met in neoplasia and
provide further proof of concept for the development of
small-molecule compounds for antineoplastic therapy, e.g. against
multiple myeloma (Hov et al. (2004) Clin. Cancer Res.
10(19):6686-6694). Inhibition of Met results in slowing tumor
growth in tumor xenograft mouse models. Antibodies specific for
c-Met have been expressed to block binding of HGF to c-Met (US
2005/0037431; US 2004/0166544).
[0006] Protein kinases (PK) are enzymes that catalyze the
phosphorylation of hydroxy groups on tyrosine, serine and threonine
residues of proteins by transfer of the terminal (gamma) phosphate
from ATP. Through signal transduction pathways, these enzymes
modulate cell growth, differentiation and proliferation, i.e.,
virtually all aspects of cell life in one way or another depend on
PK activity. Furthermore, abnormal PK activity has been related to
a host of disorders, ranging from relatively non-life threatening
diseases such as psoriasis to extremely virulent diseases such as
glioblastoma (brain cancer). Protein kinases include two classes;
protein tyrosine kinases (PTK) and serine-threonine kinases
(STK).
[0007] One of the prime aspects of PTK activity is their
involvement with growth factor receptors which are cell-surface
proteins. When bound by a growth factor ligand, growth factor
receptors are converted to an active form which interacts with
proteins on the inner surface of a cell membrane. This leads to
phosphorylation on tyrosine residues of the receptor and other
proteins and to the formation inside the cell of complexes with a
variety of cytoplasmic signaling molecules that, in turn, effect
numerous cellular responses such as cell division (proliferation),
cell differentiation, cell growth, expression of metabolic effects
to the extracellular microenvironment, etc. For a more complete
discussion, see Schlessinger and Ullrich, (1992) Neuron
9:303-391.
[0008] Growth factor receptors with PTK activity are known as
receptor tyrosine kinases (RTK, Plowman et al. (1994) DN&P,
7(6):334-339), which comprise a large family of transmembrane
receptors with diverse biological activity. At present, at least
nineteen (19) distinct subfamilies of RTK have been identified. An
example of these is the subfamily designated the "HER" RTK, which
include EGFR (epithelial growth factor receptor), HER2, HER3 and
HER4. These RTK consist of an extracellular glycosylated ligand
binding domain, a transmembrane domain and an intracellular
cytoplasmic catalytic domain that can phosphorylate tyrosine
residues on proteins. Another RTK subfamily consists of insulin
receptor (IR), insulin-like growth factor I receptor (IGF-1R) and
insulin receptor related receptor (IRR). IR and IGF-1R interact
with insulin, IGF-I and IGF-II to form a heterotetramer of two
entirely extracellular glycosylated alpha subunits and two beta
subunits which cross the cell membrane and which contain the
tyrosine kinase domain. A third RTK subfamily is referred to as the
platelet derived growth factor receptor (PDGFR) group, which
includes PDGFR-alpha, PDGFR-beta, CSFIR, c-kit and c-fms. These
receptors consist of glycosylated extracellular domains composed of
variable numbers of immunoglobin-like loops and an intracellular
domain wherein the tyrosine kinase domain is interrupted by
unrelated amino acid sequences. Another group which, because of its
similarity to the PDGFR subfamily, is sometimes subsumed into the
later group is the fetus liver kinase (flk) receptor subfamily.
This group is believed to be made up of kinase insert
domain-receptor fetal liver kinase-1 (KDR/FLK-1), flk-1R, flk-4 and
fins-like tyrosine kinase 1 (flt-1). Another member of the tyrosine
kinase growth factor receptor family is the fibroblast growth
factor ("FGF") receptor subgroup. This group consists of four
receptors, FGFR1-4, and seven ligands, FGF1-7. While not yet well
defined, it appears that these receptors consist of a glycosylated
extracellular domain containing a variable number of
immunoglobin-like loops and an intracellular domain in which the
tyrosine kinase sequence is interrupted by regions of unrelated
amino acid sequences. Still another member of the tyrosine kinase
growth factor receptor family is the vascular endothelial growth
factor (VEGF) receptor subgroup. VEGF is a dimeric glycoprotein
similar to PDGF but has different biological functions and target
cell specificity in vivo. In particular, VEGF is presently thought
to play an essential role is vasculogenesis and angiogenesis.
[0009] Met is still another member of the tyrosine kinase growth
factor receptor family, and often referred to as c-Met or human
hepatocyte growth factor receptor tyrosine kinase (hHGFR). The
expression of c-Met is thought to play a role in primary tumor
growth and metastasis (Kim et al. Clin. Cancer Res. (2003)
9(14):5161-5170).
[0010] Modulation of the HGF/c-Met signaling pathway may be
effected by regulating binding of HGF beta chain to cMet. In
particular embodiments, the zymogen-like form of HGF beta mutant
was shown to bind Met with 14-fold lower affinity than the
wild-type serine protease-like form, suggesting optimal
interactions result from conformational changes upon cleavage of
the single-chain form (US 2005/0037431). Extensive mutagenesis of
the HGF beta region corresponding to the active site and activation
domain of serine proteases showed that 17 of the 38 purified
two-chain HGF mutants resulted in impaired cell migration or Met
phosphorylation but no loss in Met binding. However, reduced
biological activities were well correlated with reduced Met binding
of corresponding mutants of HGF beta itself in assays eliminating
dominant alpha-chain binding contributions.
[0011] Protein-tyrosine kinases (PTK) are critical components of
signaling pathways that control cellular proliferation and
differentiation. PTK are subdivided into two large families,
receptor tyrosine kinases (RTK) and non-receptor tyrosine kinases
(NRTK). RTK span the plasma membrane and contain an extra-cellular
domain, which binds ligand, and an intracellular portion, which
possesses catalytic activity and regulatory sequences. Most RTK,
like the hepatocyte growth factor receptor c-met, possess a single
polypeptide chain and are monomeric in the absence of a ligand.
Ligand binding to the extracellular portion of RTK, dimerizes
monomeric receptors, resulting in autophosphorylation of specific
tyrosine residues in the cytoplasmic portion (for review see:
Blume-Jensen, P., and Hunter, T., Nature (2001) 411:355-365;
Hubbard, S. R., et al., J. Biol. Chem. 273 (1998) 11987-11990;
Zwick, E., et al., Trends Mol. Med. (2002) 8:17-23). In general,
tyrosine autophosphorylation either stimulates the intrinsic
catalytic kinase activity of the receptor or generates recruitment
sites for downstream signaling proteins containing
phosphotyrosine-recognition domains, such as the Src homology 2
(SH2) domain or the phosphotyrosine-binding (PTB) domain.
[0012] PTK have become primary targets for the development of novel
therapeutics designed to block cancer cell proliferation,
metastasis, and angiogenesis and promote apoptosis. The strategy
that has progressed farthest in clinical development is the use of
monoclonal antibodies to target growth factor receptor tyrosine
kinases. The use of small molecule tyrosine kinase inhibitors
however could have significant theoretical advantages over
monoclonal antibodies. Small molecule inhibitors could have better
tissue penetration, could have activity against intracellular
targets and mutated targets and could be designed to have oral
bioavailability. Several lead compounds have shown promising
activity against such targets as the EGFR, the vascular endothelial
cell growth factor receptor and bcr-abl. The hepatocyte growth
factor receptor c-Met was first identified as an activated oncogene
in an N-methyl-N'-nitrosoguanidinic treated human osteogenic
sarcoma cell line (MUNG-HOS) by its ability to transform NIH 3T3
mouse fibroblasts. The receptor encoded by the c-Met protooncogene
(located on chromosome 7) is a two-chain protein composed of 50 kDa
(alpha) chain disulfide linked to a 145 kDa (beta) chain in an
alpha-beta complex of 190 kDa. The alpha-chain is exposed at the
cell surface while the beta chain spans the cell membrane and
possesses an intracellular tyrosine kinase domain. The presence of
this intracellular tyrosine kinase domain groups c-Met as a member
of the receptor tyrosine kinase (RTK) family of cell surface
molecules.
[0013] Much evidence supports the role of HGF as a regulator of
carcinogenesis, cancer invasion and metastasis (for review see:
Herynk, M. H., and Radinsky, R. (2000) In Vivo 14:587-596; Jiang et
al. (1999) Crit. Rev. Oncol. Hematol. 29:209-248; Longati (2001)
Curr. Drug Targets 2:41-55; Maulik et al., (2002) Cytokine Growth
Factor Rev. 13:41-59; Parr, C., and Jiang, W. G., (2001) Histol.
Histopathol. 16:251-268). HGF binds to and induces tyrosine
phosphorylation of the mature c-met receptor beta-chain. Such
events are thought to promote binding of intracellular signaling
proteins containing src homology (SH) regions such as PLC-gamma,
Ras-GAP, PI-3 kinase pp.sup.60c-src and the GRB-2 Socs complex to
the activated receptor. Each SH2-containing protein may activate a
different subset of signaling phosphopeptides, thus eliciting
different responses within the cell. c-Met mutations have been
well-described in hereditary and sporadic human papillary renal
carcinomas and have been reported in ovarian cancer, childhood
hepatocellular carcinoma, metastatic head and neck squamous cell
carcinomas, and gastric cancer. c-Met is also over-expressed in
both non-small cell lung cancer and small cell lung cancer cells,
in lung, breast, colon and prostate tumors (Herynk et al. (2003)
Cancer Res. 63(11):2990-2996; Maulik et al. (2002) Clin. Cancer
Res. 8:620-627). Since c-Met appears to play an important role in
oncogenesis of a variety of tumors, various inhibition strategies
have been employed to therapeutically target this receptor tyrosine
kinase. The usefulness of inhibiting the protein-tyrosine kinase
c-Met for inhibiting tumor growth and invasion has been shown in
many well documented preclinical experiments (Abounader et al.
(1999) J. Natl. Cancer Inst. 91:1548-1556; Laterra et al. (1997)
Lab. Invest. 76:565-577; Tomioka, D. (2001) Cancer Res.
61:7518-7524; Wang et al. (2001) J. Cell Biology
153:1023-1033).
[0014] c-Met inhibitors have been reported (US 2004/0242603; US
2004/0110758; US 2005/0009845; WO 2003/000660; WO 98/007695; U.S.
Pat. No. 5,792,783; U.S. Pat. No. 5,834,504; U.S. Pat. No.
5,880,141; US 2003/0125370; U.S. Pat. No. 6,599,902; WO
2005/030140; WO 2005/070891; US 2004/0198750; U.S. Pat. No.
6,790,852; WO 2003/087026; U.S. Pat. No. 6,790,852; WO 2003/097641;
U.S. Pat. No. 6,297,238; WO 2005/005378; WO 2004/076412; WO
2005/004808; WO 2005/010005; US 2005/0009840; WO 2005/121125; WO
2006/014325). PHA-665752 is a small molecule, ATP-competitive,
active-site inhibitor of the catalytic activity of c-Met, as well
as phenotypes such as cell growth, cell motility, invasion, and
morphology of a variety of tumor cells (Ma et al. (2005) Clin.
Cancer Res. 11:2312-2319; Christensen et al. (2003) Cancer Res.
63:7345-7355).
SUMMARY OF THE INVENTION
[0015] In one aspect, the invention relates to heterobicyclic
pyrazole compounds that are inhibitors of receptor tyrosine kinases
(RTK), including c-Met. Certain hyperproliferative disorders are
characterized by the overactivation of c-Met kinase function, for
example by mutations or overexpression of the protein. Accordingly,
the compounds of the invention are useful in the treatment of
hyperproliferative disorders such as cancer.
[0016] More specifically, one aspect of the invention provides
heterobicyclic pyrazole compounds of Formulas Ia and Ib:
##STR00002##
[0017] and stereoisomers, geometric isomers, tautomers, solvates,
metabolites and pharmaceutically acceptable salts and prodrugs
thereof, wherein R.sup.1, R.sup.2, R.sup.3, X, Z.sup.2 and Z.sup.3
are as defined herein.
[0018] Another aspect of the invention provides a pharmaceutical
composition comprising a heterobicyclic pyrazole compound of
Formulas Ia or Ib and a pharmaceutically acceptable carrier. The
pharmaceutical composition may further comprise one or more
additional therapeutic agents selected from anti-proliferative
agents, anti-inflammatory agents, immunomodulatory agents,
neurotropic factors, agents for treating cardiovascular disease,
agents for treating liver disease, anti-viral agents, agents for
treating blood disorders, agents for treating diabetes, and agents
for treating immunodeficiency disorders.
[0019] Another aspect of the invention provides methods of
inhibiting or modulating receptor tyrosine kinase activity,
comprising contacting the kinase with an effective inhibitory
amount of a compound of Formula Ia or Ib.
[0020] Another aspect of the invention provides methods of
inhibiting c-Met kinase activity, comprising contacting a c-Met
kinase with an effective inhibitory amount of a compound of Formula
Ia or Ib, or a stereoisomer, geometric isomer, tautomer, solvate,
metabolite, or pharmaceutically acceptable salt or prodrug
thereof.
[0021] Another aspect of the invention provides methods of
preventing or treating a disease or disorder modulated by c-Met
kinases, comprising administering to a mammal in need of such
treatment an effective amount of a compound of Formula Ia or Ib, or
a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or
pharmaceutically acceptable salt or prodrug thereof. Examples of
such diseases, conditions and disorders include, but are not
limited to, hyperproliferative disorders (e.g., cancer, including
melanoma and other cancers of the skin), neurodegeneration, cardiac
hypertrophy, pain, migraine, neurotraumatic diseases, stroke,
diabetes, hepatomegaly, cardiovascular disease, Alzheimer's
disease, cystic fibrosis, viral diseases, autoimmune diseases,
atherosclerosis, restenosis, psoriasis, allergic disorders,
inflammation, neurological disorders, hormone-related diseases,
conditions associated with organ transplantation, immunodeficiency
disorders, destructive bone disorders, proliferative disorders,
infectious diseases, conditions associated with cell death,
thrombin-induced platelet aggregation, chronic myelogenous leukemia
(CML), liver disease, pathologic immune conditions involving T cell
activation, and CNS disorders.
[0022] Another aspect of the invention provides methods of
preventing or treating a hyperproliferative disorder, comprising
administering to a mammal in need of such treatment an effective
amount of a compound of Formula Ia or Ib, or a stereoisomer,
geometric isomer, tautomer, solvate, metabolite, or
pharmaceutically acceptable salt or prodrug thereof, alone or in
combination with one or more additional compounds having
anti-hyperproliferative properties.
[0023] In a further aspect the present invention provides a method
of using a compound of this invention to treat a disease or
condition modulated by c-Met in a mammal.
[0024] An additional aspect of the invention is the use of a
compound of this invention in the preparation of a medicament for
the treatment or prevention of a disease or condition modulated by
c-Met in a mammal.
[0025] Another aspect of the invention includes kits comprising a
compound of Formula Ia or Ib, or a stereoisomer, geometric isomer,
tautomer, solvate, metabolite, or pharmaceutically acceptable salt
or prodrug thereof, a container, and optionally a package insert or
label indicating a treatment.
[0026] Another aspect of the invention includes methods of
preparing, methods of separating, and methods of purifying
compounds of Formula Ia and Ib.
[0027] Additional advantages and novel features of this invention
shall be set forth in part in the description that follows, and in
part will become apparent to those skilled in the art upon
examination of the following specification or may be learned by the
practice of the invention. The advantages of the invention may be
realized and attained by means of the instrumentalities,
combinations, compositions, and methods particularly pointed out in
the appended claims.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0028] Reference will now be made in detail to certain embodiments
of the invention, examples of which are illustrated in the
accompanying structures and formulas. While the invention will be
described in conjunction with the enumerated embodiments, it will
be understood that they are not intended to limit the invention to
those embodiments. On the contrary, the invention is intended to
cover all alternatives, modifications, and equivalents which may be
included within the scope of the present invention as defined by
the claims. One skilled in the art will recognize many methods and
materials similar or equivalent to those described herein, which
could be used in the practice of the present invention. The present
invention is in no way limited to the methods and materials
described. In the event that one or more of the incorporated
literature, patents, and similar materials differs from or
contradicts this application, including but not limited to defined
terms, term usage, described techniques, or the like, this
application controls.
DEFINITIONS
[0029] The term "alkyl" as used herein refers to a saturated linear
or branched-chain monovalent hydrocarbon radical of one to twelve
carbon atoms, wherein the alkyl radical may be optionally
substituted independently with one or more substituents described
below. Examples of alkyl groups include, but are not limited to,
methyl (Me, --CH.sub.3), ethyl (Et, --CH.sub.2CH.sub.3), 1-propyl
(n-Pr, n-propyl, --CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr,
i-propyl, --CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2 CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3, 1-heptyl,
1-octyl, and the like.
[0030] The term "alkyl" includes saturated linear or branched-chain
monovalent hydrocarbon radicals of one to six carbon atoms (e.g.,
C.sub.1-C.sub.6 alkyl), wherein the alkyl radical may be optionally
substituted independently with one or more substituents described
below.
[0031] The term "C.sub.1-C.sub.6 fluoroalkyl" includes an alkyl
group of 1-6 carbons substituted with a fluoro group. The fluoro
group can be substituted at any place on the alkyl group. Examples
include, but are not limited to, CH.sub.2F, CH.sub.2CH.sub.2F,
CH.sub.2CH.sub.2CH.sub.2F, CH.sub.2CH.sub.2CH.sub.2CH.sub.2F,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2F, and the like.
[0032] The term "alkenyl" refers to linear or branched-chain
monovalent hydrocarbon radical of two to twelve carbon atoms with
at least one site of unsaturation, i.e., a carbon-carbon, sp.sup.2
double bond, wherein the alkenyl radical may be optionally
substituted independently with one or more substituents described
herein, and includes radicals having "cis" and "trans"
orientations, or alternatively, "E" and "Z" orientations. Examples
include, but are not limited to, ethylenyl or vinyl
(--CH.dbd.CH.sub.2), allyl (--CH.sub.2CH.dbd.CH.sub.2), and the
like.
[0033] The term "alkynyl" refers to a linear or branched monovalent
hydrocarbon radical of two to twelve carbon atoms with at least one
site of unsaturation, i.e., a carbon-carbon, sp triple bond,
wherein the alkynyl radical may be optionally substituted
independently with one or more substituents described herein.
Examples include, but are not limited to, ethynyl (--C.ident.CH),
propynyl (propargyl, --CH.sub.2C.ident.CH), and the like.
[0034] The terms "carbocycle", "carbocyclyl", "carbocyclic ring"
and "cycloalkyl" refer to a monovalent non-aromatic, saturated or
partially unsaturated ring having 3 to 12 carbon atoms as a
monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring.
Bicyclic carbocycles having 7 to 12 atoms can be arranged, for
example, as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, and
bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a
bicyclo[5,6] or [6,6] system, or as bridged systems such as
bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and
bicyclo[3.2.2]nonane. Examples of monocyclic carbocycles include,
but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,
cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,
1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl,
cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the
like.
[0035] "Aryl" means a monovalent aromatic hydrocarbon radical of
6-20 carbon atoms derived by the removal of one hydrogen atom from
a single carbon atom of a parent aromatic ring system. Some aryl
groups are represented in the exemplary structures as "Ar". Aryl
includes bicyclic radicals comprising an aromatic ring fused to a
saturated, partially unsaturated ring, or aromatic carbocyclic or
heterocyclic ring. Typical aryl groups include, but are not limited
to, radicals derived from benzene, substituted benzenes,
naphthalene, anthracene, biphenyl, indenyl, indanyl,
1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the
like.
[0036] The terms "heterocycle," "heterocyclyl" and "heterocyclic
ring" are used interchangeably herein and refer to a saturated or a
partially unsaturated (i.e., having one or more double and/or
triple bonds within the ring) carbocyclic radical of 3 to 20 ring
atoms in which at least one ring atom is a heteroatom selected from
nitrogen, oxygen and sulfur, the remaining ring atoms being C,
where one or more ring atoms is optionally substituted
independently with one or more substituents described below. A
heterocycle may be a monocycle having 3 to 7 ring members (2 to 6
carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S)
or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1
to 3 heteroatoms selected from N, O, P, and S), for example: a
bicyclo[4,5], [5,5], [5,6], or [6,6] system. Heterocycles are
described in Paquette, Leo A.; "Principles of Modern Heterocyclic
Chemistry" (W. A. Benjamin, New York, 1968), particularly Chapters
1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A
series of Monographs" (John Wiley & Sons, New York, 1950 to
present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am.
Chem. Soc. (1960) 82:5566. The heterocyclyl may be a carbon radical
or heteroatom radical. The term "heterocycle" includes
heterocycloalkoxy. "Heterocyclyl" also includes radicals where
heterocycle radicals are fused with a saturated, partially
unsaturated ring, or aromatic carbocyclic or heterocyclic ring.
Examples of heterocyclic rings include, but are not limited to,
pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl,
piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl,
homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl,
oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl,
dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,
dihydropyranyl, dihydrothienyl, dihydrofuranyl,
pyrazolidinylimidazolinyl, imidazolidinyl,
3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,
azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl
ureas. Spiro moieties are also included within the scope of this
definition. Examples of a heterocyclic group wherein 2 ring carbon
atoms are substituted with oxo (.dbd.O) moieties are pyrimidinonyl
and 1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are
optionally substituted independently with one or more substituents
described herein.
[0037] The term "heteroaryl" refers to a monovalent aromatic
radical of 5-, 6-, or 7-membered rings, and includes fused ring
systems (at least one of which is aromatic) of 5-20 atoms,
containing one or more heteroatoms independently selected from
nitrogen, oxygen, and sulfur. Examples of heteroaryl groups are
pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl,
imidazopyridinyl, pyrimidinyl (including, for example,
4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,
furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl,
pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,
benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,
pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,
oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.
Heteroaryl groups are optionally substituted independently with one
or more substituents described herein.
[0038] The heterocycle or heteroaryl groups may be C-attached or
N-attached where such is possible. By way of example and not
limitation, carbon bonded heterocycles or heteroaryls are bonded at
position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of
a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,
3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,
tetrahydrofuran, thiofuran, thiophene, pyrrole or
tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or
thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or
isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4
of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or
position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
[0039] By way of example and not limitation, nitrogen bonded
heterocycles or heteroaryls are bonded at position 1 of an
aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline,
3-pyrroline, imidazole, imidazolidine, 2-imidazoline,
3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,
piperidine, piperazine, indole, indoline, 1H-indazole, position 2
of a isoindole, or isoindoline, position 4 of a morpholine, and
position 9 of a carbazole, or .beta.-carboline.
[0040] "Substituted alkyl", "substituted alkenyl", "substituted
alkynyl", "substituted aryl", "substituted heteroaryl",
"substituted heterocyclyl" and "substituted cycloalkyl" mean alkyl,
alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl,
respectively, in which one or more hydrogen atoms are each
independently replaced with a substituent. Typical substituents
include, but are not limited to, F, Cl, Br, I, CN, CF.sub.3, OR, R,
.dbd.O, .dbd.S, .dbd.NR, .dbd.N.sup.+(O)(R), .dbd.N(OR),
.dbd.N.sup.+(O)(OR), .dbd.N--NRR', --C(.dbd.O)R, --C(.dbd.O)OR,
--C(.dbd.O)NRR', --NRR', --N.sup.+RR'R'', --N(R)C(.dbd.O)R',
--N(R)C(.dbd.O)OR', --N(R)C(.dbd.O)NR'R'', --SR, --OC(.dbd.O)R,
--OC(.dbd.O)OR, --OC(.dbd.O)NRR', --OS(O).sub.2(OR),
--OP(.dbd.O)(OR)(OR'), --OP(OR)(OR'), --P(.dbd.O)(OR)(OR'),
--P(.dbd.O)(OR)NR'R'', --S(O)R, --S(O).sub.2R, --S(O).sub.2NR,
--S(O)(OR), --S(O).sub.2(OR), --SC(.dbd.O)R, --SC(.dbd.O)OR, .dbd.O
and --SC(.dbd.O)NRR'; wherein each R, R' and R'' is independently
selected from H, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, C.sub.6-C.sub.20 aryl and C.sub.2-C.sub.20
heterocyclyl. Substituents may also be combinations of alkyl,
alkenyl, alkynyl, carbocycle, aryl, and heteroaryl radicals, such
as cyclopropylmethyl, cyclohexylethyl, benzyl, and
N-ethylmorpholino, and substituted forms thereof.
[0041] The terms "treat" and "treatment" refer to both therapeutic
treatment and prophylactic or preventative measures, wherein the
object is to prevent or slow down (lessen) an undesired
physiological change or disorder, such as the development or spread
of cancer. For purposes of this invention, beneficial or desired
clinical results include, but are not limited to, alleviation of
symptoms, diminishment of extent of disease, stabilized (i.e., not
worsening) state of disease, delay or slowing of disease
progression, amelioration or palliation of the disease state, and
remission (whether partial or total), whether detectable or
undetectable. "Treatment" can also mean prolonging survival as
compared to expected survival if not receiving treatment. Those in
need of treatment include those already with the condition or
disorder as well as those prone to have the condition or disorder
or those in which the condition or disorder is to be prevented.
[0042] The phrase "therapeutically effective amount" means an
amount of a compound of the present invention that (i) treats or
prevents the particular disease, condition, or disorder, (ii)
attenuates, ameliorates, or eliminates one or more symptoms of the
particular disease, condition, or disorder, or (iii) prevents or
delays the onset of one or more symptoms of the particular disease,
condition, or disorder described herein. In the case of cancer, the
therapeutically effective amount of the drug may reduce the number
of cancer cells; reduce the tumor size; inhibit (i.e., slow to some
extent and preferably stop) cancer cell infiltration into
peripheral organs; inhibit (i.e., slow to some extent and
preferably stop) tumor metastasis; inhibit, to some extent, tumor
growth; and/or relieve to some extent one or more of the symptoms
associated with the cancer. To the extent the drug may prevent
growth and/or kill existing cancer cells, it may be cytostatic
and/or cytotoxic. For cancer therapy, efficacy can be measured, for
example, by assessing the time to disease progression (TTP) and/or
determining the response rate (RR).
[0043] The term "bioavailability" refers to the systemic
availability (i.e., blood/plasma levels) of a given amount of drug
administered to a patient. Bioavailability is an absolute term that
indicates measurement of both the time (rate) and total amount
(extent) of drug that reaches the general circulation from an
administered dosage form.
[0044] The terms "cancer" and "cancerous" refer to or describe the
physiological condition in mammals that is typically characterized
by unregulated cell growth. A "tumor" comprises one or more
cancerous cells. Examples of cancer include, but are not limited
to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or
lymphoid malignancies. More particular examples of such cancers
include squamous cell cancer (e.g., epithelial squamous cell
cancer), lung cancer including small-cell lung cancer, non-small
cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous
carcinoma of the lung, cancer of the peritoneum, hepatocellular
cancer, gastric or stomach cancer including gastrointestinal
cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian
cancer, liver cancer, bladder cancer, hepatoma, breast cancer,
colon cancer, rectal cancer, colorectal cancer, endometrial or
uterine carcinoma, salivary gland carcinoma, kidney or renal
cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic
carcinoma, anal carcinoma, penile carcinoma, as well as head and
neck cancer.
[0045] A "chemotherapeutic agent" is a chemical compound useful in
the treatment of cancer. Examples of chemotherapeutic agents
include Erlotinib (TARCEVA.RTM., Genentech/OSI Pharm.), Bortezomib
(VELCADE.RTM., Millennium Pharm.), Fulvestrant (FASLODEX.RTM.,
AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA.RTM.,
Novartis), Imatinib mesylate (GLEEVEC.RTM., Novartis), PTK787/ZK
222584 (Novartis), Oxaliplatin (Eloxatin.RTM., Sanofi), 5-FU
(5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE.RTM.,
Wyeth), Lapatinib (GSK572016, Glaxo Smith Kline), Lonafarnib (SCH
66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib
(IRESSA.RTM., AstraZeneca), AG1478, AG1571 (SU 5271; Sugen),
alkylating agents such as thiotepa and CYTOXAN.RTM.
cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan
and piposulfan; aziridines such as benzodopa, carboquone,
meturedopa, and uredopa; ethylenimines and methylamelamines
including altretamine, triethylenemelamine,
triethylenephosphoramide, triethylenethiophosphoramide and
trimethylomelamine; acetogenins (especially bullatacin and
bullatacinone); a camptothecin (including the synthetic analog
topotecan); bryostatin; callystatin; CC-1065 (including its
adozelesin, carzelesin and bizelesin synthetic analogs);
cryptophycins (particularly cryptophycin 1 and cryptophycin 8);
dolastatin; duocarmycin (including the synthetic analogs, KW-2189
and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin;
spongistatin; nitrogen mustards such as chlorambucil,
chlornaphazine, cholophosphamide, estramustine, ifosfamide,
mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,
novembichin, phenesterine, prednimustine, trofosfamide, uracil
mustard; nitrosureas such as carmustine, chlorozotocin,
fotemustine, lomustine, nimustine, and ranimustine; antibiotics
such as the enediyne antibiotics (e.g., calicheamicin, especially
calicheamicin gamma1I and calicheamicin omegaI1 (Angew Chem. Intl.
Ed. Engl. (1994) 33:183-186); dynemicin, including dynemicin A;
bisphosphonates, such as clodronate; an esperamicin; as well as
neocarzinostatin chromophore and related chromoprotein enediyne
antibiotic chromophores), aclacinomysins, actinomycin, authramycin,
azaserine, bleomycins, cactinomycin, carabicin, caminomycin,
carzinophilin, chromomycinis, dactinomycin, daunorubicin,
detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN.RTM.
(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,
2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin,
esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin
C, mycophenolic acid, nogalamycin, olivomycins, peplomycin,
potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin,
streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;
anti-metabolites such as methotrexate and 5-fluorouracil (5-FU);
folic acid analogs such as denopterin, methotrexate, pteropterin,
trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine,
thiamiprine, thioguanine; pyrimidine analogs such as ancitabine,
azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine,
doxifluridine, enocitabine, floxuridine; androgens such as
calusterone, dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane,
trilostane; folic acid replenisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate;
defofamine; demecolcine; diaziquone; elformithine; elliptinium
acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea;
lentinan; lonidainine; maytansinoids such as maytansine and
ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine;
pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic
acid; 2-ethylhydrazide; procarbazine; PSK.RTM. polysaccharide
complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;
sizofiran; spirogermanium; tenuazonic acid; triaziquone;
2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2
toxin, verracurin A, roridin A and anguidine); urethan; vindesine;
dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;
gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa;
taxoids, e.g., TAXOL.RTM. (paclitaxel; Bristol-Myers Squibb
Oncology, Princeton, N.J.), ABRAXANE.RTM. (Cremophor-free),
albumin-engineered nanoparticle formulations of paclitaxel
(American Pharmaceutical Partners, Schaumberg, Ill.), and
TAXOTERE.RTM. (doxetaxel; Rhone-Poulenc Rorer, Antony, France);
chloranbucil; GEMZAR.RTM. (gemcitabine); 6-thioguanine;
mercaptopurine; methotrexate; platinum analogs such as cisplatin
and carboplatin; vinblastine; etoposide (VP-16); ifosfamide;
mitoxantrone; vincristine; NAVELBINE.RTM. (vinorelbine);
novantrone; teniposide; edatrexate; daunomycin; aminopterin;
xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;
difluoromethylornithine (DMFO); retinoids such as retinoic acid;
capecitabine; and pharmaceutically acceptable salts, acids and
derivatives of any of the above.
[0046] Also included in the definition of "chemotherapeutic agent"
are: (i) anti-hormonal agents that act to regulate or inhibit
hormone action on tumors such as anti-estrogens and selective
estrogen receptor modulators (SERMs), including, for example,
tamoxifen (including NOLVADEX.RTM.; tamoxifen citrate), raloxifene,
droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018,
onapristone, and FARESTON.RTM. (toremifine citrate); (ii) aromatase
inhibitors that inhibit the enzyme aromatase, which regulates
estrogen production in the adrenal glands, such as, for example,
4(5)-imidazoles, aminoglutethimide, MEGASE.RTM. (megestrol
acetate), AROMASIN.RTM. (exemestane; Pfizer), formestanie,
fadrozole, RIVISOR.RTM. (vorozole), FEMARA.RTM. (letrozole;
Novartis), and ARIMIDEX.RTM. (anastrozole; AstraZeneca); (iii)
anti-androgens such as flutamide, nilutamide, bicalutamide,
leuprolide, and goserelin; as well as troxacitabine (a
1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase
inhibitors; (v) lipid kinase inhibitors; (vi) antisense
oligonucleotides, particularly those which inhibit expression of
genes in signaling pathways implicated in aberrant cell
proliferation, such as, for example, PKC-alpha, Ralf and H-Ras;
(vii) ribozymes such as VEGF expression inhibitors (e.g.,
ANGIOZYME.RTM.) and HER2 expression inhibitors; (viii) vaccines
such as gene therapy vaccines, for example, ALLOVECTIN.RTM.,
LEUVECTIN.RTM., and VAXID.RTM.; PROLEUKIN.RTM. rIL-2; a
topoisomerase 1 inhibitor such as LURTOTECAN.RTM.; ABARELIX.RTM.
rmRH; (ix) anti-angiogenic agents such as bevacizumab
(AVASTIN.RTM., Genentech); and (x) pharmaceutically acceptable
salts, acids and derivatives of any of the above.
[0047] The term "prodrug" as used in this application refers to a
precursor or derivative form of a compound of the invention that is
less cytotoxic to cells compared to the parent compound or drug and
is capable of being enzymatically or hydrolytically activated or
converted into the more active parent form. See, e.g., Wilman,
"Prodrugs in Cancer Chemotherapy" Biochemical Society Transactions,
14, pp. 375-382, 615th Meeting Belfast (1986) and Stella et al.,
"Prodrugs: A Chemical Approach to Targeted Drug Delivery," Directed
Drug Delivery, Borchardt et al., (ed.), pp. 247-267, Humana Press
(1985). The prodrugs of this invention include, but are not limited
to, phosphate-containing prodrugs, thiophosphate-containing
prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs,
D-amino acid-modified prodrugs, glycosylated prodrugs,
.beta.-lactam-containing prodrugs, optionally substituted
phenoxyacetamide-containing prodrugs, optionally substituted
phenylacetamide-containing prodrugs, 5-fluorocytosine and other
5-fluorouridine prodrugs which can be converted into the more
active cytotoxic free drug. Examples of cytotoxic drugs that can be
derivatized into a prodrug form for use in this invention include,
but are not limited to, compounds of the invention and
chemotherapeutic agents such as described above.
[0048] A "metabolite" is a product produced through metabolism in
the body of a specified compound or salt thereof. Metabolites of a
compound may be identified using routine techniques known in the
art and their activities determined using tests such as those
described herein. Such products may result for example from the
oxidation, reduction, hydrolysis, amidation, deamidation,
esterification, deesterification, enzymatic cleavage, and the like,
of the administered compound. Accordingly, the invention includes
metabolites of compounds of the invention, including compounds
produced by a process comprising contacting a compound of this
invention with a mammal for a period of time sufficient to yield a
metabolic product thereof.
[0049] A "liposome" is a small vesicle composed of various types of
lipids, phospholipids and/or surfactant which is useful for
delivery of a drug (such as the cMet inhibitors disclosed herein
and, optionally, a chemotherapeutic agent) to a mammal. The
components of the liposome are commonly arranged in a bilayer
formation, similar to the lipid arrangement of biological
membranes.
[0050] The term "package insert" is used to refer to instructions
customarily included in commercial packages of therapeutic
products, that contain information about the indications, usage,
dosage, administration, contraindications and/or warnings
concerning the use of such therapeutic products.
[0051] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0052] The term "stereoisomers" refers to compounds which have
identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
[0053] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties, e.g.
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0054] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0055] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds",
John Wiley & Sons, Inc., New York, 1994. The compounds of the
invention may contain asymmetric or chiral centers, and therefore
exist in different stereoisomeric forms. It is intended that all
stereoisomeric forms of the compounds of the invention, including
but not limited to, diastereomers, enantiomers and atropisomers, as
well as mixtures thereof such as racemic mixtures, form part of the
present invention. Many organic compounds exist in optically active
forms, i.e., they have the ability to rotate the plane of
plane-polarized light. In describing an optically active compound,
the prefixes D and L, or R and S, are used to denote the absolute
configuration of the molecule about its chiral center(s). The
prefixes d and l or (+) and (-) are employed to designate the sign
of rotation of plane-polarized light by the compound, with (-) or l
meaning that the compound is levorotatory. A compound prefixed with
(+) or d is dextrorotatory. For a given chemical structure, these
stereoisomers are identical except that they are mirror images of
one another. A specific stereoisomer may also be referred to as an
enantiomer, and a mixture of such isomers is often called an
enantiomeric mixture. A 50:50 mixture of enantiomers is referred to
as a racemic mixture or a racemate, which may occur where there has
been no stereoselection or stereospecificity in a chemical reaction
or process. The terms "racemic mixture" and "racemate" refer to an
equimolar mixture of two enantiomeric species, devoid of optical
activity.
[0056] The term "tautomer" or "tautomeric form" refers to
structural isomers of different energies which are interconvertible
via a low energy barrier. For example, proton tautomers (also known
as prototropic tautomers) include interconversions via migration of
a proton, such as keto-enol and imine-enamine isomerizations.
Valence tautomers include interconversions by reorganization of
some of the bonding electrons.
[0057] The phrase "pharmaceutically acceptable salt," as used
herein, refers to pharmaceutically acceptable organic or inorganic
salts of a compound of the invention. Exemplary salts include, but
are not limited, to sulfate, citrate, acetate, oxalate, chloride,
bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,
isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate,
tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A
pharmaceutically acceptable salt may involve the inclusion of
another molecule such as an acetate ion, a succinate ion or other
counter ion. The counter ion may be any organic or inorganic moiety
that stabilizes the charge on the parent compound. Furthermore, a
pharmaceutically acceptable salt may have more than one charged
atom in its structure. Instances where multiple charged atoms are
part of the pharmaceutically acceptable salt can have multiple
counter ions. Hence, a pharmaceutically acceptable salt can have
one or more charged atoms and/or one or more counter ion.
[0058] The compounds of Formulas Ia and Ib also include other salts
of such compounds which are not necessarily pharmaceutically
acceptable salts, and which may be useful as intermediates for
preparing and/or purifying compounds of Formulas Ia or Ib and/or
for separating enantiomers of compounds of Formulas Ia or Ib.
[0059] If the compound of the invention is a base, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method available in the art, for example, treatment of the free
base with an inorganic acid, such as hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid and the like, or
with an organic acid, such as acetic acid, maleic acid, succinic
acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,
oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid,
such as glucuronic acid or galacturonic acid, an alpha hydroxy
acid, such as citric acid or tartaric acid, an amino acid, such as
aspartic acid or glutamic acid, an aromatic acid, such as benzoic
acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic
acid or ethanesulfonic acid, or the like.
[0060] If the compound of the invention is an acid, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method, for example, treatment of the free acid with an inorganic
or organic base, such as an amine (primary, secondary or tertiary),
an alkali metal hydroxide or alkaline earth metal hydroxide, or the
like. Illustrative examples of suitable salts include, but are not
limited to, organic salts derived from amino acids, such as glycine
and arginine, ammonia, primary, secondary, and tertiary amines, and
cyclic amines, such as piperidine, morpholine and piperazine, and
inorganic salts derived from sodium, calcium, potassium, magnesium,
manganese, iron, copper, zinc, aluminum and lithium.
[0061] The phrase "pharmaceutically acceptable" indicates that the
substance or composition must be compatible chemically and/or
toxicologically, with the other ingredients comprising a
formulation, and/or the mammal being treated therewith.
[0062] A "solvate" refers to an association or complex of one or
more solvent molecules and a compound of the invention. Examples of
solvents that form solvates include, but are not limited to, water,
isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,
and ethanolamine. The term "hydrate" refers to the complex where
the solvent molecule is water.
[0063] The term "protecting group" or "Pg" refers to a substituent
that is commonly employed to block or protect a particular
functionality while reacting other functional groups on the
compound. For example, an "amino-protecting group" is a substituent
attached to an amino group that blocks or protects the amino
functionality in the compound. Suitable amino-protecting groups
include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),
benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
Similarly, a "hydroxy-protecting group" refers to a substituent of
a hydroxy group that blocks or protects the hydroxy functionality.
Suitable protecting groups include acetyl and silyl. A
"carboxy-protecting group" refers to a substituent of the carboxy
group that blocks or protects the carboxy functionality. Common
carboxy-protecting groups include --CH.sub.2CH.sub.2SO.sub.2Ph,
cyanoethyl, 2-(trimethylsilyl)ethyl,
2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,
2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl,
nitroethyl and the like. For a general description of protecting
groups and their use, see T. W. Greene, Protective Groups in
Organic Synthesis, John Wiley & Sons, New York, 1991.
[0064] The terms "compound of this invention," and "compounds of
the present invention" and "compounds of Formula Ia and Ib" include
compounds of Formulas Ia and Ib and stereoisomers, geometric
isomers, tautomers, solvates, metabolites, and pharmaceutically
acceptable salts and prodrugs thereof.
[0065] The term "mammal" includes, but is not limited to, humans,
dogs, cats, horses, cows, pigs, sheep, and poultry.
c-Met Inhibitor Compounds
[0066] The present invention provides heterobicyclic pyrazole
compounds, and pharmaceutical formulations thereof, that are
potentially useful in the treatment of diseases, conditions and/or
disorders modulated by c-Met. More specifically, the present
invention provides compounds of Formulas Ia and Ib
##STR00003##
[0067] and stereoisomers, geometric isomers, tautomers, solvates,
metabolites and pharmaceutically acceptable salts and prodrugs
thereof, wherein:
[0068] X is O, S or NR.sup.10;
[0069] Z.sup.2 and Z.sup.3 are independently selected from CR.sup.4
and N, wherein zero or one of Z.sup.2 and Z.sup.3 is N;
[0070] R.sup.1 is H, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, --C(.dbd.O)NR.sup.10R.sup.11, or
--(CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11, or
[0071] R.sup.1 is C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl or C.sub.1-C.sub.20 heteroaryl,
wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl and heteroaryl are optionally substituted with one or more
groups independently selected from F, Cl, Br, I, CN, CF.sub.3, oxo,
--OR.sup.10, SR.sup.10, --C(.dbd.Y)R.sup.10, --C(.dbd.Y)OR.sup.10,
--C(.dbd.Y)NR.sup.10R.sup.11,
--(CR.sup.14R.sup.15).sub.n--NR.sup.10R.sup.11,
--NR.sup.10C(.dbd.Y)R.sup.13, --NR.sup.10C(.dbd.Y)OR.sup.11,
--NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11, --NR.sup.12SO.sub.2R.sup.10,
--OC(.dbd.Y)R.sup.10, --OC(.dbd.Y)OR.sup.10,
--OC(.dbd.Y)NR.sup.10R.sup.11, --OS(O).sub.2(OR.sup.10),
--OP(.dbd.Y)(OR.sup.10)(OR.sup.11), --OP(OR.sup.10)(OR.sup.11),
--S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --S(O)(OR.sup.10),
--S(O).sub.2(OR.sup.10), --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, --SC(.dbd.Y)NR.sup.10R.sup.11,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl, C.sub.1-C.sub.20
heteroaryl,
--(CR.sup.14R.sup.15)--NR.sup.12C(.dbd.O)(CR.sup.14R.sup.15)NR.sup.10R.su-
p.11, and (CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11, or
[0072] R.sup.1 is NR.sup.xR.sup.y;
[0073] R.sup.2 is H, CF.sub.3, CN, --C(.dbd.Y)R.sup.10,
--C(.dbd.Y)OR.sup.10, --C(.dbd.Y)NR.sup.10R.sup.11,
--C(.dbd.O)NR.sup.12(CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11,
--SR.sup.10, --S(O)R.sup.10, --S(O).sub.2R.sup.10,
S(O).sub.2NR.sup.10R.sup.11, --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 carbocyclyl,
C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl, or
C.sub.1-C.sub.20 heteroaryl, wherein said alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally
substituted with one or more groups independently selected from F,
Cl, Br, I, (CH.sub.2).sub.nOR.sup.10,
(CH.sub.2).sub.nNR.sup.10R.sup.11, heteroaryl and heterocyclyl;
[0074] R.sup.3 is C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl or C.sub.1-C.sub.20 heteroaryl,
wherein said carbocyclyl, heterocyclyl, aryl and heteroaryl are
optionally substituted with one or more groups independently
selected from F, Cl, Br, I, CN, CF.sub.3, OR.sup.10, SR.sup.10,
--C(.dbd.Y)R.sup.10, --C(.dbd.Y)OR.sup.10,
--C(.dbd.Y)NR.sup.10R.sup.11, --NR.sup.10R.sup.11,
--NR.sup.10C(.dbd.Y)R.sup.13, --NR.sup.10C(.dbd.Y)OR.sup.11,
--NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11,
--NR.sup.12C(.dbd.O)C(.dbd.O)R.sup.10R.sup.11,
--NR.sup.12C(.dbd.O)C(.dbd.O)OR.sup.a, --NR.sup.12SO.sub.2R.sup.10,
--NR.sup.12C(.dbd.Y.sup.1)(CR.sup.14R.sup.15).sub.nC(.dbd.Y.sup.2)NR.sup.-
10R.sup.11,
--NR.sup.12C(.dbd.Y.sup.1)NR.sup.10C(.dbd.Y.sup.2)(CR.sup.14R.sup.15).sub-
.nR.sup.11,
--NR.sup.12C(.dbd.Y.sup.1)(CR.sup.14R.sup.15).sub.nC(.dbd.Y.sup.2)(CR.sup-
.14R.sup.15).sub.mR.sup.10, --OC(.dbd.Y)R.sup.10,
--OC(.dbd.Y)OR.sup.10, --OC(.dbd.Y)NR.sup.10R.sup.11,
--OS(O).sub.2(OR.sup.10), --OP(.dbd.Y)(OR.sup.10)(OR.sup.11),
--OP(OR.sup.10)(OR.sup.11), --S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --S(O)(OR.sup.10),
--S(O).sub.2(OR.sup.10), --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, --SC(.dbd.Y)NR.sup.10R.sup.11,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl and C.sub.1-C.sub.20
heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl and heteroaryl are optionally substituted with
one or more groups independently selected from F, Cl, Br, I, OH,
C.sub.1-C.sub.12 alkyl, NR.sup.10R.sup.11, and
(CR.sup.14R.sup.15).sub.n-aryl;
[0075] R.sup.4 is H, F, Cl, Br, CF.sub.3, CN, --C(.dbd.Y)R.sup.10,
--C(.dbd.Y)OR.sup.10, --C(.dbd.Y)NR.sup.10R.sup.11,
--NR.sup.10R.sup.11, NR.sup.10C(.dbd.Y)R.sup.11,
NR.sup.10C(.dbd.Y)OR.sup.11, NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11,
--NR.sup.12SO.sub.2NR.sup.10R.sup.11, --OR.sup.10,
--OC(.dbd.Y)R.sup.10, --OC(.dbd.Y)OR.sup.10,
--OC(.dbd.Y)NR.sup.10R.sup.11,
--C(.dbd.O)NR.sup.12(CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11,
--OP(.dbd.Y)(OR.sup.10)(OR.sup.11), --OP(OR.sup.10)(OR.sup.11),
--SR.sup.10, --S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 carbocyclyl,
C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl, or
C.sub.1-C.sub.20 heteroaryl;
[0076] R.sup.10, R.sup.11 and R.sup.12 are independently H,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 carbocyclyl,
(CR.sup.14R.sup.15).sub.nC.sub.2-C.sub.20 heterocyclyl,
(CR.sup.14R.sup.15).sub.nC.sub.6-C.sub.20 aryl, or C.sub.1-C.sub.20
heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, and heteroaryl are optionally substituted with
one or more groups independently selected from F, Cl, Br, I,
SO.sub.2R.sup.c, CN, OR.sup.a, NR.sup.aR.sup.b,
C(.dbd.O)NR.sup.aR.sup.b, CR.sup.aC(.dbd.O)R.sup.b,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 carbocyclyl, C.sub.6-C.sub.20 aryl, and
C.sub.1-C.sub.20 heteroaryl,
[0077] or R.sup.10 and R.sup.11 together with the nitrogen to which
they are attached optionally form a saturated, partially
unsaturated or fully unsaturated C.sub.3-C.sub.20 heterocyclic ring
optionally containing one or more additional ring atoms selected
from N, O or S, wherein said heterocyclic ring is optionally
substituted with one or more groups independently selected from
oxo, (CH.sub.2).sub.nOR.sup.a, NR.sup.aR.sup.b, CF.sub.3, F, Cl,
Br, I, SO.sub.2R.sup.a, C(.dbd.O)R.sup.a,
NR.sup.10C(.dbd.Y)R.sup.11, C(.dbd.Y)NR.sup.10R.sup.11,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl and C.sub.1-C.sub.20
heteroaryl,
[0078] or R.sup.10 and R.sup.12 together with the atoms to which
they are attached form an oxo-substituted C.sub.3-C.sub.20
heterocyclic ring optionally fused to a benzene ring;
[0079] R.sup.13 is H, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl,
(CR.sup.14R.sup.15).sub.n-cycloalkyl,
(CR.sup.14R.sup.15).sub.n-heterocyclyl,
(CR.sup.14R.sup.15).sub.n-aryl,
(CR.sup.14R.sup.15).sub.n-heteroaryl,
(CR.sup.14R.sup.15).sub.n--O--(CR.sup.14R.sup.15).sub.m-aryl,
(CR.sup.14R.sup.15).sub.n--OR.sup.10,
(CR.sup.14R.sup.15).sub.n--NR.sup.10R.sup.11,
(CR.sup.14R.sup.15).sub.n--NR.sup.10C(.dbd.O)R.sup.11, or
(CR.sup.14R.sup.15).sub.n--NR.sup.10(SO.sub.2Me)--R.sup.11, wherein
said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and
heteroaryl portions are optionally substituted with one or more
groups independently selected from F, Cl, Br, I, oxo,
SO.sub.2R.sup.c, CN, OR.sup.a, C(.dbd.O)R.sup.a, C(.dbd.O)OR.sup.a,
NR.sup.aR.sup.b, NR.sup.aC(.dbd.O)R.sup.b, C.sub.1-C.sub.12 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12
cycloalkyl, C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl,
and C.sub.1-C.sub.20 heteroaryl;
[0080] each R.sup.14 and R.sup.15 is independently H,
C.sub.1-C.sub.12 alkyl, or (CH.sub.2).sub.t-aryl,
[0081] or R.sup.14 and R.sup.15 together with the atoms to which
they are attached form a saturated or partially unsaturated
C.sub.3-C.sub.12 carbocyclic ring,
[0082] or R.sup.10 and R.sup.15 together with the atoms to which
they are attached form an oxo-substituted saturated or partially
unsaturated monocyclic or bicyclic C.sub.1-C.sub.20 heterocyclic
ring optionally further substituted with one or more groups
independently selected from F, Cl, Br, I, OR.sup.a,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl, or C.sub.1-C.sub.20
heteroaryl, wherein said alkyl and aryl are optionally substituted
with one or more groups independently selected from F, Cl, Br, and
I,
[0083] or R.sup.14 is null and R.sup.10 and R.sup.15 together with
the atoms to which they are attached form a C.sub.1-C.sub.20
heteroaryl ring having one or more heteroatoms;
[0084] R.sup.a and R.sup.b are independently H, C.sub.1-C.sub.12
alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20 heterocyclyl,
C.sub.6-C.sub.20 aryl, or C.sub.1-C.sub.20 heteroaryl, wherein said
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl are optionally substituted with one or more groups
independently selected from C.sub.1-C.sub.6 alkyl and halogen;
[0085] R.sup.c is C.sub.1-C.sub.12 alkyl or C.sub.6-C.sub.20 aryl,
wherein said alkyl and aryl are optionally substituted with one or
more groups independently selected from F, Cl, Br, I, OR.sup.a and
C(.dbd.O)NR.sup.aR.sup.b;
[0086] R.sup.x is H or C.sub.1-C.sub.6 alkyl;
[0087] R.sup.y is (i) (C.sub.1-C.sub.6 alkyl)NR.sup.jR.sup.k
wherein R.sup.j and R.sup.k are independently H or C.sub.1-C.sub.6
alkyl; (ii) C.sub.5-C.sub.6 cycloalkyl optionally substituted with
OH or --OC(.dbd.O)CF.sub.3; or (iii) a 5-6 membered heterocyclic
ring having 1 to 2 ring heteroatoms independently selected from N
and O and optionally substituted with a halogen group,
C.sub.1-C.sub.6 alkyl, (C.sub.1-C.sub.6 alkyl)OH, (C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), or C.sub.1-C.sub.6 fluoroalkyl;
[0088] Y, Y.sup.1 and Y.sup.2 are independently O or S;
[0089] t is 1, 2, 3, 4, 5 or 6; and
[0090] n and m are independently 0, 1, 2, 3, 4, 5 or 6.
[0091] Compound of Formula Ia and Ib include compounds wherein:
[0092] X is O, S or NR.sup.10;
[0093] Z.sup.2 and Z.sup.3 are independently selected from CR.sup.4
and N, wherein zero or one of Z.sup.2 and Z.sup.3 is N;
[0094] R.sup.1 is H, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, --C(.dbd.O)NR.sup.10R.sup.11, or
--(CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11, or
[0095] R.sup.1 is C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl or C.sub.1-C.sub.20 heteroaryl,
wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl and heteroaryl are optionally substituted with one or more
groups independently selected from F, Cl, Br, I, CN, CF.sub.3, oxo,
--OR.sup.10, SR.sup.10, --C(.dbd.Y)R.sup.10, --C(.dbd.Y)OR.sup.10,
--C(.dbd.Y)NR.sup.10R.sup.11,
--(CR.sup.14R.sup.15).sub.n--NR.sup.10R.sup.11,
--NR.sup.10C(.dbd.Y)R.sup.13, --NR.sup.10C(.dbd.Y)OR.sup.11,
--NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11, --NR.sup.12SO.sub.2R.sup.10,
--OC(.dbd.Y)R.sup.10, --OC(.dbd.Y)OR.sup.10,
--OC(.dbd.Y)NR.sup.10R.sup.11, --OS(O).sub.2(OR.sup.10),
--OP(.dbd.Y)(OR.sup.10)(OR.sup.11), --OP(OR.sup.10)(OR.sup.11),
--S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --S(O)(OR.sup.10),
--S(O).sub.2(OR.sup.10), --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, --SC(.dbd.Y)NR.sup.10R.sup.11,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl, C.sub.1-C.sub.20
heteroaryl,
--(CR.sup.14R.sup.15)--NR.sup.12C(.dbd.O)(CR.sup.14R.sup.15)NR.sup.10R.su-
p.11, and (CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11, or R.sup.2 is
H, CF.sub.3, CN, --C(.dbd.Y)R.sup.10, --C(.dbd.Y)OR.sup.10,
--C(.dbd.Y)NR.sup.10R.sup.11,
--C(.dbd.O)NR.sup.12(CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11,
--SR.sup.10, --S(O)R.sup.10, --S(O).sub.2R.sup.10,
S(O).sub.2NR.sup.10R.sup.11, --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 carbocyclyl,
C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl, or
C.sub.1-C.sub.20 heteroaryl, wherein said alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally
substituted with one or more groups independently selected from F,
Cl, Br, I, (CH.sub.2).sub.nOR.sup.10,
(CH.sub.2).sub.nNR.sup.10R.sup.11, heteroaryl and heterocyclyl;
[0096] R.sup.3 is C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl or C.sub.1-C.sub.20 heteroaryl,
wherein said carbocyclyl, heterocyclyl, aryl and heteroaryl are
optionally substituted with one or more groups independently
selected from F, Cl, Br, I, CN, CF.sub.3, OR.sup.10, SR.sup.10,
--C(.dbd.Y)R.sup.10, --C(.dbd.Y)OR.sup.10,
--C(.dbd.Y)NR.sup.10R.sup.11, --NR.sup.10R.sup.11,
--NR.sup.10C(.dbd.Y)R.sup.13, --NR.sup.10C(.dbd.Y)OR.sup.11,
--NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11,
--NR.sup.12C(.dbd.O)C(.dbd.O)R.sup.10R.sup.11,
--NR.sup.12C(.dbd.O)C(.dbd.O)OR.sup.a, --NR.sup.12SO.sub.2R.sup.10,
--NR.sup.12C(.dbd.Y.sup.1)(CR.sup.14R.sup.15).sub.nC(.dbd.Y.sup.2)NR.sup.-
10R.sup.11,
--NR.sup.12C(.dbd.Y.sup.1)NR.sup.10C(.dbd.Y.sup.2)(CR.sup.14R.sup.15).sub-
.nR.sup.11,
--NR.sup.12C(.dbd.Y.sup.1)(CR.sup.14R.sup.15).sub.nC(.dbd.Y.sup.2)(CR.sup-
.14R.sup.15).sub.mR.sup.10, --OC(.dbd.Y)R.sup.10,
--OC(.dbd.Y)OR.sup.10, --OC(.dbd.Y)NR.sup.10R.sup.11,
--OS(O).sub.2(OR.sup.10), --OP(.dbd.Y)(OR.sup.10)(OR.sup.11),
--OP(OR.sup.10)(OR.sup.11), --S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --S(O)(OR.sup.10),
--S(O).sub.2(OR.sup.10), --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, --SC(.dbd.Y)NR.sup.10R.sup.11,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl and C.sub.1-C.sub.20
heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl and heteroaryl are optionally substituted with
one or more groups independently selected from F, Cl, Br, I, OH,
C.sub.1-C.sub.12 alkyl, NR.sup.10R.sup.11, and
(CR.sup.14R.sup.15).sub.n-aryl;
[0097] R.sup.4 is H, F, Cl, Br, CF.sub.3, CN, --C(.dbd.Y)R.sup.10,
--C(.dbd.Y)OR.sup.10, --C(.dbd.Y)NR.sup.10R.sup.11,
--NR.sup.10R.sup.11, NR.sup.10C(.dbd.Y)R.sup.11,
NR.sup.10C(.dbd.Y)OR.sup.11, NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11,
--NR.sup.12SO.sub.2NR.sup.10R.sup.11, --OR.sup.10,
--OC(.dbd.Y)R.sup.10, --OC(.dbd.Y)OR.sup.10,
--OC(.dbd.Y)NR.sup.10R.sup.11,
--C(.dbd.O)NR.sup.12(CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11,
--OP(.dbd.Y)(OR.sup.10)(OR.sup.11), --OP(OR.sup.10)(OR.sup.11),
--SR.sup.10, --S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 carbocyclyl,
C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl, or
C.sub.1-C.sub.20 heteroaryl;
[0098] R.sup.10, R.sup.11 and R.sup.12 are independently H,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl, or C.sub.1-C.sub.20
heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, and heteroaryl are optionally substituted with
one or more groups independently selected from F, Cl, Br, I,
SO.sub.2R.sup.c, CN, OR.sup.a, NR.sup.aR.sup.b,
C(.dbd.O)NR.sup.aR.sup.b, CR.sup.aC(.dbd.O)R.sup.b,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 carbocyclyl, C.sub.6-C.sub.20 aryl, and
C.sub.1-C.sub.20 heteroaryl,
[0099] or R.sup.10 and R.sup.11 together with the nitrogen to which
they are attached optionally form a saturated, partially
unsaturated or fully unsaturated C.sub.3-C.sub.20 heterocyclic ring
optionally containing one or more additional ring atoms selected
from N, O or S, wherein said heterocyclic ring is optionally
substituted with one or more groups independently selected from
oxo, (CH.sub.2).sub.nOR.sup.a, NR.sup.aR.sup.b, CF.sub.3, F, Cl,
Br, I, SO.sub.2R.sup.a, C(.dbd.O)R.sup.a,
NR.sup.10C(.dbd.Y)R.sup.11, C(.dbd.Y)NR.sup.10R.sup.11,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl and C.sub.1-C.sub.20
heteroaryl,
[0100] or R.sup.10 and R.sup.12 together with the atoms to which
they are attached form an oxo-substituted C.sub.3-C.sub.20
heterocyclic ring optionally fused to a benzene ring;
[0101] R.sup.13 is H, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl,
(CR.sup.14R.sup.15).sub.n-cycloalkyl,
(CR.sup.14R.sup.15).sub.n-heterocyclyl,
(CR.sup.14R.sup.15).sub.n-aryl,
(CR.sup.14R.sup.15).sub.n-heteroaryl,
(CR.sup.14R.sup.15).sub.n--O--(CR.sup.14R.sup.15).sub.m-aryl,
(CR.sup.14R.sup.15).sub.n--OR.sup.10,
(CR.sup.14R.sup.15).sub.n--NR.sup.10R.sup.11,
(CR.sup.14R.sup.15).sub.n--NR.sup.10C(.dbd.O)R.sup.11, or
(CR.sup.14R.sup.15).sub.n--NR.sup.10(SO.sub.2Me)--R.sup.11, wherein
said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and
heteroaryl portions are optionally substituted with one or more
groups independently selected from F, Cl, Br, I, oxo,
SO.sub.2R.sup.c, CN, OR.sup.a, C(.dbd.O)R.sup.a, C(.dbd.O)OR.sup.a,
NR.sup.aR.sup.b, NR.sup.aC(.dbd.O)R.sup.b, C.sub.1-C.sub.12 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12
cycloalkyl, C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl,
and C.sub.1-C.sub.20 heteroaryl;
[0102] each R.sup.14 and R.sup.15 is independently H,
C.sub.1-C.sub.12 alkyl, or (CH.sub.2).sub.t-aryl,
[0103] or R.sup.14 and R.sup.15 together with the atoms to which
they are attached form a saturated or partially unsaturated
C.sub.3-C.sub.12 carbocyclic ring,
[0104] or R.sup.10 and R.sup.15 together with the atoms to which
they are attached form an oxo-substituted saturated or partially
unsaturated C.sub.1-C.sub.20 heterocyclic ring optionally further
substituted with one or more groups independently selected from F,
Cl, Br, I, OR.sup.a, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 cycloalkyl,
C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl, or
C.sub.1-C.sub.20 heteroaryl, wherein said alkyl and aryl are
optionally substituted with one or more groups independently
selected from F, Cl, Br, and I,
[0105] or R.sup.14 is null and R.sup.10 and R.sup.15 together with
the atoms to which they are attached form a C.sub.1-C.sub.20
heteroaryl ring having one or more heteroatoms;
[0106] R.sup.a and R.sup.b are independently H, C.sub.1-C.sub.12
alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20 heterocyclyl,
C.sub.6-C.sub.20 aryl, or C.sub.1-C.sub.20 heteroaryl, wherein said
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl are optionally substituted with one or more alkyl
groups;
[0107] R.sup.c is C.sub.1-C.sub.12 alkyl or C.sub.6-C.sub.20 aryl,
wherein said alkyl and aryl are optionally substituted with one or
more groups independently selected from F, Cl, Br, I, OR.sup.a and
C(.dbd.O)NR.sup.aR.sup.b;
[0108] Y, Y.sup.1 and Y.sup.2 are independently O or S;
[0109] t is 1, 2, 3, 4, 5 or 6; and
[0110] n and m are independently 0, 1, 2, 3, 4, 5 or 6.
[0111] Compounds of Formula Ia and Ib further include compounds of
Formula Ia' and Ib':
##STR00004##
wherein R.sup.1 is H, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, --C(.dbd.O)NR.sup.10R.sup.11, or
--(CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11, or
[0112] R.sup.1 is C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl or C.sub.1-C.sub.20 heteroaryl,
wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl and heteroaryl are optionally substituted with one or more
groups independently selected from F, Cl, Br, I, CN, CF.sub.3, oxo,
--OR.sup.10, SR.sup.10, --C(.dbd.Y)R.sup.10, --C(.dbd.Y)OR.sup.10,
--C(.dbd.Y)NR.sup.10R.sup.11,
--(CR.sup.14R.sup.15).sub.n--NR.sup.10R.sup.11,
--NR.sup.10C(.dbd.Y)R.sup.13, --NR.sup.10C(.dbd.Y)OR.sup.11,
--NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11, --NR.sup.12SO.sub.2R.sup.10,
--OC(.dbd.Y)R.sup.10, --OC(.dbd.Y)OR.sup.10,
--OC(.dbd.Y)NR.sup.10R.sup.11, --OS(O).sub.2(OR.sup.10),
--OP(.dbd.Y)(OR.sup.10)(OR.sup.11), --OP(OR.sup.10)(OR.sup.11),
--S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --S(O)(OR.sup.10),
--S(O).sub.2(OR.sup.10), --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, --SC(.dbd.Y)NR.sup.10R.sup.11,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl, C.sub.1-C.sub.20 heteroaryl,
--(CR.sup.14R.sup.15)--NR.sup.12C(.dbd.O)(CR.sup.14R.sup.15)NR.sup.10R.su-
p.11, and (CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11, or
[0113] R.sup.1 is NR.sup.xR.sup.y; and
[0114] R.sup.3 is C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl or C.sub.1-C.sub.20 heteroaryl,
wherein said carbocyclyl, heterocyclyl, aryl and heteroaryl are
optionally substituted with one or more groups independently
selected from F, Cl, Br, I, CN, CF.sub.3, OR.sup.10, SR.sup.10,
--C(.dbd.Y)R.sup.10, --C(.dbd.Y)OR.sup.10,
--C(.dbd.Y)NR.sup.10R.sup.11, --NR.sup.10R.sup.11,
--NR.sup.10C(.dbd.Y)R.sup.13, --NR.sup.10C(.dbd.Y)OR.sup.11,
--NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11,
--NR.sup.12C(.dbd.O)C(.dbd.O)R.sup.10R.sup.11,
--NR.sup.12C(.dbd.O)C(.dbd.O)OR.sup.a, --NR.sup.12SO.sub.2R.sup.10,
--NR.sup.12C(.dbd.Y.sup.1)(CR.sup.14R.sup.15).sub.nC(.dbd.Y.sup.2)NR.sup.-
10R.sup.11,
--NR.sup.12C(.dbd.Y.sup.1)NR.sup.10C(.dbd.Y.sup.2)(CR.sup.14R.sup.15).sub-
.nR.sup.11,
--NR.sup.12C(.dbd.Y.sup.1)(CR.sup.14R.sup.15).sub.nC(.dbd.Y.sup.2)(CR.sup-
.14R.sup.15).sub.mR.sup.10, --OC(.dbd.Y)R.sup.10,
--OC(.dbd.Y)OR.sup.10, --OC(.dbd.Y)NR.sup.10R.sup.11,
--OS(O).sub.2(OR.sup.10), --OP(.dbd.Y)(OR.sup.10)(OR.sup.11),
--OP(OR.sup.10)(OR.sup.11), --S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --S(O)(OR.sup.10),
--S(O).sub.2(OR.sup.10), --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, --SC(.dbd.Y)NR.sup.10R.sup.11,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl and C.sub.1-C.sub.20
heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl and heteroaryl are optionally substituted with
one or more groups independently selected from F, Cl, Br, I, OH,
C.sub.1-C.sub.12 alkyl, NR.sup.10R.sup.11, and
(CR.sup.14R.sup.15).sub.n-aryl.
[0115] In certain embodiments, X is O.
[0116] In certain embodiments, X is S.
[0117] In certain embodiments, X is NR.sup.10. In certain
embodiments, R.sup.10 is C.sub.1-C.sub.6 alkyl. In certain
embodiments, X is NH.
[0118] In certain embodiments, X is NR.sup.10. In certain
embodiments, R.sup.10 is (CR.sup.14R.sup.15).sub.nC.sub.2-C.sub.20
heterocyclyl. In certain embodiments, R.sup.14 and R.sup.15 are
hydrogen. In certain embodiments n is 2. In certain embodiments
R.sup.10 is (CH.sub.2CH.sub.2)C.sub.4 heterocyclyl. In certain
embodiments, the heterocyclyl is a morpholinyl group.
[0119] Exemplary embodiments of X include the following
structures:
##STR00005##
wherein the wavy lines indicate the points of attachment to the
pyrazolo[3,4-b]pyridine and R.sup.3.
[0120] In certain embodiments, Z.sup.2 is CH, CCl, CF, or
CC(.dbd.O)NH.sub.2.
[0121] In certain embodiments, Z.sup.3 is CH.
[0122] Formula Ia and Ib compounds are regioisomers, differing by
the attachment of R.sup.2 at the non-equivalent nitrogen atoms of
the pyrazole ring. Formula Ia and Ib compounds include embodiments
wherein:
TABLE-US-00001 (i) Z.sup.2 and Z.sup.3 are CR.sup.4, wherein each
R.sup.4 is independent of the other ##STR00006## ##STR00007## (ii)
Z.sup.3 is N and Z.sup.2 is CR.sup.4 ##STR00008## ##STR00009##
(iii) Z.sup.2 is N and Z.sup.3 is CR.sup.4 ##STR00010##
##STR00011##
[0123] Exemplary embodiments of Formula Ia and Ib compounds
include, but are not limited to, the following structures:
##STR00012##
[0124] In certain embodiments, R.sup.2 is H, C.sub.1-C.sub.4 alkyl,
CF.sub.3, CHF.sub.2 or CH.sub.2F.
[0125] In particular embodiments, R.sup.2 is C.sub.3-C.sub.6
alkyl.
[0126] In other embodiments, R.sup.2 is H.
[0127] In certain embodiments, R.sup.1 is H, C.sub.1-C.sub.4 alkyl,
CF.sub.3, CHF.sub.2 or CH.sub.2F.
[0128] In certain embodiments, R.sup.1 is optionally substituted
alkynyl. For example, in certain embodiments R.sup.1 is alkynyl
optionally substituted by --(CR.sup.14R.sup.15)--NR.sup.12C(.dbd.O)
(CR.sup.14R.sup.15)NR.sup.10R.sup.11 or
--(CR.sup.4R.sup.5).sub.tNR.sup.10R.sup.11, wherein t, R.sup.10,
R.sup.11, R.sup.12, R.sup.14, and R.sup.15 are as defined
herein.
[0129] In certain embodiments, t is 1.
[0130] In certain embodiments, R.sup.10 is H or C.sub.1-C.sub.6
alkyl.
[0131] In certain embodiments, R.sup.11 is H or C.sub.1-C.sub.6
alkyl.
[0132] In other embodiments, R.sup.10 and R.sup.11 together with
the nitrogen atom to which they are attached form a 5-6 membered
heterocyclic ring optionally having a second ring heteroatom
selected from N, O, SO and SO.sub.2 and optionally substituted with
one or two groups independently selected from N(C.sub.1-C.sub.6
alkyl).sub.2, OH, CF.sub.3 and C(.dbd.O)(C.sub.1-C.sub.6
alkyl).
[0133] In certain embodiments, R.sup.12 is H or C.sub.1-C.sub.6
alkyl.
[0134] In certain embodiments, R.sup.14 and R.sup.15 are H or
Me.
[0135] Exemplary embodiments include the following structures:
##STR00013## ##STR00014##
[0136] In certain embodiments, R.sup.1 is an optionally substituted
aryl or heteroaryl.
[0137] In certain embodiments, R.sup.1 is phenyl optionally
substituted with halogen (e.g., F or Cl), C.sub.1-C.sub.6 alkyl,
C(.dbd.O)C.sub.1-C.sub.6 alkyl, C(.dbd.O)(C.sub.3-C.sub.6
cycloalkyl), C(.dbd.O)O(C.sub.1-C.sub.6 alkyl), CH.sub.2-heteroaryl
(wherein said heteroaryl is a 5 membered ring having 2-3 ring
nitrogen atoms), CH.sub.2-hetCyc (wherein hetCyc is a 6 membered
ring having 1 to 2 ring heteroatoms independently selected from N
and O and optionally substituted with C.sub.1-C.sub.6 alkyl),
C(.dbd.O)NH(CH.sub.2).sub.2-hetCyc wherein hetCyc is a 6 membered
ring having 1 to 2 ring heteroatoms independently selected from N
and O), SO.sub.2NH(C.sub.1-C.sub.6 alkyl), NMeOMe,
C(.dbd.O)NR.sup.hR.sup.i, or NR.sup.hR.sup.i wherein R.sup.h and
R.sup.i are independently H or C.sub.1-C.sub.6 alkyl.
[0138] In certain embodiments, R.sup.1 is a phenyl group fused to a
6, 7, or 8 membered azacyclic ring (such as a piperidinyl ring)
optionally substituted with oxo.
[0139] In certain embodiments, R.sup.1 is a 5-6 membered heteroaryl
having a ring heteroatom selected from N and O and optionally
substituted with C(.dbd.O)NH(C.sub.1-C.sub.6 alkyl) or
CH.sub.2-hetCyc wherein hetCyc is a 6 membered azacycle (such as a
piperazinyl group) optionally substituted with C.sub.1-C.sub.6
alkyl.
[0140] Exemplary embodiments of R.sup.1 include the following
structures:
##STR00015## ##STR00016##
[0141] and substituted forms thereof.
[0142] Further exemplary embodiments of R.sup.1 include the
following structures:
##STR00017##
[0143] In certain embodiments, R.sup.1 is a 5 membered heteroaryl
having at least one N heteroatom and optionally substituted with
C.sub.1-C.sub.6 alkyl.
[0144] Exemplary embodiments of R.sup.1 include the following
structures:
##STR00018##
[0145] In certain embodiments, R.sup.1 is
--C(.dbd.O)NR.sup.10R.sup.11 or
--(CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11.
[0146] In certain embodiments, R.sup.14 and R.sup.15 are H.
[0147] In certain embodiments, R.sup.10 is H or C.sub.1-C.sub.6
alkyl.
[0148] In certain embodiments, R.sup.11 is C.sub.1-C.sub.6 alkyl or
(C.sub.1-C.sub.6 alkyl)OR.sup.h wherein R.sup.h is H or
C.sub.1-C.sub.6 alkyl.
[0149] In certain embodiments, R.sup.10 and R.sup.11 together with
the nitrogen atom to which they are attached form a 6 membered ring
optionally having a second ring heteroatom selected from N and O
optionally substituted with C.sub.1-C.sub.6 alkyl.
[0150] Exemplary embodiments of R.sup.1 include the following
structures:
##STR00019##
[0151] and substituted forms thereof.
[0152] Further exemplary embodiments of R.sup.1 include the
following structures:
##STR00020##
[0153] Further exemplary embodiments of R1 include the following
structure:
##STR00021##
[0154] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.1 is alkyl optionally substituted with one or more groups
independently selected from OR.sup.10,
(CH.sub.2).sub.nNR.sup.10R.sup.11, heterocyclyl and heteroaryl.
[0155] In certain embodiments, R.sup.1 is alkyl substituted with a
6 membered heterocyclic group having a ring nitrogen atom and
optionally having a second ring heteroatom selected from N and O,
wherein said heterocyclic ring is optionally substituted with
--O(C.sub.1-C.sub.6 alkyl) or C.sub.1-C.sub.6 alkyl.
[0156] In certain embodiments, R.sup.1 is alkyl substituted with a
5 membered heteroaryl group having one or two ring nitrogen
heteroatoms.
[0157] Exemplary embodiments of R.sup.1 include, but are not
limited to, methyl, CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2CH.sub.2OH, CH(OH)CH.sub.2OH,
##STR00022##
[0158] A further exemplary embodiment includes
##STR00023##
[0159] A further exemplary embodiment of R.sup.1 includes the
structure:
##STR00024##
[0160] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.1 is optionally substituted heteroaryl.
[0161] In certain embodiments, R.sup.1 is a 5-6 membered heteroaryl
ring having 1 to 2 ring heteroatoms independently selected from N
and O and optionally substituted with one or two groups
independently selected from Br, hetCyc and CH.sub.2-hetCyc, wherein
hetCyc is a 6 membered heterocyclic ring having a ring nitrogen
atom and optionally having a second ring heteroatom selected from N
and O, wherein hetCyc is optionally substituted with
C.sub.1-C.sub.6 alkyl or (C.sub.1-C.sub.6 alkyl)OH.
[0162] Exemplary embodiments of R.sup.1 include, but are not
limited to, the following structures:
##STR00025##
[0163] Further exemplary embodiments of R.sup.1 include, but are
not limited to, the following structures:
##STR00026##
[0164] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.1 is a saturated or partially unsaturated 5-10 membered
monocyclic or bicyclic heterocyclic ring, wherein said ring has one
or two ring atoms independently selected from N and O and is
optionally substituted with C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6 alkyl),
NR.sup.10R.sup.11 or CH.sub.2NR.sup.10R.sup.11 wherein R.sup.10 and
R.sup.11 are independently H, C.sub.1-C.sub.6 alkyl, hetCyc or
CH.sub.2hetCyc wherein hetCyc is a 5-6 membered ring having one or
2 ring nitrogen atoms. Exemplary embodiments of R.sup.1 include,
but are not limited to, the following structures:
##STR00027##
[0165] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.1 is NR.sup.xR.sup.y.
[0166] In certain embodiments, R.sup.x is H or Me.
[0167] In certain embodiments, R.sup.y is (i) (C.sub.1-C.sub.6
alkyl)NR.sup.jR.sup.k wherein R.sup.j and R.sup.k are independently
H or C.sub.1-C.sub.6 alkyl; (ii) cyclohexyl optionally substituted
with OH or OC(.dbd.O)CF.sub.3; or (iii) a 5-6 membered heterocyclic
ring having a ring heteroatom selected from N and O and optionally
substituted with F, (C.sub.1-C.sub.6 alkyl), (C.sub.1-C.sub.6
alkyl)OH, (C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6 alkyl) or
(C.sub.1-C.sub.6 fluoroalkyl).
[0168] Exemplary embodiments of R.sup.1 include, but are not
limited to, the following structures:
##STR00028## ##STR00029##
[0169] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.1 is --CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11. In certain
embodiments, t is 0. In certain embodiments, R.sup.10 is H. In
certain embodiments R.sup.11 is an 8 membered bicyclic heterocyclic
ring having a N heteroatom and optionally substituted with
C.sub.1-C.sub.6 alkyl.
[0170] Exemplary embodiments of R1 include the structure:
##STR00030##
[0171] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.1 is --C(.dbd.Y)OR.sup.10. In certain embodiments, Y is O. In
certain embodiments, R.sup.10 is C.sub.1-C.sub.6 alkyl. A
particular example is --C(O)OCH.sub.3.
[0172] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.3 has the structure:
##STR00031##
[0173] wherein the wavy line indicates the point of attachment to
X;
[0174] Z.sup.4, Z.sup.5, Z.sup.6, and Z.sup.7 are independently
CR.sup.4a or N and 0, 1, or 2 of Z.sup.4, Z.sup.5, Z.sup.6, and
Z.sup.7 is N, wherein when Z.sup.4 and Z.sup.5 or Z.sup.6 and
Z.sup.7 are CR.sup.4a, then Z.sup.4 and Z.sup.5 or Z.sup.6 and
Z.sup.7 optionally form a saturated, partially unsaturated or fully
unsaturated carbocyclic or heterocyclic ring;
[0175] each R.sup.4a is independently H, F, Cl, Br, CF.sub.3, CN,
--C(.dbd.Y)R.sup.10, --C(.dbd.Y)OR.sup.10,
--C(.dbd.Y)NR.sup.10R.sup.11, --NR.sup.10R.sup.11,
NR.sup.10C(.dbd.Y)R.sup.11, NR.sup.10C(.dbd.Y)OR.sup.11,
NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11,
--NR.sup.12SO.sub.2NR.sup.10R.sup.11, --OR.sup.10,
--OC(.dbd.Y)R.sup.10, --OC(.dbd.Y)OR.sup.10,
--OC(.dbd.Y)NR.sup.10R.sup.11,
--C(.dbd.O)NR.sup.12(CR.sup.14R.sup.15).sub.tNR.sup.10R.sup.11,
--OP(.dbd.Y)(OR.sup.10)(OR.sup.11), --OP(OR.sup.10)(OR.sup.11),
--SR.sup.10, --S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.12 carbocyclyl,
C.sub.2-C.sub.20 heterocyclyl, C.sub.6-C.sub.20 aryl, or
C.sub.1-C.sub.20 heteroaryl; and
[0176] R.sup.5 is F, Cl, Br, I, CN, CF.sub.3, OR.sup.10, SR.sup.10,
--C(.dbd.Y)R.sup.10, --C(.dbd.Y)OR.sup.10,
--C(.dbd.Y)NR.sup.10R.sup.11, --NR.sup.10R.sup.11,
--NR.sup.10C(.dbd.Y)R.sup.13, --NR.sup.10C(.dbd.Y)OR.sup.11,
--NR.sup.12C(.dbd.Y)NR.sup.10R.sup.11,
--NR.sup.12C(.dbd.O)C(.dbd.O)R.sup.10R.sup.11,
--NR.sup.12C(.dbd.O)C(.dbd.O)OR.sup.a, --NR.sup.12SO.sub.2R.sup.10,
--NR.sup.12C(.dbd.Y.sup.1)(CR.sup.14R.sup.15).sub.nC(.dbd.Y.sup.2)NR.sup.-
10R.sup.11,
--NR.sup.12C(.dbd.Y.sup.1)NR.sup.10C(.dbd.Y.sup.2)(CR.sup.14R.sup.15).sub-
.nR.sup.11,
--NR.sup.12C(.dbd.Y.sup.1)(CR.sup.14R.sup.15).sub.nC(.dbd.Y.sup.2)(CR.sup-
.14R.sup.15).sub.mR.sup.10, --OC(.dbd.Y)R.sup.10,
--OC(.dbd.Y)OR.sup.10, --OC(.dbd.Y)NR.sup.10R.sup.11,
--OS(O).sub.2(OR.sup.10), --OP(.dbd.Y)(OR.sup.10)(OR.sup.11),
--OP(OR.sup.10)(OR.sup.11), --S(O)R.sup.10, --S(O).sub.2R.sup.10,
--S(O).sub.2NR.sup.10R.sup.11, --S(O)(OR.sup.10),
--S(O).sub.2(OR.sup.10), --SC(.dbd.Y)R.sup.10,
--SC(.dbd.Y)OR.sup.10, --SC(.dbd.Y)NR.sup.10R.sup.11,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.20
heterocyclyl, C.sub.6-C.sub.20 aryl and C.sub.1-C.sub.20
heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,
heterocyclyl, aryl and heteroaryl are optionally substituted with
one or more groups independently selected from alkyl,
NR.sup.10R.sup.11, and (CR.sup.14R.sup.15).sub.n-aryl.
[0177] In certain embodiments of R.sup.3 as defined above, R.sup.4a
is CH or N.
[0178] For example, in certain embodiments of Formula Ia and Ib
compounds, R.sup.3 is selected from the structures:
##STR00032##
[0179] and substituted forms thereof, wherein the wavy line
indicates the point of attachment to X, and R.sup.5 is as defined
herein. Exemplary embodiments of R.sup.3 include the following
structures:
##STR00033##
[0180] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.3 is a bicyclic heteroaryl ring substituted with an R.sup.5
group, wherein R.sup.5 is as defined above. An exemplary embodiment
is the structure:
##STR00034##
[0181] In certain embodiments of Formula Ia and Ib compounds,
R.sup.3 is selected from the structure:
##STR00035##
[0182] wherein the wavy line indicates the point of attachment to
X, and R.sup.4a and R.sup.5 are as defined herein.
[0183] In certain embodiments, each R.sup.4a is independently
selected from H, F, Cl, C.sub.1-C.sub.6 alkyl, O--(C.sub.1-C.sub.6
alkyl), and CN.
[0184] Exemplary embodiments of R.sup.3 include the following
structures:
##STR00036##
[0185] wherein the wavy line indicates the point of attachment to
X, and R.sup.5 is as defined herein.
[0186] Additional exemplary embodiments of R.sup.3 include the
structures:
##STR00037##
[0187] Further exemplary embodiments of Formula Ia and Ib compounds
include compounds wherein R.sup.3 is
##STR00038##
[0188] wherein R.sup.4a and R.sup.5 are as defined herein and two
adjacent R.sup.4a groups together with the atoms to which they are
attached form a saturated, partially unsaturated or fully
unsaturated carbocyclic or heterocyclic ring. For example, in
certain embodiments R.sup.3 is selected from the following
structures:
##STR00039##
[0189] Exemplary embodiments of compounds of Formulas Ia and Ib
include the following structures:
##STR00040## ##STR00041##
[0190] In certain embodiments of compounds of Formulas Ia and Ib,
R.sup.5 has the structure:
##STR00042##
[0191] wherein R.sup.10, R.sup.11, R.sup.12, R.sup.14, R.sup.15,
Y.sup.1 and Y.sup.2 are as defined herein.
[0192] In certain embodiments, Y.sup.1 is O.
[0193] In certain embodiments, Y.sup.2 is O.
[0194] In certain embodiments, R.sup.12 is H or C.sub.1-C.sub.6
alkyl.
[0195] In certain embodiments, R.sup.14 is H.
[0196] In certain embodiments, R.sup.15 is H.
[0197] In certain embodiments, R.sup.10 is H.
[0198] In certain embodiments, R.sup.11 is phenyl optionally
substituted with a halogen group.
[0199] Exemplary embodiments of R.sup.5 include the structure
##STR00043##
[0200] In further exemplary embodiments, R.sup.14 and R.sup.15
together with the atom to which they are attached form an
optionally substituted carbocyclic ring. In certain embodiments,
R.sup.14 and R.sup.15 together with the carbon atom to which they
are attached form a cyclopropylidene group.
[0201] For example, in certain embodiments R.sup.5 is:
##STR00044##
[0202] In further exemplary embodiments, R.sup.15 and R.sup.10
together with the atom to which they are attached form an
oxo-substituted heterocyclic ring, wherein said heterocyclic ring
is optionally further substituted.
[0203] In certain embodiments, R.sup.10 and R.sup.15 together with
the atoms to which they are attached form an oxo-substituted 5, 6,
or 7 membered azacyclic ring.
[0204] For example, in certain embodiments R.sup.5 is selected from
the structures:
##STR00045##
[0205] In certain embodiments, R.sup.12 is H.
[0206] In certain embodiments, R.sup.14 is H, methyl or benzyl.
[0207] In certain embodiments, R.sup.11 is H, C.sub.1-C.sub.6
alkyl, or phenyl optionally substituted with one or two groups
independently selected from F and Cl.
[0208] For example, in certain embodiments R.sup.5 is selected from
the structures:
##STR00046## ##STR00047##
[0209] Further exemplary embodiments of R.sup.5 include the
structures:
##STR00048##
[0210] In further exemplary embodiments, R.sup.15 and R.sup.10
together with the atoms to which they are attached form an
oxo-substituted bicyclic azacyclic ring, for example an
oxo-substituted 6 membered bicyclic azacyclic ring such as an
azabicyclo[3.1.0]hexane group. An exemplary embodiment of R.sup.5
includes the structure:
##STR00049##
[0211] In further exemplary embodiments, R.sup.14 is null and
R.sup.10 and R.sup.15 together with the atoms to which they are
attached form a heteroaryl ring having a ring nitrogen atom and
substituted with .dbd.Y, wherein said heteroaryl ring optionally
has one or more additional heteroatoms independently selected from
N, O and S
[0212] In certain embodiments, R.sup.10 and R.sup.15 together with
the atoms to which they are attached form an oxo-substituted 6
membered heteroaryl ring having one or two ring nitrogen atoms.
[0213] For example, in certain embodiments R.sup.5 is selected from
the structures:
##STR00050##
and substituted forms thereof, wherein Y.sup.1, Y.sup.2 and
R.sup.11 are as defined herein. In certain embodiments, R.sup.11 is
optionally substituted aryl, cycloalkyl, or alkyl.
[0214] In certain embodiments, Y.sup.1 is O.
[0215] In certain embodiments, Y.sup.2 is O.
[0216] In certain embodiments, R.sup.11 is phenyl optionally
substituted with F.
[0217] In certain embodiments, R.sup.11 is benzyl.
[0218] In certain embodiments, R.sup.11 is C.sub.1-C.sub.6
alkyl.
[0219] For example, in certain embodiments R.sup.5 is selected from
the structures:
##STR00051## ##STR00052##
[0220] wherein the phenyl and cyclohexyl groups are optionally
substituted with one or more R.sup.d groups independently selected
from F, Cl, Br, I, SO.sub.2R.sup.c, CN, OR.sup.a, NR.sup.aR.sup.b,
C(.dbd.O)NR.sup.aR.sup.b, CR.sup.aC(.dbd.O)R.sup.b,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.6-C.sub.20 aryl, and C.sub.1-C.sub.20 heteroaryl. In
certain embodiments, the phenyl and cyclohexyl groups are
optionally substituted with one R.sup.d group. In certain
embodiments, R.sup.d is F.
[0221] Exemplary embodiments of R.sup.5 include the structures:
##STR00053##
[0222] Further exemplary embodiments of R5 include the
structure:
##STR00054##
[0223] In certain embodiments, R.sup.11 is an optionally
substituted heteroaryl, such as a pyridyl group. An exemplary
embodiment of R.sup.5 includes the structure:
##STR00055##
[0224] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.5 has the structure:
##STR00056##
[0225] wherein R.sup.10, R.sup.12, R.sup.14, R.sup.15, Y.sup.1 and
Y.sup.2 are as defined herein. In certain embodiments, R.sup.14 and
R.sup.15 together with the atoms to which they are attached form an
optionally substituted carbocyclic ring.
[0226] A particular example of R.sup.5 is the structure:
##STR00057##
[0227] wherein R.sup.10, R.sup.12, Y.sup.1 and Y.sup.2 are as
defined herein and R.sup.14a and R.sup.15a together with the carbon
atom to which they are both attached form a spirocyclic carbocycle,
such as a cyclopropylidene group.
[0228] In certain embodiments, Y.sup.1 is O.
[0229] In certain embodiments, Y.sup.2 is O.
[0230] In certain embodiments, R.sup.14 and R.sup.15 are H.
[0231] In certain embodiments, R.sup.10 is phenyl optionally
substituted with a halogen group. In certain embodiment, said
phenyl is substituted with F.
[0232] For example, in certain embodiments R.sup.5 is selected from
the structures:
##STR00058##
[0233] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.5 has the structure:
##STR00059##
[0234] wherein Y.sup.1, Y.sup.2, R.sup.10, R.sup.11, R.sup.12,
R.sup.14 and R.sup.15 are as defined herein. In certain
embodiments, R.sup.11 is optionally substituted aryl.
[0235] In certain embodiments, R.sup.12 is H or C.sub.1-C.sub.6
alkyl.
[0236] In certain embodiments, R.sup.10 is H or C.sub.1-C.sub.6
alkyl.
[0237] In certain embodiments, R.sup.14 is H.
[0238] In certain embodiments, R.sup.15 is H.
[0239] In certain embodiments, R.sup.11 is phenyl optionally
substituted with halogen, for example a fluoro group.
[0240] For example, in certain embodiments R.sup.5 is:
##STR00060##
[0241] A further exemplary embodiment of R.sup.5 is:
##STR00061##
[0242] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.5 has the following structure:
##STR00062##
[0243] wherein Y, R.sup.10 and R.sup.13 are as defined herein.
[0244] In certain embodiments, Y is O.
[0245] In certain embodiments, R.sup.10 is H.
[0246] In certain embodiments, R.sup.10 is CH.sub.2Ph.
[0247] In certain embodiments, R.sup.13 is alkyl,
(CR.sup.14R.sup.15).sub.n--O--(CR.sup.14R.sup.15).sub.m-aryl,
(CR.sup.14R.sup.15)-aryl, (CR.sup.14R.sup.15)-heteroaryl,
(CR.sup.14R.sup.15)-heterocyclyl,
(CR.sup.14R.sup.15)--N(SO.sub.2R.sup.a)(CR.sup.14R.sup.15)R.sup.11,
or (CR.sup.14R.sup.15)NR.sup.10C(.dbd.O)-aryl, wherein said alkyl,
aryl, heteroaryl and heterocyclyl portions are optionally
substituted.
[0248] In particular embodiments, R.sup.13 is
CR.sup.14R.sup.15O(CH.sub.2).sub.m-phenyl, wherein phenyl is
optionally substituted with halogen (for example Cl), R.sup.14 and
R.sup.15 are independently H or methyl and m is 0 or 1.
[0249] In particular embodiments, R.sup.13 is OR.sup.a, wherein
R.sup.a is C.sub.1-C.sub.6 alkyl or phenyl.
[0250] In particular embodiments, R.sup.13 is (C.sub.1-C.sub.3
alkyl)-phenyl.
[0251] In particular embodiments, R.sup.13 is (C.sub.1-C.sub.2
alkyl)-hetAr wherein hetAr is a 6 membered heteroaryl ring having
one or two ring nitrogen atoms. A particular example of R.sup.13 is
(C.sub.1-C.sub.2 alkyl)-pyridyl.
[0252] In particular embodiments, R.sup.13 is a 5-6 membered
heteroaryl ring having 1 to 2 ring atoms independently selected
from N, O and S and optionally substituted with one or two groups
independently selected from NH-phenyl, morpholinyl, phenyl, and
C.sub.1-C.sub.6 alkyl.
[0253] In particular embodiments, R.sup.13 is phenyl optionally
substituted with one or two groups independently selected from CN,
F, phenyl, O-phenyl, N(C.sub.1-C.sub.6 alkyl).sub.2, and
NHC(.dbd.O)(C.sub.1-C.sub.6 alkyl).
[0254] In particular embodiments, R.sup.13 is
CH.sub.2--N(C.sub.1-C.sub.4 alkyl)SO.sub.2R.sup.a or
CH.sub.2--N(CH.sub.2Ph)SO.sub.2R.sup.a. In particular embodiments,
R.sup.a is C.sub.1-C.sub.6 alkyl, phenyl or a 5 membered heteroaryl
ring having one or two ring heteroatoms independently selected from
N and O and optionally substituted with C.sub.1-C.sub.6 alkyl.
[0255] In certain embodiments, R.sup.13 is (CH.sub.2).sub.n-hetCyc
wherein n is 0 or 1 and hetCyc is a saturated or partially
saturated 6 membered heterocyclic ring having a ring nitrogen atom
and optionally substituted with oxo, C(.dbd.O)(C.sub.1-C.sub.6
alkyl), SO.sub.2(C.sub.1-C.sub.6 alkyl), SO.sub.2-phenyl or
C(O)O(C.sub.1-C.sub.6 alkyl).
[0256] In particular embodiments, R.sup.13 is C.sub.1-C.sub.6 alkyl
optionally substituted with (C.sub.3-C.sub.6)cycloalkyl or
O--(C.sub.1-C.sub.6 alkyl).
[0257] In particular embodiments, R.sup.13 is
CH.sub.2N(C.sub.1-C.sub.6 alkyl)C(.dbd.O)phenyl.
[0258] For example, in certain embodiments R.sup.5 is selected from
the structures:
##STR00063## ##STR00064## ##STR00065## ##STR00066##
[0259] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.5 has the following structure:
##STR00067##
[0260] wherein Y and R.sup.10 are as defined herein and R.sup.13 is
alkyl or (CR.sup.14R.sup.15)-hetAr. In certain embodiments,
R.sup.14 and R.sup.15 are H. In other embodiments, R.sup.14 and
R.sup.15 together with the carbon to which they are attached from a
cyclopropylidene ring. In certain embodiments, Y is O. In certain
embodiments, hetAr is a 5-9 membered monocyclic or bicyclic ring
having one or two ring heteroatoms independently selected from N
and O. Exemplary embodiments of R.sup.5 include the structures:
##STR00068##
[0261] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.5 has the structure:
##STR00069##
[0262] wherein R.sup.10, R.sup.11, and R.sup.12 are as defined
herein.
[0263] In certain embodiments, R.sup.11 is optionally substituted
aryl or heteroaryl.
[0264] In certain embodiments, R.sup.11 is a 5-10 membered
monocyclic or bicyclic heteroaryl having a ring nitrogen atom and
optionally having a second heteroatom selected from N and O,
wherein said heteroaryl is optionally substituted with
C.sub.1-C.sub.6 alkyl.
[0265] In certain embodiments, R.sup.12 is H.
[0266] In certain embodiments, R.sup.10 is H or methyl.
[0267] For example, in certain embodiments R.sup.5 is selected from
the structures:
##STR00070##
[0268] In other embodiments, R.sup.10 and R.sup.12 together with
the atoms to which they are attached form an oxo-substituted
heterocyclic ring, wherein said heterocyclic ring is optionally
fused to a phenyl ring. For example, in certain embodiments R.sup.5
is selected from the structures:
##STR00071##
[0269] In a particular embodiment, R.sup.11 is H.
[0270] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.5 is NR.sup.12SO.sub.2R.sup.10, wherein R.sup.10 and R.sup.12
are as defined herein.
[0271] In certain embodiments, R.sup.12 is H.
[0272] In certain embodiments, R.sup.10 is phenyl optionally
substituted with halogen, O--(C.sub.1-C.sub.6 alkyl), or
C(.dbd.O)NH(C.sub.1-C.sub.6 alkyl).
[0273] In certain embodiments, R.sup.10 is an optionally
substituted aryl. Exemplary embodiments of R.sup.5 include the
structures:
##STR00072##
[0274] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.5 is NR.sup.12C(.dbd.O)C(.dbd.O)NR.sup.10R.sup.11, wherein
R.sup.10, R.sup.11 and R.sup.12 are as defined herein.
[0275] In certain embodiments, R.sup.11 is H.
[0276] In certain embodiments, R.sup.12 is H.
[0277] In certain embodiments, R.sup.10 is H, C.sub.1-C.sub.6
alkyl, (CH.sub.2).sub.0-2-phenyl optionally substituted with
halogen, or a 5 membered azacyclic ring such as pyrrolidinyl.
[0278] For example, in certain embodiments R.sup.5 is selected from
the structures:
##STR00073##
[0279] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.5 is NR.sup.12C(.dbd.O)C(.dbd.O)OR.sup.a, wherein R.sup.12
and R.sup.a are as defined herein.
[0280] In certain embodiments, R.sup.12 is H.
[0281] In certain embodiments, R.sup.a is C.sub.1-C.sub.6
alkyl.
[0282] For example, in certain embodiments R.sup.5 is
##STR00074##
[0283] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.5 is an optionally substituted heteroaryl. For example, in
certain embodiments, R.sup.5 is selected from the structures:
##STR00075##
[0284] wherein R.sup.20 is alkyl, cycloalkyl, aryl, or heteroaryl,
and R.sup.21 and R.sup.22 are independently selected from H or
alkyl, wherein said alkyl, cycloalkyl, aryl, and heteroaryl are
optionally substituted with one or more groups independently
selected from F, Cl, Br, I, alkyl and C.sub.3-C.sub.6
cycloalkyl.
[0285] Exemplary embodiments of R.sup.5 include the following
structures:
##STR00076##
[0286] wherein R.sup.d is as defined herein and R.sup.e is H or an
optionally substituted C.sub.1-C.sub.4 alkyl.
[0287] In certain embodiments, the phenyl group is substituted with
one R.sup.d group.
[0288] In certain embodiments, R.sup.d is F, Cl, Br, I,
SO.sub.2R.sup.c, CN, OR.sup.a, NR.sup.aR.sup.b,
C(.dbd.O)NR.sup.aR.sup.b, CR.sup.aC(.dbd.O)R.sup.b,
C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.6-C.sub.20 aryl, and C.sub.1-C.sub.20
heteroaryl.
[0289] In certain embodiments, R.sup.e is independently H or
C.sub.1-C.sub.4 alkyl.
[0290] Further exemplary embodiments of R.sup.5 include the
structures:
##STR00077##
[0291] Particular embodiments of R.sup.5 include the
structures:
##STR00078##
[0292] In certain embodiments of compounds of Formula Ia and Ib,
R.sup.5 is NR.sup.10R.sup.11. In certain embodiments, R.sup.10 is
H. In certain embodiments, R.sup.11 is hetAr, wherein hetAr is a
substituted or unsubstituted 5-6 membered heteroaryl group having
at least one ring nitrogen atom and optionally having a second ring
heteroatom selected from N and O. Examples of hetAr include
pyridyl, isoxazolyl, and pyridazinyl groups. In certain
embodiments, hetAr is substituted with one or two groups
independently selected from C.sub.1-C.sub.6 alkyl and
C(.dbd.O)NR.sup.aR.sup.b. In certain embodiments, R.sup.a is H. In
certain embodiments, R.sup.b is phenyl optionally substituted with
a halogen group. In certain embodiment, R.sup.b is C.sub.1-C.sub.6
alkyl, such as, but not limited to, methyl, ethyl or isopropyl. In
certain embodiments, R.sup.b is a 6 membered heteroaryl having at
least one nitrogen atom, for example pyridyl.
[0293] Exemplary embodiment of R.sup.5 includes the structures:
##STR00079##
[0294] A particular embodiment of R.sup.5 is the structure:
##STR00080##
[0295] Particular embodiments of R.sup.3 include the
structures:
##STR00081## ##STR00082## ##STR00083## ##STR00084##
##STR00085##
[0296] The heterobicyclic pyrazole compounds of the invention may
contain asymmetric or chiral centers, and therefore exist in
different stereoisomeric forms. It is intended that all
stereoisomeric forms of the compounds of the invention, including
but not limited to, diastereomers, enantiomers and atropisomers, as
well as mixtures thereof such as racemic mixtures, form part of the
present invention.
[0297] In addition, the present invention embraces all geometric
and positional isomers. For example, if a heterobicyclic pyrazole
compound of the present invention incorporates a double bond or a
fused ring, the cis- and trans-forms, as well as mixtures thereof,
are embraced within the scope of the invention. Both the single
positional isomers and mixture of positional isomers, e.g.,
resulting from the N-oxidation of the pyrimidine and pyrazine
rings, are also within the scope of the present invention.
[0298] In the structures shown herein, where the stereochemistry of
any particular chiral atom is not specified, then all stereoisomers
are contemplated and included as the compounds of the invention.
Where stereochemistry is specified by a solid wedge or dashed line
representing a particular configuration, then that stereoisomer is
so specified and defined.
[0299] The compounds of the present invention may exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like, and it is
intended that the invention embrace both solvated and unsolvated
forms.
[0300] The compounds of the present invention may also exist in
different tautomeric forms, and all such forms are embraced within
the scope of the invention. The term "tautomer" or "tautomeric
form" refers to structural isomers of different energies which are
interconvertible via a low energy barrier. For example, proton
tautomers (also known as prototropic tautomers) include
interconversions via migration of a proton, such as keto-enol and
imine-enamine isomerizations. Valence tautomers include
interconversions by reorganization of some of the bonding
electrons.
[0301] The present invention also embraces isotopically-labeled
compounds of the present invention which are identical to those
recited herein, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different
from the atomic mass or mass number usually found in nature. All
isotopes of any particular atom or element as specified are
contemplated within the scope of the compounds of the invention,
and their uses. Exemplary isotopes that can be incorporated into
compounds of the invention include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and
iodine, such as .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C,
.sup.13N, .sup.15N, .sup.15O, .sup.17O, .sup.18O, .sup.32P,
.sup.33P, .sup.35S, .sup.18F, .sup.36Cl, .sup.123I and .sup.125I.
Certain isotopically-labeled compounds of the present invention
(e.g., those labeled with .sup.3H and .sup.14C) are useful in
compound and/or substrate tissue distribution assays. Tritiated
(.sup.3H) and carbon-14 (.sup.14C) isotopes are useful for their
ease of preparation and detectability. Further, substitution with
heavier isotopes such as deuterium (i.e., .sup.2H) may afford
certain therapeutic advantages resulting from greater metabolic
stability (e.g., increased in vivo half-life or reduced dosage
requirements) and hence may be preferred in some circumstances.
Positron emitting isotopes such as .sup.15O, .sup.13N, .sup.11C and
.sup.18F are useful for positron emission tomography (PET) studies
to examine substrate receptor occupancy. Isotopically labeled
compounds of the present invention can generally be prepared by
following procedures analogous to those disclosed in the Schemes
and/or in the Examples herein below, by substituting an
isotopically labeled reagent for a non-isotopically labeled
reagent.
Synthesis of cMet Inhibitor Compounds
[0302] Heterobicyclic pyrazole compounds of Formula Ia and Ib of
the present invention may be synthesized by synthetic routes that
include processes analogous to those well-known in the chemical
arts, particularly in light of the description contained herein.
The starting materials are generally available from commercial
sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily
prepared using methods well known to those skilled in the art
(e.g., prepared by methods generally described in Louis F. Fieser
and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley,
N.Y. (1967-1999 ed.), or Beilsteins Handbuch der organischen
Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements
(also available via the Beilstein online database).
[0303] In certain embodiments, compounds of Formula Ia or Ib may be
readily prepared using procedures well-known to prepare
pyrazolo[3,4-b]pyridines (U.S. Pat. No. 6,531,475, WO 01/098301, WO
01/081348, and WO 99/030710); and other heterocycles, which are
described in: Comprehensive Heterocyclic Chemistry, Editors
Katrizky and Rees, Pergamon Press, 1984; Klemm et al. (1970) J.
Hetero. Chem. 7(2):373-379; Klemm et al. (1974) J. Hetero. Chem.
11(3): 355-361; Klemm et al. (1976) J. Hetero. Chem. 13:273-275;
Klemm et al. (1985) J. Hetero. Chem. 22(5):1395-1396; Bisagni et
al. (1974) Bull. Soc. Chim. Fr. (3-4, Pt. 2):515-518; Frehel et al.
(1984) Heterocycles 22(5):1235-1247; WO 93/13664; WO 2004/012671;
WO 2005/061476; U.S. Application Publication Nos. 2003/0045540, US
2003/0105089, and 2004/0024210; and U.S. Pat. Nos. 5,252,581,
6,232,320, and 6,579,882.
[0304] Compounds of Formula Ia and Ib may be prepared singly or as
compound libraries comprising at least 2, for example 5 to 1,000
compounds, or 10 to 100 compounds. Libraries of compounds of
Formula Ia or Ib may be prepared by a combinatorial `split and mix`
approach or by multiple parallel syntheses using either solution
phase or solid phase chemistry, by procedures known to those
skilled in the art. Thus according to a further aspect of the
invention there is provided a compound library comprising at least
2 compounds, or pharmaceutically acceptable salts thereof.
[0305] For illustrative purposes, Schemes 1-25 show general methods
for preparing the compounds of the present invention as well as key
intermediates. For a more detailed description of the individual
reaction steps, see the Examples section below. Those skilled in
the art will appreciate that other synthetic routes may be used to
synthesize the inventive compounds. Although specific starting
materials and reagents are depicted in the Schemes and discussed
below, other starting materials and reagents can be easily
substituted to provide a variety of derivatives and/or reaction
conditions. In addition, many of the compounds prepared by the
methods described below can be further modified in light of this
disclosure using conventional chemistry well known to those skilled
in the art.
[0306] In preparing compounds of Formulas I, protection of remote
functionality (e.g., primary or secondary amine) of intermediates
may be necessary. The need for such protection will vary depending
on the nature of the remote functionality and the conditions of the
preparation methods. Suitable amino-protecting groups (NH-Pg)
include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),
benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).
The need for such protection is readily determined by one skilled
in the art. For a general description of protecting groups and
their use, see T. W. Greene, Protective Groups in Organic
Synthesis, John Wiley & Sons, New York, 1991.
##STR00086##
[0307] Scheme 1 shows a general scheme for the synthesis of
intermediate compound 5, which is useful for the synthesis of
compounds of Formula I. As shown in Scheme 1, reaction of a
substituted 5-aminopyrazole 1 (R.sup.1 is, for example, H, alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or
halogen; see, Misra, R. N., et al., Bioorg. Med. Chem. Lett. 2003,
13, 1133-1136), wherein N1 is protected by an appropriate
protecting group (PG may be p-methoxybenzyl, phenylsulfonyl, or the
like), with a vinyl ether of Meldrum's acid 2 (R=alkyl, such as
methyl or ethyl) upon heating provides a Meldrum's acid enamine of
the 5-aminopyrazole (not shown). Such an enamine can be cyclized
upon heating to provide phenol 3, wherein R.sup.1 may be
independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
aryl, heteroaryl, etc. Conversion of the phenol 3 to an aryl halide
4 (Y=halogen or other leaving group such as triflate, etc.) can be
achieved upon reaction with an appropriate electrophilic reagent
(e.g. POCl.sub.3, oxalyl chloride, NCS/PPh.sub.3, POBr.sub.3,
NBS/PPh.sub.3, CF.sub.3SO.sub.2Cl/2,6-lutidine, etc.). Nucleophilic
substitution of aryl halide 4 with a compound of the formula
HX--Ar--NH.sub.2, wherein X is O, N or S, and Ar is an aryl or
heteroaryl ring as defined herein, can be conducted using an
appropriate base (e.g. Cs.sub.2CO.sub.3, NaH, KOt-Bu, DMAP, or the
like) to give intermediate 5.
##STR00087##
[0308] Scheme 2 shows an alternative method of preparing
intermediate 5 wherein X is O, N or S. Intermediate 5 can be
prepared by nucleophilic substitution of phenol 3 with a compound
of the formula X.sup.1--Ar--NO.sub.2 (wherein X.sup.1 is F, Cl,
triflate or other appropriate leaving group and Ar is an aryl or
heteroaryl ring as defined herein) in the presence of an
appropriate base (e.g. Cs.sub.2CO.sub.3, NaH, KOt-Bu, DMAP, or the
like) to give intermediate 6 (where X=O). Intermediate 6 may
subsequently be reduced to give aniline 5 using an appropriate
reducing agent (e.g. Zn, Fe, H.sub.2/Pd, SnCl.sub.2-2H.sub.2O, or
the like). Alternatively, intermediate 6 wherein X is O, N, or S
(as determined by the choice of HX--Ar--NO.sub.2) may also be
prepared by nucleophilic substitution of intermediate 4 with a
compound of formula HX--Ar--NO.sub.2 according to the protocol
described for Scheme 1.
##STR00088##
[0309] Scheme 3 shows a general scheme for the synthesis of
intermediate 11 containing an electron withdrawing group (EWG),
which is useful for the synthesis of compounds of Formula I.
According to Scheme 3, a 5-substituted pyrazolopyridine 11 may be
obtained by reacting a protected 5-aminopyrazole 1 with a vinyl
ether of a malonate isostere 7 (e.g. diethyl malonate, ethyl
2-cyanoacetate, ethyl 3-oxobutanoate, or the like) containing
appropriate electron-withdrawing group EWG, wherein EWG is, e.g.,
carboxyl, carbonyl, cyano, sulfonyl, and the like, to provide
compound 8. Similar methodology has been described in WO 01/081348
and WO 99/030710. Compound 8 may be further elaborated in a similar
manner as described for Schemes 1 or 2 to give intermediate 11,
wherein X, Ar, and R.sup.1 are as defined in Scheme 1.
##STR00089##
[0310] Scheme 4 shows a general scheme for the synthesis of
intermediate 15, which is useful for the synthesis of compounds of
Formula I. As shown in Scheme 4, substitution at the 5-position of
the pyrazolopyridine core may be executed by halogenation of
compound 3 with an appropriate halogenation reagent (e.g.,
Selectfluor, bromine, sodium hypochlorite or the like) to give
compound 12 wherein X.sup.2 is halogen. Compound 12 may be further
elaborated in a similar manner as described for Schemes 1 or 2 to
give intermediate 15, wherein X, Ar, and R.sup.1 are as defined in
Scheme 1.
##STR00090##
[0311] Scheme 5 shows a general scheme for the synthesis of
intermediates 19 and 20 (R.sup.1=H; protecting groups PG and
PG.sup.1 may vary independently), which are useful for the
synthesis of compounds of Formula I. As shown in Scheme 5,
substitution at the 3-position of the pyrazolopyridine core may be
achieved by halogenation (using I.sub.2, Br.sub.2, NIS, NBS or
other halogenation reagent) of intermediate 6 (PG=phenylsulfonyl or
other appropriate protecting group) which may require the presence
of a base such as KOH, KOt-Bu, n-BuLi or the like, to give 17
(X.sup.2=halogen, for example iodine or bromine). Alternatively,
removal of protecting group PG using TFA, strong acid, or other
deprotection conditions appropriate for PG removal provides
intermediate 16. Intermediate 16 may be halogenated in like manner
as intermediate 6 followed by introduction of a second protecting
group (PG.sup.1 may be p-methoxybenzyl, Boc, phenylsulfonyl, or the
like; and Y may be an appropriate leaving group such as halogen) to
give compound 18. Intermediates 17 and 18 may be reduced to their
corresponding anilines 19 and 20, respectively, according to the
protocol described for Scheme 2.
##STR00091##
[0312] Scheme 6 shows a general scheme for the synthesis of
intermediates 21 and 22, which are useful for the synthesis of
compounds of Formula I. Intermediate 17 (X.sup.2=bromo or iodo) may
be further elaborated at the 3-position by a
transition-metal-mediated coupling reaction (e.g. Sonogashira,
Stille, Suzuki, Negishi, Heck, or similar coupling reactions known
to those skilled in the art) to give intermediate 21, wherein
R.sup.1 is, for example, aryl, heteroaryl, alkyl, alkenyl, alkynyl,
or other functionality that can be incorporated via related
transition-metal mediated coupling with intermediate 17, and X and
Ar are as defined in Scheme 1. Intermediate 21 may be elaborated
further as described below or converted to aniline 22 using an
appropriate reducing agent as described for Scheme 2.
Alternatively, aniline 20 can be elaborated in like manner as
intermediate 17 by a transition-metal mediated coupling reaction to
give intermediate 22. Intermediates 18 and 19, synthesized
according to Scheme 5, may also be modified according to the method
of Scheme 6.
##STR00092##
[0313] Scheme 7 shows a general scheme for the synthesis of amides,
sulfonamides, carbamates, and ureas 23. Compounds 23 can be
prepared by reaction of an amino-containing intermediate 5
(prepared as in Schemes 1 or 2) with an activated carboxyl- or
sulfonyl-containing reagent in the presence of an appropriate base
(e.g. TEA, DIEA, N-methylmorpholine, pyridine, DMAP, or the like),
as needed. Suitable carboxyl- or sulfonyl-containing reagents
include, but are not limited to, acid chlorides, acid fluorides,
sulfonyl chlorides, sulfonyl fluorides,
polystyrene-2,3,5,6-tetrafluoro-4-(methylcarbamoyl)phenol
(PS-TFP)-carboxylates, PS-TFP-sulfonates, carbamoyl chlorides,
isocyanates, isothiocyanates, anhydrides, chloroformates, HOBt
ester, carbodiimide-derived O-acylurea, and the like. For example,
compounds 23 wherein R.sup.10 is acyl, thiocarbonyl, carbamoyl,
alkoxycarbonyl, or sulfonyl have been prepared by this method.
Alternatively, intermediate 5 may be converted to compound 23
wherein R.sup.10 is alkyl by reductive alkylation methods.
Intermediate 5 can also be coupled with an aryl or heteroaryl
halide according to the procedures of Buchwald and Hartwig to
provide a substituted amine 23 wherein R.sup.10=aryl or
heteroaryl.
[0314] Intermediate compounds 11, 15, 19, 20 and 22, described in
earlier schemes, can similarly be converted to the corresponding
substituted amines by any of the above methods described for
intermediate 5.
##STR00093##
[0315] Scheme 8 shows an alternative method of preparing compound
23 from intermediate 20 (X.sup.2=bromo or iodo) in a two-step
process. Elaboration of the amino group of intermediate 20 using an
activated carboxyl- or sulfonyl-containing reagent such as
described for Scheme 7 provides intermediate 24, wherein R.sup.10
is as described in Scheme 7. Intermediate 24 can be elaborated by
Pd-mediated coupling (or other transition metal-mediated coupling
conditions known to those skilled in the art) using the protocol
described for Scheme 6 to yield compound 23, wherein R.sup.1=aryl,
heteroaryl, alkyl, alkenyl, alkynyl, or other functionality that
can be incorporated via related transition-metal mediated coupling
with intermediate 24, and X and Ar are as defined in Scheme 1.
##STR00094##
[0316] Scheme 9 shows a general method for the synthesis of
alcohols 26a-c (wherein Z may be NO.sub.2, NH.sub.2, or R.sup.10NH;
R.sup.e, R.sup.f, and R.sup.g are independently H, alkyl,
cycloalkyl, heterocyclic, aryl, or heteroaryl, or R.sup.f and
R.sup.g together may form a carbocyclic or heterocyclic ring with
the carbon atom to which they are attached, alternatively R.sup.g
and R.sup.e together may form a carbocyclic or heterocyclic ring
containing the 2 carbon atoms derived from the alkene functionality
in 25a-c; R.sup.10 is as described in Scheme 7) from alkenes 25a-c,
which may be derived using synthetic methods described for Schemes
6 and 8 (e.g. Heck or Suzuki coupling and variations known to those
skilled in the art, such as published by Molander, et al.).
Hydroboration of 25a-c using 9-BBN or another suitable
hydroboration reagent followed by an oxidative quench by addition
of base NaOH or the like and oxidant H.sub.2O.sub.2 provides
compounds 26a-c, wherein X, Ar, and PG are as defined in Scheme 1.
Compounds 26a and 26b may be further elaborated as described for
Schemes 2 and 7.
[0317] Intermediate compounds 4, 5, 6, 9, 10, 11, 13, 14, 15, 16,
21, 22, and 23 described in earlier schemes, wherein R.sup.1
contains an alkenyl group can similarly be converted to the
corresponding alcohols by the above method described for
intermediates 25a-c.
##STR00095##
[0318] Scheme 10 shows a general method for the synthesis of amines
29a-c, wherein Z, R.sup.e, R.sup.f, and R.sup.g are as defined for
Scheme 9, and R.sup.10 is as described for Scheme 7. Activation of
the hydroxyl group in compounds 26a-c by reaction with LG-Y
(wherein LG is an appropriate leaving group, e.g. mesylate,
tosylate, halogen, diazo-dicarboxylate adduct or the like; and Y is
halogen or other leaving group appropriate to hydroxy-activating
reagents known to those skilled in the art) provides intermediates
27a-c. Subsequent nucleophilic substitution of compounds 27a-c with
an amine of the formula R.sup.10R.sup.11NH (wherein R.sup.10 and
R.sup.11 are independently selected from H, alkyl, aryl and
heteroaryl, or R.sup.10 and R.sup.11 together with the nitrogen to
which they are attached form a heterocyclic ring) in the presence
of an appropriate base as needed (DIEA, TEA, pyridine, DMAP,
Cs.sub.2CO.sub.3 or the like) provides amines 29a-c. Alternatively,
alcohols 26a-c can be oxidized with an appropriate oxidation
reagent (Dess-Martin, Swern, or the like) to provide intermediate
ketones or aldehydes 28a-c. Reductive amination of intermediates
28a-c using an amine of the formula R.sup.10R.sup.11NH mediated by
an appropriate reducing agent (e.g. sodium cyanoborohydride, sodium
triacetoxyborohydride, or the like) provides amines 29a-c, wherein
X, Ar, and PG are as defined in Scheme 1. Compounds 29a and 29b may
be further elaborated as described for Schemes 2 and 7.
##STR00096##
[0319] Scheme 11 shows a general method for the synthesis of alkyne
31, which can be used to prepare alkynylated derivatives 32a and
32b. Propargylic amine 31 can be prepared by reaction of propargyl
bromide 30 with an amine of the formula R.sup.10R.sup.11NH (wherein
R.sup.10 and R.sup.11 are independently selected from H, alkyl,
cycloalkyl, heterocyclic, aryl and heteroaryl, or R.sup.10 and
R.sup.11 together with the nitrogen to which they are attached form
a heterocyclic ring) in the presence of an appropriate base
(Cs.sub.2CO.sub.3 or the like). For reviews of alkynyl amines and
related syntheses see Booker-Milburn, K. I., Comprehensive Organic
Functional Group Transformations, 1995, 2, 1039-1074; and Viehe, H.
G., Angew. Chem., Int. Ed. Eng. 1967, 6(9), 767-778. Alkyne 31 can
subsequently be reacted with intermediate 20 or 24 (via Sonogashira
coupling), according to the descriptions provided for Schemes 6 and
8, to provide compounds 32a and 32b, respectively, wherein X, Ar,
and PG are as defined in Scheme 1, and NHR.sup.10 is as described
in Scheme 7. Compound 32a may be further elaborated as described
for Scheme 7.
##STR00097##
[0320] Scheme 12 shows a general method for the synthesis of
alkynes 34, which can be used to prepare alkynylated derivatives
32c and 32d. Gem-dialkyl propargylic amines 34 may be prepared
using methods described by Zaragoza, F., et al. J. Med. Chem. 2004,
47, 2833. According to Scheme 12, alkynyl chloride 33 (wherein each
R is independently methyl, ethyl or other alkyl group, or the R
groups together with the atom to which they are attached form a
carbocyclic ring) can be reacted with an amine of the formula
R.sup.10R.sup.11NH (wherein R.sup.10 and R.sup.11 are independently
H, alkyl, aryl or heteroaryl, or R.sup.10 and R.sup.11 together
with the nitrogen to which they are attached form a heterocyclic
ring) in the presence of CuCl and an appropriate base (e.g. TEA or
the like) to provide the alkyne 34. Alkyne 34 can be reacted with
intermediate 20 or 24 (via Sonogashira coupling), according to the
descriptions provided for Schemes 6 and 8, to provide compounds 32c
and 32d, respectively, wherein X, Ar, and PG are as defined in
Scheme 1, and NHR.sup.10 is as described in Scheme 7. Compound 32c
may be further elaborated as described for Scheme 7.
##STR00098##
[0321] Scheme 13 shows a general scheme for the synthesis of
alkynes 36, which can be used to prepare alkynylated derivatives
32e and 32f. But-3-yn-1-amine 36 (wherein R.sup.8 and R.sup.9 are
independently H, alkyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl, or R.sup.8 and R.sup.9 together with the carbon atom to
which they are attached form a carbocyclic or heterocyclic ring)
can be prepared from reaction of alkynes 35 (LG=tosylate or other
leaving group) with an amine of the formula R.sup.10R.sup.11NH
(wherein R.sup.10 and R.sup.11 are independently SH, alkyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R.sup.10 and
R.sup.11 together with the nitrogen to which they are attached form
a heterocyclic ring) using the protocol described by Olomucki, M.,
et al., Ann. Chim. 1960, 5, 845. Alkynes 36 can subsequently be
reacted with intermediates 20 or 24 (via Sonogashira coupling),
according to the descriptions provided for Schemes 6 and 8 to
provide compounds 32e and 32f, respectively, wherein X, Ar, and PG
are as defined in Scheme 1, and NHR.sup.10 is as described in
Scheme 7. Compound 32e may be further elaborated as described in
Scheme 7.
##STR00099##
[0322] Scheme 14 shows several routes for the synthesis of
3-alkylpyrazolopyridine 37 and the corresponding amide 38. Pd or
Ni-catalyzed hydrogenation of the double or triple bond of
intermediate 5 (R.sup.1 is an optionally substituted alkenyl or
alkynyl), provides alkyl-substituted pyrazolopyridine 37 (wherein
R.sup.1a is optionally substituted alkyl, cycloalkyl or
heterocyclyl). Intermediate 37 may subsequently be elaborated into
amide 38 using methods described for Scheme 7.
[0323] Alternatively, substitution at the 3-position of the
pyrazolopyridine core with an alkyl group may be achieved by
Negishi coupling of intermediate 20 or 24 with an appropriate alkyl
zinc reagent (R.sup.1a).sub.2Zn [wherein R.sup.1a is optionally
substituted alkyl, cycloalkyl or heterocyclyl] according to the
descriptions provided for Schemes 6 and 8.
##STR00100##
[0324] Scheme 15 shows several synthetic routes for the synthesis
of amine and amide compounds 41 and 42, respectively (wherein
R.sup.10 and R.sup.11 are independently H, alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl, or R.sup.10 and R.sup.11 together
with the nitrogen to which they are attached form a heterocyclic
ring; Z is NO.sub.2, NH.sub.2 or R.sup.2NH depending on the choice
of 17, 20, or 24, respectively, as starting material).
Transition-metal mediated (e.g. Pd, Zn, Ni, and the like)
carbonylations and carboxylations using carbon monoxide or other
formyl source (e.g. sodium formate) provides either aldehydes 39 or
carboxylic acids or esters 40 (R is H or alkyl, respectively) under
appropriate reaction conditions known to those skilled in the art.
Aldehydes 39 can also be prepared by reduction of carboxylates 40
to a benzyl alcohol intermediate (not shown), followed by oxidation
using Swern, Dess-Martin reagent, or like conditions. Reductive
amination of aldehyde 39 with an amine of the formula
R.sup.10R.sup.11NH according to the protocol described for Scheme
10 provides amine 41, wherein X, Ar, and PG are as defined in
Scheme 1. Alternatively, amine 41 can be derived by reduction
(using LiAlH.sub.4 or similar reducing agent) of amide 42, prepared
by coupling of an amine with formula R.sup.10R.sup.11NH to
carboxylic acid 40 (wherein R is H) using amide forming conditions
as described for Scheme 7.
##STR00101##
[0325] Scheme 16 shows a method for preparing N-alkylated
pyrazolopyridines 43 and 44 (R.sup.2 is alkyl). Reaction of
intermediate 16 (wherein X is O), prepared according to the
description for Scheme 5, with an alkylation agent R.sup.2--Y
(wherein Y is an appropriate leaving group such as halogen,
tosylate, mesylate, triflate, or the like) mediated by an
appropriate base (e.g. sodium alkoxides, sodium hydride, or the
like) provides a mixture of isomers 43 and 44. Isomers 43 and 44
can be separated using purification techniques known to those
skilled in the art (e.g. flash chromatography, reverse phase HPLC,
or the like). Alternatively, compound 43 can be selectively
prepared according to Schemes 1 and 2 by replacing protecting group
PG with an alternative alkyl group of choice during synthesis of
the starting material aminopyrazole 1 using the methodology
described by Misra, R. N., et al. Bioorg. Med. Chem. Lett. 2003,
13, 1133-1136. Compounds 43 and 44 can be further elaborated as
described for Schemes 2 and 5.
##STR00102##
[0326] Scheme 17 shows routes for the preparation of acid
intermediate 48. Acids of this type may be prepared from either
reaction of the commercially available carboxypyrone ester 45 with
an appropriate amine NH.sub.2R.sup.11 (wherein R.sup.11 is, for
example, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl), or
from the commercially available carboxy pyridone ester 46 via
reaction with the appropriate activated electrophile Y--R.sup.11
(wherein Y is an appropriate leaving group such as halogen,
mesylate or tosylate; and R.sup.11 is, for example, alkyl,
cycloalkyl, or heterocyclyl) followed by hydrolysis of the
resulting methyl ester 47 to the acid 48. The acid 48 may then be
coupled to an appropriate aniline intermediate as in Schemes 7 or
14.
##STR00103##
[0327] Scheme 18 shows a route for the preparation of acid
intermediate 52 according to the general methods described by McNab
H., et al., J. Chem. Soc. Perkin Trans. 1, 1982, 1845. Substituted
hydrazine 49 (wherein R.sup.11 is, for example, alkyl, cycloalkyl,
heterocyclyl, aryl or heteroaryl) can be converted to hydrazono
acetaldehyde 50 with standard dehydrating conditions such as in the
presence of acetic acid at room temperature. The aldehyde/Meldrum's
acid condensation product 51 is prepared in a suitable organic
solvent such as toluene, benzene or dioxane at room temperature
using piperidinium acetate as catalyst. Carboxylic acid
pyridazinone 52 is prepared from hydrazono ethylidene 51 by
cyclization under basic conditions (sodium methoxide in methanol)
at 70.degree. C. The acid can then be coupled to appropriate
aniline intermediates as in Schemes 7 or 14.
##STR00104##
[0328] Scheme 19 shows a route for the preparation of phenol
intermediate 57. Commercially available
2-chloro-4-methoxypyrimidine 53 is reacted with the appropriate
zinc reagent (wherein R.sup.14 is, for example, alkyl, cycloalkyl,
heterocyclyl, heteroaryl or aryl) and palladium catalyst to give
2-substituted 4-methoxypyrimidine 54. Deprotection of the
methoxypyrimidine with HBr in acetic acid provides 2-substituted
pyrimidinone 55. Bromination in the 5-position gives pyrimidinone
intermediate 56. Suzuki coupling of 56 to an appropriate boronic
acid gives a bicyclic intermediate which after final deprotection
of the phenol gives intermediate 57. Intermediate 57 can be
substituted for a phenoxy aniline derivative and reacted with
appropriate core intermediates as in Schemes 1, 2, 3 and 4.
##STR00105##
[0329] Scheme 20 shows a method for preparing phenol intermediate
63 (wherein R.sup.10 and R.sup.11 are independently selected from
H, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl).
Nucleophilic substitution of 2-chloro-4-methoxypyrimidine 53 with a
compound of the formula H--X--R.sup.10 (wherein X is O, N or S) can
be accomplished in an appropriate solvent such as n-butanol, at
refluxing temperature. Deprotection of the methoxypyrimidine with
HBr in acetic acid provides 2-substituted pyrimidinone 59.
Alkylation of 59 to provide the 1-substituted pyrimidinone 61 can
be accomplished with an alkylation agent R.sup.11--X.sup.1 (wherein
X.sup.1 is an appropriate leaving group such as halogen, mesylate,
or tosylate) mediated by an appropriate base (e.g. sodium alkoxide,
lithium or sodium hydride, or the like) providing a mixture of
isomers 60 and 61. Isomers 60 and 61 can be separated using
purification techniques known to those skilled in the art (e.g.
flash chromatography, reverse phase HPLC, or the like). Bromination
in the 5-position with a brominating agent such as Br.sub.2 or NBS
gives pyrimidinone intermediate 62. Suzuki coupling of 62 to an
appropriate boronic acid gives a bicyclic intermediate which after
final deprotection of the phenol gives intermediate 63 as described
for Scheme 19. Intermediate 63 can be substituted for a phenoxy
aniline derivative and reacted with appropriate core intermediates
as in Schemes 1, 2, 3 and 4.
##STR00106##
[0330] Alternatively, phenol intermediate 63 (wherein R.sup.10 and
R.sup.11 are independently selected from H, alkyl, cycloalkyl,
heterocyclic, aryl and heteroaryl) can be prepared as shown in
Scheme 21. 5-Bromo-2,4-dichloropyrimidine 64 is hydrolyzed with
NaOH to give 5-bromo-2-chloropyrimidin-4(.sup.3H)-one 65 as
described in EP 1506967A1. Alkylation of 65 to provide the
1-substituted pyrimidinone 67 can be accomplished with an
alkylation agent R.sup.11--X.sup.1 (wherein X.sup.1 is an
appropriate leaving group such as halogen, mesylate, or tosylate)
mediated by an appropriate base (e.g. sodium alkoxide, lithium or
sodium hydride, or the like) providing a mixture of isomers 66 and
67. Isomers 66 and 67 can be separated using purification
techniques known to those skilled in the art (e.g. flash
chromatography, reverse phase HPLC, or the like). Nucleophilic
substitution of 67 with a compound of the formula H--X--R.sup.10,
(wherein X is O, N or S) can be accomplished at elevated
temperature with a base such as NaHCO.sub.3 in an appropriate
solvent such as n-butanol. Suzuki coupling of 62 to an appropriate
boronic acid gives a bicyclic intermediate which after final
deprotection of the phenol gives intermediate 63. Intermediate 63
can be substituted for a phenoxy aniline derivative and reacted
with appropriate core intermediates as in Schemes 1, 2, 3 and
4.
##STR00107##
[0331] The substituted pyrazino carboxylic acid 70 can be prepared
according to Scheme 22. Methyl
3-oxo-3,4-dihydropyrazine-2-carboxylate 68 can be converted to
alkyl pyrazino carboxylate 69 by standard basic alkylation
conditions using an appropriate alkyl halide R.sup.11--X.sup.1
(wherein R.sup.11 may be alkyl, cycloalkyl, or heterocyclic, and
X.sup.1 is an appropriate leaving group such as halogen, mesylate,
or tosylate). Suitable alkylation conditions include but are not
limited to K.sub.2CO.sub.3 in a suitable solvent such as acetone or
DMF at room temperature or elevated temperature, or NaH in THF at
ambient or elevated temperature followed by addition of
R.sup.11--X.sup.1. Preferably this alkylation is achieved with LiH
in DMF at 0.degree. C., followed by addition of alkyl chloride or
alkyl bromide or alkyl iodide and warming to room temperature. When
R.sup.11=aryl or heteroaryl, the pyrazinone ester 69 can be
prepared by a copper mediated cross-coupling reaction with
iodobenzene, CuI catalyst, a diamine ligand and an appropriate base
in a suitable organic solvent such as THF, DMF, PhMe, MeCN or
dioxane at elevated temperature. For example, in certain
embodiments the reaction conditions include, CuI,
N,N'-dimethylethylenediamine and K.sub.3PO.sub.4 in dioxane at
110.degree. C. Carboxylic acid 70 can then be obtained using
standard saponification conditions such as LiOH or NaOH in mixed
aqueous/organic solvent systems. The acid 70 can then be coupled to
appropriate aniline intermediates as in Schemes 7 or 14.
##STR00108##
[0332] An alternative synthesis of substituted pyrazino carboxylic
acid 74 (wherein R.sup.h and R.sup.i are independently H, alkyl,
cycloalkyl, heterocyclic, or heteroaryl, and R.sup.18 may be phenyl
or heteroaryl) is shown in Scheme 23. Compound 71 can be converted
to imino carbonyl compound 72 by standard dehydrating conditions
such as in the presence of acetic acid at room temperature. The
carbonyl condensation/cyclization product 73 is prepared in two
steps using amino malonate followed by cyclization of the resulting
intermediate (not depicted). Compound 72 can be condensed with
amino malonate under standard dehydrating conditions using a
Dean-Stark trap and a suitable organic solvent such as benzene or
toluene at temperatures ranging from 80 to 120.degree. C. The
cyclization product 73 is then prepared under basic conditions
(sodium methoxide in methanol) at 70.degree. C. Carboxylic acid 74
can then be prepared by ester hydrolysis as described for Scheme
22. The acid 74 can then be coupled to appropriate aniline
intermediates as in Schemes 7 or 14.
##STR00109##
[0333] N-alkylated-2-oxopyrrolidine-3-carboxylic acid 77 (wherein
R.sup.11 may be alkyl, cycloalkyl, heterocyclic, heteroaryl, or
aryl) may be synthesized according to Scheme 24. Compound 75 can be
converted to ester 76 by reaction with methyl chloroformate or
methyl carbono-brominate in the presence of an appropriate base
(e.g. LDA, LHMDS, or the like). Carboxylic acid 77 can then be
prepared from 76 by ester hydrolysis as described for Scheme 22 or
using potassium trimethylsilanolate, or the like. The acid 77 can
then be coupled to appropriate aniline intermediates as in Schemes
7 or 14.
##STR00110##
[0334] Scheme 25 shows a method for the preparation of compound 78,
wherein R.sup.1, X, and Ar are as described for Scheme 1, and
R.sup.10 is as described for Scheme 7. Compound 78 can be prepared
from compound 23 (prepared as in Scheme 7) by removal of protecting
group PG (e.g. p-methoxybenzyl, phenylsulfonyl, or the like) by
heating (40-80.degree. C.) as needed with TFA or strong acid, or
using alternative deprotection conditions as necessary to remove PG
(see T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic
Synthesis, Second Edition, Wiley, New York, 1991). Compounds 26,
29, 32, 38, 41, and 42 may be substituted for compounds 23 for
removal of PG as appropriate.
##STR00111##
[0335] Scheme 26 shows a route for the preparation of pyrazinone
acid intermediate 84 wherein R.sup.h is independently selected from
H, alkyl, cycloalkyl, heterocyclic, or heteroaryl, which is useful
for the synthesis of compounds of Formula I. Substituted aniline 79
can be converted to amino acetonitrile compound 80 by treating with
KCN and a formaldehyde equivalent with standard dehydrating
conditions, such as in the presence of acetic acid at room
temperature. The cyclization product 81 is prepared by treating 80
with oxalyl dichloride in a suitable organic solvent such as
dichlorobenzene at elevated temperature (100.degree. C.).
Pyrazinone 82 can be made in a two step sequence from the
3,5-dichloro pyrazinone compound 81. First, compound 81 is treated
with sodium methoxide in a suitable organic solvent such as MeOH or
THF or MeOH/THF mixture at temperatures ranging from 0.degree. C.
to reflux, followed by conversion of the intermediate
5-chloropyrazinone (not shown) to the 5-H pyrazinone 82. The
conversion can be carried out either under reductive conditions,
or, when R.sup.h is alkyl, cycloalkyl, heterocyclic, or heteroaryl,
using Pd mediated cross-coupling conditions. Nitrile 83 can be
synthesized from methoxy pyrazinone 82 by chlorination followed by
nitrilation. The chlorination can be accomplished with POCl.sub.3,
thionyl chloride, oxalyl chloride, or PCl.sub.5. Preferably, this
transformation is achieved with POCl.sub.3 using DMF as solvent at
elevated temperature (about 90.degree. C.). Nitrilation can be
achieved by standard conditions with CuCN in a suitable organic
solvent such as NMP at elevated temperature (150.degree. C.).
Carboxylic acid pyrazinone 84 can be made in a three step, one-pot
reaction. First, nitrile compound 83 is treated with concentrated
H.sub.2SO.sub.4 neat at room temperature. The resulting amide
intermediate is then treated with MeOH, and this mixture is
refluxed to generate methyl ester pyrazinone intermediate. Then
desired carboxylic acid pyrazinone 74 can be prepared by basic
hydrolysis of the methyl ester pyrazinone intermediate under
standard conditions using either NaOH or LiOH in standard mixture
aqueous/organic solvent systems. The acid 84 may then be coupled to
an appropriate aniline intermediate as in Schemes 7 or 14 to
provide compounds of Formula I.
##STR00112##
[0336] Scheme 27 shows a general scheme for the synthesis of
intermediate 90, wherein Het is a substituted or unsubstituted 5-6
membered heteroaryl group having at least one ring nitrogen atom
and optionally having a second ring heteroatom selected from N and
O. Intermediate compounds 90 are useful for the synthesis of
compounds of Formula I. As shown in Scheme 27, elaboration of the
pyrazolopyridine 4-position phenoxy group into an amino linked
heteroaryl amide may proceed via several pathways. Intermediate 85
bearing an appropriate leaving group X.sup.1 may be reacted with a
heteroaryl amino ester 87 typically under transition metal
catalysis to provide ester 89. Ester 89 may then be converted to
compound 90 using standard ester hydrolysis conditions followed by
standard amide bond forming conditions. Alternatively, 85 may be
reacted with a heteroaryl amino amide 91 under transition metal
catalysis to give intermediate 90 directly. Alternatively, the mode
of coupling may be reversed, wherein an intermediate 86 bearing an
amino group may be reacted with a heteroaryl ester 88 bearing
leaving group X.sup.2 typically under transition metal catalyzed or
thermal conditions to give intermediate 89. Intermediate 89 may
then be converted to intermediate 90 using standard ester
hydrolysis conditions followed by standard amide bond forming
conditions. Alternatively, 86 may be reacted with a heteroaryl
amide 92 bearing leaving group X.sup.2, typically under transition
metal catalyzed or thermal conditions to give intermediate 90
directly. When R.sup.1 is an appropriate substituent, intermediate
90 may be deprotected to give final compounds of Formula I. If
R.sup.1 is a handle for further elaboration, intermediate 90 may be
subjected to further elaboration as in Schemes 6, 8, 9, 10, 11, 12,
13 and 15 for example followed by deprotection to give compounds of
Formula I.
Methods of Separation
[0337] In the methods of preparing the compounds of this invention,
it may be advantageous to separate reaction products from one
another and/or from starting materials. The desired products of
each step or series of steps is separated and/or purified
(hereinafter separated) to the desired degree of homogeneity by the
techniques common in the art. Typically such separations involve
multiphase extraction, crystallization from a solvent or solvent
mixture, distillation, sublimation, or chromatography.
Chromatography can involve any number of methods including, for
example: reverse-phase and normal phase; size exclusion; ion
exchange; high, medium and low pressure liquid chromatography
methods and apparatus; small scale analytical; simulated moving bed
(SMB) and preparative thin or thick layer chromatography, as well
as techniques of small scale thin layer and flash
chromatography.
[0338] Another class of separation methods involves treatment of a
mixture with a reagent selected to bind to or render otherwise
separable a desired product, unreacted starting material, reaction
by product, or the like. Such reagents include adsorbents or
absorbents such as activated carbon, molecular sieves, ion exchange
media, or the like. Alternatively, the reagents can be acids in the
case of a basic material, bases in the case of an acidic material,
binding reagents such as antibodies, binding proteins, selective
chelators such as crown ethers, liquid/liquid ion extraction
reagents (LIX), or the like.
[0339] Selection of appropriate methods of separation depends on
the nature of the materials involved. For example, boiling point
and molecular weight in distillation and sublimation, presence or
absence of polar functional groups in chromatography, stability of
materials in acidic and basic media in multiphase extraction, and
the like. One skilled in the art will apply techniques most likely
to achieve the desired separation.
[0340] Diastereomeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as by chromatography and/or fractional crystallization. Enantiomers
can be separated by converting the enantiomeric mixture into a
diastereomeric mixture by reaction with an appropriate optically
active compound (e.g., chiral auxiliary such as a chiral alcohol or
Mosher's acid chloride), separating the diastereomers and
converting (e.g., hydrolyzing) the individual diastereoisomers to
the corresponding pure enantiomers. Also, some of the compounds of
the present invention may be atropisomers (e.g., substituted
biaryls) and are considered as part of this invention. Enantiomers
can also be separated by use of a chiral HPLC column.
[0341] A single stereoisomer, e.g., an enantiomer, substantially
free of its stereoisomer may be obtained by resolution of the
racemic mixture using a method such as formation of diastereomers
using optically active resolving agents (Eliel, E. and Wilen, S.
"Stereochemistry of Organic Compounds," John Wiley & Sons,
Inc., New York, 1994; Lochmuller, C. H., (1975) J. Chromatogr.,
113(3):283-302). Racemic mixtures of chiral compounds of the
invention can be separated and isolated by any suitable method,
including: (1) formation of ionic, diastereomeric salts with chiral
compounds and separation by fractional crystallization or other
methods, (2) formation of diastereomeric compounds with chiral
derivatizing reagents, separation of the diastereomers, and
conversion to the pure stereoisomers, and (3) separation of the
substantially pure or enriched stereoisomers directly under chiral
conditions. See: "Drug Stereochemistry, Analytical Methods and
Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc., New York
(1993).
[0342] Under method (1), diastereomeric salts can be formed by
reaction of enantiomerically pure chiral bases such as brucine,
quinine, ephedrine, strychnine,
.alpha.-methyl-.beta.-phenylethylamine (amphetamine), and the like
with asymmetric compounds bearing acidic functionality, such as
carboxylic acid and sulfonic acid. The diastereomeric salts may be
induced to separate by fractional crystallization or ionic
chromatography. For separation of the optical isomers of amino
compounds, addition of chiral carboxylic or sulfonic acids, such as
camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid
can result in formation of the diastereomeric salts.
[0343] Alternatively, by method (2), the substrate to be resolved
is reacted with one enantiomer of a chiral compound to form a
diastereomeric pair (E. and Wilen, S. "Stereochemistry of Organic
Compounds", John Wiley & Sons, Inc., 1994, p. 322).
Diastereomeric compounds can be formed by reacting asymmetric
compounds with enantiomerically pure chiral derivatizing reagents,
such as menthyl derivatives, followed by separation of the
diastereomers and hydrolysis to yield the pure or enriched
enantiomer. A method of determining optical purity involves making
chiral esters, such as a menthyl ester, e.g., (-) menthyl
chloroformate in the presence of base, or Mosher ester,
.alpha.-methoxy-.alpha.-(trifluoromethyl)phenyl acetate (Jacob III.
J. Org. Chem., (1982) 47:4165), of the racemic mixture, and
analyzing the .sup.1H NMR spectrum for the presence of the two
atropisomeric enantiomers or diastereomers. Stable diastereomers of
atropisomeric compounds can be separated and isolated by normal-
and reverse-phase chromatography following methods for separation
of atropisomeric naphthyl-isoquinolines (WO 96/15111). By method
(3), a racemic mixture of two enantiomers can be separated by
chromatography using a chiral stationary phase ("Chiral Liquid
Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New
York; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or
purified enantiomers can be distinguished by methods used to
distinguish other chiral molecules with asymmetric carbon atoms,
such as optical rotation and circular dichroism.
Biological Evaluation
[0344] Determination of the activity of c-Met kinase activity of a
compound of Formula Ia or Ib is possible by a number of direct and
indirect detection methods. One example of an assay used for the
determination of c-Met kinase activity is based on an enzyme linked
immunosorbant assay (ELISA). The assay includes a compound of
Formula Ia or Ib, c-Met (His-tagged recombinant human Met (amino
acids 974-end), expressed by baculovirus), and ATP in assay buffer,
as described in Example A.
[0345] In MKN45 cells, the activity of cMet inhibitors of Formulas
Ia and Ib was determined by the in vitro fluorescence assay as
described in Example B.
[0346] Certain exemplary compounds described herein were prepared,
characterized, and assayed for their c-Met binding activity and in
vitro activity against tumor cells. The range of c-Met binding
activities was less than 1 nM to about 10 .mu.M. Certain exemplary
compounds of the invention had c-Met binding activity IC.sub.50
values less than 10 nM. Certain compounds of the invention had
MKN45 cell-based activity IC.sub.50 values less than 100 nM.
Administration of Compounds of Formulas Ia and Ib
[0347] The compounds of the invention may be administered by any
route appropriate to the condition to be treated. Suitable routes
include oral, parenteral (including subcutaneous, intramuscular,
intravenous, intraarterial, intradermal, intrathecal and epidural),
transdermal, rectal, nasal, topical (including buccal and
sublingual), vaginal, intraperitoneal, intrapulmonary and
intranasal. For local immunosuppressive treatment, the compounds
may be administered by intralesional administration, including
perfusing or otherwise contacting the graft with the inhibitor
before transplantation. It will be appreciated that the preferred
route may vary with for example the condition of the recipient.
Where the compound is administered orally, it may be formulated as
a pill, capsule, tablet, etc. with a pharmaceutically acceptable
carrier or excipient. Where the compound is administered
parenterally, it may be formulated with a pharmaceutically
acceptable parenteral vehicle and in a unit dosage injectable form,
as detailed below.
Methods of Treatment with Compounds of Formulas Ia or Ib
[0348] Compounds of the present invention are useful for treating
diseases, conditions and/or disorders including, but not limited
to, those characterized by over expression of receptor tyrosine
kinases (RTK), e.g. c-Met kinase. Accordingly, another aspect of
this invention includes methods of treating or preventing diseases
or conditions that can be treated or prevented by inhibiting
receptor tyrosine kinases (RTK), including c-Met. In one
embodiment, the method comprises administering to a mammal in need
thereof a therapeutically effective amount of a compound of Formula
Ia or Ib, or a stereoisomer, geometric isomer, tautomer, solvate,
metabolite, or pharmaceutically acceptable salt or prodrug
thereof.
[0349] Diseases and conditions treatable according to the methods
of this invention include, but are not limited to, cancer, stroke,
diabetes, hepatomegaly, cardiovascular disease, Alzheimer's
disease, cystic fibrosis, viral disease, autoimmune diseases,
atherosclerosis, restenosis, psoriasis, allergic disorders,
inflammation, neurological disorders, a hormone-related disease,
conditions associated with organ transplantation, immunodeficiency
disorders, destructive bone disorders, proliferative disorders,
infectious diseases, conditions associated with cell death,
thrombin-induced platelet aggregation, chronic myelogenous leukemia
(CML), liver disease, pathologic immune conditions involving T cell
activation, and CNS disorders in a patient. In one embodiment, a
human patient is treated with a compound of Formula Ia or Ib and a
pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein
said compound of Formula Ia or Ib is present in an amount to
detectably inhibit cMet kinase activity.
[0350] Cancers which can be treated according to the methods of
this invention include, but are not limited to, breast, ovary,
cervix, prostate, testis, genitourinary tract, esophagus, larynx,
glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung,
epidermoid carcinoma, large cell carcinoma, non-small cell lung
carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone,
colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular
carcinoma, undifferentiated carcinoma, papillary carcinoma,
seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and
biliary passages, kidney carcinoma, myeloid disorders, lymphoid
disorders, hairy cells, buccal cavity and pharynx (oral), lip,
tongue, mouth, pharynx, small intestine, colon-rectum, large
intestine, rectum, brain and central nervous system, Hodgkin's and
leukemia.
[0351] Cardiovascular diseases which can be treated according to
the methods of this invention include, but are not limited to,
restenosis, cardiomegaly, atherosclerosis, myocardial infarction,
and congestive heart failure.
[0352] Neurodegenerative disease which can be treated according to
the methods of this invention include, but are not limited to,
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, Huntington's disease, and cerebral ischemia, and
neurodegenerative disease caused by traumatic injury, glutamate
neurotoxicity and hypoxia.
[0353] Inflammatory diseases which can be treated according to the
methods of this invention include, but are not limited to,
rheumatoid arthritis, psoriasis, contact dermatitis, and delayed
hypersensitivity reactions.
[0354] Another aspect of this invention provides a compound of this
invention for use in the treatment of the diseases or conditions
described herein in a mammal, for example, a human, suffering from
such disease or condition. Also provided is the use of a compound
of this invention in the preparation of a medicament for the
treatment of the diseases and conditions described herein in a
warm-blooded animal, such as a mammal, for example a human,
suffering from such disorder.
Pharmaceutical Formulations
[0355] In order to use a compound of this invention for the
therapeutic treatment (including prophylactic treatment) of mammals
including humans, it is normally formulated in accordance with
standard pharmaceutical practice as a pharmaceutical composition.
According to this aspect of the invention there is provided a
pharmaceutical composition comprising a compound of this invention
in association with a pharmaceutically acceptable diluent or
carrier.
[0356] A typical formulation is prepared by mixing a compound of
the present invention and a carrier, diluent or excipient. Suitable
carriers, diluents and excipients are well known to those skilled
in the art and include materials such as carbohydrates, waxes,
water soluble and/or swellable polymers, hydrophilic or hydrophobic
materials, gelatin, oils, solvents, water and the like. The
particular carrier, diluent or excipient used will depend upon the
means and purpose for which the compound of the present invention
is being applied. Solvents are generally selected based on solvents
recognized by persons skilled in the art as safe (GRAS) to be
administered to a mammal. In general, safe solvents are non-toxic
aqueous solvents such as water and other non-toxic solvents that
are soluble or miscible in water. Suitable aqueous solvents include
water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG
400, PEG 300), etc. and mixtures thereof. The formulations may also
include one or more buffers, stabilizing agents, surfactants,
wetting agents, lubricating agents, emulsifiers, suspending agents,
preservatives, antioxidants, opaquing agents, glidants, processing
aids, colorants, sweeteners, perfuming agents, flavoring agents and
other known additives to provide an elegant presentation of the
drug (i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0357] The formulations may be prepared using conventional
dissolution and mixing procedures. For example, the bulk drug
substance (i.e., compound of the present invention or stabilized
form of the compound (e.g., complex with a cyclodextrin derivative
or other known complexation agent) is dissolved in a suitable
solvent in the presence of one or more of the excipients described
above. The compound of the present invention is typically
formulated into pharmaceutical dosage forms to provide an easily
controllable dosage of the drug and to enable patient compliance
with the prescribed regimen.
[0358] The pharmaceutical composition (or formulation) for
application may be packaged in a variety of ways depending upon the
method used for administering the drug. Generally, an article for
distribution includes a container having deposited therein the
pharmaceutical formulation in an appropriate form. Suitable
containers are well known to those skilled in the art and include
materials such as bottles (plastic and glass), sachets, ampoules,
plastic bags, metal cylinders, and the like. The container may also
include a tamper-proof assemblage to prevent indiscreet access to
the contents of the package. In addition, the container has
deposited thereon a label that describes the contents of the
container. The label may also include appropriate warnings.
[0359] Pharmaceutical formulations of the compounds of the present
invention may be prepared for various routes and types of
administration. For example, a compound of Formula Ia or Ib having
the desired degree of purity may optionally be mixed with
pharmaceutically acceptable diluents, carriers, excipients or
stabilizers (Remington's Pharmaceutical Sciences (1980) 16th
edition, Osol, A. Ed.), in the form of a lyophilized formulation,
milled powder, or an aqueous solution. Formulation may be conducted
by mixing at ambient temperature at the appropriate pH, and at the
desired degree of purity, with physiologically acceptable carriers,
i.e., carriers that are non-toxic to recipients at the dosages and
concentrations employed. The pH of the formulation depends mainly
on the particular use and the concentration of compound, but may
range from about 3 to about 8. Formulation in an acetate buffer at
pH 5 is a suitable embodiment.
[0360] The compound of this invention for use herein is preferably
sterile. In particular, formulations to be used for in vivo
administration must be sterile. Such sterilization is readily
accomplished by filtration through sterile filtration
membranes.
[0361] The compound ordinarily can be stored as a solid
composition, a lyophilized formulation or as an aqueous
solution.
[0362] The pharmaceutical compositions of the invention will be
formulated, dosed and administered in a fashion, i.e., amounts,
concentrations, schedules, course, vehicles and route of
administration, consistent with good medical practice. Factors for
consideration in this context include the particular disorder being
treated, the particular mammal being treated, the clinical
condition of the individual patient, the cause of the disorder, the
site of delivery of the agent, the method of administration, the
scheduling of administration, and other factors known to medical
practitioners. The "therapeutically effective amount" of the
compound to be administered will be governed by such
considerations, and is the minimum amount necessary to prevent,
ameliorate, or treat the coagulation factor mediated disorder. Such
amount is preferably below the amount that is toxic to the host or
renders the host significantly more susceptible to bleeding.
[0363] As a general proposition, the initial pharmaceutically
effective amount of the inhibitor administered parenterally per
dose will be in the range of about 0.01-100 mg/kg, namely about 0.1
to 20 mg/kg of patient body weight per day, with the typical
initial range of compound used being 0.3 to 15 mg/kg/day.
[0364] Acceptable diluents, carriers, excipients and stabilizers
are nontoxic to recipients at the dosages and concentrations
employed, and include buffers such as phosphate, citrate and other
organic acids; antioxidants including ascorbic acid and methionine;
preservatives (such as octadecyldimethylbenzyl ammonium chloride;
hexamethonium chloride; benzalkonium chloride, benzethonium
chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as
methyl or propyl paraben; catechol; resorcinol; cyclohexanol;
3-pentanol; and m-cresol); low molecular weight (less than about 10
residues) polypeptides; proteins, such as serum albumin, gelatin,
or immunoglobulins; hydrophilic polymers such as
polyvinylpyrrolidone; amino acids such as glycine, glutamine,
asparagine, histidine, arginine, or lysine; monosaccharides,
disaccharides and other carbohydrates including glucose, mannose,
or dextrins; chelating agents such as EDTA; sugars such as sucrose,
mannitol, trehalose or sorbitol; salt-forming counter-ions such as
sodium; metal complexes (e.g., Zn-protein complexes); and/or
non-ionic surfactants such as TWEEN.TM., PLURONICS.TM. or
polyethylene glycol (PEG). The active pharmaceutical ingredients
may also be entrapped in microcapsules prepared, for example, by
coacervation techniques or by interfacial polymerization, for
example, hydroxymethylcellulose or gelatin-microcapsules and
poly-(methylmethacylate) microcapsules, respectively, in colloidal
drug delivery systems (for example, liposomes, albumin
microspheres, microemulsions, nano-particles and nanocapsules) or
in macroemulsions. Such techniques are disclosed in Remington's
Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).
[0365] Sustained-release preparations of compounds of Formulas I
may be prepared. Suitable examples of sustained-release
preparations include semipermeable matrices of solid hydrophobic
polymers containing a compound of Formula Ia or Ib, which matrices
are in the form of shaped articles, e.g., films, or microcapsules.
Examples of sustained-release matrices include polyesters,
hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or
poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919),
copolymers of L-glutamic acid and gamma-ethyl-L-glutamate,
non-degradable ethylene-vinyl acetate, degradable lactic
acid-glycolic acid copolymers such as the LUPRON DEPOT.RTM.
(injectable microspheres composed of lactic acid-glycolic acid
copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric
acid.
[0366] The formulations include those suitable for the
administration routes detailed herein. The formulations may
conveniently be presented in unit dosage form and may be prepared
by any of the methods well known in the art of pharmacy. Techniques
and formulations generally are found in Remington's Pharmaceutical
Sciences (Mack Publishing Co., Easton, Pa.). Such methods include
the step of bringing into association the active ingredient with
the carrier which constitutes one or more accessory ingredients. In
general the formulations are prepared by uniformly and intimately
bringing into association the active ingredient with liquid
carriers or finely divided solid carriers or both, and then, if
necessary, shaping the product.
[0367] Formulations of a compound of Formula Ia or Ib suitable for
oral administration may be prepared as discrete units such as
pills, capsules, cachets or tablets each containing a predetermined
amount of a compound of Formula Ia or Ib.
[0368] Compressed tablets may be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form such
as a powder or granules, optionally mixed with a binder, lubricant,
inert diluent, preservative, surface active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered active ingredient moistened with an inert
liquid diluent. The tablets may optionally be coated or scored and
optionally are formulated so as to provide slow or controlled
release of the active ingredient therefrom.
[0369] Tablets, troches, lozenges, aqueous or oil suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
e.g., gelatin capsules, syrups or elixirs may be prepared for oral
use. Formulations of compounds of Formula Ia or Ib intended for
oral use may be prepared according to any method known to the art
for the manufacture of pharmaceutical compositions and such
compositions may contain one or more agents including sweetening
agents, flavoring agents, coloring agents and preserving agents, in
order to provide a palatable preparation. Tablets containing the
active ingredient in admixture with non-toxic pharmaceutically
acceptable excipient which are suitable for manufacture of tablets
are acceptable. These excipients may be, for example, inert
diluents, such as calcium or sodium carbonate, lactose, calcium or
sodium phosphate; granulating and disintegrating agents, such as
maize starch, or alginic acid; binding agents, such as starch,
gelatin or acacia; and lubricating agents, such as magnesium
stearate, stearic acid or talc. Tablets may be uncoated or may be
coated by known techniques including microencapsulation to delay
disintegration and adsorption in the gastrointestinal tract and
thereby provide a sustained action over a longer period. For
example, a time delay material such as glyceryl monostearate or
glyceryl distearate alone or with a wax may be employed.
[0370] For treatment of the eye or other external tissues, e.g.,
mouth and skin, the formulations are preferably applied as a
topical ointment or cream containing the active ingredient(s) in an
amount of, for example, 0.075 to 20% w/w. When formulated in an
ointment, the active ingredients may be employed with either a
paraffinic or a water-miscible ointment base. Alternatively, the
active ingredients may be formulated in a cream with an
oil-in-water cream base.
[0371] If desired, the aqueous phase of the cream base may include
a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl
groups such as propylene glycol, butane 1,3-diol, mannitol,
sorbitol, glycerol and polyethylene glycol (including PEG 400) and
mixtures thereof. The topical formulations may desirably include a
compound which enhances absorption or penetration of the active
ingredient through the skin or other affected areas. Examples of
such dermal penetration enhancers include dimethyl sulfoxide and
related analogs.
[0372] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier, it desirably comprises a
mixture of at least one emulsifier with a fat or an oil or with
both a fat and an oil. Preferably, a hydrophilic emulsifier is
included together with a lipophilic emulsifier which acts as a
stabilizer. It is also preferred to include both an oil and a fat.
Together, the emulsifier(s) with or without stabilizer(s) make up
the so-called emulsifying wax, and the wax together with the oil
and fat make up the so-called emulsifying ointment base which forms
the oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
invention include Tween.RTM. 60, Span.RTM. 80, cetostearyl alcohol,
benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium
lauryl sulfate.
[0373] Aqueous suspensions of Formula Ia or Ib compounds contain
the active materials in admixture with excipients suitable for the
manufacture of aqueous suspensions. Such excipients include a
suspending agent, such as sodium carboxymethylcellulose,
croscarmellose, povidone, methylcellulose, hydroxypropyl
methylcellulose, sodium alginate, polyvinylpyrrolidone, gum
tragacanth and gum acacia, and dispersing or wetting agents such as
a naturally occurring phosphatide (e.g., lecithin), a condensation
product of an alkylene oxide with a fatty acid (e.g.,
polyoxyethylene stearate), a condensation product of ethylene oxide
with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension may also contain one or more preservatives such as ethyl
or n-propyl p-hydroxybenzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose or saccharin.
[0374] The pharmaceutical compositions of compounds of Formula Ia
or Ib may be in the form of a sterile injectable preparation, such
as a sterile injectable aqueous or oleaginous suspension. This
suspension may be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents which
have been mentioned above. The sterile injectable preparation may
also be a sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, such as a solution in
1,3-butanediol or prepared as a lyophilized powder. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile fixed oils may conventionally be employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid may likewise be used in
the preparation of injectables.
[0375] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95% of the total compositions (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion may contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur.
[0376] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents.
[0377] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredient is dissolved
or suspended in a suitable carrier, especially an aqueous solvent
for the active ingredient. The active ingredient is preferably
present in such formulations in a concentration of about 0.5 to 20%
w/w, for example about 0.5 to 10% w/w, for example about 1.5%
w/w.
[0378] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0379] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0380] Formulations suitable for intrapulmonary or nasal
administration have a particle size for example in the range of 0.1
to 500 microns (including particle sizes in a range between 0.1 and
500 microns in increments microns such as 0.5, 1, 30 microns, 35
microns, etc.), which is administered by rapid inhalation through
the nasal passage or by inhalation through the mouth so as to reach
the alveolar sacs. Suitable formulations include aqueous or oily
solutions of the active ingredient. Formulations suitable for
aerosol or dry powder administration may be prepared according to
conventional methods and may be delivered with other therapeutic
agents such as compounds heretofore used in the treatment or
prophylaxis disorders as described below.
[0381] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0382] The formulations may be packaged in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water, for
injection immediately prior to use. Extemporaneous injection
solutions and suspensions are prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredient.
[0383] The invention further provides veterinary compositions
comprising at least one active ingredient as above defined together
with a veterinary carrier therefore. Veterinary carriers are
materials useful for the purpose of administering the composition
and may be solid, liquid or gaseous materials which are otherwise
inert or acceptable in the veterinary art and are compatible with
the active ingredient. These veterinary compositions may be
administered parenterally, orally or by any other desired
route.
[0384] Also provided are compositions comprising a compound of
claim 1 in an amount to detectably inhibit Met kinase activity and
a pharmaceutically acceptable carrier, adjuvant, or vehicle.
Combination Therapy
[0385] The compounds of Formulas Ia and Ib may be employed alone or
in combination with other therapeutic agents for the treatment of a
disease or disorder described herein, such as a hyperproliferative
disorder (e.g., cancer). In certain embodiments, a compound of
Formula Ia or Ib is combined in a pharmaceutical combination
formulation, or dosing regimen as combination therapy, with a
second compound that has anti-hyperproliferative properties or that
is useful for treating a hyperproliferative disorder (e.g.,
cancer). The second compound of the pharmaceutical combination
formulation or dosing regimen preferably has complementary
activities to the compound of Formula Ia or Ib such that they do
not adversely affect each other. Such compounds are suitably
present in combination, in amounts that are effective for the
purpose intended. In one embodiment, a composition of this
invention comprises a compound of Formula Ia or Ib, or a
stereoisomer, geometric isomer, tautomer, solvate, metabolite, or
pharmaceutically acceptable salt or prodrug thereof, in combination
with a chemotherapeutic agent such as described herein.
[0386] The combination therapy may be administered as a
simultaneous or sequential regimen. When administered sequentially,
the combination may be administered in two or more administrations.
The combined administration includes coadministration, using
separate formulations or a single pharmaceutical formulation, and
consecutive administration in either order, wherein preferably
there is a time period while both (or all) active agents
simultaneously exert their biological activities.
[0387] Suitable dosages for any of the above coadministered agents
are those presently used and may be lowered due to the combined
action (synergy) of the newly identified agent and other
chemotherapeutic agents or treatments.
[0388] The combination therapy may provide "synergy" and prove
"synergistic", i.e., the effect achieved when the active
ingredients used together is greater than the sum of the effects
that results from using the compounds separately. A synergistic
effect may be attained when the active ingredients are: (1)
co-formulated and administered or delivered simultaneously in a
combined, unit dosage formulation; (2) delivered by alternation or
in parallel as separate formulations; or (3) by some other regimen.
When delivered in alternation therapy, a synergistic effect may be
attained when the compounds are administered or delivered
sequentially, e.g., by different injections in separate syringes.
In general, during alternation therapy, an effective dosage of each
active ingredient is administered sequentially, i.e., serially,
whereas in combination therapy, effective dosages of two or more
active ingredients are administered together.
[0389] In a particular embodiment of anti-cancer therapy, a
compound of Formula Ia or Ib, or a stereoisomer, geometric isomer,
tautomer, solvate, metabolite, or pharmaceutically acceptable salt
or prodrug thereof, may be combined with other chemotherapeutic,
hormonal or antibody agents such as those described herein, as well
as combined with surgical therapy and radiotherapy. Combination
therapies according to the present invention thus comprise the
administration of at least one compound of Formula Ia or Ib, or a
stereoisomer, geometric isomer, tautomer, solvate, metabolite, or
pharmaceutically acceptable salt or prodrug thereof, and the use of
at least one other cancer treatment method. The amounts of the
compound(s) of Formula Ia or Ib and the other pharmaceutically
active chemotherapeutic agent(s) and the relative timings of
administration will be selected in order to achieve the desired
combined therapeutic effect.
[0390] Also provided are compositions comprising a compound of
Formula Ia or Ib in combination with an additional therapeutic
agent selected from an anti-proliferative agent, an
anti-inflammatory agent, an immunomodulatory agent, a neurotropic
factor, an agent for treating cardiovascular disease, an agent for
treating liver disease, an anti-viral agent, an agent for treating
blood disorders, an agent for treating diabetes, or an agent for
treating immunodeficiency disorders.
Metabolites of Compounds of Formulas Ia and Ib
[0391] Also falling within the scope of this invention are the in
vivo metabolic products of heterobicyclic pyrazole compounds of
Formulas Ia and Ib described herein. Such products may result for
example from the oxidation, reduction, hydrolysis, amidation,
deamidation, esterification, deesterification, enzymatic cleavage,
and the like, of the administered compound. Accordingly, the
invention includes metabolites of compounds of Formulas Ia and Ib,
including compounds produced by a process comprising contacting a
compound of this invention with a mammal for a period of time
sufficient to yield a metabolic product thereof.
[0392] Metabolite products typically are identified by preparing a
radiolabelled (e.g., .sup.14C or .sup.3H) isotope of a compound of
the invention, administering it parenterally in a detectable dose
(e.g., greater than about 0.5 mg/kg) to an animal such as rat,
mouse, guinea pig, monkey, or to man, allowing sufficient time for
metabolism to occur (typically about 30 seconds to 30 hours) and
isolating its conversion products from the urine, blood or other
biological samples. These products are easily isolated since they
are labeled (others are isolated by the use of antibodies capable
of binding epitopes surviving in the metabolite). The metabolite
structures are determined in conventional fashion, e.g., by MS,
LC/MS or NMR analysis. In general, analysis of metabolites is done
in the same way as conventional drug metabolism studies well known
to those skilled in the art. The metabolite products, so long as
they are not otherwise found in vivo, are useful in diagnostic
assays for therapeutic dosing of the compounds of the
invention.
Prodrugs of Compounds of Formulas Ia and Ib
[0393] In addition to compounds of Formulas Ia and Ib, the
invention also includes pharmaceutically acceptable prodrugs of
such compounds. Prodrugs include compounds wherein an amino acid
residue, or a polypeptide chain of two or more (e.g., two, three or
four) amino acid residues, is covalently joined through an amide or
ester bond to a free amino, hydroxy or carboxylic acid group of a
compound of the present invention. The amino acid residues include
but are not limited to the 20 naturally occurring amino acids
commonly designated by three letter symbols and also includes
phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline,
hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate,
hippuric acid, octahydroindole-2-carboxylic acid, statine,
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,
ornithine, 3-methylhistidine, norvaline, beta-alanine,
gamma-aminobutyric acid, cirtulline, homocysteine, homoserine,
methyl-alanine, para-benzoylphenylalanine, phenylglycine,
propargylglycine, sarcosine, methionine sulfone and
tert-butylglycine.
[0394] Additional types of prodrugs are also encompassed. For
instance, a free carboxyl group of a compound of Formula Ia or Ib
can be derivatized as an amide or alkyl ester. As another example,
compounds of this invention comprising free hydroxy groups may be
derivatized as prodrugs by converting the hydroxy group into a
group such as, but not limited to, a phosphate ester,
hemisuccinate, dimethylaminoacetate, or
phosphoryloxymethyloxycarbonyl group, as outlined in Advanced Drug
Delivery Reviews, (1996) 19:115. Carbamate prodrugs of hydroxy and
amino groups are also included, as are carbonate prodrugs,
sulfonate esters and sulfate esters of hydroxy groups.
Derivatization of hydroxy groups as (acyloxy)methyl and
(acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester
optionally substituted with groups including, but not limited to,
ether, amine and carboxylic acid functionalities, or where the acyl
group is an amino acid ester as described above, are also
encompassed. Prodrugs of this type are described in J. Med. Chem.,
(1996), 39:10. More specific examples include replacement of the
hydrogen atom of the alcohol group with a group such as
(C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxycarbonyloxymethyl,
N--(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanoyl,
arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl, where each .alpha.-aminoacyl
group is independently selected from the naturally occurring
L-amino acids, P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate).
[0395] Free amine groups of compounds of Formulas Ia and Ib can
also be derivatized as amides, sulfonamides or phosphonamides. All
of these moieties may incorporate groups including, but not limited
to, ether, amine and carboxylic acid functionalities. For example,
a prodrug can be formed by the replacement of a hydrogen atom in
the amine group with a group such as R-carbonyl, RO-carbonyl,
NRR'-carbonyl, wherein R and R' are each independently
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.7)cycloalkyl, or benzyl, or
R-carbonyl is a natural .alpha.-aminoacyl or natural
.alpha.-aminoacyl-natural .alpha.-aminoacyl, --C(OH)C(O)OY wherein
Y is H, (C.sub.1-C.sub.6)alkyl or benzyl, --C(OY.sub.0)Y.sub.1
wherein Y.sub.0 is (C.sub.1-C.sub.4) alkyl and Y.sub.1 is
(C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.4)alkyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylaminoalkyl, or --C(Y.sub.2)Y.sub.3
wherein Y.sub.2 is H or methyl and Y.sub.3 is mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylamino, morpholino, piperidin-1-yl or
pyrrolidin-1-yl.
[0396] For additional examples of prodrug derivatives, see, for
example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier,
1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K.
Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design
and Development, edited by Krogsgaard-Larsen and H. Bundgaard,
Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard p.
113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews,
8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical
Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm.
Bull., 32:692 (1984).
Articles of Manufacture
[0397] In another embodiment of the invention, an article of
manufacture, or "kit", containing materials useful for the
treatment of the diseases and disorders described above is
provided. In one embodiment, the kit comprises a container
comprising a heterobicyclic pyrazole compound of Formula Ia or Ib,
or a stereoisomer, geometric isomer, tautomer, solvate, metabolite,
or pharmaceutically acceptable salt or prodrug thereof. The kit may
further comprise a label or package insert on or associated with
the container. The term "package insert" is used to refer to
instructions customarily included in commercial packages of
therapeutic products, that contain information about the
indications, usage, dosage, administration, contraindications
and/or warnings concerning the use of such therapeutic products.
Suitable containers include, for example, bottles, vials, syringes,
blister pack, etc. The container may be formed from a variety of
materials such as glass or plastic. The container may hold a
compound of Formula Ia or Ib or a formulation thereof which is
effective for treating the condition and may have a sterile access
port (for example, the container may be an intravenous solution bag
or a vial having a stopper pierceable by a hypodermic injection
needle). At least one active agent in the composition is a compound
of Formula Ia or Ib. The label or package insert indicates that the
composition is used for treating the condition of choice, such as
cancer. In addition, the label or package insert may indicate that
the patient to be treated is one having a disorder such as a
hyperproliferative disorder, neurodegeneration, cardiac
hypertrophy, pain, migraine or a neurotraumatic disease or event.
In one embodiment, the label or package inserts indicates that the
composition comprising a compound of Formula Ia or Ib can be used
to treat a disorder resulting from abnormal cell growth. The label
or package insert may also indicate that the composition can be
used to treat other disorders. Alternatively, or additionally, the
article of manufacture may further comprise a second container
comprising a pharmaceutically acceptable buffer, such as
bacteriostatic water for injection (BWFI), phosphate-buffered
saline, Ringer's solution and dextrose solution. It may further
include other materials desirable from a commercial and user
standpoint, including other buffers, diluents, filters, needles,
and syringes.
[0398] The kit may further comprise directions for the
administration of the compound of Formula Ia or Ib and, if present,
the second pharmaceutical formulation. For example, if the kit
comprises a first composition comprising a compound of Formula Ia
or Ib and a second pharmaceutical formulation, the kit may further
comprise directions for the simultaneous, sequential or separate
administration of the first and second pharmaceutical compositions
to a patient in need thereof.
[0399] In another embodiment, the kits are suitable for the
delivery of solid oral forms of a compound of Formula Ia or Ib,
such as tablets or capsules. Such a kit preferably includes a
number of unit dosages. Such kits can include a card having the
dosages oriented in the order of their intended use. An example of
such a kit is a "blister pack". Blister packs are well known in the
packaging industry and are widely used for packaging pharmaceutical
unit dosage forms. If desired, a memory aid can be provided, for
example in the form of numbers, letters, or other markings or with
a calendar insert, designating the days in the treatment schedule
in which the dosages can be administered.
[0400] According to one embodiment, a kit may comprise (a) a first
container with a compound of Formula Ia or Ib contained therein;
and optionally (b) a second container with a second pharmaceutical
formulation contained therein, wherein the second pharmaceutical
formulation comprises a second compound with
anti-hyperproliferative activity. Alternatively, or additionally,
the kit may further comprise a third container comprising a
pharmaceutically-acceptable buffer, such as bacteriostatic water
for injection (BWFI), phosphate-buffered saline, Ringer's solution
and dextrose solution. It may further include other materials
desirable from a commercial and user standpoint, including other
buffers, diluents, filters, needles, and syringes.
[0401] In certain other embodiments wherein the kit comprises a
composition of Formula Ia or Ib and a second therapeutic agent, the
kit may comprise a container for containing the separate
compositions such as a divided bottle or a divided foil packet,
however, the separate compositions may also be contained within a
single, undivided container. Typically, the kit comprises
directions for the administration of the separate components. The
kit form is particularly advantageous when the separate components
are preferably administered in different dosage forms (e.g., oral
and parenteral), are administered at different dosage intervals, or
when titration of the individual components of the combination is
desired by the prescribing physician.
EXAMPLES
[0402] In order to illustrate the invention, the following examples
are included. However, it is to be understood that these examples
do not limit the invention and are only meant to suggest a method
of practicing the invention. Persons skilled in the art will
recognize that the chemical reactions described may be readily
adapted to prepare a number of other c-Met inhibitors of the
invention, and alternative methods for preparing the compounds of
this invention are deemed to be within the scope of this invention.
For example, the synthesis of non-exemplified compounds according
to the invention may be successfully performed by modifications
apparent to those skilled in the art, e.g., by appropriately
protecting interfering groups, by utilizing other suitable reagents
known in the art other than those
Example 1
Preparation of
N-(4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenylcarbamothioyl)-2-p-
henylacetamide
##STR00113##
[0404] described, and/or by making routine modifications of
reaction conditions. Alternatively, other reactions disclosed
herein or known in the art will be recognized as having
applicability for preparing other compounds of the invention.
[0405] In the examples described below, unless otherwise indicated
all temperatures are set forth in degrees Celsius. Reagents were
purchased from commercial suppliers such as Aldrich Chemical
Company, Lancaster, TCI or Maybridge, and were used without further
purification unless otherwise indicated.
[0406] The reactions set forth below were done generally under a
positive pressure of nitrogen or argon or with a drying tube
(unless otherwise stated) in anhydrous solvents, and the reaction
flasks were typically fitted with rubber septa for the introduction
of substrates and reagents via syringe. Glassware was oven dried
and/or heat dried.
[0407] Column chromatography was conducted on a Biotage system
(Manufacturer: Dyax Corporation) having a silica gel column or on a
silica SEP PAK.RTM. cartridge (Waters). .sup.1H NMR spectra were
recorded on a Varian instrument operating at 400 MHz. .sup.1H NMR
spectra were obtained as CDCl.sub.3, d.sub.6-DMSO, CH.sub.3OD or
d.sub.6-acetone solutions (reported in ppm), using
tetramethylsilane (0.00 ppm) or residual solvent (CDCl.sub.3: 7.25
ppm; d.sub.6-DMSO: 2.50 ppm; CD.sub.3OD: 3.31 ppm) as the reference
standard. When peak multiplicities are reported, the following
abbreviations are used: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), br (broadened), dd (doublet of doublets),
dt (doublet of triplets). Coupling constants, when given, are
reported in Hertz (Hz).
[0408] Step A: Preparation of
5-((1-(4-methoxybenzyl)-1H-pyrazol-5-ylamino)methylene)-2,2-dimethyl-1,3--
dioxane-4,6-dione: A stirred mixture of triethoxymethane (339 mL,
2037 mmol), and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid)
(35.2 g, 244 mmol) was heated to 80.degree. C. for 1 hour. A
suspension of 1-(4-methoxybenzyl)-1H-pyrazol-5-amine [41.4 g, 204
mmol; prepared according to the procedure described by Misra, R.
N., et al. Bioorg. Med. Chem. Lett. 2003, 13, 1133-1136, except
desalting was performed as follows:
1-(4-methoxybenzyl)-1H-pyrazol-5-amine hydrochloride (44 g) was
partitioned between MTBE (300 mL) and 1N aqueous NaOH (300 mL),
after separating the phases, the aqueous suspension was
re-extracted with MTBE (8.times.100 mL), followed by drying
(Na.sub.2SO.sub.4) the combined organic phases, and concentration
in vacuo to obtain the free-based
1-(4-methoxybenzyl)-1H-pyrazol-5-amine (30 g)] in triethoxymethane
(339 mL, 2037 mmol) was added at once and heating at 80.degree. C.
was continued for 18 hours under N.sub.2. After cooling to room
temperature, toluene azeotrope (2.times.200 mL) was utilized to
remove EtOH. The resulting suspension was diluted with diethyl
ether (500 mL) and filtered to obtain a yellow solid (33.5 g, 46%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.13 (d, J=13 Hz, 1H),
8.26 (d, J=13 Hz, 1H), 7.50 (d, J=2 Hz, 1H), 7.25 (d, J=9 Hz, 2H),
6.88 (d, J=9 Hz, 2H), 6.21 (d, J=2 Hz, 1H), 5.28 (s, 2H), 3.78 (s,
3H), 1.74 (s, 6H).
[0409] Step B: Preparation of
1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol: To a stirred
biphenyl-diphenyl ether eutectic (also called Dowtherm) (100 mL) at
240.degree. C. under N.sub.2 was added
5-((1-(4-methoxybenzyl)-1H-pyrazol-5-ylamino)methylene)-2,2-dimethyl-1,3--
dioxane-4,6-dione (33.5 g, 93.7 mmol) in portions as a solid over a
10 minute period. After addition was complete, the mixture was
heated at 240.degree. C. for 10 minutes. After cooling to room
temperature, the mixture was diluted with hexanes (300 mL), and the
hexanes were decanted along with the majority of the Dowtherm. The
remaining residue was diluted with diethyl ether (200 mL), and the
ether was decanted from the residue and discarded. Lastly the
residue was suspended in DCM (100 mL). The stirred suspension was
diluted with diethyl ether (300 mL) and filtered. The resulting
off-white solid (22.7 g, 91%) was dried under high vacuum. .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 11.7 (br s, 1H), 8.17 (br s, 1H),
8.08 (s, 1H), 7.20 (d, J=9 Hz, 2H), 6.86 (d, J=9 Hz, 2H), 6.45 (br
s, 1H), 5.50 (s, 2H), 3.70 (s, 3H).
[0410] Step C: Preparation of
1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridin-
e: A stirred mixture of
1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (22.00 g, 86.18
mmol) cesium carbonate (28.08 g, 86.18 mmol),
1,2-difluoro-4-nitrobenzene (13.71 g, 86.18 mmol) and DMA (100 mL)
was heated to 100.degree. C. for 1 hour. After cooling to room
temperature, the mixture was partitioned between DCM (500 mL) and
water (500 mL). The phases were separated, and the organic phase
washed with water (3.times.200 mL), dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The resulting residue was
triturated with diethyl ether (100 mL) and hexanes (200 mL)
co-solvent, and the resulting beige powder was filtered. A second
crop was obtained after cooling in a -10.degree. C. freezer
overnight. The two crops were combined (28 g, 82%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.45 (d, J=5.5 Hz, 1H), 8.16 (m, 2H),
7.86 (s, 1H), 7.39 (m, 1H), 7.35 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.2
Hz, 2H), 6.48 (d, J=5.5 Hz, 1H), 5.65 (s, 2H), 3.76 (s, 3H).
.sup.19F NMR (376 MHz, CDCl.sub.3) .delta. -124.2 (m).
[0411] Step D: Preparation of
4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzena-
mine: To a stirred solution of
1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridin-
e (0.560 g, 1.42 mmol) in a MeOH (20 mL) and THF (5 mL) co-solvent
was added zinc (0.464 g, 7.10 mmol), followed by saturated aqueous
NH.sub.4Cl (5 mL). Next 6N aqueous HCl (3-4 mL) was added until all
solids dissolved and the pH was 1-2. The reaction was stirred at
room temperature for 18 hours. The resulting mixture was
partitioned between DCM (30 mL) and saturated aqueous NH.sub.4Cl
(30 mL). The phases were separated, and the aqueous phase was
re-extracted with DCM (20 mL). The combined organic phases were
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
resulting waxy solid (504 mg, 72%) was used in the next step
without purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.35 (d, J=5.5 Hz, 1H), 7.72 (s, 1H), 7.32 (d, J=8.6 Hz, 2H), 7.02
(m, 1H), 6.82 (d, J=9.0 Hz, 2H), 6.40-6.55 (m, 3H), 5.61 (s, 2H),
3.82 (br s, 2H), 3.75 (s, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3)
.delta. -129.0 (m).
[0412] Step E: Preparation of
1-(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophen-
yl)-3-(2-phenylacetyl)thiourea: To a stirred solution of
4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzena-
mine (0.504 g, 1.38 mmol; obtained from Example 1, Step D in THF (5
mL) was added 2-phenylethanoyl isothiocyanate (0.294 g, 1.66 mmol;
prepared according to J. Org. Chem. 1964, 29, 1115-1119). The
reaction was stirred at room temperature for 30 minutes. The
reaction mixture was loaded directly onto a preparative TLC plate,
eluting with 5% MeOH/DCM. The product was obtained as a waxy solid
(630 mg, 71%). LRMS (APCI+): 93% purity, 220 nm, m/z 542 (M+1)
detected; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 12.49 (br s,
1H), 8.50 (br s, 1H), 8.38 (d, J=5.5 Hz, 1H), 7.94 (m, 1H), 7.82
(s, 1H), 7.42 (m, 4H), 7.32 (m, 4H), 7.26 (m, 1H, overlaps
CHCl.sub.3), 6.83 (d, J=8.6 Hz, 2H), 6.42 (d, J=5.5 Hz, 1H), 5.63
(s, 2H), 3.76 (s, 3H), 3.75 (s, 2H); .sup.19F NMR (376 MHz,
CDCl.sub.3) .delta. -126.3 (m).
[0413] Step F: Preparation of
N-(4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenylcarbamothioyl)-2-p-
henylacetamide: A stirred mixture of
1-(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophen-
yl)-3-(2-phenylacetyl)thiourea (0.630 g, 1.16 mmol) and
2,2,2-trifluoroacetic acid (TFA) (1.79 mL, 23.3 mmol) was heated to
65.degree. C. for 3 hours under N.sub.2. The mixture was
concentrated in vacuo using toluene (3.times.5 mL) to azeotrope
residual TFA. The residue was partitioned between saturated aqueous
NaHCO.sub.3 (10 mL) and EtOAc (10 mL). The phases were separated,
and the organic phase washed with brine (10 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
residue was partially purified by preparative TLC eluting with
EtOAc. The crude was then triturated with DCM (5 mL) and chilled to
-10.degree. C. to obtain the product as a white powder. The solid
was suspended in abs EtOH (2.times.2 mL) and concentrated in vacuo
to remove residual DCM. The white powder (61 mg, 12%) was then
dried at 60.degree. C. under high vacuum for 1 hour. LRMS (APCI+):
100% purity, 220 nm, m/z 422 (M+1); .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 13.79 (s, 1H), 12.49 (s, 1H), 11.84 (s, 1H), 8.39 (d, J=5.5
Hz, 1H), 7.99 (d, J=12.1 Hz, 1H), 7.79 (s, 1H), 7.54 (m, 2H), 7.35
(m, 4H), 7.29 (m, 1H), 6.51 (d, J=5.5 Hz, 1H), 3.84 (s, 2H);
.sup.19F NMR (376 MHz, DMSO-d6) .delta. -129.2 (m).
Example 2
Preparation of
N-(4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluoropheny-
l)cyclopropane-1,1-dicarboxamide
##STR00114##
[0415] Step A: Preparation of
N-(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophen-
yl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: To a stirred
mixture of
4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenz-
enamine (73 mg, 0.20 mmol; obtained from Example 1, Step D) and
((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (49 mg,
0.220 mmol; prepared from cyclopropane-1,1-dicarboxylic acid and
4-fluoroaniline using the methods of WO 2005/030140 and by Shih and
Rankin, Synth. Comm. 1996, 26(4), 833-836) in DMA (2 mL) was added
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (EDCI) (77 mg, 0.400 mmol). The reaction was stirred
for 1 hour at room temperature. The reaction was diluted with EtOAc
(10 mL) and water (10 mL). The phases were separated, and the
organic phase washed with water (3.times.10 mL), brine (10 mL),
dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
crude was purified by preparative TLC eluting with 3% MeOH/DCM. The
product was obtained as a waxy solid (42 mg, 33%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.97 (s, 1H), 8.36 (d, J=5 Hz, 1H), 8.20
(s, 1H), 7.77 (m, 2H), 7.46 (m, 2H), 7.26 (m, 4H), 7.06 (m, 2H),
6.83 (d, J=9 Hz, 2H), 6.40 (d, J=5 Hz, 1H), 5.62 (s, 2H), 3.76 (s,
3H), 1.79 (m, 2H), 1.62 (m, 2H, overlaps with water).
[0416] Step B: Preparation of
N-(4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluoropheny-
l)cyclopropane-1,1-dicarboxamide: Prepared according to the
procedure for Example 1, Step F, substituting
(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl-
)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.040 g, 0.0702
mmol) for
1-(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
phenyl)-3-(2-phenylacetyl)thiourea. The product was obtained as a
white powder (7 mg, 20%). LRMS (ESI+): 94% purity, 220 nm, m/z 450
(M+1) detected; .sup.1H NMR (MeOD, 400 MHz) .delta. 8.34 (d, J=5
Hz, 1H), 7.85 (m, 2H), 7.56 (m, 2H), 7.42 (m, 1H), 7.35 (m, 1H),
7.06 (m, 2H), 6.49 (d, J=5 Hz, 1H), 1.64 (s, 4H).
Example 3
Preparation of
N-(3-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fl-
uorophenyl)cyclopropane-1,1-dicarboxamide
##STR00115##
[0418] Step A: Preparation of
4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine: A stirred
mixture of
1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyri-
dine (27.6 g, 70.0 mmol; obtained from Example 1, Step C) and TFA
(53.9 mL, 700 mmol) was heated to reflux for 18 hours under
N.sub.2. The reaction was allowed to cool to room temperature, and
then concentrated in vacuo using toluene (4.times.100 mL) to
azeotrope residual TFA. The residue was diluted with EtOAc (200 mL)
and carefully neutralized (pH=8-9) with saturated aqueous
NaHCO.sub.3 (100 mL). The biphasic suspension was stirred at room
temperature for 30 minutes. The suspension was filtered. The
resulting solid was dried by toluene azeotrope (2.times.200 mL) to
obtain the product (18.7 g, 97%). .sup.1H NMR (DMSO-d6, 400 MHz)
.delta. 13.85 (br s, 1H), 8.40 (m, 2H), 8.15 (m, 1H), 7.91 (s, 1H),
7.66 (m, 1H), 6.65 (m, 1H).
[0419] Step B: Preparation of
4-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-pyrazolo[3,4-b]pyridine: A
similar pyrazole alkylation protocol was utilized by Lynch, B. et
al. Can. J. Chem. 1988, 66, 420-428. To a stirred mixture of
4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (0.250 g,
0.912 mmol) absolute EtOH (0.5 mL), and a 1.5 M sodium
ethoxide-ethanol solution (1.22 mL, 1.82 mmol; prepared from
absolute EtOH and Na metal) at 0.degree. C. under N.sub.2 was added
iodomethane (0.114 mL, 1.82 mmol). The suspension was allowed to
warm to room temperature slowly as the ice melted, and stirring was
continued for 18 hours at room temperature. The reaction was
concentrated in vacuo, suspended in DCM and loaded onto a
preparative TLC plate, eluting with 3% MeOH/DCM to separate the two
pyrazole regioisomers. The desired 1-methyl isomer was obtained as
a white solid (49 mg, 19%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.44 (d, J=5 Hz, 1H), 8.17 (m, 2H), 7.85 (s, 1H), 7.41 (m,
1H), 6.49 (d, J=5 Hz, 1H), 4.18 (s, 3H).
[0420] Step C: Preparation of
3-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)benzenamine:
Prepared according to the procedure of Example 1, Step D,
substituting
4-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-pyrazolo[3,4-b]pyridine (49
mg, 0.17 mmol; obtained from Example 3, Step B) for
1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridin-
e. Yield: 22 mg, 42%. The product was used in the next step without
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.34 (d,
J=6 Hz, 1H), 7.71 (s, 1H), 7.04 (m, 1H), 6.55 (m, 1H), 6.49 (m,
1H), 6.42 (d, J=6 Hz, 1H), 4.13 (s, 3H), 3.86 (br s, 2H).
[0421] Step D: Preparation of
N-(3-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fl-
uorophenyl)cyclopropane-1,1-dicarboxamide: Prepared according to
the procedure for Example 2, Step A, substituting
3-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)benzenamine
(22 mg, 0.085 mmol; obtained from Example 3, Step C) for
4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzena-
mine. In addition, the amount of EDCI (94 mg, 0.51 mmol) and
((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (117 mg,
0.51 mmol) were both increased. The crude was purified by
preparative TLC eluting with EtOAc. The product was obtained as a
white solid (1.4 mg, 3%). LRMS (ESI+): 97% purity, 220 nm, m/z 464
(M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.0 (br
s, 1H), 8.35 (d, J=5 Hz, 1H), 8.10 (s, 1H), 7.78 (m, 1H), 7.76 (s,
1H), 7.45 (m, 2H), 7.23 (m, 1H), 7.07 (m, 2H), 6.41 (d, J=5 Hz,
1H), 4.14 (s, 3H), 1.81 (m, 2H), 1.62 (m, 2H).
Example 4
Preparation of
N-(3-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fl-
uorophenyl)cyclopropane-1,1-dicarboxamide
##STR00116##
[0423] Step A: Preparation of
4-(2-fluoro-4-nitrophenoxy)-2-methyl-2H-pyrazolo[3,4-b]pyridine:
Prepared from
4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (250 mg,
0.91 mmol; obtained from Example 3, Step A) according to the
procedure of Example 3, Step B. The two pyrazole regioisomers were
separated by preparative TLC, eluting with 3% MeOH/DCM. The desired
2-methyl isomer was obtained as a white solid (63 mg, 23%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.57 (d, J=5 Hz, 1H), 8.16 (m,
2H), 7.91 (s, 1H), 7.38 (m, 1H), 6.36 (d, J=5 Hz, 1H), 4.27 (s,
3H).
[0424] Step B: Preparation of
3-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-4-yloxy)benzenamine:
Prepared according to the procedure for Example 1, Step D,
substituting
4-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-pyrazolo[3,4-b]pyridine (63
mg, 0.22 mmol; obtained from Example 4, Step A) for
1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridin-
e. Yield: 22 mg, 30%. The product was used in the next step without
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.48 (d,
J=5 Hz, 1H), 7.81 (s, 1H), 7.02 (m, 1H), 6.56 (m, 1H), 6.48 (m,
1H), 6.25 (d, J=5 Hz, 1H), 4.22 (s, 3H), 3.89 (br s, 2H).
[0425] Step C: Preparation of
N-(3-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fl-
uorophenyl)cyclopropane-1,1-dicarboxamide: Prepared according to
the procedure of Example 3, Step D substituting
3-fluoro-4-(2-methyl-2H-pyrazolo[3,4-b]pyridin-4-yloxy)benzenamine
(22 mg, 0.085 mmol; obtained from Example 4, Step B) for
3-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)benzenamine.
The crude was purified by preparative TLC eluting with 10%
MeOH/EtOAc. The product was obtained as a white solid (3.5 mg, 9%).
LCMS (ESI+): 99% purity, 220 nm, m/z 464 (M+1) detected; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 10.25 (br s, 1H), 8.48 (m, 2H),
7.85 (s, 1H), 7.77 (m, 1H), 7.47 (m, 2H), 7.29 (m, 1H), 7.20 (m,
1H), 7.05 (m, 2H), 6.25 (m, 1H), 4.22 (s, 3H), 1.81 (m, 2H), 1.65
(m, 2H).
Example 5
Preparation of
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenylcarbamoth-
ioyl)-2-phenylacetamide
##STR00117##
[0427] Step A: Preparation of
5-((1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-ylamino)methylene)-2,2-dime-
thyl-1,3-dioxane-4,6-dione: A stirred mixture of trimethoxymethane
(118 mL, 1077 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione
(Meldrum's acid) (15.5 g, 108 mmol) was heated under reflux for 1
hour. A suspension of
1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-amine (23.4 g, 108 mmol;
prepared according to the procedure described by Misra, R. N.; et
al. Bioorg. Med. Chem. Lett. 2003, 13, 1133-1136) in trimethyl
orthoformate (110 mL, 1075 mmol) was added at once, and the dark
orange reaction was refluxed for 3 hours under N.sub.2. After
cooling to room temperature, the reaction was concentrated in
vacuo, using toluene (3.times.100 mL) to azeotrope residual
trimethyl orthoformate. The resulting deep orange residue was
triturated/sonicated with diethyl ether (200 mL). The resulting
peach colored solid was filtered, washing with diethyl ether
(3.times.50 mL). Yield: 28.0 g, 70%. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 11.13 (d, J=11 Hz, 1H), 8.06 (d, J=11 Hz, 1H), 7.10 (d, J=9
Hz, 2H), 6.87 (d, J=9 Hz, 2H), 6.32 (s, 1H), 5.19 (s, 2H), 3.70 (s,
3H), 2.14 (s, 3H), 1.65 (s, 6H).
[0428] Step B: Preparation of
1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol:
Prepared according to the procedure of Example 1, Step B
substituting
5-((1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-ylamino)-methylene)-2,2-dim-
ethyl-1,3-dioxane-4,6-dione (9.3 g, 25 mmol) for
5-((1-(4-methoxybenzyl)-1H-pyrazol-5-ylamino)methylene)-2,2-dimethyl-1,3--
dioxane-4,6-dione and performing the reaction at 220.degree. C.
rather than 240.degree. C. The crude was purified by Biotage Flash
65, eluting with 1:1 EtOAc/hexanes, neat EtOAc, then 5% MeOH/EtOAc
to elute the product. The product was obtained as a pale yellow
solid (5.0 g, 74%). .sup.1H NMR (400 MHz, CDCl.sub.3+ few drops
DMSO-d6) .delta. 11.34 (br s, 1H), 7.91 (br s, 1H), 7.21 (d, J=9
Hz, 2H), 6.80 (d, J=9 Hz, 2H), 6.32 (br s, 1H), 5.44 (s, 2H), 3.74
(s, 3H), 2.63 (s, 3H).
[0429] Step C: Preparation of
1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-3-methyl-1H-pyrazolo[3,4--
b]pyridine: Prepared according to the procedure of Example 1, Step
C substituting
1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (2.69
g, 10.0 mmol) for
1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol and substituting
EtOAc for DCM during the workup. The product was obtained as a
beige solid (3.90 g, 96%) and used in the next step without
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.36 (d,
J=5 Hz, 1H), 8.16 (m, 2H), 7.37 (m, 1H), 7.34 (d, J=9 Hz, 2H), 6.83
(d, J=9 Hz, 2H), 6.27 (d, J=5 Hz, 1H), 5.58 (s, 2H), 3.76 (s, 3H),
2.65 (s, 3H).
[0430] Step D: Preparation of
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluo-
robenzenamine: Prepared according to the procedure of Example 1,
Step D, substituting
1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-3-methyl-1H-pyrazolo[3,4--
b]pyridine (7.4 g, 18 mmol) for
1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridin-
e, and substituting EtOAc for DCM during the workup. The product
was obtained as a gum (7.2 g, 94%) and used in the next step
without purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.25 (d, J=5 Hz, 1H), 7.30 (d, J=9 Hz, 2H), 7.00 (m, 1H), 6.82 (d,
J=9 Hz, 2H), 6.54 (m, 1H), 6.48 (m, 1H), 6.16 (d, J=5 Hz, 1H), 5.55
(s, 2H), 3.83 (br s, 2H), 3.75 (s, 3H), 2.71 (s, 3H).
[0431] Step E: Preparation of
1-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-f-
luorophenyl)-3-(2-phenylacetyl)thiourea: Prepared according to the
procedure of Example 1, Step E, substituting
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluo-
robenzenamine (378 mg, 1.00 mmol) for
4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzena-
mine, and using 1:1 ethanol/toluene (2 mL) as the solvent. The
crude was purified by preparative TLC, eluting with 1:1
EtOAc/hexanes. The resulting solid was further purified by
digestion from hot ethanol (10 mL) and trituration in hot ethanol,
followed by cooling to room temperature and filtration. Yield: 260
mg, 46%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 12.48 (s, 1H),
8.59 (s, 1H), 8.28 (d, J=6 Hz, 1H), 7.91 (d, J=11 Hz, 1H), 7.42 (m,
4H), 7.31 (m, 5H), 6.83 (d, J=9 Hz, 2H), 6.19 (d, J=6 Hz, 1H), 5.56
(s, 2H), 3.76 (s, 3H), 3.75 (s, 2H), 2.70 (s, 3H).
[0432] Step F: Preparation of
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenylcarbamoth-
ioyl)-2-phenylacetamide: Prepared according to the procedure of
Example 1, Step F, substituting
1-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-f-
luorophenyl)-3-(2-phenylacetyl)thiourea (250 mg, 0.45 mmol) for
1-(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophen-
yl)-3-(2-phenylacetyl)thiourea. The crude was purified by
preparative TLC, eluting with 10% MeOH/DCM. The product was
obtained as a white powder (120 mg, 61%). LRMS (APCI-): 100%
purity, 220 nm, m/z 434 (M-1) detected; .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 13.32 (s, 1H), 12.51 (s, 1H), 11.84 (s, 1H), 8.29
(d, J=5 Hz, 1H), 8.03 (m, 1H), 7.52 (m, 2H), 7.36 (m, 5H), 6.23 (d,
J=5 Hz, 1H), 3.84 (s, 2H), 2.62 (s, 3H).
Example 6
Preparation of
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fl-
uorophenyl)cyclopropane-1,1-dicarboxamide
##STR00118##
[0434] Step A: Preparation of
1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl fluoride: Based
on a procedure from Ryan, K., et. al. Tetrahedron, 2000, 56,
3309-3318. A 100 mL round-bottomed flask was charged with
2,4,6-trifluoro-1,3,5-triazine (2.66 mL, 19.7 mmol) and DCM (25
mL), and then 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic
acid (2.20 g, 9.86 mmol) and pyridine (0.797 mL, 9.86 mmol) in DCM
(20 mL) were added under nitrogen. The reaction mixture was stirred
for 2 hours, and then diluted with water (50 mL). The organic
layers were separated, dried over sodium sulfate, filtered, and
concentrated to provide the acid fluoride as a white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 10.44 (s, 1H), 7.61 (m, 2H), 7.17
(m, 2H), 1.69 (m, 4H).
[0435] Step B:
N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-f-
luorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: A
stirred mixture of
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluo-
robenzenamine (1.89 g, 5.00 mmol; prepared as in Example 5, Step
D), 1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl fluoride
(1.69 g, 7.50 mmol; obtained from Example 6, Step A), and anhydrous
THF (50 mL) was heated to reflux for 22 hours under N.sub.2. The
reaction mixture was concentrated in vacuo, and partially purified
by Biotage Flash 40M, eluting with 1:1 EtOAc/hexanes, 3:1
EtOAc/hexanes, then neat EtOAc (1 L). The product was
re-chromatographed on Biotage Flash 40M, eluting with 1% MeOH/DCM,
then 1.5% MeOH/DCM to elute the product. The product was obtained
as a waxy solid (1.79 g, 61%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 10.01 (s, 1H), 8.27 (m, 2H), 7.73 (m, 1H), 7.46 (m, 2H),
7.25 (m, 4H), 7.06 (m, 2H), 6.82 (d, J=9 Hz, 2H), 6.14 (d, J=6 Hz,
1H), 5.56 (s, 2H), 3.75 (s, 3H), 2.71 (s, 3H), 1.78 (m, 2H), 1.60
(m, 2H).
[0436] Step C: Preparation of
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fl-
uorophenyl)cyclopropane-1,1-dicarboxamide: Prepared according to
the procedure of Example 1, Step F substituting
N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-f-
luorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (320
mg, 0.55 mmol) for
1-(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophen-
yl)-3-(2-phenylacetyl)thiourea. The crude was purified by
preparative TLC, eluting with 10% MeOH/DCM. Yield: 180 mg. LRMS
(APCI-): 100% purity, 220 nm, m/z 462 (M-1) detected; .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 13.29 (s, 1H), 10.39 (s, 1H), 10.01 (s,
1H), 8.26 (d, J=6 Hz, 1H), 7.91 (m, 1H), 7.64 (m, 2H), 7.51 (m,
1H), 7.43 (m, 1H), 7.16 (m, 2H), 6.17 (d, J=6 Hz, 1H), 2.62 (s,
3H), 1.48 (m, 4H).
Example 7
Preparation of
N-(3-fluoro-4-(3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)-1H-pyrazolo[3,4--
b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00119##
[0438] Step A: Preparation of
1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrazolo[3,4-b]-
pyridine: To a stirred solution of
4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (16.7 g,
60.9 mmol; obtained from Example 3, Step A) in DMF (250 mL) was
added freshly ground potassium hydroxide (10.3 g, 183 mmol)
followed by iodine (23.2 g, 91.4 mmol) under N.sub.2 at room
temperature. The dark reaction was stirred at room temperature for
18 hours, covered by a foil to minimize light exposure. The
reaction was then heated to 50.degree. C. for 3 hours. The reaction
was allowed to cool to room temperature. The crude reaction mixture
was transferred via cannula into a stirred solution of
1-(chloromethyl)-4-methoxybenzene (11.1 g, 70.7 mmol) in DMF (100
mL) which was cooled in an ice bath under N.sub.2. The reaction was
allowed to stir for 18 hours under N.sub.2 at room temperature. The
mixture was then diluted with DCM (1 L) and washed with 5% aqueous
Na.sub.2S.sub.2O.sub.3 (1 L). The aqueous phase was back-extracted
with DCM (2.times.200 mL). The combined organic phases were washed
with water (4.times.500 mL), dried (Na.sub.2SO.sub.4), filtered,
and concentrated in vacuo. The resulting residue was triturated
with DCM (100 mL), and the undissolved solid removed by filtration.
The filtrate was purified by Biotage Flash 65, eluting with 10%
EtOAc/hexanes, 20% EtOAc/hexanes, then 30% EtOAc/hexanes to elute
the desired product. The product was obtained as a pale yellow
solid (16.6 g, 47%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.42
(d, J=6 Hz, 1H), 8.16 (m, 2H), 7.38 (d, J=9 Hz, 2H), 7.34 (m, 1H),
6.84 (d, J=9 Hz, 2H), 6.36 (d, J=6 Hz, 1H), 5.63 (s, 2H), 3.77 (s,
3H).
[0439] Step B: Preparation of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine: A stirred mixture of
1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrazolo[3,4-b]-
pyridine (10.4 g, 20.0 mmol), stannous chloride-dihydrate (22.6 g,
100.0 mmol), and absolute EtOH (200 mL) was heated to 65.degree. C.
for 1.5 hours under N.sub.2. After cooling to room temperature, the
reaction was concentrated in vacuo, and then diluted with DCM (100
mL) and water (100 mL). Aqueous 2N NaOH was added until the pH of
the aqueous phase was in the 11-12 range. The biphasic suspension
was filtered through a pad of celite, rinsing with DCM (3.times.100
mL). The filtered biphase was separated, and the aqueous phase was
re-extracted with DCM (3.times.75 mL). The combined organic phases
were dried (Na.sub.2SO.sub.4), filtered, and concentrated. Yield:
7.90 g, 78%. The product was used in the next step without
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.30 (d,
J=6 Hz, 1H), 7.35 (d, J=9 Hz, 2H), 7.03 (t, J=9 Hz, 1H), 6.83 (d,
J=9 Hz, 2H), 6.53 (m, 2H), 6.24 (m, 1H), 5.61 (s, 2H), 3.81 (s,
2H), 3.76 (s, 3H).
[0440] Step C: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: To a
stirred solution of
1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (0.341 g,
1.53 mmol; prepared from cyclopropane-1,1-dicarboxylic acid and
4-fluoroaniline using the methods of WO 2005/030140 and by Shih and
Rankin, Synth. Comm., 1996, 26(4), 833-836), catalytic DMF (5
microliters), and THF (5 mL), was added oxalyl dichloride (0.194 g,
1.53 mmol) at room temperature under N.sub.2. The reaction was
stirred for 30 minutes at room temperature as CO.sub.2 evolved.
Then
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (0.500 g, 1.02 mmol) was added as a solution in THF (2
mL). After stirring for 1 hour at room temperature, the reaction
mixture was diluted with 5% MeOH/DCM (100 mL), saturated aqueous
NaHCO.sub.3 (25 mL), and water (125 mL). The cloudy phases were
filtered through celite. The phases were separated, and the organic
phase washed with 1N NaOH (50 mL) and then brine (50 mL). The
organic phases were dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The resulting residue was triturated with
diethyl ether (50 mL) and filtered. The solid was discarded. The
filtrate was concentrated, and the residue purified by preparative
TLC, eluting with 10% MeOH/DCM. The product was used in the next
step without further purification. Yield: 25 mg, 2.5%. LRMS
(APCI+): m/z 696 (M+1) detected.
[0441] Step D: Preparation of 1-methyl-4-(prop-2-ynyl)piperazine:
To a stirred, chilled suspension of 1-methylpiperazine (10.0 g,
100.0 mmol) and cesium carbonate (32.6 g, 100.0 mmol) in acetone
(200 mL) was added 3-bromoprop-1-yne (11.0 mL, 100 mmol) (80% in
toluene). The reaction was stirred for 18 hours at room temperature
under N.sub.2. The suspension was diluted with diethyl ether (200
mL) and filtered, and the filtrate was concentrated in vacuo. The
resulting residue was resuspended in diethyl ether (100 mL) and
refiltered. The filtrate was concentrated to an orange oil (8.2 g).
The product was distilled under high vacuum. The product distilled
between 95-120.degree. C. head temperature. The product was
obtained as a colorless oil (5.46 g, 32%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.31 (m, 2H), 2.89 (m, 1H), 2.3-2.6 (m, 8H),
2.30 (m, 3H).
[0442] Step E: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)-1H-py-
razolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropa-
ne-1,1-dicarboxamide: A stirred mixture of
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (25 mg,
0.036 mmol), 1-methyl-4-(prop-2-ynyl)piperazine (10 mg, 0.072 mmol;
obtained from Example 7, Step D), copper(I)iodide (0.3 mg, 0.002
mmol), triethylamine (0.25 mL, 1.8 mmol), and THF (0.5 mL) was
sparged with N.sub.2 for 2 minutes, then
tetrakis(triphenylphosphine)palladium (2 mg, 0.002 mmol) was added.
The sealed reaction was heated to 50.degree. C. for 18 hours.
Additional 1-methyl-4-(prop-2-ynyl)piperazine (10 mg, 0.07 mmol),
copper(I)iodide (0.3 mg, 0.002 mmol), and
tetrakis(triphenylphosphine)palladium (2 mg, 0.002 mmol) were added
and heating was continued at 80.degree. C. for 5 hours. After
cooling to room temperature, the entire reaction mixture was loaded
directly on to a preparative TLC plate, eluting with 10% MeOH
(containing 7N NH.sub.3) in CHCl.sub.3. The product was obtained as
a waxy solid (10 mg, 37%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 10.06 (s, 1H), 8.30 (d, J=6 Hz, 1H), 8.25 (s, 1H), 7.77 (m,
1H), 7.45 (m, 2H), 7.34 (d, J=9 Hz, 2H), 7.24 (m, 2H), 7.06 (m,
2H), 6.82 (d, J=9 Hz, 2H), 6.25 (d, J=6 Hz, 1H), 5.60 (s, 2H), 3.76
(s, 3H), 3.55 (s, 2H), 2.68 (m, 4H), 2.39 (m, 4H), 2.23 (s, 3H),
1.81 (m, 2H), 1.62 (m, 2H).
[0443] Step F: Preparation of
N-(3-fluoro-4-(3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)-1H-pyrazolo[3,4--
b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide-
: Prepared according to the procedure of Example 1, Step F,
substituting
N-(4-(1-(4-methoxybenzyl)-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)-1H-py-
razolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropa-
ne-1,1-dicarboxamide (10 mg, 0.01 mmol) for
1-(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophen-
yl)-3-(2-phenylacetyl)thiourea. The crude was purified by
preparative TLC, eluting with 10% MeOH (containing 7N NH.sub.3) in
CHCl.sub.3. The product was obtained as a waxy solid (4 mg, 44%).
LRMS (APCI+): 92% purity, 220 nm, m/z 586 (M+1) detected; .sup.1H
NMR (400 MHz, MeOD-d3) .delta. 8.24 (d, J=5 Hz, 1H), 7.81 (m, 1H),
7.51 (m, 2H), 7.36 (m, 1H), 7.28 (m, 1H), 7.03 (m, 2H), 6.29 (d,
J=5 Hz, 1H), 3.60 (s, 2H), 2.69 (m, 4H), 2.36 (m, 4H), 2.16 (s,
3H), 1.60 (m, 4H).
Example 8
Preparation of
N-(3-fluoro-4-(3-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pheny-
l)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00120##
[0445] Step A: Preparation of
4-(1-(4-methoxybenzyl)-3-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluor-
obenzenamine: A stirred mixture of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (2.45 g, 5.00 mmol; prepared as in Example 7, Step B),
potassium vinyltrifluoroborate (0.804 g, 6.00 mmol), triethylamine
(0.693 mL, 5.00 mmol), and n-propanol (20 mL) was sparged with
N.sub.2 for 5 minutes, and then Pd(dppf)Cl.sub.2 (82 mg, 0.10 mmol)
was added. The sealed reaction was heated at 10.degree. C. for 2
hours. The product and residual starting material were separated
from catalyst and other by-products and re-subjected to the
reaction conditions as follows. The reaction was concentrated in
vacuo. The residue was partitioned between DCM (30 mL) and water
(30 mL). The phases were separated, and the aqueous phase was
re-extracted with DCM (2.times.10 mL). The combined organic phases
were dried (Na.sub.2SO.sub.4), filtered, and concentrated in vacuo.
The crude was separated from catalyst and other by-products by
Biotage Flash 40, eluting with 20% EtOAc/hexanes then 1:1
EtOAc/hexanes. The product and starting material (1:1 ratio by
.sup.1H NMR) was resubjected to the same reaction conditions as
above. After 2 hours at 100.degree. C., all starting material had
been consumed. After workup and Biotage Flash 40 purification as
before, the product was obtained as an off-white solid (1.29 g,
66%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.27 (d, J=6 Hz,
1H), 7.33 (d, J=9 Hz, 2H), 7.18 (m, 1H), 7.01 (t, J=9 Hz, 1H), 6.82
(d, J=9 Hz, 2H), 6.52 (m, 2H), 6.34 (m, 1H), 6.23 (m 1H), 5.62 (s,
2H), 5.45 (m, 1H), 3.81 (br s, 2H), 3.76 (s, 3H).
[0446] Step B: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fl-
uorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
Prepared according to the procedure for Example 7, Step C,
substituting
4-(1-(4-methoxybenzyl)-3-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluor-
obenzenamine (0.781 g, 2.00 mmol; obtained from Example 8, Step C)
for
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine. The crude was purified by Biotage Flash 40M, eluting
with 20% EtOAc/hexanes, 1:1 EtOAc/hexanes, then neat EtOAc. The
product was obtained as a waxy solid (479 mg, 39%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 10.07 (s, 1H), 8.28 (d, J=5 Hz, 1H),
8.15 (s, 1H), 7.77 (m, 1H), 7.46 (m, 2H), 7.33 (d, J=9 Hz, 2H),
7.1-7.3 (m, 3H), 7.07 (t, J=9 Hz, 2H), 6.82 (d, J=9 Hz, 2H), 6.31
(d, J=18 Hz, 1H), 6.21 (d, J=5 Hz, 1H), 5.62 (s, 2H), 5.45 (d, J=13
Hz, 1H), 3.75 (s, 3H), 1.80 (m, 2H), 1.60 (m, 2H).
[0447] Step C: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
To a stirred solution of
N-(4-(1-(4-methoxybenzyl)-3-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fl-
uorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.357
g, 0.60 mmol) in THF (5 mL) was added a 0.5 M solution of 9-BBN
(3.60 mL, 1.80 mmol) in THF. The reaction was stirred for 18 hours
at room temperature. The reaction was cooled in an ice bath, and
then was quenched by addition of 2N aqueous NaOH (3 mL). After
stirring for 10 minutes in the ice bath, 30% aqueous hydrogen
peroxide (0.577 mL, 6.00 mmol) was added. The reaction mixture was
partitioned between water (20 mL) and EtOAc (20 mL). The phases
were separated, and the aqueous phase was re-extracted with EtOAc
(2.times.10 mL). The combined organic phases were washed with brine
(20 mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated. The
crude was partially purified by Biotage Flash 40, eluting with 30%
EtOAc/hexanes, 1:1 EtOAc/hexanes, 2:1 EtOAc/hexanes, then neat
EtOAc. The resulting solid was further purified by preparative TLC,
eluting with 5% MeOH (containing 7N NH.sub.3) in DCM. The product
was obtained as a waxy, white solid (179 mg, 48%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 10.18 (s, 1H), 8.49 (s, 1H), 8.28 (d, J=6
Hz, 1H), 7.75 (m, 1H), 7.46 (m, 2H), 7.32 (d, J=9 Hz, 2H), 7.27 (m,
1H, overlaps chloroform), 7.18 (t, J=9 Hz, 1H), 7.06 (t, J=9 Hz,
2H), 6.83 (d, J=9 Hz, 2H), 6.17 (d, J=6 Hz, 1H), 5.57 (s, 2H), 4.09
(m, 2H), 3.76 (s, 3H), 3.36 (t, J=6 Hz, 2H), 2.76 (s, 1H), 1.80 (m,
2H), 1.63 (m, 2H).
[0448] Step D: Preparation of
N-(3-fluoro-4-(3-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pheny-
l)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Prepared
according to the procedure for Example 1, Step F, substituting
N-(4-(1-(4-methoxybenzyl)-3-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
(20 mg, 0.033 mmol) for
1-(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophen-
yl)-3-(2-phenylacetyl)thiourea, except the following modification
was made. After removal of TFA in vacuo, using toluene (3.times.5
mL) to azeotrope, the crude was used in the next step in
saponification of the resulting TFA-ester without purification. The
crude was dissolved in MeOH (1 mL), and a solution of
K.sub.2CO.sub.3 (22 mg, 0.16 mmol) in water (0.5 mL) was added. The
dark mixture was vigorously stirred at room temperature for 45
minutes. The mixture was concentrated in vacuo. The residue was
partitioned between EtOAc (10 mL) and a 1:1 water/saturated aqueous
NaHCO.sub.3 (10 mL) mixture. The phases were separated, and the
aqueous phase was re-extracted with EtOAc (2.times.5 mL). The
combined organic phases were dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude was purified by preparative TLC, eluting
with 10% MeOH/DCM. The product was obtained as a white powder (5
mg, 31%). LCMS (ESI+): 99% purity, 220 nm, m/z 494 (M+1) detected;
.sup.1H NMR (400 MHz, THF-d8) .delta. 12.36 (br s, 0.7H), 10.83 (s,
0.3H; pyrazole tautomer), 10.29 (s, 1H), 9.52 (s, 1H), 8.16 (d, J=5
Hz, 1H), 7.91 (m, 1H), 7.61 (m, 2H), 7.40 (m, 1H), 7.29 (t, J=9 Hz,
1H), 7.04 (t, J=9 Hz, 2H), 6.14 (d, J=5 Hz, 1H), 3.93 (m, 2H), 3.63
(t, J=6 Hz, 1H), 3.25 (t, J=7 Hz, 2H), 1.58 (m, 4H).
Example 9
Preparation of
N-(3-fluoro-4-(3-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-b]pyri-
din-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00121##
[0450] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(2-(4-methylpiperazin-1-yl)ethyl)-1H-
-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-
-dicarboxamide: To a stirred mixture of
N-(4-(1-(4-methoxybenzyl)-3-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
(100 mg, 0.16 mmol; prepared as in Example 8, Step C), DIEA (0.057
mL, 0.33 mmol), and chloroform (5 mL), cooled in an ice bath under
N.sub.2 was added methanesulfonyl chloride (0.0189 mL, 0.244 mmol).
The reaction was allowed to warm to room temperature slowly as the
ice melted. The solution was stirred for 30 minutes at room
temperature. A portion of the reaction mixture (1.25 mL) was
transferred to a second flask and concentrated in vacuo. To the
residue was added 1-methylpiperazine (0.023 mL, 0.20 mmol). The
neat reaction mixture was heated to 100.degree. C. for 1 hour. The
crude was partitioned between DCM (2 mL) and a 1:1 saturated
aqueous NaHCO.sub.3/water mixture (2 mL). The phases were
separated, and the organic phase was dried (Na.sub.2SO.sub.4) and
loaded directly on to a preparative TLC plate, eluting with 10%
MeOH (containing 7N NH.sub.3) in CHCl.sub.3. Yield: 4 mg, 12%.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.02 (s, 1H), 8.36 (s,
1H), 8.28 (d, J=6 Hz, 1H), 7.76 (m, 1H), 7.47 (m, 2H), 7.30 (d, J=9
Hz, 2H), 7.26 (m, 1H, overlaps chloroform), 7.18 (t, J=9 Hz, 1H),
7.06 (t, J=9 Hz, 2H), 6.82 (d, J=9 Hz, 2H), 6.18 (d, J=6 Hz, 1H),
5.57 (s, 2H), 3.76 (s, 3H), 3.29 (m, 2H), 2.93 (m, 2H), 2.5-2.8 (m,
8H), 2.42 (s, 3H), 1.82 (m, 2H), 1.64 (m, 2H).
[0451] Step B: Preparation of
N-(3-fluoro-4-(3-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-b]pyri-
din-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
A stirred mixture of
N-(4-(1-(4-methoxybenzyl)-3-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-
-dicarboxamide (4 mg, 0.006 mmol) and TFA (0.5 mL) was heated to
70.degree. C. for 18 hours. The mixture was concentrated in vacuo,
using toluene (2.times.5 mL) to azeotrope residual TFA. The residue
was partitioned between EtOAc (5 mL) and a 1:1 water/saturated
aqueous NaHCO.sub.3 (5 mL) mixture. The phases were separated, and
the aqueous phase was re-extracted with EtOAc (2.times.2 mL). The
combined organic phases were concentrated in vacuo. The residue was
loaded on to a preparative TLC plate, eluting with 10% MeOH
(containing 7N NH.sub.3) in CHCl.sub.3. The product was further
purified on a Waters SepPak silica gel column (2 g silica), eluting
with DCM, 5% MeOH/DCM, then 5% MeOH (containing 7N NH.sub.3) in DCM
to elute the product. The product was obtained as a waxy solid (1.2
mg, 34%). LCMS (ESI+): 93% purity, 220 nm, m/z 576 (M+1) detected;
.sup.1H NMR (400 MHz, MeOD-d3) .delta. 8.27 (d, J=6 Hz, 1H), 7.84
(m, 1H), 7.55 (m, 2H), 7.43 (m, 1H), 7.37 (t, J=9 Hz, 1H), 7.07 (t,
J=9 Hz, 2H), 6.29 (d, J=6 Hz, 1H), 3.65 (m, 1H, overlaps MeOD),
3.57 (m, 1H), 2.94 (m, 2H), 2.64 (m, 8H), 2.37 (s, 3H), 1.64 (m,
4H).
Example 10
Preparation of
N-(3-fluoro-4-(3-(2-morpholinoethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)ph-
enyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00122##
[0453] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(2-morpholinoethyl)-1H-pyrazolo[3,4--
b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide-
: Prepared according to the procedure of Example 9, Step A,
substituting morpholine (0.018 mL, 0.20 mmol) for
1-methylpiperazine. Yield: 4 mg, 10%. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 10.04 (s, 1H), 8.27 (d, J=6 Hz, 1H), 8.16 (s,
1H), 7.78 (m, 1H), 7.47 (m, 2H), 7.29 (d, J=9 Hz, 2H), 7.26 (m,
1H), 7.20 (t, J=9 Hz, 1H), 7.07 (t, J=9 Hz, 2H), 6.82 (d, J=9 Hz,
2H), 6.17 (d, J=6 Hz, 1H), 5.57 (s, 2H), 3.76 (s, 3H), 3.74 (m,
4H), 3.35 (m, 2H), 2.97 (m, 2H), 2.63 (m, 4H), 1.81 (m, 2H), 1.61
(m, 2H).
[0454] Step B: Preparation of
N-(3-fluoro-4-(3-(2-morpholinoethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)ph-
enyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Prepared
according to the procedure of Example 9, Step B, substituting
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(2-morpholinoethyl)-1H-pyrazolo[3,4--
b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
(4 mg, 0.006 mmol; obtained from Example 10, Step A) for
N-(4-(1-(4-methoxybenzyl)-3-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-
-dicarboxamide. Yield: 0.5 mg, 13%. LCMS (ESI+): 86% purity, 220
nm, m/z 563 (M+1) detected; .sup.1H NMR (400 MHz, MeOD-d3) .delta.
8.27 (d, J=6 Hz, 1H), 7.84 (m, 1H), 7.55 (m, 2H), 7.42 (m, 1H),
7.37 (t, J=9 Hz, 1H), 7.07 (t, J=9 Hz, 2H), 6.29 (d, J=6 Hz, 1H),
3.69 (m, 4H), 3.2-3.7 (m, 2H, overlaps MeOD), 2.94 (m, 2H), 2.62
(m, 4H), 1.64 (m, 4H).
Example 11
Preparation of
N-(3-fluoro-4-(3-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl-
oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00123##
[0456] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(2-(piperidin-1-yl)ethyl)-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarbo-
xamide: Prepared according to the procedure of Example 9, Step A,
substituting piperidine (0.020 mL, 0.20 mmol) for
1-methylpiperazine. Yield: 5 mg, 7%. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 10.01 (s, 1H), 8.31 (s, 1H), 8.26 (d, J=6 Hz,
1H), 7.75 (m, 1H), 7.46 (m, 2H), 7.29 (d, J=9 Hz, 2H), 7.26 (m,
1H), 7.19 (t, J=9 Hz, 1H), 7.06 (m, 2H), 6.82 (d, J=9 Hz, 2H), 6.15
(d, J=6 Hz, 1H), 5.57 (s, 2H), 3.76 (s, 3H), 3.32 (m, 2H), 2.90 (m,
2H), 2.54 (m, 4H), 1.79 (m, 2H), 1.60 (m, 2H), 1.60 (m, 4H), 1.42
(m, 2H).
[0457] Step B: Preparation of
N-(3-fluoro-4-(3-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl-
oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
Prepared according to the procedure of Example 9, Step B,
substituting
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(2-(piperidin-1-yl)ethyl)-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarbo-
xamide (5 mg, 0.007 mmol; obtained from Example 11, Step A) for
N-(4-(1-(4-methoxybenzyl)-3-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-
-dicarboxamide. Yield: 0.9 mg. LCMS (ESI+): 88% purity, 220 nm, m/z
561 (M+1) detected; .sup.1H NMR (400 MHz, MeOD-d3) .delta. 8.28 (m,
1H), 7.88 (m, 1H), 7.58 (m, 2H), 7.43 (m, 1H), 7.37 (m, 1H), 7.07
(m, 2H), 6.30 (m, 1H), 3.2-3.7 (m, 6H, overlaps MeOD), 3.01 (m,
2H), 2.71 (m, 4H), 1.65 (m, 4H), 1.50 (m, 2H).
Example 12
Preparation of
N-(3-fluoro-4-(3-(2-(4-(hydroxymethyl)piperidin-1-yl)ethyl)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxam-
ide
##STR00124##
[0459] Step A: Preparation of
N-(3-fluoro-4-(3-(2-(4-(hydroxymethyl)piperidin-1-yl)ethyl)-1-(4-methoxyb-
enzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopr-
opane-1,1-dicarboxamide: Prepared according to the procedure of
Example 9, Step A, substituting piperidin-4-ylmethanol (23 mg, 0.20
mmol) for 1-methylpiperazine. Yield: 1 mg (3%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 10.04 (s, 1H), 8.91 (s, 1H), 8.30 (d, J=6
Hz, 1H), 7.80 (m, 1H), 7.50 (m, 2H), 7.29 (d, J=9 Hz, 2H), 7.27 (m,
1H), 7.21 (t, J=9 Hz, 1H), 7.03 (t, J=9 Hz, 2H), 6.82 (d, J=9 Hz,
2H), 6.21 (d, J=6 Hz, 1H), 5.55 (s, 2H), 3.76 (s, 3H), 3.57 (m,
2H), 3.48 (d, J=6 Hz, 2H), 3.36 (m, 4H), 2.55 (m, 2H), 1.82 (m,
4H), 1.67 (m, 6H).
[0460] Step B: Preparation of
N-(3-fluoro-4-(3-(2-(4-(hydroxymethyl)piperidin-1-yl)ethyl)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxam-
ide: Prepared according to the procedure of Example 8, Step D,
substituting
N-(3-fluoro-4-(3-(2-(4-(hydroxymethyl)piperidin-1-yl)ethyl)-1-(4-methoxyb-
enzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopr-
opane-1,1-dicarboxamide (1 mg, 0.001 mmol) for
N-(4-(1-(4-methoxybenzyl)-3-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.
The crude was purified by preparative TLC, eluting with 10% MeOH
(containing 7N NH.sub.3) in DCM. The product was further purified
on a Waters SepPak silica gel column (2 g silica), eluting with
DCM, 5% MeOH/DCM, then 5% MeOH (containing 7N NH.sub.3) in DCM to
elute the product. The product was obtained as a waxy solid (0.8
mg, 85%). LRMS (ESI+): m/z 591 (M+1) detected; .sup.1H NMR (400
MHz, MeOD-d3) .delta. 8.31 (d, J=6 Hz, 1H), 7.88 (m, 1H), 7.56 (m,
2H), 7.42 (m, 2H), 7.07 (t, J=9 Hz, 2H), 6.34 (d, J=6 Hz, 1H), 3.56
(m, 4H), 3.46 (m, 4H), 3.13 (m, 2H), 3.04 (m, 2H), 2.02 (m, 2H),
1.78 (m, 1H), 1.65 (m, 4H).
Example 13
Preparation of
N-(4-fluorophenyl)-N-(4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pheny-
l)cyclopropane-1,1-dicarboxamide
##STR00125##
[0462] Step A: Preparation of
1-(4-methoxybenzyl)-3-methyl-4-(4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridin-
e: A 20 mL sealable tube under nitrogen was charged with
1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150
g, 0.557 mmol; prepared as in from Example 5, Step B),
1-fluoro-4-nitrobenzene (0.0786 g, 0.557 mmol), Cs.sub.2CO.sub.3
(0.272 g, 0.836 mmol), and DMA (4 mL). The reaction mixture was
heated to 90.degree. C. for 2 hours, then cooled to room
temperature, diluted with water (10 mL) and extracted with EtOAc
(15 mL). The organic layer was dried over sodium sulfate, filtered
and concentrated. The crude was purified by Biotage 40S column
eluting with Hexane/EtOAc 3:1, then EtOAc. Obtained the product
(185 mg, 79%) as an off white solid. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 8.39 (d, J=5.1 Hz, 1H), 8.32 (d, J=9.4 Hz, 1H), 7.34
(d, J=8.6 Hz, 1H), 7.26 (d, J=9.4 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H),
6.40 (d, J=5.5 Hz, 1H), 3.77 (s, 3H), 2.58 (s, 3H). LRMS (esi pos)
m/e 391 (M+1).
[0463] Step B: Preparation of
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline-
: To a 100 mL round-bottomed flask with stir bar containing
1-(4-methoxybenzyl)-3-methyl-4-(4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridin-
e (0.185 g, 0.474 mmol) was added MeOH (10 mL) and THF (10 mL)
followed by zinc (0.155 g, 2.37 mmol). Next, saturated NH.sub.4Cl
(0.5 mL) was added with stirring. Concentrated HCl (0.5 mL) was
added until all solids dissolved (except for some zinc powder) and
the pH had dropped to 2. The reaction was stirred for 18 hours at
room temperature. The reaction was concentrated and partitioned
between EtOAc (100 mL) and 1:1 saturated NaHCO.sub.3/water (100
mL). The aqueous phase washed with EtOAc (75 mL). The combined
organic phases were washed with brine (50 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
product (160 mg, 82%) was obtained as a yellow gum. LRMS (esi pos)
m/e 361 (M+1).
[0464] Step C: Preparation of
N-(4-fluorophenyl)-N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)phenyl)cyclopropane-1,1-dicarboxamide: A 100 mL
round-bottomed flask was charged with
1-((4-fluorophenyl)carbamoyl)cyclopropane carboxylic acid (0.3516
g, 0.9767 mmol; prepared from cyclopropane-1,1-dicarboxylic acid
and 4-fluoroaniline in THF (25 mL) using the methods of WO
2005/030140 and Shih and Rankin, Synth. Comm., 1996, 26(4),
833-836). Next, catalytic DMF (10 microliters) was added. While
stirring oxalyl dichloride (0.08387 mL, 0.9767 mmol) was added. The
reaction mixture was stirred for 30 minutes and
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)ben-
zenamine (0.160 g, 0.3907 mmol) in THF (2 mL) was added. The
reaction mixture was stirred for 1 hour, the diluted with water (50
mL) and saturated NaHCO.sub.3 (50 mL). The reaction mixture was
extracted with EtOAc, washed with brine, dried organic over sodium
sulfate, filtered and concentrated. The reaction mixture was
purified by preparative TLC (0.5 mm) eluting with EtOAc. The
product (90 mg, 28%) was obtained as a white solid. LRMS (esi pos)
m/e 566 (M+1).
[0465] Step D: Preparation of
N-(4-fluorophenyl)-N-(4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pheny-
l)cyclopropane-1,1-dicarboxamide: A 40 mL vial was charged with
N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phen-
yl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (90 mg, 0.11
mmol) and TFA (2.0 mL). The reaction mixture was heated to
65.degree. C. under nitrogen for 2 hours, the diluted with
saturated Na.sub.2CO.sub.3 (15 mL) and extracted with EtOAc. The
organic layer was dried over sodium sulfate, filtered and
concentrated. The crude material was purified by preparative TLC
(0.5 mm) eluting with EtOAc/MeOH (9:1) to provide the product as a
white solid. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.22 (d,
J=5.5 Hz, 1H), 7.71 (d, J=9.0 Hz, 2H), 7.56 (m, 2H), 7.22 (d, J=9.0
Hz, 2H), 7.06 (t, J=9.0 Hz, 2H), 6.27 (d, J=5.5 Hz, 1H), 2.68 (s,
3H), 1.64 (s, 4H). LRMS (esi pos) m/e 446 (M+1).
Example 14
Preparation of
N-(2-chloro-5-methyl-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl-
)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00126##
[0467] Step A: Preparation of
4-(5-chloro-2-methyl-4-nitrophenoxy)-1-(4-methoxybenzyl)-3-methyl-1H-pyra-
zolo[3,4-b]pyridine: Prepared from
1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150
g, 0.557 mmol; prepared as in Example 5, Step B) and
1-chloro-5-fluoro-4-methyl-2-nitrobenzene (0.106 g, 0.557 mmol),
according to the procedure of Example 13, Step A. Purified by
Biotage 40S column eluting with 3:1 hexane/EtOAc then EtOAc to
obtain the product (184 mg, 75%) as an off white solid. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.36 (d, J=5.1 Hz, 1H), 7.95 (s, 1H),
7.35 (d, J=9.0 Hz, 1H), 7.21 (s, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.23
(d, J=5.1 Hz, 1H), 5.58 (s, 1H), 3.77 (s, 3H), 2.63 (s, 3H), 2.31
(s, 3H). LRMS (APCI pos) m/e 439 (M+1).
[0468] Step B: Preparation of
2-chloro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylox-
y)-5-methylaniline: Prepared from
1-(4-methoxybenzyl)-4-(5-chloro-2-methyl-4-nitrophenoxy)-3-methyl-1H-pyra-
zolo[3,4-b]pyridine (0.184 g, 0.419 mmol) according to the
procedure of Example 13, Step B. Obtain the product (170 mg, 48%)
as a red gum. LRMS (esi pos) m/e 409 (M+1).
[0469] Step C: Preparation of
N-(2-chloro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)-5-methylphenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
Prepared from 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic
acid (0.1796 g, 0.4989 mmol (prepared from
cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the
methods of WO 2005/030140 and by Shih and Rankin, Synth. Comm.
1996, 26(4), 833-836) and
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-chlo-
ro-5-methylbenzenamine (0.170 g, 0.1996 mmol) according to the
procedure of Example 13, Step C. Purified by preparative TLC (0.5
mm) eluting with EtOAc. The product (23 mg, 17%) was obtained as an
orange solid. LRMS (esi pos) m/e 614 (M+1).
[0470] Step D: Preparation of
N-(2-chloro-5-methyl-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl-
)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Prepared from
N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-c-
hloro-5-methylphenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
(23 mg, 0.034 mmol) according to the procedure of Example 13, Step
D. Purified by preparative TLC (0.5 mm) eluting with EtOAc/MeOH
(9:1) to provide the product as a white solid (6 mg, 33%). .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 8.24 (d, J=5.5 Hz, 1H), 8.09 (s,
1H), 7.55 (m, 2H), 7.35 (s, 1H), 7.08 (t, J=8.8 Hz, 2H), 6.19 (d,
J=5.5 Hz, 1H), 2.71 (s, 3H), 2.18 (s, 3H), 1.73 (m, 4H). LRMS (esi
pos) m/e 494 (M+1).
Example 15
Preparation of
N-(3-cyano-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-flu-
orophenyl)cyclopropane-1,1-dicarboxamide
##STR00127##
[0472] Step A: Preparation of
4-(5-chloro-2-methyl-4-nitrophenoxy)-1-(4-methoxybenzyl)-3-methyl-1H-pyra-
zolo[3,4-b]pyridine: Prepared from
1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150
g, 0.557 mmol; prepared as in Example 5, Step B) and
2-fluoro-5-nitrobenzonitrile (0.0925 g, 0.557 mmol), according to
the procedure of Example 13, Step A. The crude product was purified
by Biotage 40S column eluting with 3:1 hexane/EtOAc then EtOAc to
obtain the product (200 mg, 69%) as a off white solid. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.65 (d, J=2.7 Hz, 1H), 8.51 (d,
J=5.5 Hz, 1H), 8.42 (dd, J=2.7, 9.4 Hz, 1H), 7.35 (d, J=8.6 Hz,
2H), 7.17 (d, J=9.4 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.60 (d, J=5.5
Hz, 1H), 5.60 (s, 2H), 3.77 (s, 3H), 2.53 (s, 3H). LRMS (esi pos)
m/e 416 (M+1).
[0473] Step B: Preparation of
5-amino-2-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy-
)benzonitrile: Prepared from
5-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-nitr-
obenzonitrile (0.200 g, 0.481 mmol) according to the procedure of
Example 13, Step B. The product (170 mg, 50%) was obtained as a
yellow gum. LRMS (esi pos) m/e 386 (M+1).
[0474] Step C: Preparation of
N-(3-cyano-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl-
oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
Prepared from 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic
acid (0.2183 g, 0.6065 mmol; prepared from
cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the
methods of WO 2005/030140 and by Shih and Rankin, Synth. Comm.
1996, 26(4), 833-836) and
5-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-amin-
obenzonitrile (0.170 g, 0.2426 mmol) according to the procedure of
Example 13, Step C. The crude product was purified by preparative
TLC (0.5 mm) eluting with EtOAc. The product (80 mg, 29%) was
obtained as a orange solid. LRMS (esi pos) m/e 591 (M+1).
[0475] Step D: Preparation of
N-(3-cyano-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-flu-
orophenyl)cyclopropane-1,1-dicarboxamide: Prepared from
N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-c-
yanophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (80
mg, 0.069 mmol) according to the procedure of Example 13, Step D.
The crude product was purified by preparative TLC (0.5 mm) eluting
with EtOAc/MeOH (9:1) and the product was obtained as a white solid
(11 mg, 31%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.31 (d,
J=5.5 Hz, 1H), 8.23 (s, 1H), 7.93 (m, 1H), 7.55 (m, 2H), 7.43 (d,
J=9.0 Hz, 1H), 7.06 (t, J=8.8 Hz, 2H), 6.34 (d, J=5.5 Hz, 1H), 2.70
(s, 3H), 1.65 (s, 4H). LRMS (esi pos) m/e 471 (M+1).
Example 16
Preparation of
N-(3,4-dichloro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(-
4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00128##
[0477] Step A: Preparation of
4-(2,6-dichloro-4-nitrophenoxy)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[-
3,4-b]pyridine: Prepared from
1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150
g, 0.557 mmol; prepared as in Example 5, Step B) and
1,3-dichloro-2-fluoro-5-nitrobenzene (0.117 g, 0.557 mmol),
according to the procedure of Example 13, Step A. The crude product
was purified Biotage 40S column eluting with 3:1 hexane/EtOAc then
EtOAc to obtain the product (195 mg, 73%) as an off white solid.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.37 (s, 1H), 8.29 (d,
J=5.5 Hz, 1H), 7.37 (d, J=8.6 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 5.93
(d, J=5.5 Hz, 1H), 5.58 (s, 2H), 3.77 (s, 3H), 2.75 (s, 3H). LRMS
(esi pos) m/e 460 (M+1).
[0478] Step B: Preparation of
3,5-dichloro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)aniline: Prepared from
1-(4-methoxybenzyl)-4-(2,6-dichloro-4-nitrophenoxy)-3-methyl-1H-pyrazolo[-
3,4-b]pyridine (0.195 g, 0.425 mmol) according to the procedure of
Example 13, Step B. The product (170 mg, 35%) was obtained as a
yellow gum. LRMS (esi pos) m/e 430 (M+1).
[0479] Step C: Preparation of
N-(3,5-dichloro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-
-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
Prepared from 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic
acid (0.1354 g, 0.3762 mmol; prepared from
cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the
methods of WO 2005/030140 and by Shih and Rankin, Synth. Comm.
1996, 26(4), 833-836) and
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3,5-di-
chlorobenzenamine (0.170 g, 0.1505 mmol) according to the procedure
of Example 13, Step C. The crude product was purified preparative
TLC (0.5 mm) eluting with EtOAc. Product (12 mg, 7%) was obtained
as a orange solid. LRMS (esi pos) m/e 634 (M+1).
[0480] Step D: Preparation of
N-(3,5-dichloro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(-
4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Prepared from
N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3,5-
-dichlorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
(12 mg, 0.011 mmol) according to the procedure of Example 13, Step
D. The crude product was purified by preparative TLC (0.5 mm)
eluting with EtOAc/MeOH (9:1) to provide the product as a white
solid (1.3 mg, 19%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.24
(d, J=5.9 Hz, 1H), 7.91 (s, 2H), 7.56 (m, 2H), 7.07 (t, J=8.8 Hz,
2H), 6.13 (d, J=5.5 Hz, 1H), 2.74 (s, 3H), 1.64 (s, 4H). LRMS (esi
pos) m/e 514 (M+1).
Example 17
Preparation of
N-(4-fluorophenyl)-N-(3-methyl-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl-
oxy)phenyl)cyclopropane-1,1-dicarboxamide
##STR00129##
[0482] Step A: Preparation of
1-(4-methoxybenzyl)-3-methyl-4-(2-methyl-4-nitrophenoxy)-1H-pyrazolo[3,4--
b]pyridine: Prepared from
1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150
g, 0.557 mmol; prepared as in Example 5, Step B) and
1-fluoro-2-methyl-4-nitrobenzene (0.0864 g, 0.557 mmol) according
to the procedure of Example 13, Step A. The crude product was
purified by Biotage 40S column eluting with 3:1 hexane/EtOAc then
EtOAc to obtain the product (107 mg, 48%) as a off white solid.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.33 (d, J=5.5 Hz, 1H),
8.25 (m, 1H), 8.15 (m, 1H), 7.35 (d, J=8.6 Hz, 2H), 7.17 (d, J=9.0
Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.18 (d, J=5.5 Hz, 1H), 5.57 (s,
2H), 3.77 (s, 3H), 2.64 (s, 3H), 2.36 (s, 3H). LRMS (esi pos) m/e
405 (M+1).
[0483] Step B: Preparation of
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-meth-
ylaniline: Prepared from
1-(4-methoxybenzyl)-3-methyl-4-(2-methyl-4-nitrophenoxy)-1H-pyrazolo[3,4--
b]pyridine (0.107 g, 0.265 mmol) according to the procedure of
Example 13, Step B. The product (91 mg, 48%) was obtained as a
yellow gum. LRMS (esi pos) m/e 375 (M+1).
[0484] Step C: Preparation of
N-(4-fluorophenyl)-N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)-3-methylphenyl)cyclopropane-1,1-dicarboxamide:
Prepared from 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic
acid (0.2187 g, 0.6076 mmol; prepared from
cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the
methods of WO 2005/030140 and by Shih and Rankin, Synth. Comm.
1996, 26(4), 833-836) and
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-meth-
ylbenzenamine (0.091 g, 0.2430 mmol) according to the procedure of
Example 13, Step C. The crude product was purified by preparative
TLC (0.5 mm) eluting with EtOAc. The product (18 mg, 11%) was
obtained as an orange solid. LRMS (esi pos) m/e 579 (M+1).
[0485] Step D: Preparation of
N-(4-fluorophenyl)-N-(3-methyl-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl-
oxy)phenyl)cyclopropane-1,1-dicarboxamide: Prepared from
N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-m-
ethylphenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (18
mg, 0.027 mmol) according to the procedure of Example 13, Step D.
The crude product was purified by preparative TLC (0.5 mm) eluting
with EtOAc/MeOH (9:1) to provide the product as a white solid (3.6
mg, 29%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.20 (d, J=5.5
Hz, 1H), 7.57 (m, 4H), 7.14 (d, J=9.0 Hz, 1H), 7.07 (t, J=9.0 Hz,
2H), 6.13 (d, J=5.5 Hz, 1H), 2.72 (s, 3H), 2.18 (s, 3H), 1.63 (s,
4H). LRMS (esi pos) m/e 460 (M+1).
Example 18
Preparation of
N-(4-fluorophenyl)-N-(6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyrid-
in-3-yl)cyclopropane-1,1-dicarboxamide
##STR00130##
[0487] Step A: Preparation of
1-(4-methoxybenzyl)-3-methyl-4-(2-methyl-4-nitrophenoxy)-1H-pyrazolo[3,4--
b]pyridine: Prepared from
1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (1.00
g, 3.71 mmol; obtained from Example 5, Step B) and
2-chloro-5-nitropyridine (0.589 g, 3.71 mmol) according to the
procedure of Example 13, Step A. The crude material was purified on
a Biotage 40S column, eluting with 3:1 hexane/EtOAc and then EtOAc,
to obtain the product (107 mg, 48%) as a brown solid. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 9.06 (d, J=2.3 Hz, 1H), 8.59 (dd,
J=2.3, 8.6 Hz, 1H), 8.53 (d, J=5.1 Hz, 1H), 7.35 (d, J=8.6 Hz, 2H),
7.22 (d, J=9.0 Hz, 1H), 6.88 (d, J=5.5 Hz, 1H), 6.84 (d, J=9.0 Hz,
2H), 5.59 (s, 2H), 3.77 (s, 3H), 2.40 (s, 3H). LRMS (esi pos) m/e
392 (M+1).
[0488] Step B: Preparation of
6-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyridin-
-3-amine: A 25 mL round-bottomed flask was charged with
1-(4-methoxybenzyl)-3-methyl-4-(5-nitropyridin-2-yloxy)-1H-pyrazolo[3,4-b-
]pyridine (1.25 g, 3.19 mmol) and EtOH (10 mL). SnCl.sub.2
dihydrate (3.60 g, 16.0 mmol) was added under nitrogen and the
reaction mixture was heated to 80.degree. C. for 4 hours. The
reaction mixture was cooled to room temperature, diluted with
Na.sub.2CO.sub.3 (100 mL, 2N) and extracted with chloroform
(2.times.100 mL). The organic layer was dried over sodium sulfate,
filtered and concentrated to a dark oil. The crude material was
purified on a Biotage 40S column, eluting with EtOAc, to provide
the product (800 mg, 65%) as a green oil. .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 8.31 (d, J=5.1 Hz, 1H), 7.82 (m, 1H), 7.29 (m,
2H), 7.18 (m, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.82 (m, 2H), 6.40 (d,
J=5.5 Hz, 1H), 5.56 (s, 2H), 3.76 (m, 5H), 2.63 (s, 3H). LRMS (APCI
pos) m/e 362 (M+1).
[0489] Step C: Preparation of
N-(4-fluorophenyl)-N-(6-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)pyridin-3-yl)cyclopropane-1,1-dicarboxamide: A 100
mL round-bottomed flask was charged with
6-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyridin-
-3-amine (0.500 g, 1.38 mmol),
1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl fluoride (0.545
g, 2.42 mmol; prepared as in Example 6, Step A), and DMF (10 mL).
DIEA (0.723 mL, 4.15 mmol) was added under nitrogen and the
reaction mixture was heated at 50.degree. C. for 18 hours. The
reaction mixture was cooled to room temperature, diluted with water
(100 mL), and extracted with EtOAc (50 mL). The organic layer was
dried over sodium sulfate, filtered and concentrated to provide the
crude product (1.55 g, 59%). LRMS (esi +) 567 (M+H).
[0490] Step D: Preparation of
N-(4-fluorophenyl)-N-(6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyrid-
in-3-yl)cyclopropane-1,1-dicarboxamide: Prepared from
N-(6-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyri-
din-3-yl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (1.55 g,
0.821 mmol) according to the procedure of Example 13, Step D. The
crude material was purified by preparative TLC (0.5 mm) eluting
with EtOAc/MeOH (9:1) to provide the product as a white solid (6.0
mg, 1.6%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 11.50 (br s,
1H), 10.12 (s, 1H), 8.40 (m, 2H), 8.27 (s, 1H), 8.22 (m, 1H), 7.44
(m, 2H), 7.13 (d, J=9.0 Hz, 1H), 7.08 (m, 2H), 6.64 (d, J=5.5 Hz,
1H), 2.61 (s, 3H), 1.82 (m, 2H), 1.63 (m, 2H). LRMS (esi pos) m/e
446 (M+1).
Example 19
Preparation of
2-(4-fluorophenyl)-N-(6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyrid-
in-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00131##
[0492] Step A: Preparation of
(E)-2-(2-(4-fluorophenyl)hydrazono)acetaldehyde: A mixture of
1-(4-fluorophenyl)hydrazine hydrochloride (5.0 g, 30.75 mmol),
water (20 mL), and acetic acid (20 mL) was added with stirring to a
40% aqueous solution of glyoxal (17.6 mL, 153.8 mmol) over 20
minutes. Stirring was continued for 2 hours and the mixture was
then filtered. The precipitate washed with water and dried to
afford 5.0 g (98%) of the desired product. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.56 (d, 1H), 8.63 (br s, 1H), 7.24 (m, 1H),
7.16 (m, 2H), 7.06 (m, 2H); .sup.19F NMR (376 MHz, CDCl.sub.3)
.delta. -120.3. LRMS (ESI pos) m/e 151.1 (M-16).
[0493] Step B: Preparation of
(E)-5-(2-(2-(4-fluorophenyl)hydrazono)ethylidene)-2,2-dimethyl-1,3-dioxan-
e-4,6-dione: A suspension of dioxan-dione (1.44 g, 10.0 mmol) and
(E)-2-(2-(4-fluorophenyl)hydrazono)acetaldehyde (1.66 g, 10.0 mmol)
in toluene (15 mL) was treated with acetic acid (5 drops) and
piperidine (5 drops). The reaction mixture was then stirred at room
temp for 17 hours. The precipitated condensation product was
filtered and thoroughly washed with light petroleum to afford 2.87
g (98%) of the desired product. .sup.1H NMR (400 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. 8.72 (d, 1H), 8.24 (d, 1H), 7.32 (m,
2H), 7.08 (t, 2H), 1.76 (s, 6H); .sup.19F NMR (376 MHz, CDCl.sub.3)
.delta. -119.1.
[0494] Step C: Preparation of
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid: A
mixture of
(E)-5-(2-(2-(4-fluorophenyl)hydrazono)ethylidene)-2,2-dimethyl-1,3-dioxan-
e-4,6-dione (0.60 g, 2.05 mmol) and NaOMe (0.133 g, 2.46 mmol) in
MeOH (10 mL) was heated under reflux for 15 hours. The salt was
treated with cold 1 N HCl solution, extracted with DCM, dried over
MgSO.sub.4, and concentrated to afford 0.42 g (87%) of the desired
product. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 13.57 (br s,
1H), 8.29 (m, 2H), 7.63 (m, 2H), 7.24 (m, 2H); .sup.19F NMR (376
MHz, CDCl.sub.3) .delta. -110.7. LRMS (ESI pos) m/e 235.1
(M+1).
[0495] Step D: Preparation of
2-(4-fluorophenyl)-N-(6-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)pyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
A 25 mL round-bottomed flask was charged with
6-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyridin-
-3-amine (15 mg, 0.0415 mmol),
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(24.3 mg, 0.104 mmol; prepared as in Example 19, Step C)
HOBT-H.sub.2O (6.36 mg, 0.0415 mmol), EDCI (7.96 mg, 0.0415 mmol),
N-ethyl-N-isopropylpropan-2-amine (5.36 mg, 0.0415 mmol) and DMF (3
mL). The reaction mixture was stirred at room temperature for 18
hours. Diluted with water (20 mL) and extracted with EtOAc (20 mL).
The organic layer was dried over sodium sulfate, filtered and
concentrated to obtain product (30 mg, 90%) as a light brown solid.
LRMS (esi +) 578 (M+H).
[0496] Step E: Preparation of
2-(4-fluorophenyl)-N-(6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyrid-
in-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide: Prepared from
N-(6-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyri-
din-3-yl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
(30 mg, 0.037 mmol) according to the procedure of Example 13, Step
D. Purified by preparative TLC (0.5 mm) eluting with EtOAc/MeOH
(9:1) to provide the product as a white solid (6.0 mg, 1.6%).
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 11.50 (br s, 1H), 10.12
(s, 1H), 8.40 (m, 2H), 8.27 (s, 1H), 8.22 (m, 1H), 7.44 (m, 2H),
7.13 (d, J=9.0 Hz, 1H), 7.08 (m, 2H), 6.64 (d, J=5.5 Hz, 1H), 2.61
(s, 3H). LRMS (esi pos) m/e 458 (M+1).
Example 20
1-(3-Fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-(pyrid-
in-2-yl)urea
##STR00132##
[0498] Step A: Preparation of
1-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-3-(pyridin-2-yl)urea: A 100 mL round-bottomed flask
was charged with pyridine-2-carbonyl azide (39.1 mg, 0.264 mmol)
and THF (10 mL). The reaction mixture was stirred at 80.degree. C.
for 4 hours.
4-(1-(4-Methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluo-
robenzenamine (20.0 mg, 0.0529 mmol; prepared as in Example 5, Step
D) was added and the reaction mixture was stirred overnight. Water
(10 mL) was added, and the reaction mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.100 mL). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered, and concentrated, and the
residue was purified by column chromatography (Silica gel, DCM/7M
NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to afford the product (21
mg, 81%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.20-8.30 (m,
2H), 7.81 (m, 1H), 7.70 (m, 1H), 7.36 (m, 1H), 7.32 (d, J=8.8 Hz,
2H), 7.22 (m, 1H), 7.00 (m, 1H), 6.87 (m, 1H), 6.83 (d, J=8.8 Hz,
2H), 6.19 (d, J=5.6 Hz, 1H), 5.57 (s, 2H), 3.77 (s, 3H), 2.73 (s,
3H).
[0499] Step B: Preparation of
1-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-(pyri-
din-2-yl)urea: A100 mL round-bottomed flask was charged with
1-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-f-
luorophenyl)-3-(pyridin-2-yl)urea (21.3 mg, 0.0427 mmol) from
Example 20, Step A and 2,2,2-trifluoroacetic acid (487 mg, 4.27
mmol). The reaction mixture was stirred at 80.degree. C. for 8
hours. The CF.sub.3COOH was removed under reduced pressure and the
residue was purified by column chromatography (Silica gel, DCM/7M
NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to provide the product (14
mg, 85%). LRMS (APCI-): 100% purity, 220 nm, m/z 377 (M-1)
detected; .sup.1H NMR (400 MHz, CD.sub.3OD-d4) .delta. 8.31 (m,
1H), 8.25 (d, J=5.6 Hz, 1H), 7.83 (m, 1H), 7.75 (m, 1H), 7.36 (m,
2H), 7.21 (d, J=8.4 Hz, 1H), 7.04 (m, 1H), 6.28 (d, J=5.6 Hz, 1H),
2.72 (s, 3H)
Example 21
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-1-(4-flu-
orophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
##STR00133##
[0501] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide:
A mixture of
1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (37
mg, 0.16 mmol), EDCI (91 mg, 0.48 mmol), and HOBt (64 mg, 0.48
mmol) in DMF (2 mL) was stirred at room temperature for 1 hour.
3-Fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylox-
y)aniline (30 mg, 0.079 mmol; prepared as in Example 5, Step D) was
added, followed by Et.sub.3N (0.066 mL, 0.48 mmol). After stirring
for 15 hours, the reaction mixture was diluted with EtOAc and
washed with saturated aqueous NH.sub.4Cl, saturated aqueous
NaHCO.sub.3, and brine. The organic layer was dried over MgSO.sub.4
and concentrated under reduced pressure to give the crude material
that was purified by silica gel flash column chromatography (2%
MeOH in CH.sub.2Cl.sub.2) to afford 45 mg (96%) of the desired
product. LRMS (ESI pos) m/e 594.2 (M+1). .sup.1H-NMR (400 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. 8.72 (dd, 1H), 8.28 (d, 1H), 7.99
(dd, 1H), 7.92 (dd, 1H), 7.51 (m, 2H), 7.41 (m, 1H), 7.32 (m, 3H),
7.24 (d, 2H), 6.84 (d, 2H), 6.75 (t, 1H), 6.28 (d, 1H), 5.54 (s,
2H), 3.76 (s, 3H), 2.71 (s, 3H); .sup.19F NMR (376 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. -113.2, -128.7.
[0502] Step B: Preparation of
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-1-(4-fl-
uorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide: A mixture of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
(0.045 g, 0.0758 mmol) and TFA (0.58 mL, 7.58 mmol) was placed in a
vial and heated at 50.degree. C. for 4 hours. The reaction mixture
was concentrated under reduced pressure using toluene to azeotrope.
The crude was treated with THF and Et.sub.3N and purified by silica
gel flash column chromatography (2% MeOH in CH.sub.2Cl.sub.2) to
afford 26.5 mg (74%) of the desired product. LRMS (ESI pos) m/e
474.2 (M+1). .sup.1H-NMR (400 MHz, CD.sub.3OD/CDCl.sub.3) .delta.
8.72 (dd, 1H), 8.24 (d, 1H), 7.99 (dd, 1H), 7.92 (dd, 1H), 7.51 (m,
2H), 7.42 (m, 1H), 7.32 (t, 3H), 6.75 (t, 1H), 6.26 (d, 1H), 2.73
(s, 3H); .sup.19F NMR (376 MHz, CD.sub.3OD/CDCl.sub.3) .delta.
-113.2, -128.8.
Example 22
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-flu-
orophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00134##
[0504] Prepared by a 2-step process from
3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylox-
y)aniline (obtained from Example 5, Step D) and
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(prepared as in Example 19, Step C) according to the method of
Example 21, Steps A and B. The crude material was purified by
silica gel flash column chromatography (2% MeOH in
CH.sub.2Cl.sub.2) to afford 25 mg (68% for 2-step process) of the
desired product. LRMS (ESI pos) m/e 475.2 (M+1). .sup.1H-NMR (400
MHz, CD.sub.3OD/CDCl.sub.3) .delta. 8.42 (d, 1H), 8.33 (d, 1H),
8.24 (d, 1H), 7.99 (dd, 1H), 7.64 (m, 2H), 7.46 (m, 1H), 7.34 (d,
1H), 7.28 (m, 2H), 6.26 (d, 1H), 2.75 (s, 3H); .sup.19F NMR (376
MHz, CD.sub.3OD/CDCl.sub.3) .delta. -112.6, -127.6.
Example 23
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-methyl-
-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00135##
[0506] Prepared by 2-step process from
3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylox-
y)aniline (prepared as in Example 5, Step D) and
2-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (prepared
according to the 3-step procedure of Example 19, Steps A-C,
substituting methylhydrazine for 1-(4-fluorophenyl)hydrazine
hydrochloride) according to the procedure of Example 21, Steps A
and B. The crude material was purified by silica gel flash column
chromatography (3% MeOH in CH.sub.2Cl.sub.2) to afford 17 mg (64%
for 2-step process) of the desired product. LRMS (ESI pos) m/e
395.2 (M+1). .sup.1H-NMR (400 MHz, CD.sub.3OD/CDCl.sub.3) .delta.
8.30 (d, 1H), 8.25 (d, 1H), 8.17 (d, 1H), 8.02 (dd, 1H), 7.51 (m,
1H), 7.37 (t, 1H), 6.27 (d, 1H), 3.79 (s, 3H), 2.75 (s, 3H);
.sup.19F NMR (376 MHz, CD.sub.3OD/CDCl.sub.3) .delta. -128.3.
Example 24
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-1-(4-flu-
orophenyl)-2-oxopyrrolidine-3-carboxamide
##STR00136##
[0508] Prepared by a 2-step process from
3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylox-
y)aniline (prepared as in Example 5, Step D) and
1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid according to
the procedure of Example 21, Steps A and B. The crude was purified
by silica gel flash column chromatography (3% MeOH in
CH.sub.2Cl.sub.2) to afford 4 mg (47% for 2-step process) of the
desired product. LRMS (ESI pos) m/e 464.2 (M+1). .sup.1H-NMR (400
MHz, CD.sub.3OD/CDCl.sub.3) .delta. 8.25 (d, 1H), 7.88 (dd, 1H),
7.64 (m, 2H), 7.46 (m, 1H), 7.36 (t, 1H), 7.14 (t, 2H), 6.27 (d,
1H), 3.97 (m, 2H), 3.81 (m, 1H), 2.71 (s, 3H), 2.61 (m, 1H), 2.49
(m, 1H); .sup.19F NMR (376 MHz, CD.sub.3OD/CDCl.sub.3) .delta.
-119.2, -130.1.
[0509] Additional compounds which can be made according to the
methods of this invention include the following structures:
TABLE-US-00002 Example # 25 ##STR00137##
N-(4-(3-(1,2-dihydroxyethyl)-1H- pyrazolo[3,4-b]pyridin-4-yloxy)-3-
fluorophenyl)-N-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide 26
##STR00138## N-(3-fluoro-4-(3-(3-morpholinopropyl)-
1H-pyrazolo[3,4-b]pyridin-4- yloxy)phenyl)-N-(4-
fluorophenyl)cyclopropane-1,1- dicarboxamide 27 ##STR00139##
N-(3-fluoro-4-(3-(morpholinomethyl)-1H-
pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-
N-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 28 ##STR00140##
N-(3-fluoro-4-(3-(5-((4-methylpiperazin-1-
yl)methyl)furan-2-yl)-1H-pyrazolo[3,4-
b]pyridin-4-yloxy)phenyl)-N-(4- fluorophenyl)cyclopropane-1,1-
dicarboxamide 29 ##STR00141## N-(3-fluoro-4-(3-(5-
(morpholinomethyl)furan-2-yl)-1H-
pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-
(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 30 ##STR00142##
N-(3-fluoro-4-(3-(3-hydroxypropyl)-1H-
pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-
(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 31 ##STR00143##
N-(3-fluoro-4-(3-(hydroxymethyl)-1H-
pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-
(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 32 ##STR00144##
N-(3-fluoro-4-(3-((4-methylpiperazin-1-
yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4- yloxy)phenyl)-N-(4-
fluorophenyl)cyclopropane-1,1- dicarboxamide 33 ##STR00145##
N-(4-(3-(2-(1H-imidazol-1-yl)ethyl)-1H-
pyrazolo[3,4-b]pyridin-4-yloxy)-3- fluorophenyl)-N-(4-
fluorophenyl)cyclopropane-1,1- dicarboxamide 34 ##STR00146##
N-(4-fluorophenyl)-N-(5-methyl-6-(3-
methyl-1H-pyrazolo[3,4-b]pyridin-4-
yloxy)pyridin-3-yl)cyclopropane-1,1- dicarboxamide 35 ##STR00147##
N-(4-fluorophenyl)-N-(5-(3-methyl-1H-
pyrazolo[3,4-b]pyridin-4-yloxy)pyridin-2-
yl)cyclopropane-1,1-dicarboxamide 36 ##STR00148##
N-(4-fluorophenyl)-N-(2-(3-methyl-1H-
pyrazolo[3,4-b]pyridin-4-yloxy)pyrimidin-
5-yl)cyclopropane-1,1-dicarboxamide 37 ##STR00149##
N-(5-chloro-6-(3-methyl-1H-pyrazolo[3,4-
b]pyridin-4-yloxy)pyridin-3-yl)-N-(4-
fluorophenyl)cyclopropane-1,1- dicarboxamide 38 ##STR00150##
N-(2-chloro-4-(3-methyl-1H-pyrazolo[3,4-
b]pyridin-4-yloxy)phenyl)-N-(4- fluorophenyl)cyclopropane-1,1-
dicarboxamide 39 ##STR00151## N-(4-fluorophenyl)-N-(5-(3-methyl-1H-
pyrazolo[3,4-b]pyridin-4-yloxy)pyrimidin-
2-yl)cyclopropane-1,1-dicarboxamide 40 ##STR00152##
N-(4-(5-chloro-3-methyl-1H-pyrazolo[3,4-
b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-
fluorophenyl)cyclopropane-1,1- dicarboxamide 41 ##STR00153##
N-(3-fluoro-4-(5-fluoro-3-methyl-1H-
pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-
(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 42 ##STR00154##
N-(4-(5-carbamoyl-3-methyl-1H- pyrazolo[3,4-b]pyridin-4-yloxy)-3-
fluorophenyl)-N-(4- fluorophenyl)cyclopropane-1,1-
dicarboxamide
Example 43
3-(4-chlorobenzyl)-5-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)pyrimidin-4(3H)-one
##STR00155##
[0511] Step A: Preparation of 5-bromopyrimidin-4(3H)-one: Bromine
(16.0 mL, 312 mmol) was added to a suspension of
pyrimidin-4(3H)-one (30 g, 312 mmol) in chloroform (1 L) at
0.degree. C. Methanol (10 mL) was added and the reaction mixture
was stirred for 12 hours. The resulting solid was collected by
filtration, washed with hexane and ether, and dried under vacuum to
afford the title compound as a white solid (50 g, 91.5% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.15 (broad s, 1H),
8.42 (s, 1H), 8.40 (s, 1H).
[0512] Step B: Preparation of
3-(4-chlorobenzyl)-5-bromopyrimidin-4(3H)-one: Sodium hydride
(0.343 g, 8.57 mmol) was added to a solution of
5-bromopyrimidin-4(3H)-one (1.5 g, 8.57 mmol) in THF (10 mL) and
DMF (6 mL) and the reaction mixture was stirred for 10 minutes.
4-Chlorobenzyl bromide (1.76 g, 8.57 mmol) was added and the
reaction mixture was stirred for an additional 1 hour. The reaction
was quenched by pouring the reaction mixture into ice and diluting
with ethyl acetate. The organic layer washed with brine, dried with
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by silica gel chromatography (Biotage 40S) to afford the
title compound as white solid (0.388 g, 15.1%). LRMS (APCI pos) m/e
300.9 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.20 (s,
1H), 8.10 (s, 1H), 7.29-7.37 (m, 4H), 5.15 (s, 2H).
[0513] Step C: Preparation of
3-(4-chlorobenzyl)-5-(4-(benzyloxy)-3-fluorophenyl)pyrimidin-4(3H)-one:
To a round bottom flask was added
3-(4-chlorobenzyl)-5-bromopyrimidin-4(3H)-one (0.388 g, 1.30 mmol),
4-benzyloxy-3-fluorophenylboronic acid (0.382 g, 1.55 mmol),
Pd(PPh.sub.3).sub.4 (0.0748 g, 0.0648 mmol), LiCl (0.275 g, 6.48
mmol), dioxane (10 mL) and 2 M aqueous sodium carbonate solution (5
mL). The reaction mixture was stirred at 10.degree. C. for 1 hour,
then quenched the reaction by pouring the mixture into water and
diluting with ethyl acetate. The organic layer washed with brine,
dried with Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified by silica gel chromatography (Biotage 40S) to afford
the title compound as white solid (0.17 g, 31.2% yield). LRMS (APCI
pos) m/e 421.0 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
8.15 (s, 1H), 8.02 (s, 1H), 7.49-7.54 (m, 1H), 7.42-7.46 (m, 2H),
7.36-7.41 (m, 3H), 7.32-7.35 (m, 5H), 5.18 (s, 2H), 5.12 (s,
2H).
[0514] Step D: Preparation of
3-(4-chlorobenzyl)-5-(3-fluoro-4-hydroxyphenyl)pyrimidin-4(3H)-one:
In a small round bottom flask, a solution of
3-(4-chlorobenzyl)-5-(4-(benzyloxy)-3-fluorophenyl)pyrimidin-4(3H)-one
(0.17 g, 0.40 mmol) was heated in trifluoroacetic acid (5 mL) for 4
hours. The solvent was evaporated and the residue was dried under
vacuum to afford the title compound as a white colored solid (0.1
g, 75%). LRMS (APCI pos) m/e 331.0 (M+1).
[0515] Step E: Preparation of
4-chloro-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine:
To a 500 mL round bottom flask was added phosphorous oxychloride
(6.63 mL, 72.4 mmol) followed by dichloroethane (120 mL).
1-(4-Methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (6.5 g,
24.1 mmol), prepared according to the procedure of Example 5, Step
B, was added directly as a solid. The reaction mixture was stirred
for 1 hour at refluxing temperature (115.degree. C.) under N.sub.2.
The reaction mixture was cooled to room temperature and the solvent
was evaporated under reduce pressure. Any remaining solvent was
removed by toluene azeotrope (2.times.50 mL). The resulting crude
material was dissolved in dichloromethane (50 mL), and saturated
NaHCO.sub.3 was added slowly until vigorous bubbling ceased. The
biphasic mixture was diluted with additional dichloromethane and
aqueous sodium bicarbonate and the organic layer washed separated,
washed with brine, dried over sodium sulfate and evaporated to
afford 6.6 g of off-white solid. The crude was chromatographed on
Silica (Biotage 40M) loading with dichloromethane and eluting with
80/20 hexanes/ethyl acetate to obtain the product (6.0 g, 87%) as a
white crystalline solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
8.41 (d, J=5.1 Hz, 1H), 7.24 (d, J=5.1 Hz, 1H), 7.15 (d, J=9.0 Hz,
2H), 6.80 (d, J=9.0 Hz, 2H), 5.46 (s, 2H), 3.64 (s, 3H), 2.57 (s,
3H).
[0516] Step F: Preparation of
3-(4-chlorobenzyl)-5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)phenyl)pyrimidin-4(3H)-one: To a 10 mL
round bottom flask was added
1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine
(13.0 mg, 0.0454 mmol), prepared according to the procedure of
Example 43, Step E,
3-(4-chlorobenzyl)-5-(3-fluoro-4-hydroxyphenyl)pyrimidin-4(3H)-one
(10 mg, 0.0302 mmol) prepared according to the procedure of Example
43, Step D and dissolved in DMF (0.5 mL). A 1M solution of
potassium t-butoxide in THF (0.0454 mL, 0.0454 mmol) and potassium
carbonate (6.27 mg, 0.0454 mmol) were both added and the resulting
mixture was stirred at 110.degree. C. for 3 hours. The reaction
mixture was cooled to room temperature and the crude mixture was
partitioned between water (10 mL) and ethyl acetate (15 mL). The
organic layer washed with brine, dried over sodium sulfate and
evaporated to afford 24.1 mg of brown oil. The crude product was
purified by silica gel chromatography (Biotage 12M), loading with
chloroform and eluting with 1.5% MeOH in CHCl.sub.3 to afford the
desired product as an off-white solid (5 mg, 28%). LRMS (APCI pos)
m/e 583.2 (M+1).
[0517] Step G: Preparation of
3-(4-chlorobenzyl)-5-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl-
oxy)phenyl)pyrimidin-4(3H)-one: To a 15 mL capacity reaction tube
was added
3-(4-chlorobenzyl)-5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-p-
yrazolo[3,4-b]pyridin-4-yloxy)phenyl)pyrimidin-4(3H)-one (5 mg,
0.00859 mmol) and dissolved in trifluoroacetic acid (0.5 mL). The
solution was stirred at 80.degree. C. for 30 minutes in a sealed
tube under nitrogen. The reaction mixture was cooled to room
temperature and the solvent was evaporated under reduced pressure.
The crude residue was triturated with a 1:1 mixture of
ether:hexane. The resulting solid was filtered, washed with ether,
and dried to afford off-white solid as the mono-TFA salt (3.2 mg,
65%). .sup.1H NMR (400 MHz, MeOD-d4) .delta. 8.64 (s, 1H), 8.38
(broad s, 1H), 8.25 (s, 1H), 7.80 (d, J=11.78 Hz, 1H), 7.65 (d,
J=7.8 Hz, 1H), 7.50-7.37 (m, 6H), 6.42 (d, J=5.5 Hz, 1H), 5.25 (s,
2H), 2.78 (s, 3H).
Example 44
3-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3,4-dihy-
droquinazolin-2(1H)-one
##STR00156##
[0519] Step A: Preparation of
2-amino-N-(3-fluoro-4-methoxyphenyl)benzamide: To a stirred
suspension of isatoic anhydride (1.63 g, 10 mmol) in 15 mL dioxane
at room temperature under nitrogen was added powdered sodium
hydroxide followed by 3-fluoro-4-methoxyaniline (1.41 g, 10 mmol).
The mixture was immersed in a room temperature oil bath and slowly
heated to reflux. Carbon dioxide gas evolution was evident. After
stirring at reflux for 2 hours, the reaction mixture was cooled to
room temperature and inorganics were filtered off with dioxane. The
filtrate was concentrated to dryness to a brown solid. The crude
product was dissolved in a minimum of hot 95% EtOH and crystals
formed upon cooling. The crystals were filtered off and rinsed with
a minimum of ice cold 95% EtOH to give a tan solid (1.0 g, 39%).
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.66 (br s, 1H), 7.50
(dd, 1H), 7.44 (dd, 1H), 7.26 (m, 1H), 7.17 (m, 1H), 6.95 (m, 1H),
6.71 (m, 2H), 5.50 (br s, 2H), 3.89 (s, 3H).
[0520] Step B: Preparation of
N-(2-aminobenzyl)-3-fluoro-4-methoxyaniline: To a stirred
suspension of lithium aluminum hydride (121 mg, 3.2 mmol) in 2 mL
dioxane at reflux under nitrogen was added
2-amino-N-(3-fluoro-4-methoxyphenyl)benzamide (260 mg, 1 mmol) as a
solution in 2 mL dioxane. After refluxing overnight the reaction
was cooled to room temperature and quenched by sequential treatment
with H.sub.2O (150 .mu.L), 15% NaOH (150 .mu.L) and H.sub.2O (450
.mu.L). After stirring for several minutes, the heterogeneous
mixture was filtered through GF/F filter paper with dioxane and
concentrated to a brown residue (246 mg, 100%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.14 (m, 2H), 6.86 (m, 1H), 6.74 (m, 2H),
6.60 (dd, 1H), 6.42 (dd, 1H), 4.15 (d, 2H), 4.12 (br s, 2H), 3.83
(s, 3H), 3.54 (br s, 1H).
[0521] Step C: Preparation of
3-(3-fluoro-4-methoxyphenyl)-3,4-dihydroquinazolin-2(1H)-one: To a
stirred suspension of crude
N-(2-aminobenzyl)-3-fluoro-4-methoxyaniline (246 mg, 1 mmol) in 10
mL toluene at 0.degree. C. under a drying tube was added phosgene
solution (20% in toluene, 683 .mu.L, 1.30 mmol). The cooling bath
was removed and the reaction allowed to warm to room temperature
over 30 minutes. The solution was then warmed to reflux. After 1
hour, the reaction was concentrated to dryness and the residue
dissolved in a minimum of hot 95% EtOH. A precipitate formed which
was isolated by filtration with 95% EtOH and dried to give a tan
solid (65 mg, 24%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.23
(m, 1H), 7.14 (m, 1H), 7.08 (m, 2H), 7.01 (m, 2H), 6.81 (d, 1H),
4.80 (s, 2H), 3.91 (s, 3H).
[0522] Step D: Preparation of
3-(3-fluoro-4-hydroxyphenyl)-3,4-dihydroquinazolin-2(1H)-one: To a
stirred solution of
3-(3-fluoro-4-methoxyphenyl)-3,4-dihydroquinazolin-2(1H)-one (60
mg, 0.22 mmol) in 2.2 mL dichloromethane at 0.degree. C. under a
drying tube was added boron tribromide (104 .mu.L, 1.1 mmol) neat
by syringe. After 5 minutes, TLC in 1/1 EtOAc/hexanes showed
complete consumption of starting material and a new slightly lower
rf spot. The reaction was quenched by pouring into saturated
NaHCO.sub.3 (30 mL) with stirring. 9/1 Dichloromethane/methanol (30
mL) was added and the mixture stirred rapidly. The layers were
separated and the organics were dried (MgSO.sub.4), filtered, and
concentrated to a white solid (40 mg, 70%). LRMS (APCI pos) m/e 259
(M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.40 (m, 1H), 7.22
(m, 1H), 7.07 (m, 2H), 6.98 (m, 2H), 6.83 (m, 1H), 4.78 (s,
2H).
[0523] Step E: Preparation of
3-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-3,4-dihydroquinazolin-2(1H)-one: To a round bottom
flask were added
3-(3-fluoro-4-hydroxyphenyl)-3,4-dihydroquinazolin-2(1H)-one (19
mg, 0.074 mmol) and DMF (0.7 mL).
1-(4-Methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine
(25.4 mg, 0.088 mmol), prepared according to the procedure of
Example 43, Step E, was added followed by potassium carbonate (12.2
mg, 0.088 mmol) and a 1 M solution of potassium t-butoxide in THF
(0.088 mL, 0.088 mmol). The mixture was stirred at 110.degree. C.
for 4 hours under nitrogen. The reaction was cooled to room
temperature and the reaction mixture was partitioned between water
(10 mL) and ethyl acetate (20 mL). The organic layer was separated
and the aqueous layer was extracted with a second portion of ethyl
acetate (10 mL). The combined organic layers were washed with
brine, dried over sodium sulfate and evaporated to give 29.8 mg of
brown oil. The crude oil was triturated with a
dichloromethane:ether mixture and the resulting solid was filtered
and dried to afford the desired product as a tan solid (17.6 mg,
47%). LRMS (APCI pos): m/e 510.2 (M+1).
[0524] Step F: Preparation of
3-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3,4-dih-
ydroquinazolin-2(1H)-one: To a reaction tube were added
3-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-3,4-dihydroquinazolin-2(1H)-one (17.6 mg, 0.035 mmol)
and excess trifluoroacetic acid (0.5 mL). The solution was stirred
at 80.degree. C. for 30 minutes in a sealed tube under nitrogen.
The reaction mixture was cooled to room temperature and the solvent
was evaporated under reduced pressure. The crude residue was
triturated with diethylether. The resulting solid was filtered,
washed with ether, and dried to afford the desired product as an
off-white solid as the mono-TFA salt (12.8 mg, 74%). LRMS (APCI
pos) m/e 390.3 (M+1). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.77
(s, 1H), 8.30 (d, J=5.5 Hz, 1H), 7.60 (d, J=12.5 Hz, 1H), 7.50 (t,
J=9.0 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 7.20 (d, J=7.4 Hz, 2H), 6.96
(t, J=7.0 Hz, 3H), 6.90 (d, J=8.2 Hz, 2H), 6.23 (d, J=5.5 Hz, 1H),
4.89 (s, 2H), 2.64 (s, 3H).
Example 45
5-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methyl-
-2-(phenylamino)pyrimidin-4(3H)-one
##STR00157##
[0526] Step A: Preparation of 4-methoxy-N-phenylpyrimidin-2-amine:
In a sealed tube was 2-chloro-4-methoxypyrimidine (1.00 g, 6.92
mmol) in 2-propanol (5 mL). Aniline (0.757 mL, 8.30 mmol) and DIEA
(1.45 mL, 8.30 mmol) were added and the reaction mixture was
stirred at 100.degree. C. until the reaction was complete by HPLC.
The reaction mixture was cooled to room temperature. The resulting
thick suspension was filtered, washed with ethanol, collected and
dried under vacuum to yield the desired product (0.164 g) as a
white solid. The filtrate was concentrated and then partitioned
between EtOAc and saturated aqueous NaCl. The phases were
separated, and the aqueous phase was re-extracted with EtOAc
(1.times.). The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a yellow
solid. The crude product was purified by flash column
chromatography, eluting with 25:1 dichloromethane/EtOAc. The
desired product (0.548 g) was obtained as a white solid, which was
combined with the filtered product to yield 0.712 g (51%) total
desired product. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.51
(s, 1H), 8.20 (d, J=5.5 Hz, 1H), 7.77 (d, J=7.8 Hz, 2H), 7.27 (t,
J=8.0 Hz, 2H), 6.94 (t, J=7.4 Hz, 1H), 6.28 (d, J=5.5 Hz, 1H), 3.91
(s, 3H). LRMS (ESI pos) m/e 202 (M+1).
[0527] Step B: Preparation of 2-(phenylamino)pyrimidin-4(3H)-one:
To a solution of 4-methoxy-N-phenylpyrimidin-2-amine (0.632 g, 3.14
mmol) in acetic acid (20 mL) was added HBr (2.132 mL, 18.84 mmol;
48 wt % in H.sub.2O). The reaction mixture was stirred at
90-95.degree. C. for 3 hours. The reaction mixture was cooled to
room temperature and diluted with H.sub.2O. The pH of the reaction
mixture was adjusted to 5-6 with 6 M aqueous NaOH which resulted in
the formation of a solid precipitate. The solid was filtered,
washed with H.sub.2O, collected and dried under vacuum to yield the
desired product (0.553 g, 94%) as a white solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.74 (br s, 1H), 8.81 (br s, 1H), 7.76
(s, 1H), 7.60 (d, J=7.8 Hz, 2H), 7.31 (t, J=8.0 Hz, 2H), 7.02 (t,
J=7.4 Hz, 1H), 5.81 (s, 1H). LRMS (ESI pos) m/e 188 (M+1).
[0528] Step C: Preparation of
3-methyl-2-(phenylamino)pyrimidin-4(3H)-one. To a solution of
2-(phenylamino)pyrimidin-4(3H)-one (0.250 g, 1.34 mmol) in DMF (10
mL) was added LiH (0.012 g, 1.47 mmol). The reaction mixture was
stirred for 25 minutes and then iodomethane (0.166 mL, 2.67 mmol)
was added. The reaction was stirred at room temperature for 18
hours, the quenched with H.sub.2O and partitioned between EtOAc and
saturated aqueous NaCl. The phases were separated, and the aqueous
phase was re-extracted with EtOAc (1.times.). The combined organic
layers were dried (Na.sub.2SO.sub.4), filtered and concentrated to
yield a crude yellow oil. The crude product was purified by flash
column chromatography, eluting with 30:1 dichloromethane/methanol.
The desired product (0.166 g, 62%) was obtained as a white
crystalline solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.68
(d, J=6.2 Hz, 1H), 7.46 (m, 2H), 7.39 (t, J=7.8 Hz, 2H), 7.19 (t,
J=7.4 Hz, 1H), 6.48 (s, 1H), 6.01 (d, J=6.6 Hz, 1H), 3.58 (s, 3H).
LRMS (ESI pos) m/e 202 (M+1).
[0529] Step D: Preparation of
5-bromo-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one: To a solution
of 3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.104 g, 0.517
mmol) in CHCl.sub.3 (5 mL)/MeOH (1 mL) at 0.degree. C. was added
bromine (0.027 mL, 0.517 mmol). The reaction mixture was stirred
for 30 minutes at room temperature and then quenched with 10%
aqueous sodium bisulfite solution. The reaction mixture was
partitioned between EtOAc and H.sub.2O. The phases were separated,
and the aqueous phase was re-extracted with EtOAc (1.times.). The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated to yield the desired product (0.145 g; 100%) as a
white solid that was used without further purification. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.95 (s, 1H), 7.94 (s, 1H), 7.47
(m, 2H), 7.34 (t, J=7.4 Hz, 2H), 7.14 (t, J=7.4 Hz, 1H), 3.53 (s,
3H). LRMS (ESI pos) m/e 280, 282 (M+1, Br pattern).
[0530] Step E: Preparation of
5-(4-(benzyloxy)-3-fluorophenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)--
one: A suspension of
5-bromo-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.145 g, 0.518
mmol), 4-(benzyloxy)-3-fluorophenylboronic acid (0.153 g, 0.621
mmol), Pd(PPh.sub.3).sub.4 (0.030 g, 0.026 mmol) and lithium
chloride (0.110 g, 2.59 mmol) in dioxane (1.5 mL) and 2 M aqueous
Na.sub.2CO.sub.3 (1.5 mL) was stirred at 100.degree. C. for 20
minutes. The reaction mixture was cooled to room temperature and
then partitioned between EtOAc and H.sub.2O. The phases were
separated, and the aqueous phase was re-extracted with EtOAc
(1.times.). The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
black solid. The crude product was purified by flash column
chromatography, eluting with 10:1 dichloromethane/EtOAc. The
desired product (0.133 g, 64%) was obtained as an off-white waxy
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.90 (br s, 1H),
7.93 (s, 1H), 7.59 (dd, J=1.95, 13.7 Hz, 1H), 7.55-7.31 (m, 10H),
7.22 (t, J=9.0 Hz, 1H), 7.14 (t, J=7.4 Hz, 1H), 5.20 (s, 2H), 3.55
(s, 3H). LRMS (ESI pos) m/e 402 (M+1).
[0531] Step F: Preparation of
5-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one:
A solution of
5-(4-(benzyloxy)-3-fluorophenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)--
one (0.133 g, 0.331 mmol) in TFA (1.5 mL) was stirred at 40.degree.
C. for 3.5 hours The reaction mixture was concentrated to dryness
and then purified by flash column chromatography, eluting with 20:1
dichloromethane/MeOH. The desired product (0.103 g, 100%) was
obtained as a foamy white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.81 (br s, 1H), 8.96 (br s, 1H), 7.86 (s,
1H), 7.56-7.45 (m, 3H), 7.37 (t, J=7.4 Hz, 2H), 7.27 (m, 1H), 7.15
(t, J=7.2 Hz, 1H), 6.92 (t, J=9.0 Hz, 1H), 3.54 (s, 3H). LRMS (APCI
pos) m/e 312 (M+1).
[0532] Step G: Preparation of
5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one: To a 10
mL round bottom flask was added
1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine
(18.7 mg, 0.065 mmol; prepared according to the procedure of
Example 43, Step E),
5-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)--
one (13.5 mg, 0.043 mmol) and the solids were dissolved in DMF (0.5
mL). Potassium carbonate (9.0 mg, 0.065 mmol) was added followed by
a 1M solution of potassium t-butoxide in THF (0.065 mL, 0.065
mmol), and the mixture was stirred at 110.degree. C. for 18 hours.
The reaction mixture was cooled to room temperature and then
partitioned between water (5 mL) and ethyl acetate (10 mL). The
organic layer washed with water, brine, dried over Na.sub.2SO.sub.3
and concentrated to afford 24.3 mg of crude oil. The crude product
was triturated with ether to afford the desired product (16 mg,
65%) as a tan solid. LRMS (APCI pos) m/e 563.3 (M+1).
[0533] Step H: Preparation of
5-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methy-
l-2-(phenylamino)pyrimidin-4(3H)-one: To a 15 mL reaction tube was
added
5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (16 mg,
0.028 mmol) and the solids were dissolved in trifluoroacetic acid
(0.5 mL, excess). The solution was stirred in a sealed tube for 1
hour at 80.degree. C. The solvent was removed and the crude
material was purified by loading onto a 0.5 mm preparative TLC
plate, eluting with 8% MeOH in ethyl acetate. The product was
obtained as a pale orange semi-solid (1.9 mg, 15%). LRMS (APCI pos)
m/e 443.3 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) 8.26 (d, J=5.5
Hz, 1H), 7.94 (br s, 1H), 7.73 (m, 1H), 7.54 (br d, 1H), 7.48 (br
d, 1H), 7.39 (m, J=7.4 Hz, 6H), 7.23 (t, J=7.4 Hz, 1H), 6.31 (d,
J=5.5 Hz, 1H), 3.66 (s, 3H), 2.72 (s, 3H).
Example 46
2-(cyclopropylmethylamino)-5-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyrid-
in-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one
##STR00158##
[0535] Step A: Preparation of 5-bromo-2-chloropyrimidin-4(3H)-one:
5-Bromo-2-chloropyrimidin-4(3H)-one (4.59 g, 50%) was prepared from
5-bromo-2,4-dichloropyrimidine (10.00 g, 43.88 mmol) as described
in EP 1506967.
[0536] Step B: Preparation of
5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one: To a solution of
5-bromo-2-chloropyrimidin-4(3H)-one (1.00 g, 4.78 mmol) in DME (12
mL)/DMF (3 mL) under N.sub.2 at 0.degree. C. was added LiH (0.044
g, 5.25 mmol), and the reaction mixture was stirred for 15 minutes
at room temperature. Iodomethane (0.589 mL, 9.45 mmol) was then
added and the reaction mixture was stirred at room temperature for
30 minutes and then at 60.degree. C. for 1.5 hours. The reaction
mixture was quenched with H.sub.2O and then partitioned between
EtOAc and saturated aqueous NaCl. The phases were separated, and
the aqueous phase was re-extracted with EtOAc (1.times.). The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated to yield a crude yellow oil. The crude product was
purified by flash column chromatography, eluting with 25:1
dichloromethane/EtOAc. The desired product (0.764 g, 72%) was
obtained as a yellow crystalline solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.26 (s, 1H), 3.59 (s, 3H). LRMS (ESI pos)
m/e 223, 225 (M+1, Br pattern).
[0537] Step C: Preparation of
5-bromo-2-(cyclopropylmethylamino)-3-methylpyrimidin-4(3H)-one: A
mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.100 g,
0.45 mmol), cyclopropylmethanamine (0.051 mL, 0.58 mmol) and
NaHCO.sub.3 (0.150 g, 1.79 mmol) in n-BuOH (3 mL) was stirred at
60.degree. C. for 1 hour. The reaction mixture was cooled to room
temperature and then diluted with EtOAc. The EtOAc layer washed
with H.sub.2O and saturated aqueous NaCl. The aqueous phase was
re-extracted with EtOAc (1.times.). The combined EtOAc layers were
dried (Na.sub.2SO.sub.4), filtered and concentrated to yield the
desired product (0.114 g, 98%) as a pale yellow solid that was used
without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.93 (s, 1H), 7.46 (t, J=5.5 Hz, 1H), 3.33 (s, 3H), 3.19
(t, J=6.2 Hz, 2H), 1.12 (m, 1H), 0.43 (m, 2H), 0.24 (m, 2H). LRMS
(ESI pos) m/e 258, 260 (M+1, Br pattern).
[0538] Step D: Preparation of
5-(4-(benzyloxy)-3-fluorophenyl)-2-(cyclopropylmethylamino)-3-methylpyrim-
idin-4(3H)-one: A suspension of
5-bromo-2-(cyclopropylmethylamino)-3-methylpyrimidin-4(3H)-one
(0.112 g, 0.434 mmol), 4-(benzyloxy)-3-fluorophenylboronic acid
(0.128 g, 0.521 mmol), Pd(PPh.sub.3).sub.4 (0.025 g, 0.022 mmol)
and lithium chloride (0.092 g, 2.17 mmol) in dioxane (1.5 mL) and
2M aqueous Na.sub.2CO.sub.3 (1.5 mL) was stirred at 100.degree. C.
for 30 minutes. The reaction mixture was cooled to room temperature
and then partitioned between EtOAc and H.sub.2O. The phases were
separated, and the aqueous phase was re-extracted with EtOAc
(1.times.). The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
black solid. The crude product was purified by flash column
chromatography, eluting with 10:1 dichloromethane/EtOAc. The
desired product (0.128 g, 78%) was obtained as a foamy off-white
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.93 (s, 1H),
7.57 (dd, J=2.0, 13.7 Hz, 1H), 7.49-7.31 (m, 7H), 7.19 (t, J=9.0
Hz, 1H), 5.19 (s, 2H), 3.35 (s, 3H), 3.24 (t, J=6.1 Hz, 2H), 1.16
(m, 1H), 0.44 (m, 2H), 0.25 (m, 1H). LRMS (APCI pos) m/e 380
(M+1).
[0539] Step E: Preparation of
2-(cyclopropylmethylamino)-5-(3-fluoro-4-hydroxyphenyl)-3-methylpyrimidin-
-4(3H)-one: A solution of
5-(4-(benzyloxy)-3-fluorophenyl)-2-(cyclopropylmethylamino)-3-methylpyrim-
idin-4(3H)-one (0.128 g, 0.337 mmol) in TFA (2 mL) was stirred at
40.degree. C. for 2 hours and 45 minutes. The reaction mixture was
concentrated to dryness and then purified by flash column
chromatography, eluting with 20:1 dichloromethane/MeOH. The desired
product (0.080 g, 82%) was obtained as a colorless glassy solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.71 (s, 1H), 7.87 (s,
1H), 7.46 (dd, J=2.3, 13.7 Hz, 1H), 7.35 (t, J=5.3 Hz, 1H), 7.24
(dd, J=2.3, 8.4 Hz, 1H), 6.90 (dd, J=8.4, 9.6 Hz, 1H), 3.34 (s,
3H), 3.24 (t, J=6.2 Hz, 2H), 1.16 (m, 1H), 0.44 (m, 2H), 0.26 (m,
2H). LRMS (ESI pos) m/e 290 (M+1).
[0540] Step F: Preparation of
2-(cyclopropylmethylamino)-5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-
-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one:
To a 15 mL capacity reaction tube were added
1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine
(20 mg, 0.07 mmol; prepared according to the procedure of Example
43, Step E) and
2-(cyclopropylmethylamino)-5-(3-fluoro-4-hydroxyphenyl)-3-methylpyrimidin-
-4(3H)-one (22.1 mg, 0.077 mmol) and the solids were dissolved in
DMF (1 mL) under nitrogen. Potassium carbonate (10.6 mg, 0.0765
mmol) was added, followed by KOtBu (0.077 mL, 0.077 mmol, 1M
solution in THF). The reaction tube was sealed and the reaction
mixture was stirred at 110.degree. C. for 1 hour. The reaction
mixture was partitioned between water (5 mL) and ethyl acetate (10
mL). The organic layer was separated and the aqueous layer was
extracted with a second portion of ethyl acetate. The combined
organic layers were washed with saturated aqueous NaCl, dried over
sodium sulfate and evaporated to afford 37.5 mg of a red
semi-solid. The crude product was purified by silica gel
chromatography (Biotage 12M) eluting with 2% MeOH/DCM to afford a
red colored glass (23.8 mg, 63%). LRMS (APCI pos) m/e 541.3
(M+1).
[0541] Step G: Preparation of
2-(cyclopropylmethylamino)-5-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyri-
din-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one: To a 15 mL
capacity reaction tube was added
2-(cyclopropylmethylamino)-5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-
-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one
(23.8 mg, 0.044 mmol) and the solids were dissolved in TFA (0.5 mL,
excess). The reaction mixture was stirred at 80.degree. C. for 1
hour in a sealed tube. The excess solvent was evaporated and the
crude residue was purified by silica gel chromatography (Biotage
12M) loading with EtOAc and eluting with 3% MeOH/EtOAc to give the
title compound as pink solid (8.5 mg, 46%). LRMS (APCI pos) m/e
421.3 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.29 (s,
1H), 8.27 (d, J=5.5 Hz, 1H), 8.10 (s, 1H), 7.85 (br d, 1H), 7.65
(d, J=8.6 Hz, 1H), 7.53 (t, J=5.5 Hz, 1H), 7.43 (t, J=8.6 Hz, 1H),
6.23 (d, J=5.5 Hz, 1H), 3.38 (s, 3H), 3.28 (t, J=6.2 Hz, 2H), 2.63
(s, 3H), 1.17 (t, J=7.2 Hz, 1H), 0.46 (q, J=6.8 Hz, 2H), 0.28 (q,
J=4.9 Hz, 2H).
Example 47
4-benzyl-N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-
-3-oxo-3,4-dihydropyrazine-2-carboxamide
##STR00159##
[0543] Step A: Preparation of methyl
4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylate: LiH was added to
the solution of methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate
(0.10 g, 0.65 mmol) in DMF (3 mL) at 0.degree. C. After stirring
for 30 minutes, benzyl chloride (0.15 mL, 1.30 mmol) was added to
the reaction mixture at the temperature, and the reaction was
warmed to room temperature. After stirring for 3 days, the reaction
mixture was diluted with EtOAc, quenched with ice water, extracted
with EtOAc, dried over MgSO.sub.4, and concentrated to give the
desired product, which was purified by silica gel flash column
chromatography (2% MeOH in CH.sub.2Cl.sub.2, 0.102 g, 64%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.35-7.40 (m, 6H), 7.29 (d, 1H),
5.14 (s, 2H), 3.99 (s, 3H).
[0544] Step B: Preparation of
4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylic acid: LiOH (0.82
mL, 0.82 mmol, 1.0 M) was added to a solution of methyl
4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylate (0.10 g, 0.41
mmol) in a mixture of THF-MeOH (3:1 ratio, 6 mL) at room
temperature. After stirring for 4 hours, 1 N HCl (0.9 mL) was
added. The reaction mixture was extracted with EtOAc, dried over
MgSO.sub.4, and concentrated to give the desired product (0.077 g,
82%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.0 (d, 1H), 7.68
(d, 1H), 7.36-7.42 (m, 5H), 5.29 (s, 2H).
[0545] Step C: Preparation of
4-benzyl-N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl-
)-3-oxo-3,4-dihydropyrazine-2-carboxamide: Prepared by a 2-step
process from
3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-
-yloxy)aniline (prepared according to Example 5, Step D) and
4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylic acid according to
the procedure described for Example 21 (Steps A and B). The crude
was purified by silica gel flash column chromatography (5% MeOH in
CH.sub.2Cl.sub.2) to afford 18 mg with TFA salt (49% for 2-step
process) of the desired product. LRMS (APCI pos) m/e 471.3 (M+1).
.sup.1H NMR (400 MHz, CD.sub.3OD/CDCl.sub.3) .delta. 8.25 (d, 1H),
8.06 (dd, 1H), 7.99 (d, 1H), 7.75 (d, 1H), 7.55 (m, 1H), 7.35-7.46
(m, 6H), 6.28 (d, 1H), 5.33 (s, 2H), 2.73 (s, 3H); .sup.19F NMR
(376 MHz, CD.sub.3OD/CDCl.sub.3) .delta. -129.0.
Example 48
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-oxopyr-
rolidine-3-carboxamide
##STR00160##
[0547] Step A: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-f-
luorophenyl)-2-oxopyrrolidine-3-carboxamide: A 100 mL
round-bottomed flask was charged with
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluo-
robenzenamine (20.0 mg, 0.053 mmol; obtained from Example 5, Step
D), 2-oxopyrrolidine-3-carboxylic acid (34.1 mg, 0.26 mmol),
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (50.7 mg, 0.26 mmol), 1H-benzo[d][1,2,3]triazol-1-ol
(35.7 mg, 0.26 mmol), N-ethyl-N-isopropylpropan-2-amine (34.2 mg,
0.26 mmol), and THF (10 mL). The reaction mixture was stirred at
room temperature until LC-MS showed that the starting material had
been consumed (2 days). Water (10 mL) was added and extracted with
CH.sub.2Cl.sub.2 (3.times.50 mL). The organic layers were combined,
dried over Na.sub.2SO.sub.4 and concentrated. The residue purified
by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to
10/1, v/v) to afford the desired product (22.3 mg, 86.2%). LRMS
(APCI neg) m/e 488 (M-1).
[0548] Step B: Preparation of
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-oxopy-
rrolidine-3-carboxamide: A 100 mL round-bottomed flask was charged
with
N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-f-
luorophenyl)-2-oxopyrrolidine-3-carboxamide (22.3 mg, 0.046 mmol)
and 2,2,2-trifluoroacetic acid (259.7 mg, 2.28 mmol). The reaction
mixture was stirred at 60.degree. C. until LC-MS showed that the
starting material was consumed (8 hour). The CF.sub.3COOH was
removed under reduced pressure and the residue purified by column
(Silica gel, DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to
give the desired product (14.9 mg, 88.6%). HPLC: >99% purity,
1.91 min (254 nm); LRMS (APCI neg) m/e 368 (M-1). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.25 (d, J=5.6 Hz, 1H), 7.85 (dd, J=12.4,
2.4 Hz, 1H), 7.43 (m, 1H), 7.37 (t, J=8.8 Hz, 1H), 6.25 (dd, J=5.6,
0.8 Hz, 1H), 3.52-3.38 (m, 2H), 3.31 (m, 1H), 2.71 (s, 3H),
2.52-2.59 (m, 1H), 2.38-2.44 (m, 1H).
Example 49
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-1-methyl-
-2-oxopyrrolidine-3-carboxamide
##STR00161##
[0550] Step A: Preparation of methyl
1-methyl-2-oxopyrrolidine-3-carboxylate: A 250 mL round-bottomed
flask was charged with 1-methylpyrrolidin-2-one (5.05 mL, 52.5
mmol), LDA (43.8 mL, 78.8 mmol, 1.8 M), and THF (125 mL). The
reaction mixture stirred at -78.degree. C. for 1 hour. Methyl
chloroformate (6.06 mL, 78.8 mmol), was added, and the reaction
mixture was stirred at room temperature until LC-MS showed that the
starting material had been consumed (4 hours). Water (125 mL) was
added, and the aqueous layer was extracted with EtOAc (3.times.250
mL). The combined organic layers were dried over Na.sub.2SO.sub.4
and concentrated to afford the crude product 7.35 g (89%), which
was used in the next step without further purification. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 3.37 (s, 3H), 3.28-3.25 (m, 2H), 2.85
(s, 3H), 2.62-2.67 (m, 1H), 2.13-2.22 (m, 1H), 1.99-2.06 (m,
1H).
[0551] Step B: Preparation of
1-methyl-2-oxopyrrolidine-3-carboxylic acid: A 250 mL
round-bottomed flask was charged with methyl
1-methyl-2-oxopyrrolidine-3-carboxylate (1.89 g, 12.0 mmol),
potassium trimethylsilanolate (4.64 g, 36.1 mmol), and THF (100
mL). The reaction mixture was stirred at room temperature
overnight, then HCl (50 mL, 2.0 M in Et.sub.2O) was added and the
reaction mixture was stirred for 5 minutes. The solid was removed
by filtration and the filtrate concentrated to give the crude
product 1.28 g (74.2%), which was used in the next step without
further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.40-3.49 (m, 3H), 2.94 (s, 3H), 2.37-2.47 (m, 2H).
[0552] Step C: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-f-
luorophenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide: A 100 mL
round-bottomed flask was charged with
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluo-
robenzenamine (15.0 mg, 0.040 mmol; obtained from Example 5, Step
D), 1-methyl-2-oxopyrrolidine-3-carboxylic acid (28.4 mg, 0.20
mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (38.0 mg, 0.20 mmol), 1H-benzo[d][1,2,3]triazol-1-ol
(26.8 mg, 0.20 mmol), N-ethyl-N-isopropylpropan-2-amine (0.035 mL,
0.20 mmol) and CH.sub.2Cl.sub.2 (10 mL). The reaction mixture was
stirred at room temperature until LC-MS showed that the starting
material was consumed. Water (10 mL) was added, and the aqueous
layer was extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated, and the resulting residue was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to
afford the desired product (14.8 mg, 74.1%). LRMS (APCI neg) m/e
502 (M-1). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.03 (s, 1H),
8.25 (d, J=5.2 Hz, 1H), 7.78 (dd, J=12.4, 2.4 Hz, 1H), 7.31 (d,
J=8.8 Hz, 2H), 7.25-7.34 (m, 1H), 7.18 (m, 1H), 6.82 (d, J=8.8 Hz,
2H), 6.14 (m, 1H), 5.56 (s, 2H), 3.78 (s, 3H), 3.38-3.49 (m, 3H),
2.88 (s, 3H), 2.71 (s, 3H), 2.36-2.48 (m, 1H), 2.22-2.31 (m,
1H).
[0553] Step D: Preparation of
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-1-methy-
l-2-oxopyrrolidine-3-carboxamide: A 100 mL round-bottomed flask was
charged with
N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-f-
luorophenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide (14.8 mg,
0.0294 mmol) and 2,2,2-trifluoroacetic acid (335 mg, 2.94 mmol).
The reaction mixture was stirred at 60.degree. C. until LC-MS
showed that the starting material was consumed. The CF.sub.3COOH
was removed under reduced pressure and purified the resulting
residue was purified by silica gel chromatography (DCM/7 M NH.sub.3
in MeOH from 50/1 to 10/1, v/v) to give the desired product (10.2
mg, 90.5%). LRMS (APCI neg) m/e 382 (M-1). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.25 (d, J=6.0 Hz, 1H), 7.85 (dd, J=12.8, 2.4
Hz, 1H), 7.42 (m, 1H), 7.37 (m, 1H), 6.25 (m, 1H), 3.44-3.59 (m,
2H), 3.31 (m, 1H), 2.90 (s, 3H), 2.71 (s, 3H), 2.44-2.49 (m, 1H),
2.30-2.37 (m, 1H).
Example 50
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-1-methyl-
-2-oxo-1,2-dihydropyridine-3-carboxamide
##STR00162##
[0555] Step A: Preparation of methyl
1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate: LiH (10 mg, 1.3
mmol) was added to the solution of methyl
2-oxo-1,2-dihydropyridine-3-carboxylate (0.10 g, 0.65 mmol) in DMF
(3 mL) at 0.degree. C. After stirring for 30 minutes, iodomethane
(0.08 mL, 1.30 mmol) was added to the reaction mixture at the
temperature, and the reaction was warmed to room temperature. After
stirring for 3 days, the reaction mixture was diluted with EtOAc,
quenched with ice water, extracted with EtOAc, dried over
MgSO.sub.4, and concentrated to give the desired product.
[0556] Step B: Preparation of
1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid: LiOH (1.3 mL,
1.3 mmol, 1.0 M) was added to a solution of methyl
1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (0.11 g, 0.65
mmol) in a mixture of THF-MeOH (3:1 ratio, 8 mL) at room
temperature. After stirring for 2 hours, 1 N HCl (1.3 mL) was
added. The reaction mixture was extracted with EtOAc, dried over
MgSO.sub.4, and concentrated to give the desired product (0.044 g,
44% for 2 step process).
[0557] Step C: Preparation of
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-1-methy-
l-2-oxo-1,2-dihydropyridine-3-carboxamide: Prepared by a 2-step
process from
3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-
-yloxy)aniline (prepared according to Example 5, Step D) and
1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid according to
the procedure described for Example 21 (Steps A and B). The crude
was purified by silica gel flash column chromatography (3% MeOH in
CH.sub.2Cl.sub.2) to afford 16 mg (99%) of the desired product.
LRMS (ESI pos) m/e 394.2 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.56 (dd, 1H), 8.26 (d, 1H), 8.02 (m, 2H), 7.47 (m, 1H),
7.39 (t, 1H), 6.62 (t, 1H), 6.29 (d, 1H), 3.72 (s, 3H), 2.72 (s,
3H); .sup.19F-NMR (376 MHz, CD.sub.3OD) .delta. -130.0.
Example 51
5-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-flu-
orophenylamino)-3-methylpyrimidin-4(3H)-one
##STR00163##
[0559] Step A: Preparation of
5-bromo-2-(4-fluorophenylamino)-3-methylpyrimidin-4(3H)-one: A
mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.100 g,
0.448 mmol; prepared according to the procedure of Example 46, Step
B), 4-fluorobenzenamine (0.056 ml, 0.582 mmol) and NaHCO.sub.3
(0.150 g, 1.79 mmol) in n-BuOH (3 mL) was stirred at 60.degree. C.
overnight. The reaction mixture was cooled to room temperature and
then diluted with EtOAc. The EtOAc layer washed with H.sub.2O and
saturated aqueous NaCl. The aqueous phase was re-extracted with
EtOAc. The combined EtOAc layers were dried (Na.sub.2SO.sub.4),
filtered and concentrated to yield the desired product (0.132 g,
99%) as a pale yellow solid that was used without further
purification.
[0560] Step B: Preparation of
5-(4-(benzyloxy)-3-fluorophenyl)-2-(4-fluorophenylamino)-3-methylpyrimidi-
n-4(3H)-one: A suspension of
5-bromo-2-(4-fluorophenylamino)-3-methylpyrimidin-4(3H)-one (0.130
g, 0.436 mmol), 4-(benzyloxy)-3-fluorophenylboronic acid (0.129 g,
0.523 mmol), Pd(PPh.sub.3).sub.4 (0.025 g, 0.022 mmol) and lithium
chloride (0.092 g, 2.18 mmol) in dioxane (1.5 mL) and 2 M aqueous
Na.sub.2CO.sub.3 (1.5 mL) was stirred at 100.degree. C. for 30
minutes. The reaction mixture was cooled to room temperature and
then partitioned between EtOAc and H.sub.2O. The phases were
separated, and the aqueous phase was re-extracted with EtOAc
(1.times.). The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
black solid. The crude product was purified by flash column
chromatography, eluting with 10:1 dichloromethane/EtOAc. The
desired product (0.139 g, 76%) was obtained as a grey-white
solid.
[0561] Step C: Preparation of
5-(3-fluoro-4-hydroxyphenyl)-2-(4-fluorophenylamino)-3-methylpyrimidin-4(-
3H)-one: A solution of
5-(4-(benzyloxy)-3-fluorophenyl)-2-(4-fluorophenylamino)-3-methylpyrimidi-
n-4(3H)-one (0.139 g, 0.331 mmol) in TFA (1.5 mL) was stirred at
40.degree. C. for 3 hours. The reaction mixture was concentrated to
dryness and then purified by flash column chromatography, eluting
with 20:1 dichloromethane/MeOH. The desired product (0.089 g, 82%)
was obtained as a white solid.
[0562] Step D: Preparation of
5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-2-(4-fluorophenylamino)-3-methylpyrimidin-4(3H)-one:
To a mixture of
5-(3-fluoro-4-hydroxyphenyl)-2-(4-fluorophenylamino)-3-methylpyrimidin-4(-
3H)-one (25.2 mg, 0.077 mmol) and
1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine
(20 mg, 0.070 mmol) dissolved in DMF (0.5 mL), added KOtBu (0.077
ml, 0.077 mmol) 1M solution in THF, and potassium carbonate (10.6
mg, 0.077 mmol). The mixture was stirred at 110.degree. C.
overnight. Cooled to room temperature and partitioned between EtOAc
(15 mL) and water (20 mL). The organic layer was dried with brine,
Na.sub.2SO.sub.4, and evaporated to afford 27 mg of crude product.
Purified by silica gel column chromatography (Biotage 12M) eluting
with 5% MeOH/EtOAc to afford desired product as white solid (4.6
mg, 11%). LRMS (APCI pos) m/e 581.2 (M+1).
[0563] Step E: Preparation of
5-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fl-
uorophenylamino)-3-methylpyrimidin-4(3H)-one: A stirred mixture of
5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-2-(4-fluorophenylamino)-3-methylpyrimidin-4(3H)-one
(4.6 mg, 0.008 mmol) and TFA (0.5 mL) was heated to 50.degree. C.
for 1 hour. The mixture was concentrated in vacuo, using toluene
(2.times.5 mL) to azeotrope residual TFA. Purified by trituration
with 1:1 ether:hexanes and the resulting white solid was removed by
filtration and dried to afford desired product as the TFA salt (3.9
mg, 86%). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.09 (broad s,
1H), 8.28 (d, 1H), 8.07 (s, 1H), 7.86 (d, 2H), 7.67 (d, 2H), 7.53
(broad s, 1H), 7.46 (t, 1H), 7.22 (t, 2H), 6.25 (d, 1H), 3.57 (s,
3H), 2.63 (s, 3H). LRMS (APCI pos) m/e 461.4 (M+H).
Example 52
N-(3-fluoro-4-(3-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl-
)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00164##
[0565] Step A: Preparation of
4-(1-(4-methoxybenzyl)-3-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluor-
obenzenamine: A mixture of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (3.68 g, 7.50 mmol, prepared according to the procedure
for Example 7, Step B), potassium vinyltrifluoroborate (2.01 g,
15.0 mmol), triethylamine (2.08 ml, 15.0 mmol) and n-propanol (20
mL) was sparged with N.sub.2 for 5 min, and then Pd(dppf)Cl.sub.2
(0.306 g, 0.375 mmol) was added. The reaction was heated at
100.degree. C. for 3 hours in a sealed vessel. After cooling to
ambient temperature, the reaction was concentrated in vacuo. The
residue was partitioned between DCM (30 mL) and water (30 mL). The
phases were separated, and the aqueous phase was re-extracted with
DCM (2.times.10 mL). The combined organic phases were dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
was purified by Biotage Flash 65 chromatography system, eluting
with 20% EtOAc/hexanes (1 L), 1:1 EtOAc/hexanes (1 L), then 2:1
EtOAc/hexanes (2 L). The product was obtained as a reddish colored
solid (2.00 g, 64%).
[0566] Step B: Preparation of
2-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)ethanol: To a stirred solution of
4-(1-(4-methoxybenzyl)-3-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluor-
obenzenamine (1.17 g, 3.00 mmol) in THF (5 mL) was added 9-BBN
(24.0 ml, 12.0 mmol, 0.5 M in THF). The reaction was stirred for 18
hours at room temperature. The reaction was chilled (submerged in
an ice bath) and then quenched by addition of 5N aqueous sodium
hydroxide (6.00 mL, 30.0 mmol). After stirring for 30 minutes in
the ice bath, 30% aqueous hydrogen peroxide (2.88 mL, 30.0 mmol)
was added. After stirring for 5 minutes at 0.degree. C., the
reaction was allowed to stir for 30 minutes at room temperature.
The reaction mixture was partitioned between water (20 mL) and
EtOAc (20 mL). The phases were separated, and the aqueous phase was
re-extracted with EtOAc (2.times.10 mL). The combined organic
phases were washed with brine (20 mL), dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The crude was purified by Biotage Flash
40M, eluting with 2% MeOH in DCM (2 L). The product was obtained as
a waxy solid (1.0 g, 78%).
[0567] Step C: Preparation of
N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-1-methy-
l-2-oxo-1,2-dihydropyridine-3-carboxamide: Prepared by a 2-step
process from
2-(4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)ethano-
l and 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic
acid (prepared as in Example 19, Step C) according to the procedure
described for Example 21, Steps A and B, except that the crude was
treated with aqueous NaHCO.sub.3 solution. The crude was purified
by silica gel flash column chromatography (4% MeOH in
CH.sub.2Cl.sub.2) to afford 6.6 mg (64%) of the desired product.
LRMS (ESI pos) m/e 505.2 (M+1). .sup.1H NMR (400 MHz,
CDCl.sub.3/CD.sub.3OD) .delta. 8.41 (d, 1H), 8.32 (d, 1H), 8.25 (d,
1H), 8.0 (dd, 1H), 7.64 (m, 2H), 7.46 (m, 1H), 7.33 (t, 1H), 7.28
(m, 2H), 6.26 (d, 1H), 4.06 (t, 2H), 3.38 (t, 2H); .sup.19F NMR
(376 MHz, CDCl.sub.3/CD.sub.3OD) .delta. -112.4, -127.5.
Example 53
N-(3-fluoro-4-(3-(3-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00165##
[0569] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide: A stirred mixture of
N-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100
mg, 0.144 mmol; prepared as in Example 7, Step C),
3-(N-methylaminocarbonyl)phenyl boronic acid (51.47 mg, 0.288
mmol), Pd(PPh.sub.3).sub.4 (8.31 mg, 0.0072 mmol) dissolved in 3:1
DME:aqueous 2N Na.sub.2CO.sub.3 (8 mL) was heated at 70.degree. C.
Reaction was monitored by TLC (90/10 CHCl.sub.3/MeOH). After
stirring for 6 hours, the reaction mixture was partitioned between
ethyl acetate (25 mL) and water (50 mL). The organic layer washed
with brine, dried over sodium sulfate, filtered and evaporated to
afford crude product. The crude was purified by silica gel column
chromatography (Biotage 12M) eluting with 2% MeOH/DCM to give the
product as pale orange glass (36 mg, 35%). LRMS (APCI pos) m/e
703.2 (M+H).
[0570] Step B: Preparation of
N-(3-fluoro-4-(3-(3-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: A
stirred mixture of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide (35 mg, 0.050 mmol) and TFA (0.5 mL) was heated to
70.degree. C. for 3 hours, or until reaction was complete as
determined by LC/MS. The mixture was concentrated in vacuo, using
toluene (2.times.5 mL) to azeotrope residual TFA. The crude was
purified by silica gel column chromatography (Biotage 12M) eluting
with 1-10% MeOH/CHCl.sub.3 to give the desired product as off-white
solid (19 mg, 55%). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 14.03
(s, 1H), 10.39 (s, 1H), 10.00 (s, 1H), 8.49 (s, 2H), 8.38 (d, 1H),
8.12 (d, 1H), 7.87 (m, 2H), 7.64 (m, 2H), 7.55 (t, 1H), 7.47 (m,
2H), 7.15 (t, 2H), 6.32 (d, 1H), 2.78 (d, 3H), 1.47 (d, 4H). LRMS
(APCI pos) m/e 583.1 (M+H).
Example 54
N-(4-(3-(4-carbamoylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophe-
nyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00166##
[0572] Step A: Preparation of
N-(4-(3-(4-carbamoylphenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-
-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide-
: Prepared according to the procedure of Example 53, Step A,
substituting benzamide-4-boronic acid (47.4 mg, 0.288 mmol) for
3-(N-methylaminocarbonyl)phenyl boronic acid. Yield: 12 mg, 12%.
LRMS (APCI pos) m/e 689.1 (M+H).
[0573] Step B: Preparation of
N-(4-(3-(4-carbamoylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoroph-
enyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Prepared
according to the procedure of Example 53, Step B, substituting
N-(4-(3-(4-carbamoylphenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-
-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
(12 mg, 0.017 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. Yield: 5.2 mg, 53%. LRMS (APCI pos) m/e 569.1 (M+H).
Example 55
N-(3-fluoro-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyrid-
in-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00167##
[0575] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(morpholine-4-carbonyl)phenyl)-1H-
-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-
-dicarboxamide: Prepared according to the procedure of Example 53,
Step A, substituting 4-(morpholine-4-carbonyl)phenyl boronic acid
(67.6 mg, 0.288 mmol) for 3-(N-methylaminocarbonyl)phenyl boronic
acid. Yield: 62 mg at 75% purity, 43%. The crude material used as
directly in the next step without further purification. LRMS (APCI
pos) m/e 759.1 (M+H).
[0576] Step B: Preparation of
N-(3-fluoro-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyri-
din-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(morpholine-4-carbonyl)phenyl)-1H-
-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-
-dicarboxamide (62 mg, 0.0817 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. Yield: 31 mg, 50%. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
14.05 (s, 1H), 10.39 (s, 1H), 10.0 (s, 1H), 8.38 (d, 1H), 8.07 (d,
2H), 7.89 (broad d, 1H), 7.64 (q, 2H), 7.51 (d, 2H), 7.47 (m, 2H),
7.15 (t, 2H), 6.34 (d, 1H), 3.61 (broad d, 8H), 1.47 (d, 4H). LRMS
(APCI pos) m/e 639.1 (M+H).
Example 56
N-(3-fluoro-4-(3-(4-(methoxy(methyl)carbamoyl)phenyl)-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00168##
[0578] Step A: Preparation of
N-(3-fluoro-4-(3-(4-(methoxy(methyl)carbamoyl)phenyl)-1-(4-methoxybenzyl)-
-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane--
1,1-dicarboxamide: Prepared according to the procedure of Example
53, Step A, substituting
4-(N,O-dimethylhydroxylaminocarbonyl)phenyl boronic acid (60.1 mg,
0.288 mmol) for 3-(N-methylaminocarbonyl)phenyl boronic acid.
Yield: 59 mg, 56%. LRMS (APCI pos) m/e 733.0 (M+H).
[0579] Step B: Preparation of
N-(3-fluoro-4-(3-(4-(methoxy(methyl)carbamoyl)phenyl)-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting
N-(3-fluoro-4-(3-(4-(methoxy(methyl)carbamoyl)phenyl)-1-(4-methoxybenzyl)-
-1H-pyrazolo[3,4-b]pyridine-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-
-1,1-dicarboxamide (59 mg, 0.0805 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. Yield: 15.2 mg, 26%. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 14.05 (s, 1H), 10.39 (s, 1H), 10 (s, 1H), 8.38 (d, 1H),
8.07 (d, 2H), 7.90 (broad d, 1H), 7.69 (d, 2H), 7.64 (q, 2H), 7.50
(m, 2H), 7.15 (t, 2H), 6.34 (d, 1H), 3.58 (s, 3H), 3.27 (s, 3H),
1.47 (d, 4H). LRMS (APCI pos) m/e 613.1 (M+H).
Example 57
N-(4-(3-(4-((1H-pyrazol-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl-
oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00169##
[0581] Step A: Preparation of
N-(4-(3-(4-((1H-pyrazol-1-yl)methyl)phenyl)-1-(4-methoxybenzyl)-1H-pyrazo-
lo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1-
,1-dicarboxamide: Prepared according to the procedure of Example
53, Step A, substituting 1H-pyrazole-1-benzyl-4-boronic acid (58.1
mg, 0.288 mmol) for 3-(N-methylaminocarbonyl)phenyl boronic acid.
Yield: 52 mg, 47%. LRMS (APCI pos) m/e 726.2 (M+H).
[0582] Step B: Preparation of
N-(4-(3-(4-((1H-pyrazol-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting
N-(4-(3-(4-((1H-pyrazol-1-yl)methyl)phenyl)-1-(4-methoxybenzyl)-1H-pyrazo-
lo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1-
,1-dicarboxamide (51.7 mg, 0.0712 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. Yield: 12 mg, 23%. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.37 (d, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.86 (m, 1H),
7.56 (m, 2H), 7.44 (m, 1H), 7.33 (t, 1H), 7.07 (t, 2H), 6.40 (s,
1H), 5.38 (s, 2H), 1.65 (d, 4H). LRMS (APCI pos) m/e 606.2
(M+H).
Example 58
N-(4-fluorophenyl)-N-(6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)benzo[-
d]thiazol-2-yl)cyclopropane-1,1-dicarboxamide
##STR00170##
[0584] Step A: Preparation of
6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)benzo[d]thiazol-2-amine:
A 20 mL sealable tube was charged with
1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine
(0.500 g, 1.74 mmol; prepared according to the procedure of Example
43, Step E), 2-aminobenzo[d]thiazol-6-ol (0.433 g, 2.61 mmol),
N,N-dimethylpyridin-4-amine (0.0425 g, 0.348 mmol), and
bromobenzene (4 mL). The reaction mixture was heated under nitrogen
to 150.degree. C. for 12 hours, then cooled to room temperature and
concentrated under reduced pressure. The crude material was used
directly in next step. LRMS (APCI pos) m/e 418.2 (M+1).
[0585] Step B: Preparation of
N-(4-fluorophenyl)-N-(6-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)benzo-
[d]thiazol-2-yl)cyclopropane-1,1-dicarboxamide: Prepared by 2-step
process (Example 6, Steps B and C) from
6-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)benzo[d-
]thiazol-2-amine (0.700 g, 1.68 mmol), and
1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl fluoride (0.415
g, 1.84 mmol; obtained from Example 6, Step A). The crude material
was purified by preparative TLC (0.5 mm thickness, EtOAc) to afford
2 mg (1% for 2-step process) of the desired product. LRMS (ESI pos)
m/e 503.2 (M+1).
Example 59
N-(2,5-dimethyl-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-
-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00171##
[0587] Step A: Preparation of
2,5-dimethyl-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline:
Prepared according to the procedure for Example 58 step A,
substituting, 4-amino-2,5-dimethylphenol (0.358 g, 2.61 mmol), for
2-aminobenzo[d]thiazol-6-ol. The crude material was used directly
in next step. LRMS (APCI pos) m/e 389.2 (M+1).
[0588] Step B: Preparation of
N-(2,5-dimethyl-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(-
4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Prepared by 2-step
process (Example 6, Steps B and C) from
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2,5-di-
methylbenzenamine (0.675 g, 1.74 mmol) and
1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl fluoride (0.391
g, 1.74 mmol; obtained from Example 6, Step A). The crude material
was purified by preparative TLC (2.0 mm thickness, EtOAc/Hexane
4:1) to afford 5.3 mg (1% for 2-step process) of the desired
product. LRMS M+1 (474.3) observed. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 8.10 (d, J=5 Hz, 1H), 7.49 (m, 3H), 6.98 (m, 3H), 6.07 (d,
J=5 Hz, 1H), 2.63 (s, 3H), 2.19 (s, 3H), 2.05 (s, 3H), 1.60 (m,
4H).
Example 60
N-(4-fluorophenyl)-N-(2-methyl-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)cyclopropane-1,1-dicarboxamide
##STR00172##
[0590] Step A: Preparation of
2-methyl-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline:
Prepared according to the procedure for Example 58 step A,
substituting, 4-amino-3-methylphenol (0.321 g, 2.61 mmol) for
2-aminobenzo[d]thiazol-6-ol. The crude material was used directly
in next step. LRMS (APCI pos) m/e 375.2 (M+1).
[0591] Step B: Preparation of
N-(4-fluorophenyl)-N-(2-methyl-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl-
oxy)phenyl)cyclopropane-1,1-dicarboxamide: Prepared by 2-step
process (Example 6, Steps B and C) from
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-meth-
ylbenzenamine (0.650 g, 1.74 mmol), and
1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl fluoride (0.391
g, 1.74 mmol; obtained from Example 6, Step A). The crude material
was purified by preparative TLC (2.0 mm thickness, EtOAc/Hexane
4:1) to afford 11.1 mg (1% for 2-step process) of the desired
product. LRMS M+1 (460.3) observed. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 8.11 (d, J=5.5 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.44 (m,
2H), 7.03 (m, 1H), 6.96 (m, 3H), 6.19 (d, J=5.5 Hz, 1H), 2.58 (s,
3H), 2.23 (s, 3H), 1.62 (m, 4H).
Example 61
N-(4-(3-(4-(cyclopropylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy-
)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00173##
[0593] Step A: Preparation of
N-(4-(3-(4-(cyclopropylcarbamoyl)phenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[-
3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1--
dicarboxamide: Prepared according to the procedure of Example 53,
Step A, substituting 4-cyclopropylaminocarbonylphenylboronic acid
(59.0 mg, 0.288 mmol) for 3-(N-methylaminocarbonyl)phenyl boronic
acid. Yield: 37.6 mg at 80% purity, 29%. LRMS (APCI pos) m/e 729.0
(M+H).
[0594] Step B: Preparation of
N-(4-(3-(4-(cyclopropylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-ylox-
y)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting
N-(4-(3-(4-(cyclopropylcarbamoyl)phenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[-
3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1--
dicarboxamide (37 mg, 0.0508 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. Yield: 11 mg, 30%. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
10.46 (s, 1H), 9.97 (s, 1H), 8.56 (d, 1H), 8.35 (d, 2H), 8.08 (d,
2H), 7.87 (d, 1H), 7.83 (m, 1H), 7.55 (m, 2H), 7.40 (broad d, 1H),
7.30 (t, 1H), 7.06 (t, 2H), 6.39 (d, 1H), 1.63 (s, 4H), 0.80 (m,
2H), 0.64 (m, 2H). LRMS (APCI pos) m/e 609.1 (M+H).
Example 62
N-(2-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-flu-
orophenyl)cyclopropane-1,1-dicarboxamide
##STR00174##
[0596] Step A: Preparation of
2-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline:
Prepared according to the procedure for Example 58 step A,
substituting 4-amino-3-fluorophenol (0.331 g, 2.61 mmol) for
2-aminobenzo[d]thiazol-6-ol. The crude material was used directly
in next step. LRMS (APCI pos) m/e 379.1 (M+1).
[0597] Step B: Preparation of
N-(2-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fl-
uorophenyl)cyclopropane-1,1-dicarboxamide: Prepared by 2-step
process (Example 6, Steps B and C) from
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-fluo-
robenzenamine (0.250 g, 0.661 mmol) and
1-((4-fluorophenyl)carbamoyl)cyclopropanecarbonyl fluoride (0.164
g, 0.727 mmol; obtained from Example 6, Step A). The crude material
was purified by preparative TLC (1.0 mm thickness, EtOAc/Hexane
4:1) to afford 1.7 mg (0.5% for 2-step process) of the desired
product. LRMS M+1 (464.2) observed. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 10.13 (s, 1H), 8.45 (t, J=9 Hz, 1H), 8.19 (d,
J=6 Hz, 2H), 7.47 (m, 2H), 7.07 (t, J=8 Hz, 3H), 6.47 (d, J=6 Hz,
1H), 5.20 (br s, 2H), 2.90 (s, 3H), 1.83 (m, 2H), 1.68 (m, 2H).
.sup.19F NMR (376 MHz, CDCl.sub.3) .delta. -76.5 (3F), -116.8 (1F),
-123.8 (1F).
Example 63
N-(3-fluoro-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyrid-
in-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbox-
amide
##STR00175##
[0599] Step A: Preparation of
N-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
To a mixture of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (1.50 g, 3.06 mmol; prepared as in Example 7, Step B),
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(1.43 g, 6.12 mmol; prepared as in Example 19, Step C), and
HOBT-H.sub.2O (2.81 g, 18.4 mmol) dissolved in dry DMF (30 mL) was
added EDCI (3.52 g, 18.4 mmol). The mixture was stirred at room
temperature for 3 hours. The reaction mixture was then partitioned
between ethyl acetate (60 mL) and aqueous NH.sub.4Cl (100 mL). The
organic layer was separated, washed with saturated NaHCO.sub.3,
dried over NaSO.sub.4, and evaporated to dryness. The crude
material was triturated with MeOH and the solid removed by
filtration, dried to afford the title compound as yellow solid.
Yield: 1.93 g, 89%. LRMS (APCI pos) m/e 707.0 (M+H).
[0600] Step B: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(morpholine-4-carbonyl)phenyl)-1H-
-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihyd-
ropyridazine-4-carboxamide: To a small round bottom flask was added
N-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
(30 mg, 0.0425 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid
(20.0 mg, 0.0849 mmol), and Pd(PPh.sub.3).sub.4 (2.45 mg, 0.00212
mmol) and the mixture was dissolved in 3:1 DME:aqueous 2N
Na.sub.2CO.sub.3 (2 mL). The mixture was stirred at 70.degree. C.
until the reaction was determined to be complete by LC/MS (1-18
hours). The reaction mixture was then partitioned between ethyl
acetate (15 mL) and water (30 mL). The organic layer washed with
brine, dried over Na.sub.2SO.sub.4 and evaporated to afford crude
product. Purified by silica gel column chromatography (Biotage 12M)
eluting with 1-5% MeOH/CHCl.sub.3 to give the desired product.
Yield: 40.2 mg, 81%. LRMS (APCI pos) m/e 770.1 (M+H).
[0601] Step C: Preparation of
N-(3-fluoro-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyri-
din-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbo-
xamide: Prepared according to the procedure of Example 53, Step B,
substituting
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(morpholine-4-carbonyl)phenyl)-1H-
-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihyd-
ropyridazine-4-carboxamide (40 mg, 0.0520 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. Purified by silica gel column chromatography (Biotage
12M) eluting with 1-2% MeOH/CHCl.sub.3 to give the desired product
as yellow solid (16.2 mg, 48%). .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 11.71 (s, 1H), 8.39 (t, 2H), 8.27 (d, 1H), 8.07 (d, 2H),
8.03 (s, 1H), 7.69 (m, 2H), 7.58 (m, 2H), 7.53 (t, 2H), 7.41 (t,
2H), 6.40 (d, 1H), 3.61 (broad s, 8H). LRMS (APCI pos) m/e 650.1
(M+H).
Example 64
N-(3-fluoro-4-(3-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-flu-
orophenyl)cyclopropane-1,1-dicarboxamide
##STR00176##
[0603] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
Prepared according to the procedure of Example 53, Step A,
substituting phenylboronic acid (35 mg, 0.28 mmol) for
3-(N-methylaminocarbonyl)phenyl boronic acid. Purified by silica
gel column chromatography (Biotage 12M) eluting with 50:50
hexanes:ethyl acetate. Yield: 32 mg, 35%. LRMS (APCI pos) m/e 646.2
(M+H).
[0604] Step B: Preparation of
N-(3-fluoro-4-(3-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fl-
uorophenyl)cyclopropane-1,1-dicarboxamide: Prepared according to
the procedure of Example 53, Step B, substituting
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (32
mg, 0.049 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. Purified by trituration of crude with 1:1 ether:hexanes
to afford the desired product as the TFA salt. Yield: 19 mg, 61%.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 13.96 (s, 1H), 10.39 (s,
1H), 10 (s, 1H), 8.36 (d, 1H), 7.98 (d, 2H), 7.89 (d, 2H), 7.64 (d,
1H), 7.48 (m, 2H), 7.39 (t, 2H), 7.15 (t, 2H), 6.31 (d, 1H), 5.75
(s, 1H) 1.47 (d, 4H). LRMS (APCI pos) m/e 526.2 (M+H).
Example 65
4-(4-(2-fluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)pheno-
xy)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzoic acid
##STR00177##
[0606] Step A: Preparation of methyl
4-(4-(2-fluoro-4-(1-(4-fluorophenyl
carbamoyl)cyclopropanecarboxamido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazol-
o[3,4-b]pyridin-3-yl)benzoate: Prepared according to the procedure
of Example 53, Step A, substituting 4-methoxycarbonylphenylboronic
acid (207 mg, 1.15 mmol) for 3-(N-methylaminocarbonyl)phenyl
boronic acid. The crude material was purified by silica gel column
chromatography (Biotage 12M) eluting with 50:50 hexanes:ethyl
acetate. Yield: 223 mg at 92% purity, 50%. LRMS (APCI pos) m/e
704.1 (M+H).
[0607] Step B: Preparation of
4-(4-(2-fluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phen-
oxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzoic
acid: Dissolved methyl 4-(4-(2-fluoro-4-(1-(4-fluorophenyl
carbamoyl)cyclopropanecarboxamido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazol-
o[3,4-b]pyridin-3-yl)benzoate (230 mg, 0.327 mmol) in MeOH (5 mL)
and added 10% aqueous solution of NaOH (0.65 ml, 1.63 mmol). The
mixture was stirred at room temperature for 4 hours. The solvent
was evaporated to a minimal volume and the crude was partitioned
between ethyl acetate (50 mL) and water (50 mL). The organic layer
washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to
afford the desired product as white solid (191 mg at 90% purity,
76%) LRMS (APCI pos) m/e 690.2 (M+H).
[0608] Step C: Preparation of
4-(4-(2-fluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phen-
oxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzoic acid: Prepared
according to the procedure of Example 53, Step B, substituting
4-(4-(2-fluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phen-
oxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzoic
acid (20 mg, 0.029 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by trituration of crude
with 1:1 ether:hexanes to afford desired product as TFA salt.
Yield: 9.2 mg, 46%. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.39
(s, 1H), 10.01 (s, 1H), 8.39 (d, 1H), 8.12 (d, 2H), 8.02 (d, 2H),
7.92 (s, 1H), 7.64 (m, 2H), 7.50 (m, 2H), 7.15 (t, 2H), 6.35 (d,
1H), 1.47 (d, 4H). LRMS (APCI pos) m/e 570.2 (M+H).
Example 66
N-(3-fluoro-4-(3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarbo-
xamide
##STR00178##
[0610] Step A: Preparation of
1-((4-bromofuran-2-yl)methyl)-4-methylpiperazine: To a stirred
mixture of 4-bromofuran-2-carbaldehyde (2.10 g, 12.0 mmol) and THF
(10 mL) that was cooled in an ice bath was added 1-methylpiperazine
(1.60 ml, 14.4 mmol) dropwise, followed by sodium
triacetoxyborohydride (3.81 g, 18.0 mmol) in 3 portions as solid.
Acetic acid (0.343 ml, 6.00 mmol) was added, and the reaction was
stirred for 18 hours at ambient temperature. The dark mixture was
diluted with water (10 mL) and basified to pH>12 by addition of
5N NaOH. The mixture was extracted with diethyl ether (3.times.50
mL). The combined organic phases were dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The resulting black oil (2.10
g, 66%) was carried forward without purification.
[0611] Step B: Preparation of
1-methyl-4-((4-(tributylstannyl)furan-2-yl)methyl)piperazine: A
stirred mixture of 1-((4-bromofuran-2-yl)methyl)-4-methylpiperazine
(2.10 g, 8.10 mmol) and THF (50 mL) was cooled to -78.degree. C. in
a dry ice/acetone bath. tert-Butyllithium (7.60 mL, 12.2 mmol; 1.6
M in pentane) was added and the reaction mixture was stirred for 30
minutes. Next, tributylchlorostannane (2.09 ml, 7.70 mmol) was
added and the reaction mixture was stirred for 30 minutes. The
reaction was quenched by addition of pH 7 phosphate buffer (20 mL)
and warming to room temperature. The mixture was extracted with
diethyl ether, dried over sodium sulfate, filtered and
concentrated. The crude material was purified on a Biotage 40S
column, eluting with 1:1 EtOAc/hexanes (500 mL), 2:1 EtOAc/hexanes
(500 mL), then EtOAc (1 L) to provide a product mixture as a light
yellow oil (0.77 g, 86:14 ratio of
1-((4-bromo-5-(tributylstannyl)furan-2-yl)methyl)-4-methylpiperazine
to 1-methyl-4-((4-(tributylstannyl)furan-2-yl)methyl)piperazine by
.sup.1H-NMR). The mixture was carried forward without separation at
this step.
[0612] Step C: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
4-(1-(4-Methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (0.490 g, 1.0 mmol, prepared according to Example 7,
Step B) and acetonitrile (5 mL) were heated with
1-((4-fluorophenyl)carbamoyl)-cyclopropanecarbonyl fluoride (0.450
g, 2.00 mmol, prepared according to Example 6, Step A) at
100.degree. C. in a sealed vessel for 4 hours. The suspension was
allowed to cool to ambient temperature, and then in an ice bath for
15 minutes. The solid was filtered to provide pure desired product
(0.52 g, 75%) by LRMS (APCI-): 100% purity, 220 nm, m/z 694 (M-1)
detected.
[0613] Step D: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl-
)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide: A stirred mixture of
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (35 mg,
0.0503 mmol) and a 14:86 mixture of
1-methyl-4-((4-(tributylstannyl)furan-2-yl)methyl)piperazine and
1-((4-bromo-5-(tributylstannyl)furan-2-yl)methyl)-4-methylpiperazine
(26.0 mg, 0.0554 mmol, prepared in Example 66, Step B) in dioxane
(0.5 mL) was sparged with N.sub.2 for 2 minutes.
PdCl.sub.2(PPh.sub.3).sub.2 (2 mg, 0.003 mmol) was added, and the
reaction was heated to 90.degree. C. for 18 hours in a sealed
vessel. After cooling to ambient temperature, the crude reaction
mixture was loaded directly on to a preparative TLC plate (0.5 mm
thickness, Rf=0.60) eluting with 90:10 CHCl.sub.3/MeOH (containing
7N NH3). Isolated product as an off-white solid (27 mg, 83:17
mixture of
N-(4-(1-(4-methoxybenzyl)-3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)fu-
ran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluoroph-
enyl)cyclopropane-1,1-dicarboxamide and
N-(4-(1-(4-methoxybenzyl)-3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl-
)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide by .sup.1H-NMR). The mixture of
products were carried forward without further purification.
[0614] Step E: Preparation of
N-(3-fluoro-4-(3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazo-
lo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarb-
oxamide: A 17:83 mixture of
N-(4-(1-(4-methoxybenzyl)-3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl-
)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide and
N-(4-(1-(4-methoxybenzyl)-3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)fu-
ran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluoroph-
enyl)-cyclopropane-1,1-dicarboxamide (26 mg, 0.035 mmol) were
heated with TFA (0.5 mL) at 80.degree. C. for 2 hours in a sealed
vessel. After cooling to ambient temperature, the mixture was
concentrated in vacuo, using toluene to azeotrope. The resulting
solid was portioned between EtOAc (5 mL) and 1:1 saturated aqueous
NaHCO.sub.3/water (5 mL). The phases were separated, and the
aqueous phase was re-extracted with EtOAc. The combined organic
phases were washed with brine (5 mL), dried (Na2SO4), filtered, and
concentrated. The crude products were separated by preparative TLC
(0.5 mm thickness;
N-(4-(3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,-
1-dicarboxamide: Rf=0.33;
N-(3-fluoro-4-(3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazo-
lo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarb-
oxamide: Rf=0.25), eluting with 10% MeOH (containing 7N NH3) in
CHCl.sub.3. The product,
N-(3-fluoro-4-(3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazo-
lo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarb-
oxamide, was obtained as a white powder (1 mg, 5%). HPLC: 98%
purity (254 nm); LRMS (ESI+): 100% purity, 220 nm, 628 m/z (M+1)
detected; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.06 (s, 1H),
8.32 (d, J=5 Hz, 1H), 8.18 (m, 2H), 7.77 (m, 1H), 7.45 (m, 2H),
7.24 (m, 1H), 7.07 (t, J=9 Hz, 2H), 6.92 (s, 1H), 6.32 (d, J=5 Hz,
1H), 3.62 (s, 2H), 2.64 (br s, 8H), 2.37 (s, 3H), 1.83 (m, 2H),
1.63 (m, 2H).
Example 67
N-(4-(3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-
-dicarboxamide
##STR00179##
[0616] Step A: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)fu-
ran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluoroph-
enyl)cyclopropane-1,1-dicarboxamide: A stirred mixture of
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (35 mg,
0.0503 mmol, prepared according to Example 66, Step C) and a 14:86
mixture of
1-methyl-4-((4-(tributylstannyl)furan-2-yl)methyl)piperazine and
1-((4-bromo-5-(tributylstannyl)furan-2-yl)methyl)-4-methylpiperazine
(26.0 mg, 0.0554 mmol, prepared according to Example 66, Step B) in
dioxane (0.5 mL) was sparged with N.sub.2 for 2 minutes, and then
PdCl.sub.2(PPh.sub.3).sub.2 (2 mg, 0.003 mmol) was added. The
reaction was heated at 90.degree. C. for 18 hours in a sealed
vessel. After cooling to ambient temperature, the crude reaction
mixture was loaded directly on to a preparative TLC plate (0.5 mm
thickness, Rf=0.60) eluting with 90:10 CHCl.sub.3/MeOH (containing
7N NH.sub.3). The product was isolated as an off-white solid (27
mg, 83:17 mixture of
N-(4-(1-(4-methoxybenzyl)-3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)fu-
ran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluoroph-
enyl)cyclopropane-1,1-dicarboxamide and
N-(4-(1-(4-methoxybenzyl)-3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl-
)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide). .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 9.95 (s, 1H), 8.32 (d, J=6 Hz, 1H), 8.18 (s, 1H), 7.71 (m,
1H), 7.42 (m, 4H), 7.21 (m, 2H), 7.06 (t, J=9 Hz, 2H), 6.84 (d, J=9
Hz, 2H), 6.41 (s, 1H), 6.26 (d, J=6 Hz, 1H), 5.70 (s, 2H), 3.76 (s,
3H), 3.54 (m, 2H), 2.25-2.63 (m, 8H), 2.19 (s, 3H), 1.79 (m, 2H),
1.61 (m, 2H). The mixture of products was used directly in the next
step.
[0617] Step B: Preparation of
N-(4-(3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,-
1-dicarboxamide:A 17:83 mixture of
N-(4-(1-(4-methoxybenzyl)-3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl-
)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyc-
lopropane-1,1-dicarboxamide and
N-(4-(1-(4-methoxybenzyl)-3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)fu-
ran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluoroph-
enyl)-cyclopropane-1,1-dicarboxamide (26 mg, 0.035 mmol) were
heated with TFA (0.5 mL) at 80.degree. C. for 2 hours in a sealed
vessel. After cooling to ambient temperature, the mixture was
concentrated in vacuo, using toluene to azeotrope. The resulting
solid was partitioned between EtOAc (5 mL) and 1:1 saturated
aqueous NaHCO.sub.3/water (5 mL). The phases were separated, and
the aqueous phase was re-extracted with EtOAc. The combined organic
phases were washed with brine, dried (Na.sub.2SO.sub.4), filtered,
and concentrated. The crude products were separated by preparative
TLC (0.5 mm thickness;
N-(4-(3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,-
1-dicarboxamide: Rf=0.33;
N-(3-fluoro-4-(3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazo-
lo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarb-
oxamide: Rf=0.25), eluting with 10% MeOH (containing 7N NH.sub.3)
in CHCl.sub.3. The product,
N-(4-(3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,-
1-dicarboxamide, was obtained as a white powder (8 mg, 32%). HPLC:
98% purity (254 nm); LRMS (ESI+): 100% purity, 220 nm, 708, 606
(loss of piperazine) m/z (M+1) detected; .sup.1H NMR (400 MHz,
CDCl.sub.3+few drops CD.sub.3OD) .delta. 8.31 (d, J=5 Hz, 1H), 7.73
(m, 1H), 7.48 (m, 2H), 7.32 (m, 1H), 7.21 (t, J=9 Hz, 1H), 7.04 (t,
J=9 Hz, 2H), 6.48 (s, 1H), 6.33 (d, J=5 Hz, 1H), 3.55 (s, 2H), 2.48
(m, 8H), 2.21 (s, 3H), 1.69 (m, 4H). .sup.1H NMR/.sup.13C-NMR
correlation spectroscopy was consistent with the depicted
bromo-furan regioisomer.
Example 68
N-(3-fluoro-4-(3-(4-(4-methylpiperazine-1-carbonyl)phenyl)-1H-pyrazolo[3,4-
-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamid-
e
##STR00180##
[0619] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(4-methylpiperazine-1-carbonyl)ph-
enyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopro-
pane-1,1-dicarboxamide: To a mixture of
4-(4-(2-fluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phen-
oxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzoic
acid (20.7 mg, 0.0300 mmol; prepared in Example 66, Step B) and
HOBt-H.sub.2O (4.59 mg, 0.0300 mmol) in DMF (2 mL) was added EDCI
(5.74 mg, 0.030 mmol) and the reaction mixture was stirred at room
temperature for 30 minutes. 1-Methylpiperazine (0.0028 ml, 0.025
mmol) was added followed by TEA (0.0042 ml, 0.0300 mmol) and the
mixture was stirred at room temperature under nitrogen atmosphere
until all starting material was consumed as determined by LC/MS.
The crude reaction mixture was partitioned between aqueous
NH.sub.4Cl (10 mL) and ethyl acetate (15 mL). The organic layer
washed with saturated NaHCO.sub.3, dried over Na.sub.2SO.sub.4, and
evaporated to afford crude product as colorless oil. Purified by
silica gel column chromatography (Biotage 12M) eluting with 4%
MeOH/CHCl.sub.3 to give the desired product as colorless glass (10
mg at 95% purity, 49%). LRMS (APCI pos) m/e 772.2 (M+H).
[0620] Step B: Preparation of
N-(3-fluoro-4-(3-(4-(4-methylpiperazine-1-carbonyl)phenyl)-1H-pyrazolo[3,-
4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxami-
de: Prepared according to the procedure of Example 53, Step B,
substituting
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(4-methylpiperazine-1-carbonyl)ph-
enyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopro-
pane-1,1-dicarboxamide (10 mg, 0.013 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by trituration with 5%
MeOH in ether to afford desired product as the di-TFA salt (7.82
mg, 68%). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.42 (s, 1H),
9.98 (s, 1H), 8.39 (d, 1H), 8.11 (d, 2H), 7.90 (d, 1H), 7.64 (d,
2H), 7.57 (d, 2H), 7.50 (m, 2H), 7.16 (t, 2H), 6.35 (d, 1H), 1.48
(d, 4H). LRMS (APCI pos) m/e 652.2 (M+H).
Example 69
N-(3-fluoro-4-(3-(4-(2-methoxyethylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]pyr-
idin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00181##
[0622] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(2-methoxyethylcarbamoyl)phenyl)--
1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1-
,1-dicarboxamide: Prepared according to the procedure of Example
68, Step A, substituting 2-methoxyethanamine (0.0031 ml, 0.036
mmol) for 1-methylpiperazine. The crude material was purified by
silica gel column chromatography (Biotage 12M) eluting with 3%
MeOH/CHCl.sub.3 to afford desired product as colorless glass (21.7
mg at 90% purity, 73%). LRMS (APCI pos) m/e 747.1 (M+H).
[0623] Step B: Preparation of
N-(3-fluoro-4-(3-(4-(2-methoxyethylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(2-methoxyethylcarbamoyl)phenyl)--
1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1-
,1-dicarboxamide (21.7 mg, 0.029 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by silica gel column
chromatography (Biotage 12M) eluting with 5% MeOH/CHCl.sub.3 to
give the desired product as white solid (9.7 mg at 95% purity,
50%). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.4 (s, 1H), 10 (s,
1H), 8.54 (t, 1H), 8.38 (d, 1H), 8.07 (d, 2H), 7.93 (d, 2H), 7.88
(s, 1H), 7.64 (m, 2H), 7.50 (m, 2H), 7.15 (t, 2H), 6.34 (d, 1H),
3.45 (m, 4H), 3.26 (s, 3H), 1.47 (d, 4H). LRMS (APCI pos) m/e 627.2
(M+H).
Example 70
N-(3-fluoro-4-(3-(4-(2-hydroxyethylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]pyr-
idin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
##STR00182##
[0625] Step A: Preparation of
N-(3-fluoro-4-(3-(4-(2-hydroxyethylcarbamoyl)phenyl)-1-(4-methoxybenzyl)--
1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1-
,1-dicarboxamide: Prepared according to the procedure of Example
68, Step A, substituting 2-aminoethanol (0.0027 ml, 0.044 mmol) for
1-methylpiperazine. The crude material was purified by
recrystallization from DCM/ether to afford the desired product as
white solid (17.2 mg at 95% purity, 50%). LRMS (APCI pos) m/e 733.1
(M+H).
[0626] Step B: Preparation of
N-(3-fluoro-4-(3-(4-(2-hydroxyethylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting
N-(3-fluoro-4-(3-(4-(2-hydroxyethylcarbamoyl)phenyl)-1-(4-methoxybenzyl)--
1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1-
,1-dicarboxamide (17.2 mg, 0.0235 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude was dissolved in MeOH (2 mL) and added aqueous
sodium bicarbonate (.about.1 mL). The reaction mixture was stirred
for 2 hours and monitored by LC/MS. The methanol was evaporated and
the remaining aqueous was partitioned between ethyl acetate and 10%
Na.sub.2CO.sub.3 solution. The organic was separated, dried over
Na.sub.2SO.sub.4 and evaporated to afford the title compound as
white solid (12.1 mg, 84%) .sup.1H NMR (400 MHz, DMSO-d6) .delta.
10.4 (s, 1H), 10 (s, 1H), 8.45 (t, 1H), 8.38 (d, 1H), 8.07 (d, 2H),
7.94 (d, 2H), 7.88 (s, 1H), 7.66 (s, 1H), 7.62 (m, 2H), 7.50 (m,
2H), 7.15 (t, 2H), 6.34 (d, 1H), 3.50 (m, 2H), 3.34 (m, 2H), 1.47
(d, 4H). LRMS (APCI pos) m/e 613.1 (M+H).
Example 71
N-(4-(3-(4-(2-(dimethylamino)ethylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]pyri-
din-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxam-
ide
##STR00183##
[0628] Step A: Preparation of
N-(4-(3-(4-(2-(dimethylamino)ethylcarbamoyl)phenyl)-1-(4-methoxybenzyl)-1-
H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclop-
ropane-1,1-dicarboxamide: Prepared according to the procedure of
Example 68, Step A, substituting N,N-dimethylethane-1,2-diamine
(0.0035 ml, 0.032 mmol) for 1-methylpiperazine. The crude material
was purified by silica gel column chromatography (Biotage 12M)
eluting with 10% MeOH/CHCl.sub.3 to afford the desired product as
opaque semi-solid. Yield 18 mg, 75%. LRMS (APCI pos) m/e 760.2
(M+H).
[0629] Step B: Preparation of
N-(4-(3-(4-(2-(dimethylamino)ethylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]pyr-
idin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxa-
mide: Prepared according to the procedure of Example 53, Step B,
substituting
N-(4-(3-(4-(2-(dimethylamino)ethylcarbamoyl)phenyl)-1-(4-methoxybenzyl)-1-
H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclop-
ropane-1,1-dicarboxamide (18 mg, 0.0237 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was used purified by trituration of
crude with ether:hexanes to afford desired product as the di-TFA
salt (14 mg, 71%). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.42 (s,
1H), 9.97 (s, 1H), 8.69 (t, 1H), 8.39 (d, 1H), 8.11 (d, 2H), 7.96
(d, 2H), 7.90 (d, 1H), 7.63 (m, 2H), 7.50 (m, 2H), 7.16 (t, 2H),
6.35 (d, 1H), 3.62 (m, 2H), 3.27 (m, 2H), 2.85 (s, 6H) 1.48 (d,
4H). LRMS (APCI pos) m/e 640.2 (M+H).
Example 72
N-(3-fluoro-4-(3-(4-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide
##STR00184##
[0631] Step A: Preparation of
N-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide: A 100 mL
round-bottomed flask was charged with
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (300.0 mg, 0.6119 mmol),
1-methyl-2-oxopyrrolidine-3-carboxylic acid (87.59 mg, 0.6119
mmol),
N1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diamine
hydrochloride (351.9 mg, 1.836 mmol),
1H-benzo[d][1,2,3]triazol-1-ol (248.0 mg, 1.836 mmol),
N-ethyl-N-isopropylpropan-2-amine (395.4 mg, 3.060 mmol) and THF
(50 mL). The reaction mixture was stirred at ambient temperature
overnight, and then partitioned between EtOAc and H.sub.2O. The
phases were separated, and the aqueous phase was re-extracted with
EtOAc. The combined organic layers were dried (Na.sub.2SO.sub.4),
filtered and concentrated to yield a crude product. The crude
product was purified by silica gel chromatography (DCM/7 M NH.sub.3
in MeOH from 100/1 to 10/1, v/v) to afford product (0.360 g,
95.6%). LRMS (APCI pos): m/e 616 (M+1). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 10.04 (s, 1H), 8.31 (d, 1H), 7.79 (dd, 1H),
7.36 (d, 2H), 7.29 (m, 1H), 7.20 (t, 1H), 6.83 (m, 2H), 6.20 (d,
1H), 5.61 (s, 2H), 3.78 (s, 3H), 3.42-3.50 (m, 3H), 2.94 (s, 3H),
2.50-2.61 (m, 1H), 2.35-2.48 (m, 1H).
[0632] Step B: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide:
A 50 mL round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide (20.0 mg, 0.0325
mmol), 4-(methylcarbamoyl)phenylboronic acid (17.5 mg, 0.0975
mmol), tetrakis(triphenylphosphine) palladium (7.51 mg, 0.00650
mmol), Na.sub.2CO.sub.3 (0.0812 ml, 0.162 mmol) and DME (10 mL).
The reaction mixture was stirred at 60.degree. C. for 4 hours, and
then partitioned between EtOAc and H.sub.2O. The phases were
separated, and the aqueous phase was re-extracted with EtOAc. The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated to yield a crude product. The crude product was
purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 100/1 to 10/1, v/v) to afford product (10.8 mg, 53.4%). LRMS
(APCI pos) m/e 623 (M+1).
[0633] Step C: Preparation of
N-(3-fluoro-4-(3-(4-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)phenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide: A 50 mL
round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-(4-(methylcarbamoyl)phenyl)-1H-pyrazolo[3,4-b-
]pyridin-4-yloxy)-3-fluorophenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide
(10.8 mg, 0.0173 mmol) and CF.sub.3COOH (2 mL). The reaction
mixture was stirred at 80.degree. C. for 4 hours. Then the
CF.sub.3COOH was removed under reduced pressure. The residue was
purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 50/1 to 10/1, v/v) to afford product (3.9 mg, 44.7%). LRMS
(APCI pos): >99% purity, 254 nm, m/e 503 (M+1). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.35 (d, 1H), 8.10 (d, 2H), 7.83-7.90 (m,
3H), 7.40 (d, 1H), 7.32 (t, 1H), 6.40 (d, 1H), 3.44-3.60 (m, 3H),
2.92 (s, 3H), 2.90 (s, 3H), 2.28-2.51 (m, 2H).
Example 73
N-(3-fluoro-4-(3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl-
)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00185##
[0635] Step A: Preparation of
N-(3-fluoro-4-(3-(4-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-ca-
rboxamide: Prepared according to the procedure of Example 63, Step
B, substituting 4-fluorophenylboronic acid (11.9 mg, 0.0849 mmol)
for 4-(morpholine-4-carbonyl)phenylboronic acid. The crude material
was purified by silica gel column chromatography (Biotage 12M)
eluting with 1.5% MeOH/CHCl.sub.3 to afford the desired product.
Yield: 34 mg at 65% purity, 77%. LRMS (APCI pos) m/e 675.3
(M+H).
[0636] Step B: Preparation of
N-(3-fluoro-4-(3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pheny-
l)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting
N-(3-fluoro-4-(3-(4-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-ca-
rboxamide (34 mg, 0.033 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by silica gel column
chromatography (Biotage 12M) eluting with 3% MeOH/CHCl.sub.3 to
afford the desired product. Yield: 10 mg, 55%. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 13.97 (s, 1H), 11.71 (s, 1H), 8.38 (t, 2H),
8.27 (d, 1H), 8.06 (m, 3H), 7.70 (q, 2H), 7.67 (m, 2H), 7.42 (t,
2H), 7.31 (t, 2H), 6.36 (d, 1H). LRMS (APCI pos) m/e 555.3
(M+H).
Example 74
N-(2-chloro-5-methyl-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,-
4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-
-4-carboxamide
##STR00186##
[0638] Step A: Preparation of
1-(4-methoxybenzyl)-4-(5-chloro-2-methyl-4-nitrophenoxy)-1H-pyrazolo[3,4--
b]pyridine: A stirred mixture of
1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (255 g, 999
mmol, prepared using the procedure described in Example 1, Step B),
1-chloro-5-fluoro-4-methyl-2-nitrobenzene (94.7 g, 499 mmol),
cesium carbonate (325 g, 1.0 mol) and DMF (2 L) was heated to
95.degree. C. for 6 hours. The reaction was cooled to ambient
temperature and partitioned between EtOAc and water. The phases
were filtered and then separated. The aqueous phase was
re-extracted with EtOAc. The combined organic phases were washed
with water, brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The crude was purified by Biotage Flash 75 L
chromatographic system, eluting with 5% EtOAc/hexanes (12 L), 10%
EtOAc/hexanes (6 L), 20% EtOAc/hexanes (6 L), then 30%
EtOAc/hexanes (6 L). The product was obtained as a viscous oil (42
g, 9%).
[0639] Step B: Preparation of
4-(5-chloro-2-methyl-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine:
1-(4-Methoxybenzyl)-4-(5-chloro-2-methyl-4-nitrophenoxy)-1H-pyrazolo[3,4--
b]pyridine (42 g, 98.9 mmol) and 2,2,2-trifluoroacetic acid (76.2
ml, 989 mmol) were stirred at reflux for 4 h. The reaction was
concentrated in vacuo, using toluene to azeotrope. The residue was
diluted with EtOAc and saturated NaHCO.sub.3 was added to
neutralize the acid, and the resulting suspension was stirred for
20 minutes. The precipitate was filtered and washed with water to
remove residual NaHCO.sub.3. The solid was further dried by toluene
azeotrope. The tan solid was left under high vacuum for 18 hours.
The product (22 g, 70%) was carried forward without further
purification.
[0640] Step C: Preparation of
4-(5-chloro-2-methyl-4-nitrophenoxy)-3-iodo-1H-pyrazolo[3,4-b]pyridine:
To a stirred solution of
4-(5-chloro-2-methyl-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine
(21.0 g, 68.9 mmol) in DMF (100 mL) was added freshly ground
(mortar/pestle) potassium hydroxide (11.6 g, 207 mmol) flakes
followed immediately by iodine (26.2 g, 103 mmol) under N.sub.2 at
25.degree. C. The dark reaction was heated to 50.degree. C. for 6
hours. The mixture was quenched by addition of aqueous 10%
NaHSO.sub.3 (75 mL). The suspension was further diluted by addition
of water (100 mL) and filtered. The resulting precipitate washed
with water, dried by toluene azeotrope, and then left under high
vacuum for 2 days. The beige powder (26.5 g, 69%) was carried
forward without further purification.
[0641] Step D: Preparation of
1-(4-methoxybenzyl)-4-(5-chloro-2-methyl-4-nitrophenoxy)-3-iodo-1H-pyrazo-
lo[3,4-b]pyridine:
4-(5-Chloro-2-methyl-4-nitrophenoxy)-3-iodo-1H-pyrazolo[3,4-b]pyridine
(26.5 g, 61.5 mmol) was dissolved in stirring DMF (100 mL).
K.sub.2CO.sub.3 (17.0 g, 123 mmol) and
1-(chloromethyl)-4-methoxybenzene (10.1 ml, 73.9 mmol) were added
and the reaction mixture was stirred at ambient temperature under
N.sub.2 for 18 hours. The mixture was diluted with water, and then
the water was decanted. The gum washed a second time with water,
and the water decanted. The residue was partitioned between EtOAc
(250 mL) and brine (100 mL). The phases were separated, and the
organic phase was dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The resulting solid was triturated with diethyl ether
(100 mL), and the yellow powder (27.3 g, 80%) filtered. The product
was a 9:1 mixture of pyrazole regioisomers as determined by .sup.1H
NMR: (400 MHz, CDCl.sub.3, major regioisomer reported) .delta. 8.43
(d, J=5 Hz, 1H), 7.95 (s, 1H), 7.38 (d, J=9 Hz, 2H), 7.19 (s, 1H),
6.84 (d, J=9 Hz, 2H), 6.35 (d, J=5 Hz, 1H), 5.64 (s, 2H), 3.77 (s,
3H), 2.36 (s, 3H).
[0642] Step E: Preparation of
2-chloro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-
-5-methylaniline: To a 100 mL round bottom flask added
1-(4-methoxybenzyl)-4-(5-chloro-2-methyl-4-nitrophenoxy)-3-iodo-1H-pyrazo-
lo[3,4-b]pyridine (544 mg, 0.99 mmol) and suspended in absolute
ethanol (10 mL). Added tin(II)chloride dihydrate (1.1 g, 4.94 mmol)
and stirred at 25.degree. C. under N.sub.2(g) for 18 hours, during
which a white precipitate formed. The reaction mixture was cooled
to 0.degree. C. and the solid was removed by filtration and washed
with cold ethanol. The solid was air-dried to afford the desired
product as white solid. Yield: 417 mg, 81%. LRMS (APCI pos) m/e
521.1 (M+H).
[0643] Step F: Preparation of
N-(2-chloro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)-5-methylphenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbo-
xamide: Prepared according to the procedure of Example 82, Step B,
substituting
2-chloro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-
-5-methylaniline (70 mg, 0.13 mmol) for tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperazine-1-carboxylate. The crude material was purified
by silica gel column chromatography (Biotage 25M) eluting with
70/30 hexanes/EtOAc to afford the desired product. Yield: 62 mg,
63%. LRMS (APCI pos) m/e 737.1 (M+H).
[0644] Step G: Preparation of
N-(2-chloro-4-(1-(4-methoxybenzyl)-3-(4-(morpholine-4-carbonyl)phenyl)-1H-
-pyrazolo[3,4-b]pyridin-4-yloxy)-5-methylphenyl)-2-(4-fluorophenyl)-3-oxo--
2,3-dihydropyridazine-4-carboxamide: Prepared according to the
procedure of Example 63, Step B, substituting
N-(2-chloro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)-5-methylphenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbo-
xamide (22 mg, 0.030 mmol) for
N-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.
The crude material was purified by silica gel column chromatography
(Biotage 12M) eluting with 2% MeOH/CHCl.sub.3 to afford the desired
product. Yield: 23 mg, 96%. LRMS (APCI pos) m/e 800.2 (M+H).
[0645] Step H: Preparation of
N-(2-chloro-5-methyl-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazin-
e-4-carboxamide: Prepared according to the procedure of Example 53,
Step B, substituting
N-(2-chloro-4-(1-(4-methoxybenzyl)-3-(4-(morpholine-4-carbonyl)phenyl)-1H-
-pyrazolo[3,4-b]pyridin-4-yloxy)-5-methylphenyl)-2-(4-fluorophenyl)-3-oxo--
2,3-dihydropyridazine-4-carboxamide (23 mg, 0.0287 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by silica gel column
chromatography (Biotage 12M) eluting with 2% MeOH/CHCl.sub.3 to
afford the desired product. Yield: 9.7 mg, 50%. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 14.02 (s, 1H), 12.08 (s, 1H), 8.59 (s, 1H),
8.41 (d, 1H), 8.36 (t, 2H), 8.09 (d, 2H), 7.68 (m, 2H), 7.61 (s,
1H), 7.52 (d, 2H), 7.42 (t, 2H), 6.30 (d, 1H), 3.60 (broad s, 8H),
3.29 (s, 3H). LRMS (APCI pos) m/e 680.2 (M+H).
Example 75
N-(3-fluoro-4-(3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)--
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00187##
[0647] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyr-
idin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carb-
oxamide: Prepared according to the procedure of Example 63, Step B,
substituting pyridine-3-boronic acid (10.4 mg, 0.085 mmol) for
4-(morpholine-4-carbonyl)phenylboronic acid. The crude material was
purified by silica gel column chromatography (Biotage 12M) eluting
with 2% MeOH/CHCl.sub.3 to afford the desired product. Yield: 18 mg
at 85% purity, 55%. LRMS (APCI pos) m/e 658.3 (M+H).
[0648] Step B: Preparation of
N-(3-fluoro-4-(3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-
-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyr-
idin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carb-
oxamide (18 mg, 0.0274 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by silica gel column
chromatography (Biotage 12M) eluting with 3% MeOH/CHCl.sub.3 to
afford the desired product. Yield: 7 mg, 47%. LRMS (APCI pos) m/e
538.3 (M+H).
Example 76
N-(3-fluoro-4-(1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-
-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00188##
[0650] Step A: Preparation of
4-(2-fluoro-4-nitrophenoxy)-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine:
To a stirred solution of
4-(2-fluoro-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (12.0 g,
43.8 mmol, prepared using the procedure described in Example 3,
Step A) in DMF (100 mL) was added freshly ground (mortar/pestle)
potassium hydroxide (7.37 g, 131 mmol) followed immediately by
iodine (16.7 g, 65.6 mmol) under N.sub.2(g) at 25.degree. C. The
dark reaction was heated to 50.degree. C. for 3 hours. One third of
the reaction mixture volume was poured into a stirred solution of
iodomethane (3.09 g, 21.7 mmol) in DMF (25 mL) at 0.degree. C.
under N.sub.2. The reaction was allowed to warm to 25.degree. C.
and stirred for 18 hours under N.sub.2. The mixture was diluted
with CH.sub.2Cl.sub.2 (50 mL) and washed with a co-solvent of
saturated aqueous Na.sub.2S.sub.2O.sub.3 (10 mL) and water (40 mL).
The aqueous phase was extracted with 10% MeOH in CH.sub.2Cl.sub.2
(30 mL). The combined organic phases were washed with the
Na.sub.2S.sub.2O.sub.3/water mixture followed by water, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The
resulting residue was triturated with diethyl ether, and the solid
filtered to afford the desired product (4.01 g, 62%).
[0651] Step B: Preparation of
3-fluoro-4-(3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)benzenamine-
: Prepared from
4-(2-fluoro-4-nitrophenoxy)-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine
(2.07 g, 5.0 mmol) and SnCl.sub.2-dihydrate (5.64 g, 25.0 mmol)
according to the procedure of Example 18, Step B. The product (1.30
g, 68%) was used directly in the next step without
purification.
[0652] Step C: Preparation of
N-(3-fluoro-4-(3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)--
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
Prepared according to the procedure of Example 63, Step A,
substituting
3-fluoro-4-(3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline
(100 mg, 0.260 mmol) for
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine. The crude material was purified by silica gel column
chromatography (Biotage 25M) eluting with 2% MeOH/CHCl.sub.3 to
afford the desired product as yellow solid. Yield: 125 mg, 80%.
LRMS (APCI pos) m/e 601.2 (M+H).
[0653] Step D: Preparation of
N-(3-fluoro-4-(1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl-
)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
Prepared according to the procedure of Example 63, Step B,
substituting phenylboronic acid (12 mg, 0.100 mmol) for
4-(morpholine-4-carbonyl)phenylboronic acid. The crude material was
purified by silica gel column chromatography (Biotage 12M) eluting
with 2% MeOH/CHCl.sub.3 to afford the desired product. Yield: 15 mg
at 92% purity, 50%. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.7 (s,
1H), 8.42 (d, 1H), 8.38 (d, 1H), 8.27 (d, 1H), 8.05 (dd, 1H), 7.97
(d, 1H), 7.69 (q, 2H), 7.58 (m, .sup.3H), 7.47 (t, 2H), 7.41 (t,
3H), 6.41 (d, 1H), 4.13 (s, 3H). LRMS (APCI pos) m/e 551.3
(M+H).
Example 77
N-(3-fluoro-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00189##
[0655] Step A: Preparation of
N-(3-fluoro-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl-
oxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
Prepared according to the procedure of Example 63, Step B,
substituting 4-fluorophenylboronic acid (14.0 mg, 0.10 mmol) for
4-(morpholine-4-carbonyl)phenylboronic acid and using
N-(3-fluoro-4-(3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)--
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide as
prepared in Example 76, Step B. The crude material was purified by
silica gel column chromatography (Biotage 12M) eluting with 2%
MeOH/CHCl.sub.3 to afford the desired product. Yield: 19.8 mg at
93% purity, 65%. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.71 (s,
1H), 8.40 (dd, 2H), 8.27 (d, 1H), 8.03 (m, 3H), 7.69 (t, 2H), 7.58
(m, 2H), 7.41 (t, 2H), 7.32 (t, 2H), 6.41 (d, 1H), 4.12 (s, 3H).
LRMS (APCI pos) m/e 569.3 (M+H).
Example 78
N-(3-Fluoro-4-(3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridi-
n-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxa-
mide
##STR00190##
[0657] Step A: Preparation of tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate: A 100 mL
round-bottomed flask was charged with
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (250.0 mg, 0.5099 mmol, prepared in Example 7, step B),
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (315.3 mg, 1.020 mmol), tetrakis(triphenylphosphine)
palladium (117.8 mg, 0.1020 mmol), Na.sub.2CO.sub.3 (1.275 ml,
2.550 mmol) and DME (25 mL). The reaction mixture was stirred at
100.degree. C. overnight, then partitioned between EtOAc (100 mL)
and H.sub.2O (100 mL). The phases were separated and the aqueous
phase was re-extracted with EtOAc. The combined organic layers were
dried (Na.sub.2SO.sub.4), filtered and concentrated to yield a
crude product. The crude product was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 100/1 to 10/1, v/v)
to afford product (273.3 mg, 98%). LRMS (APCI pos) m/e 546
(M+1).
[0658] Step B: Preparation of tert-butyl
4-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbox-
amido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5,6-dih-
ydropyridine-1(2H)-carboxylate: A 50 mL round-bottomed flask was
charged with tert-butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (50.0 mg, 0.0916
mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic
acid (42.9 mg, 0.183 mmol),
N1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diamine
hydrochloride (52.7 mg, 0.275 mmol), 1H-benzo[d][1,2,3]triazol-1-ol
(37.1 mg, 0.275 mmol), N-ethyl-N-isopropylpropan-2-amine (0.0818
ml, 0.458 mmol) and DMF (5 mL). The reaction mixture was stirred at
room temperature until LC-MS showed that the starting material had
been consumed (2 days). The reaction was partitioned between EtOAc
and H.sub.2O. The phases were separated and the aqueous phase was
re-extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
product. The crude material was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 100/1 to 10/1, v/v)
to afford product (38.3 mg, 54.9%). LRMS (APCI pos) m/e 662
(M-99).
[0659] Step C: Preparation of
N-(3-fluoro-4-(3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyrid-
in-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbox-
amide: A 50 mL round-bottomed flask was charged with tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5,6-dih-
ydropyridine-1(2H)-carboxylate (38.3 mg, 0.0503 mmol) and
CF.sub.3COOH (5 mL). The reaction mixture was stirred at 60.degree.
C. for 4 hours. Then the solvent was removed and the residue was
purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 50/1 to 10/1, v/v) to give product 21.8 mg, the yield is
80.1%. LRMS (APCI pos): >99% purity, 254 nm, m/e 542 (M+1).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.71 (s, 1H), 8.38 (d,
1H), 8.30 (d, 1H), 8.27 (d, 1H), 8.04 (dd, 1H), 6.82 (m, 2H), 7.59
(d, 1H), 7.49 (m, 1H), 7.42 (m, 2H), 6.69 (s, 1H), 6.31 (d, 1H),
3.39 (m, 2H), 2.94 (m, 2H), 2.58 (m, 2H).
Example 79
N-(4-(3-(4-(dimethylamino)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00191##
[0661] Step A: Preparation of
N-(4-(3-(4-(dimethylamino)phenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyrida-
zine-4-carboxamide: Prepared according to the procedure of Example
63, Step B, substituting 4-(dimethylamino)phenylboronic acid (23
mg, 0.14 mmol) for 4-(morpholine-4-carbonyl)phenylboronic acid. The
crude material was purified by silica gel column chromatography
(Biotage 12M) eluting with 1% MeOH/CHCl.sub.3 to afford the desired
product. Yield: 39 mg, 79%. LRMS (APCI pos) m/e 700.3 (M+H).
[0662] Step B: Preparation of
N-(4-(3-(4-(dimethylamino)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fl-
uorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting
N-(4-(3-(4-(dimethylamino)phenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyrida-
zine-4-carboxamide (39 mg, 0.0557 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by silica gel column
chromatography (Biotage 12M) eluting with 2% MeOH/CHCl.sub.3 to
afford the desired product. Yield: 18 mg at 90% purity, 50%.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 13.68 (s, 1H), 11.7 (s, 1H),
8.38 (d, 1H), 8.32 (d, 1H), 8.27 (d, 1H), 8.04 (d, 1H), 7.83 (d,
2H), 7.69 (q, 2H), 7.55 (m, 3H), 7.41 (t, 2H), 6.80 (d, 1H), 6.29
(d, 1H), 2.93 (s, 6H). LRMS (APCI pos) m/e 580.4 (M+H).
Example 80
N-(4-(3-(3-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl-
)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00192##
[0664] Step A: Preparation of
N-(4-(3-(3-chlorophenyl)-1-(4-methoxybenzyl)-1H-carboxamide:
Prepared according to the procedure of Example 63, Step B,
substituting 3-chlorophenylboronic acid (17.7 mg, 0.113 mmol) for
4-(morpholine-4-carbonyl)phenylboronic acid. The crude material was
purified by trituration with 60/40 hexanes/EtOAc to afford the
desired product as yellow solid. Yield: 32 mg, 82%. LRMS (APCI pos)
m/e 691.2 (M+H).
[0665] Step B: Preparation of
N-(4-(3-(3-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoropheny-
l)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting
N-(4-(3-(3-chlorophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-ca-
rboxamide (32 mg, 0.0463 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by trituration with 20%
MeOH/ether to afford the desired product as pale yellow solid.
Yield: 24 mg, 90%. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.71 (s,
1H), 8.39 (t, 2H), 8.37 (d, 1H), 8.27 (dd, 2H), 7.97 (d, 2H), 7.69
(q, 2H), 7.59-7.44 (m, 3H), 7.43-7.39 (m, 2H), 6.41 (d, 1H). LRMS
(APCI pos) m/e 571.3 (M+H).
Example 81
N-(4-(3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoropheny-
l)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00193##
[0667] Step A: Preparation of tert-butyl
4-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbox-
amido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyra-
zole-1-carboxylate: A 50 mL round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
(40.0 mg, 0.0566 mmol, prepared in Example 63, step A), tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
(50.0 mg, 0.170 mmol), Pd(OAc).sub.2 (2.54 mg, 0.0113 mmol),
tricyclohexylphosphine (4.76 mg, 0.0170 mmol), cesium fluoride
(77.4 mg, 0.510 mmol) and CH.sub.3CN (10 mL). The reaction mixture
was stirred at 100.degree. C. for 1 hour. The reaction was cooled
to room temperature and then the reaction was partitioned between
EtOAc and H.sub.2O. The phases were separated and the aqueous phase
was re-extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
product. The crude material was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 100/1 to 10/1, v/v)
to afford product (29.7 mg, 70.2%). LRMS (APCI neg): >96%
purity, 254 nm, m/e 745 (M-1).
[0668] Step B: Preparation of
N-(4-(3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophen-
yl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide: A
50 mL round-bottomed flask was charged with tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)
phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrazole-1-carboxylate
(29.7 mg, 0.0398 mmol) and CF.sub.3COOH (5 mL). The reaction
mixture was stirred at 60.degree. C. for 4 hours. Then the solvent
was removed and the residue was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to
give product (17.8 mg, 85.0%). LRMS (APCI pos): >99% purity, 254
nm, m/e 527 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
13.65 (s, 1H), 13.0 (s, 1H), 11.74 (s, 1H), 8.38 (d, 1H), 8.32 (d,
1H), 8.27 (d, 1H), 8.22 (s, 1H), 8.01-8.12 (m, 2H), 7.69 (m, 2H),
7.61 (m, 2H), 7.42 (m, 2H), 6.32 (d, 1H).
Example 82
N-(3-Fluoro-4-(3-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl-
)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00194##
[0670] Step A: Preparation of tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperazine-1-carboxylate: A 100 mL round-bottomed flask
was charged with
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (100.0 mg, 0.2040 mmol, prepared in Example 7, step B),
tert-butyl piperazine-1-carboxylate (114.0 mg, 0.6119 mmol),
copper(I)iodide (7.769 mg, 0.04079 mmol),
(S)-pyrrolidine-2-carboxylic acid (9.393 mg, 0.08159 mmol),
K.sub.2CO.sub.3 (140.9 mg, 1.020 mmol) and DMSO (10 mL). The
reaction mixture was stirred at 100.degree. C. for 4 hours. The
reaction was cooled to room temperature and partitioned between
EtOAc and H.sub.2O. The phases were separated and the aqueous phase
was re-extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
product. The crude material was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to
afford product (63.5 mg, 56.75%). LRMS (APCI pos) m/e 549
(M+1).
[0671] Step B: Preparation of tert-butyl
4-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbox-
amido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperazi-
ne-1-carboxylate: A 50 mL round-bottomed flask was charged with
tert-butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperazine-1-carboxylate (63.5 mg, 0.1157 mmol),
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(54.21 mg, 0.2315 mmol),
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (110.9 mg, 0.5787 mmol),
1H-benzo[d][1,2,3]triazol-1-ol (78.20 mg, 0.5787 mmol),
N-ethyl-N-isopropylpropan-2-amine (0.2066 ml, 1.157 mmol) and DMF
(10 mL). The reaction mixture was stirred at ambient temperature
overnight. The reaction was partitioned between EtOAc and H.sub.2O.
The phases were separated and the aqueous phase was re-extracted
with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
product. The crude product was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 100/1 to 10/1, v/v)
to afford product (56.8 mg, 64.17%). LRMS (APCI pos) m/e 765
(M+1).
[0672] Step C: Preparation of
N-(3-fluoro-4-(3-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pheny-
l)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide: A
50 mL round-bottomed flask was charged with tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperazi-
ne-1-carboxylate (56.8 mg, 0.0743 mmol) and CF.sub.3COOH (5 mL).
The reaction mixture was stirred at 60.degree. C. overnight. The
solvent was removed and the residue was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to
afford product (35.3 mg, 87.3%). LRMS (APCI pos): >99% purity,
254 nm, m/e 545 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
11.83 (s, 1H), 8.41 (d, 1H), 8.24 (m, 2H), 7.90 (dd, 1H), 7.60 (m,
2H), 7.41 (d, 1H), 7.24 (m, 3H), 6.21 (d, 1H), 3.46 (m, 4H), 3.04
(m, 4H).
Example 83
N-(3-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl-
oxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00195##
[0674] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazo-
lo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyrid-
azine-4-carboxamide: A 100 mL round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
(50.0 mg, 0.0708 mmol, prepared in Example 63, step A),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(44.2 mg, 0.212 mmol), Pd(OAc).sub.2 (3.18 mg, 0.0142 mmol),
tricyclohexylphosphine (5.95 mg, 0.0212 mmol), cesium fluoride
(96.8 mg, 0.637 mmol) and CH.sub.3CN (10 mL). The reaction mixture
was stirred at 100.degree. C. 1 hour. The reaction was cooled to
room temperature and partitioned between EtOAc and H.sub.2O. The
phases were separated and the aqueous phase was re-extracted with
EtOAc. The combined organic layers were dried (Na.sub.2SO.sub.4),
filtered and concentrated to yield a crude product. The crude
material was purified by silica gel chromatography (DCM/7 M
NH.sub.3 in MeOH from 100/1 to 10/1, v/v) to afford product (23.8
mg, 50.9%). LRMS (APCI pos): >95% purity, 254 nm, m/e 661
(M+1).
[0675] Step B: Preparation of
N-(3-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
A 50 mL round-bottomed flask was charged
N-(4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]-
pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyrid-
azine-4-carboxamide (23.8 mg, 0.0360 mmol) and CF.sub.3COOH (5 mL).
The reaction mixture was stirred at 60.degree. C. until LC-MS
showed that the starting material had been consumed (overnight).
The solvent was removed under reduced pressure and the residue was
purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 50/1 to 10/1, v/v) to give product (11.3 mg, 58%). LRMS (APCI
pos): >99% purity, 254 nm, m/e 541 (M+1). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.66 (s, 1H), 11.72 (s, 1H), 8.38 (d, 1H),
8.31 (d, 1H), 8.27 (d, 1H), 8.18 (s, 1H), 8.06 (dd, 1H), 7.96 (s,
1H), 7.69 (m, 2H), 7.60 (m, 2H), 7.42 (m, 2H), 6.31 (d, 1H), 3.89
(s, 3H).
Example 84
5-(3-fluoro-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyrid-
in-4-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one
##STR00196##
[0677] Step A: Preparation of
4-chloro-1H-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine: To a
solution of phosphoryl trichloride (3.227 ml, 35.26 mmol) in
dichloroethane (60 mL) was added
1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (3.00 g, 11.75
mmol; prepared according to the procedure of Example 1, Step B) as
a solid in one portion. The reaction was stirred under N.sub.2 at
reflux for 4 hours. The reaction mixture was cooled to ambient
temperature and then poured slowly onto ice water. Saturated
NaHCO.sub.3 was slowly added until the reaction mixture was neutral
by pH paper and then extracted with CH.sub.2Cl.sub.2 (added a small
amount of methanol to help resolve layers). The aqueous phase was
re-extracted with CH.sub.2Cl.sub.2. The combined organic layers
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to yield the crude product as a black oil. The crude
material was purified by flash column chromatography, eluting with
10:1 hexanes/EtOAc. The desired product (1.056 g, 47%) was obtained
as a white crystalline solid. LRMS (APCI pos) m/e 274, 276 (M+, Cl
pattern).
[0678] Step B: Preparation of 4-chloro-1H-pyrazolo[3,4-b]pyridine:
4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (1.506 g,
5.502 mmol) was dissolved in neat TFA (8.478 ml, 110.0 mmol) and
the reaction mixture was stirred at 75.degree. C. for 2 hours. The
reaction mixture was concentrated to a dark yellow oil and MeOH was
added to give a thick white precipitate that was filtered and
washed with MeOH. The filtrate, which contained the desired
product, was concentrated to a yellow oil that was dried in vacuo
overnight to yield a yellow waxy solid. The crude solid was
partitioned between EtOAc and saturated NaHCO.sub.3. The phases
were separated, and the aqueous layer was re-extracted with EtOAc
(1.times.). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and concentrated to yield the desired
product (0.845 g, 100%) as a yellow solid. LRMS (APCI pos) m/e 154,
156 (M+, Cl pattern).
[0679] Step C: Preparation of
4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine: To a solution of
4-chloro-1H-pyrazolo[3,4-b]pyridine (0.849 g, 5.53 mmol) in DMF (25
mL) was added potassium hydroxide flakes (0.931 g, 16.6 mmol)
followed by 12 (2.53 g, 9.95 mmol). The reaction mixture was
stirred at 50.degree. C. for 1.5 hours. The reaction mixture was
cooled to room temperature and then quenched with 10% aqueous
sodium bisulfite solution during which a precipitate formed. The
resulting suspension was diluted with H.sub.2O, filtered and washed
with H.sub.2O to yield a pale yellow solid. The solid was dissolved
with CH.sub.2Cl.sub.2/MeOH, concentrated, and dried in vacuo
overnight to yield the desired product (1.41 g, 91%) as a yellow
solid. LRMS (APCI pos) m/e 280, 282 (M+, Cl pattern).
[0680] Step D: Preparation of
4-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine: To
a solution of 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (1.31 g,
4.688 mmol) in DMF (40 mL) was added K.sub.2CO.sub.3 (1.30 g, 9.38
mmol) and 1-(chloromethyl)-4-methoxybenzene (0.766 ml, 5.63 mmol).
The reaction mixture was stirred at room temperature overnight to
yield two regioisomeric products is a 5.5:1 ratio by LC-MS. The
mixture was partitioned between EtOAc and H.sub.2O. The phases were
separated and the organic layer washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford a dark yellow
solid. The crude product was purified by flash column
chromatography, eluting with 3:1 hexanes/EtOAc and loaded with
10:1:1 CH.sub.2Cl.sub.2/MeOH/THF due to poor solubility. The
desired N1-regioisomeric product (1.256 g, 67%) was obtained as a
white crystalline solid. LRMS (APCI pos) m/e 400, 402 (M+, Cl
pattern). The undesired N2-regioisomer,
4-chloro-3-iodo-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-b]pyridine, was
not isolated.
[0681] Step E: Preparation of
5-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one: A mixture
of
5-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one
(0.009 g, 0.03 mmol, prepared in Example 45, step F),
4-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine
(0.010 g, 0.0250 mmol) and DMAP (0.006 g, 0.05 mmol) in
bromobenzene (0.300 mL) under N.sub.2 was stirred at 150.degree. C.
for 3 days. The reaction was concentrated in vacuo to remove as
much bromobenzene as possible and then purified directly by flash
column chromatography, eluting with 10:1 CH.sub.2Cl.sub.2/MeOH. The
desired product (0.013 g, 76%) was obtained as a yellow solid. LRMS
(APCI pos) m/e 675 (M+1).
[0682] Step F: Preparation of
5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(morpholine-4-carbonyl)phenyl)-1H-
-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin--
4(3H)-one: A suspension of
5-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.013 g,
0.019 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (0.005 g,
0.02 mmol), Pd(PPh.sub.3).sub.4 (0.001 g, 0.0009 mmol) and lithium
chloride (0.003 g, 0.08 mmol) in dioxane (0.5 mL) and 2 M aqueous
Na.sub.2CO.sub.3 (0.5 mL) was stirred at 100.degree. C. for 1 hour.
The reaction mixture was cooled to room temperature and then
partitioned between EtOAc and H.sub.2O. The layers were separated
and the aqueous layer was re-extracted with EtOAc. The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and
concentrated to yield 0.014 g crude product as a yellow gum. The
crude material was used without further purification in the
following step. LRMS (APCI pos) m/e 738 (M+1).
[0683] Step G: Preparation of
5-(3-fluoro-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyri-
din-4-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one: A
solution of
5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(morpholine-4-carbonyl)phenyl)-1H-
-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin--
4(3H)-one (0.014 g, 0.0190 mmol) in TFA (1 mL) was stirred at
60.degree. C. for 3.5 hours. The reaction mixture was concentrated
in vacuo to yield a crude yellow gum. The crude product was
purified by flash column chromatography, eluting with 10:1
CH.sub.2Cl.sub.2/MeOH. The isolated product was then partitioned
between EtOAc and saturated NaHCO.sub.3. The layers were separated
and the aqueous layer was re-extracted with EtOAc. The combined
EtOAc layers were dried over Na.sub.2SO.sub.4, filtered and
concentrated to yield the desired product (6.9 mg; 59%) as a yellow
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.03 (br s, 1H),
8.40 (d, 1H), 8.09 (s, 1H), 8.08 (m, 2H), 7.86 (dd, 1H), 7.66 (m,
1H), 7.57-7.48 (m, 5H), 7.38 (m, 2H), 7.16 (m, 1H), 6.41 (d, 1H),
3.60 (m, 8H), 3.58 (s, 3H). LRMS (APCI pos) m/e 618 (M+1).
Example 85
N-(3-fluoro-4-(3-o-tolyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fl-
uorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00197##
[0685] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-o-tolyl-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide-
: Prepared according to the procedure of Example 63, Step B,
substituting o-tolylboronic acid (15.4 mg, 0.113 mmol) for
4-(morpholine-4-carbonyl)phenylboronic acid. The desired product
isolated as yellow oil and was not purified further. Yield: 42 mg
at 70% purity, 77%. LRMS (APCI pos) m/e 671.2 (M+H).
[0686] Step B: Preparation of
N-(3-fluoro-4-(3-o-tolyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-f-
luorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide: Prepared
according to the procedure of Example 53, Step B, substituting
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-o-tolyl-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
(42 mg, 0.0438 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by silica gel column
chromatography (Biotage 12M) eluting with 2% MeOH/CHCl.sub.3 to
afford the desired product as yellow solid. Yield: 12.5 mg, 52%.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 13.87 (s, 1H), 11.66 (s,
1H), 8.37 (d, 1H), 8.25 (d, 1H), 7.96 (dd, 2H), 7.68 (q, 2H), 7.57
(d, 1H), 7.47 (d, 1H), 7.43-7.33 (m, 4H), 7.30 (d, 2H), 6.32 (d,
1H), 2.32 (s, 3H). LRMS (APCI pos) m/e 551.3 (M+H).
Example 86
N-(3-Fluoro-4-(3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylox-
y)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00198##
[0688] Step A: Preparation of
3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,-
4-b]pyridin-4-yloxy)aniline: A 100 mL round-bottomed flask was
charged with
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-f-
luorobenzenamine (100.0 mg, 0.2040 mmol, prepared in Example 7,
step B), 1-methylpiperazine (61.29 mg, 0.6119 mmol),
copper(I)iodide (11.65 mg, 0.06119 mmol),
(S)-pyrrolidine-2-carboxylic acid (7.045 mg, 0.06119 mmol),
K.sub.2CO.sub.3 (140.9 mg, 1.020 mmol) and DMSO (10 mL). The
reaction mixture, was stirred at 100.degree. C. for 8 hours. The
reaction was cooled to room temperature and partitioned between
EtOAc and H.sub.2O. The phases were separated and the aqueous phase
was re-extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
product. The crude product was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 100/1 to 10/1, v/v)
to afford product (36.8 mg, 39.01%). LRMS (APCI pos): >99%
purity, 254 nm, m/e 463 (M+1).
[0689] Step B: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-methylpiperazin-1-yl)-3-oxo-2,3-d-
ihydropyridazine-4-carboxamide: A 100 mL round-bottomed flask was
charged with
4-(1-(4-methoxybenzyl)-3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]-
pyridin-4-yloxy)-3-fluorobenzenamine (36.8 mg, 0.07956 mmol),
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(27.95 mg, 0.1193 mmol),
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (45.76 mg, 0.2387 mmol),
1H-benzo[d][1,2,3]triazol-1-ol (32.25 mg, 0.2387 mmol),
N-ethyl-N-isopropylpropan-2-amine (0.07102 ml, 0.3978 mmol) and DMF
(10 mL). The reaction mixture was stirred at room temperature until
LC-MS showed that the starting material had been consumed
(overnight). Then the reaction was partitioned between EtOAc and
H.sub.2O. The phases were separated and the aqueous phase was
re-extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude material
was purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 100/1 to 10/1, v/v) to afford product (33.2 mg, 61.48%). LRMS
(APCI neg): >95% purity, 254 nm, m/e 677 (M-1).
[0690] Step C: Preparation of
N-(3-fluoro-4-(3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
A 50 mL round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridaz-
ine-4-carboxamide (33.2 mg, 0.0489 mmol) and CF.sub.3COOH (5 mL).
The reaction mixture was stirred at 60.degree. C. until LC-MS
showed that the starting material had been consumed (overnight).
Then the solvent was removed and the residue was purified by silica
gel chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1,
v/v) to afford product (24.6 mg, 90%). LRMS (APCI pos): >99%
purity, 254 nm, m/e 559 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 11.85 (s, 1H), 10.33 (s, 1H), 8.42 (d, 1H), 8.25 (m, 2H),
7.97 (dd, 1H), 7.61 (m, 2H), 7.41 (d, 1H), 7.23-7.30 (m, 3H), 6.20
(d, 1H), 3.56 (m, 4H), 2.69 (m, 4H), 2.40 (s, 3H).
Example 87
4-benzyl-N-(3-fluoro-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,-
4-b]pyridin-4-yloxy)phenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide
##STR00199##
[0692] Step A: Preparation of methyl
4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylate: LiH (7.8 mg,
0.980 mmol) was added to the solution of methyl
3-oxo-3,4-dihydropyrazine-2-carboxylate (100 mg, 0.65 mmol) in DMF
(3 mL) at 0.degree. C. After 30 minutes stirring,
(chloromethyl)benzene (0.15 mL, 1.30 mmol) was added to the
reaction mixture at 0.degree. C., and then the reaction was warmed
to room temperature. After stirring for 4 hours, the reaction
mixture was quenched with ice water, extracted with EtOAc, washed
with brine, dried over MgSO.sub.4, and concentrated to give the
crude material that was purified by silica gel flash column
chromatography (2% MeOH in CH.sub.2Cl.sub.2) to afford 0.102 g
(64%) of the desired product.
[0693] Step B: Preparation of
4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylic acid: LiOH (0.82
mL, 0.82 mmol, 1.0 M in H.sub.2O) was added to a solution of methyl
4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylate (100 mg, 0.41
mmol) in a mixture of THF (4.5 mL) and MeOH (1.5 mL) at ambient
temperature for 4 hours. The reaction mixture was acidified to pH 1
with aqueous 1 N HCl solution and treated with water (5 mL),
extracted with EtOAc, washed with brine, dried over MgSO.sub.4, and
concentrated to afford 77 mg (82%) of the desired product.
[0694] Step C: Preparation of
(4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyr-
idin-3-yl)phenyl)(morpholino)methanone: A mixture of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (0.30 g, 0.612 mmol; prepared as in Example 7, Step B),
Cs.sub.2CO.sub.3 (0.299 g, 0.918 mmol), and
4-(morpholine-4-carbonyl)phenylboronic acid (0.151 g, 0.643 mmol)
in DME (3 mL) was degassed under nitrogen for 10 minutes and
tetrakistriphenylphosphinepalladium (0.035 g, 0.03 mmol) was added.
The reaction mixture was heated at 85.degree. C. for 15 hours. The
precipitate was removed by filtration with a mixture of EtOAc and
MeOH. The filtrate was concentrated and the crude material was
purified by silica gel flash column chromatography (1% MeOH in
CH.sub.2Cl.sub.2) to afford 39 mg (12%) of the desired product.
LRMS (APCI pos) m/e 554.1 (M+1).
[0695] Step D: Preparation of
4-benzyl-N-(3-fluoro-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)phenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide:
Prepared by a 2-step process from
(4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyr-
idin-3-yl)phenyl)(morpholino)methanone and
4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylic acid according to
the procedure described for Example 21 (Steps A and B). The crude
was rinsed with Et.sub.2O to afford 11 mg (45% for 2-step process)
of the desired product as the TFA salt. LRMS (ESI pos) m/e 646.4
(M+1). .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 8.35 (d, 1H), 8.12
(d, 2H), 8.03 (m, 2H), 7.76 (m, 1H), 7.53 (d, 2H), 7.33-7.45 (m,
7H), 6.42 (d, 1H), 5.34 (s, 2H), 3.60-3.80 (m, 8H); .sup.19F-NMR
(376 MHz, CD.sub.3OD) .delta. -129.8.
Example 88
N-(3-fluoro-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyrid-
in-4-yloxy)phenyl)-4-methyl-3-oxo-3,4-dihydropyrazine-2-carboxamide
##STR00200##
[0697] Prepared by 2-step process from
(4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyr-
idin-3-yl)phenyl)(morpholino)methanone (prepared as in Example 87,
Step C) and 4-methyl-3-oxo-3,4-dihydropyrazine-2-carboxylic acid
(prepared from methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate with
iodomethane, followed by hydrolysis using the methods described in
Example 87, steps A and B) according to the procedure of Example
21, Steps A and B. The crude was rinsed with Et.sub.2O to afford 7
mg (35% for 2-step process) of the desired product as the TFA salt.
LRMS (ESI pos) m/e 570.3 (M+1). .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. 8.37 (d, 1H), 8.12 (d, 2H), 8.05 (m, 2H), 7.76 (d, 1H),
7.54 (m, 3H), 7.38 (t, 1H), 6.44 (d, 1H), 3.75 (s, 3H), 3.60-3.80
(m, 8H); .sup.19F-NMR (376 MHz, CD.sub.3OD) .delta. -129.8.
Example 89
N-(3-fluoro-4-(3-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl-
oxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00201##
[0699] Step A: Preparation of tert-butyl
4-(4-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-car-
boxamido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pheny-
l)piperazine-1-carboxylate: Prepared according to the procedure of
Example 63, Step B, substituting
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenylboronic acid (34.67
mg, 0.1132 mmol) for 4-(morpholine-4-carbonyl)phenylboronic acid.
The crude material was purified by silica gel column chromatography
(Biotage 12M) eluting with 2% MeOH/CHCl.sub.3 to afford the desired
product. Yield: 50 mg at 85% purity, 89%. LRMS (APCI pos) m/e 785.2
(M-Boc tert-butyl).
[0700] Step B: Preparation of
N-(3-fluoro-4-(3-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting tert-butyl
4-(4-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-car-
boxamido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pheny-
l)piperazine-1-carboxylate (50 mg, 0.0595 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by trituration of crude
with DCM:ether to afford desired product as the di-TFA salt. Yield:
29 mg (54%) at 95% purity. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
13.8 (s, 1H), 11.71 (s, 1H), 8.68 (broad s, 1H), 8.39 (d, 1H), 8.34
(d, 1H), 8.27 (d, 1H), 8.05 (dd, 1H), 7.90 (d, 2H), 7.69 (q, 2H),
7.60-7.52 (m, 2H), 7.42 (t, 2H), 7.09 (d, 2H), 6.33 (d, 1H),
3.61-3.39 (broad m, 8H). LRMS (APCI pos) m/e 621.4 (M+H).
Example 90
5-(3-fluoro-4-(3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl-
)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one
##STR00202##
[0702] Step A: Preparation of
5-(3-fluoro-4-(3-(4-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one:
A suspension of
5-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.025 g,
0.0371 mmol; prepared according to the procedure of Example 86,
Step E), 4-fluorophenylboronic acid (0.006 g, 0.04 mmol),
Pd(PPh.sub.3).sub.4 (0.002 g, 0.002 mmol) and lithium chloride
(0.006 g, 0.15 mmol) in dioxane (1 mL) and 2 M aqueous
Na.sub.2CO.sub.3 (1 mL) was stirred at 110.degree. C. for 35
minutes and then at ambient temperature overnight. The reaction
mixture was partitioned between EtOAc and H.sub.2O. The layers were
separated and the aqueous layer was re-extracted with EtOAc. The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated to yield 0.031 g crude product as a yellow gum.
The crude material was used without further purification in the
following step. LRMS (APCI pos) m/e 643 (M+1).
[0703] Step B: Preparation of
5-(3-fluoro-4-(3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pheny-
l)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one.
5-(3-fluoro-4-(3-(4-fluorophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one
(0.024 g, 0.037 mmol) was dissolved in TFA (1 mL) and the reaction
mixture was stirred at 60.degree. C. for 3 hours and then at room
temperature overnight. The reaction mixture was concentrated in
vacuo and the residue was partitioned between EtOAc and saturated
NaHCO.sub.3. The layers were separated and the aqueous layer was
re-extracted with EtOAc (1.times.). The combined EtOAc layers were
dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude
product was purified by flash column chromatography, eluting with
10:1 CH.sub.2Cl.sub.2/MeOH. The product was obtained (15.2 mg; 78%)
as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
13.97 (br s, 1H), 9.02 (br s, 1H), 8.38 (d, 1H), 8.09 (s, 1H), 8.03
(m, 2H), 7.85 (dd, 1H), 7.69-7.48 (m, 4H), 7.38 (t, 2H), 7.32 (t,
2H), 7.17 (t, 1H), 6.38 (d, 1H), 3.58 (s, 3H). LRMS (APCI pos) m/e
523 (M+1).
Example 91
2-(cyclohexylmethyl)-5-(3-fluoro-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1H-
-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one
##STR00203##
[0705] Step A: Preparation of
5-bromo-2-(cyclohexylmethyl)-3-methylpyrimidin-4(3H)-one: A
solution of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.100 g,
0.448 mmol; prepared according to the procedure of Example 46, Step
B) and PdCl.sub.2(PPh.sub.3).sub.2 (0.016 g, 0.022 mmol) in THF
(2.5 mL) was sparged with N.sub.2, and then
(cyclohexylmethyl)zinc(II)bromide (0.904 ml, 0.452 mmol; 0.5 M
solution in THF) was added. The reaction mixture was stirred at
100.degree. C. for 1.5 hours. The reaction mixture was cooled to
room temperature and then partitioned between EtOAc and H.sub.2O.
The aqueous layer was re-extracted with EtOAc (1.times.). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated. The crude material was purified by flash column
chromatography, eluting with 10:1 CH.sub.2Cl.sub.2/EtOAc to afford
0.047 g (37%) of the product as a waxy yellow solid. LRMS (APCI
pos) m/e 285, 287 (M+, Br pattern).
[0706] Step B: Preparation of
5-(4-(benzyloxy)-3-fluorophenyl)-2-(cyclohexylmethyl)-3-methylpyrimidin-4-
(3H)-one: A suspension of
5-bromo-2-(cyclohexylmethyl)-3-methylpyrimidin-4(3H)-one (0.047 g,
0.165 mmol), 4-(benzyloxy)-3-fluorophenylboronic acid (0.049 g,
0.198 mmol), Pd(PPh.sub.3).sub.4 (0.009 g, 0.008 mmol) and lithium
chloride (0.028 g, 0.659 mmol) in dioxane (1 mL) and 2 M aqueous
Na.sub.2CO.sub.3 (1 mL) was stirred at 100.degree. C. for 1 hour.
The reaction mixture was cooled to room temperature and then
partitioned between EtOAc and H.sub.2O. The layers were separated
and the aqueous layer was re-extracted with EtOAc (1.times.). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated. The crude product was purified by flash column
chromatography, eluting with 10:1 CH.sub.2Cl.sub.2/EtOAc. The
product was obtained (0.048 g; 72%) as an off-white solid. LRMS
(APCI pos) m/e 407 (M+1).
[0707] Step C: Preparation of
2-(cyclohexylmethyl)-5-(3-fluoro-4-hydroxyphenyl)-3-methylpyrimidin-4(3H)-
-one: A solution of
5-(4-(benzyloxy)-3-fluorophenyl)-2-(cyclohexylmethyl)-3-methylpyrimidin-4-
(3H)-one (0.046 g, 0.11 mmol) in TFA (2 mL) was stirred at
40.degree. C. for 2.5 hours. The reaction mixture was cooled to
room temperature and concentrated to dryness. The crude product was
purified by flash column chromatography, eluting with 20:1
CH.sub.2Cl.sub.2/MeOH. The product was obtained (0.026 g; 73%) as a
white foamy solid. LRMS (APCI pos) m/e 317 (M+1).
[0708] Step D: Preparation of
2-(cyclohexylmethyl)-5-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one: A
mixture of
2-(cyclohexylmethyl)-5-(3-fluoro-4-hydroxyphenyl)-3-methylpyrimidin-4(3H)-
-one (0.026 g, 0.082 mmol),
4-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine
(0.033 g, 0.083 mmol; prepared according to the procedure of
Example 84, Step D), and DMAP (0.020 g, 0.165 mmol) in bromobenzene
(1 mL) under N.sub.2 was stirred at 150.degree. C. for 4 days. The
reaction was concentrated in vacuo to remove as much bromobenzene
as possible and then purified directly by flash column
chromatography, eluting with 20:1 CH.sub.2Cl.sub.2/MeOH. The
desired product (0.048 g, 86%) was obtained as a pale yellow solid.
LRMS (APCI pos) m/e 680 (M+1).
[0709] Step E: Preparation of
2-(cyclohexylmethyl)-5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(morpholine--
4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methylpyrim-
idin-4(3H)-one: A suspension of
2-(cyclohexylmethyl)-5-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one (0.025
g, 0.037 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (0.010
g, 0.044 mmol), Pd(PPh.sub.3).sub.4 (0.002 g, 0.002 mmol) and
lithium chloride (0.006 g, 0.147 mmol) in dioxane (1 mL) and 2 M
aqueous Na.sub.2CO.sub.3 (1 mL) was stirred at 100.degree. C. for
35 minutes and then at room temperature overnight. The reaction
mixture was partitioned between EtOAc and H.sub.2O. The layers were
separated and the aqueous layer was re-extracted with EtOAc
(1.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated to yield 0.027 g crude
product as a yellow gum. The crude material was used without
further purification in the following step. LRMS (APCI pos) m/e 743
(M+1).
[0710] Step F: Preparation of
2-(cyclohexylmethyl)-5-(3-fluoro-4-(3-(4-(morpholine-4-carbonyl)phenyl)-1-
H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one:
A solution of
2-(cyclohexylmethyl)-5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(morpholine--
4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methylpyrim-
idin-4(3H)-one (0.027 g, 0.0363 mmol) in TFA (1 mL) was stirred at
60.degree. C. for 3 minutes and then at ambient temperature
overnight. The reaction mixture was concentrated in vacuo and the
residue was partitioned between EtOAc and saturated NaHCO.sub.3.
The layers were separated and the aqueous layer was re-extracted
with EtOAc (1.times.). The combined EtOAc layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
purified by flash column chromatography, eluting with 10:1
CH.sub.2Cl.sub.2/MeOH. The product was obtained (17.3 mg; 76%) as a
yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.41 (d,
1H), 8.27 (s, 1H), 8.08 (d, 2H), 7.89 (m, 1H), 7.71 (m, 1H),
7.59-7.49 (m, 4H), 6.43 (d, 1H), 3.60 (m, 8H), 3.53 (s, 3H), 2.73
(d, 2H), 1.96 (m, 1H), 1.82-1.59 (m, 5H), 1.34-0.99 (m, 5H). LRMS
(APCI pos) m/e 623 (M+1).
Example 92
2-(4-fluorophenyl)-N-(2-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyrimi-
din-5-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00204##
[0712] Step A:
1-(4-methoxybenzyl)-3-methyl-4-(5-nitropyrimidin-2-yloxy)-1H-pyrazolo[3,4-
-b]pyridine: A 100 mL flask was charged with
1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (1.00
g, 3.71 mmol obtained from Example 5, step B),
2-chloro-5-nitropyrimidine (0.592 g, 3.71 mmol), cesium carbonate
(1.21 g, 3.71 mmol) and DMF (20 mL). The solution was allowed to
stir overnight at room temperature for 16.5 hours. The crude
product was isolated by filtration and flash chromatography
(EtOAc/Hexane 1:2) to afford 0.44 g (29%) of the desired product.
LRMS M+1 (393.0) observed.
[0713] Step B:
2-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyrimid-
in-5-amine: A 250 mL round-bottomed flask was charged with
1-(4-methoxybenzyl)-3-methyl-4-(5-nitropyrimidin-2-yloxy)-1H-pyrazolo[3,4-
-b]pyridine (0.420 g, 1.07 mmol), SnCl.sub.2 dihydrate (1.45 g,
6.42 mmol), and EtOH (100 mL). The reaction mixture was heated to
70.degree. C. under nitrogen for 2 hours, then concentrated in
vacuo. The residue was diluted with EtOAc, water, and brine.
Aqueous saturated Na.sub.2CO.sub.3 was added until the pH was in
the 9-10 range. The combined organic phases were dried
(Na.sub.2SO.sub.4). The product was isolated by filtration and
flash chromatography (EtOAc/MeOH 95:5) to afford 0.10 g (25%). LRMS
M+1 (363.0) observed.
[0714] Step C:
2-(4-fluorophenyl)-N-(2-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyrim-
idin-5-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide: Prepared by
2-step process (Example 19, Step D and Example 13 Step D) from
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(0.103 g, 0.442 mmol obtained from Example 19, step C), and
2-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pyrimid-
in-5-amine (0.04 g, 0.110 mmol). The crude material was purified by
preparative TLC (1.0 mm thickness, EtOAc) to afford 2.3 mg (9%) of
the desired product. LRMS M+1 (459.0) observed. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 11.88 (s, 1H), 9.04 (s, 2H), 8.51 (br s,
1H), 8.40 (m, 1H), 8.27 (m, 1H), 7.59 (m, 2H), 7.23 (m, 2H), 6.94
(m, 1H), 2.50 (s, 3H).
Example 93
N-(4-(3-(4-(Dimethylamino)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylox-
y)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbox-
amide
##STR00205##
[0716] Step A: Preparation of
1-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)-N,N-dimethylpiperidin-4-amine: A 100 mL round-bottomed
flask was charged with
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (50.0 mg, 0.102 mmol, prepared in Example 7, step B),
N,N-dimethylpiperidin-4-amine (39.2 mg, 0.306 mmol),
copper(I)iodide (3.88 mg, 0.0204 mmol),
(S)-pyrrolidine-2-carboxylic acid (4.70 mg, 0.0408 mmol),
K.sub.2CO.sub.3 (70.5 mg, 0.510 mmol) and DMF (10 mL). The reaction
mixture was stirred at 100.degree. C. overnight. Then the reaction
was cooled to room temperature and partitioned between EtOAc and
H.sub.2O. The phases were separated and the aqueous phase was
re-extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
product. The crude product was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to
afford product (35.8 mg, 71.6%). LRMS (APCI pos): >98% purity,
254 nm, m/e 491 (M+1).
[0717] Step B: Preparation of
N-(4-(3-(4-(dimethylamino)piperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihyd-
ropyridazine-4-carboxamide: A 100 mL round-bottomed flask was
charged with
1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)-N,N-dimethylpiperidin-4-amine (35.8 mg, 0.07298 mmol),
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(25.63 mg, 0.1095 mmol),
N1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diamine
hydrochloride (69.95 mg, 0.3649 mmol),
1H-benzo[d][1,2,3]triazol-1-ol (49.30 mg, 0.3649 mmol),
N-ethyl-N-isopropylpropan-2-amine (47.16 mg, 0.3649 mmol) and DMF
(5 mL). The reaction mixture was stirred at room temperature
overnight. Then the reaction was partitioned between EtOAc and
H.sub.2O. The phases were separated and the aqueous phase was
re-extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
product. The crude product was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 100/1 to 10/1, v/v)
to afford product (33.1 mg, 64.18%). LRMS (APCI pos): m/e 707
(M+1).
[0718] Step C: Preparation of
N-(4-(3-(4-(dimethylamino)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbo-
xamide: A 50 mL round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-(4-(dimethylamino)piperidin-1-yl)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihyd-
ropyridazine-4-carboxamide (33.1 mg, 0.0468 mmol) and CF.sub.3COOH
(5 mL). The reaction mixture was stirred at 80.degree. C.
overnight. Then the solvent was removed and the residue was
purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 50/1 to 10/1, v/v) to afford the product (18.3 mg, 66.6%).
LRMS (APCI pos): >99% purity, 254 nm, m/e 587 (M+1). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 11.83 (s, 1H), 10.80 (s, 1H), 8.42
(d, 1H), 8.28 (d, 1H), 8.24 (m, 1H), 7.98 (dd, 1H), 7.60 (m, 2H),
7.41 (d, 1H), 7.21-7.33 (m, 3H), 6.20 (d, 1H), 4.12 (m, 2H), 2.91
(m, 2H), 2.63 (m, 1H), 2.47 (s, 6H), 2.01 (m, 2H), 1.80 (m,
2H).
Example 94
N-(3-fluoro-4-(3-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl-
)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00206##
[0720] A 50 mL round-bottomed flask was charged with tert-butyl
4-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbox-
amido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidi-
ne-1-carboxylate (30.0 mg, 0.0393 mmol) (Example 105, step D) and
CF.sub.3COOH (5 mL). The reaction mixture was stirred at 80.degree.
C. overnight. Then the solvent was removed and the residue was
purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 50/1 to 10/1, v/v) to afford product (19.5 mg, 91.3%). LRMS
(APCI pos): >99% purity, 254 nm, m/e 544 (M+1). .sup.1H NMR (400
MHz, CDCl.sub.3+CD.sub.3OD, 50/50, v/v) .delta. 11.94 (s, 1H), 8.42
(m, 1H), 8.28 (m, 2H), 8.00 (m, 1H), 7.62 (m, 2H), 7.46 (m, 1H),
7.35 (m, 1H), 7.24-7.32 (m, 2H), 6.16 (d, 1H), 3.64 (m, 1H), 3.50
(m, 2H), 3.14 (m, 2H), 2.38 (m, 2H), 2.25 (m, 2H).
Example 95
N-benzyl-N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-
acetamide
##STR00207##
[0722] Step A: Preparation of
(E)-4-(benzylideneamino)-2-fluorophenol: To a stirred solution of
4-amino-2-fluorophenol (1.27 g, 10 mmol) in 30 mL of toluene at
room temperature under nitrogen in a Dean Stark apparatus was added
benzaldehyde (1.01 ml, 10 mmol) followed by p-toluenesulfonic acid
monohydrate (38 mg, 0.2 mmol). The mixture was heated to reflux for
4 hours. The reaction was cooled to room temperature and a solid
crystallized out of the reaction mixture. The mixture was cooled to
0.degree. C. and then filtered and the solids rinsed with toluene.
The isolated tan crystals were dried under high vacuum (1.5 gm, 70%
yield).
[0723] Step B: Preparation of
N-benzyl-N-(3-fluoro-4-hydroxyphenyl)acetamide: To a stirred
solution of (E)-4-(benzylideneamino)-2-fluorophenol (430 mg, 2
mmol) in 1 mL glacial acetic acid at 0.degree. C. under nitrogen
was added a solution of trimethylamine/borane complex (160 mg, 2.2
mmol) in 1 mL glacial acetic acid dropwise by syringe. After
complete addition, the reaction was allowed to warm to room
temperature and was then heated to reflux overnight. 6N NaOH was
then added until pH was neutral. The aqueous solution was extracted
with ether, and the combined ether extracts were dried
(MgSO.sub.4), filtered and concentrated. The material was loaded
onto a Biotage 40S column with dichloromethane and eluted with 4/1
hexanes/EtOAc to afford the product as a white solid (200 mg, 39%
yield).
[0724] Step C: Preparation of
N-benzyl-N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)phenyl)acetamide: To a stirred solution of
N-benzyl-N-(3-fluoro-4-hydroxyphenyl)acetamide (34 mg, 0.13 mmol)
and
1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine
(29 mg, 0.1 mmol) (prepared in Example 43, step E) in 400 .mu.L
bromobenzene in a capped reaction vial was added DMAP (25 mg, 0.20
mmol). The solution was heated to 150.degree. C. overnight. The
reaction was cooled to ambient temperature and loaded onto a
Biotage 12S column with dichloromethane and eluted with ethyl
acetate to provide the desired product as a tan solid (38 mg, 74%
yield).
[0725] Step D: Preparation of
N-benzyl-N-(3-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl-
)acetamide: To a flask containing
N-benzyl-N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)phenyl)acetamide (38 mg, 0.074 mmol) at ambient
temperature under a drying tube was added TFA (2 mL). The mixture
was heated to 50.degree. C. and stirred for 4 hours. The reaction
was cooled to ambient temperature and concentrated. The residue was
treated with 5 mL 10% sodium carbonate and then 5 mL
dichloromethane. The mixture was rapidly stirred and the layers
separated. The aqueous phase was extracted with dichloromethane and
the combined organic layers were dried (MgSO.sub.4), filtered, and
concentrated. The crude material was loaded onto a Biotage 12S
column with dichloromethane and eluted with 7/3 EtOAc/hexanes to
provide the desired product as a white foam (17 mg, 59% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.68 (br s, 1H), 8.35
(m, 1H), 7.31 (m, 3H), 7.23 (m, 3H), 6.93 (m, 2H), 6.16 (d, 1H),
4.93 (s, 2H), 2.73 (s, 3H), 2.00 (br s, 3H). LCMS (APCI+): m/z 391
(M+1) detected.
Example 96
N-(2,5-difluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-
-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00208##
[0727] Step A:
4-(2,5-difluoro-4-nitrophenoxy)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[-
3,4-b]pyridine: A 100 mL flask was charged with
1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (1.00
g, 3.71 mmol obtained from Example 5, step B),
1,2,4-trifluoro-5-nitrobenzene (1.32 g, 7.43 mmol), potassium
carbonate (1.03 g, 7.43 mmol), and DMF (25 mL). The solution was
allowed to stir overnight at room temperature for 3 days. The crude
material was isolated by filtration and flash chromatography
(EtOAc/Hexane 1:3) to afford 2.50 g (55%) of the desired product.
LRMS M+1 (426.9) observed.
[0728] Step B:
2,5-difluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)aniline: Prepared by process from Example 92 Step B using
1-(4-methoxybenzyl)-4-(2,5-difluoro-4-nitrophenoxy)-3-methyl-1H-pyrazolo[-
3,4-b]pyridine (2.50 g, 5.86 mmol). The crude material was purified
by silica gel chromotography (EtOAc/Hexane 1:2) to afford 0.75 g
(35%) of the desired product. LRMS M+1 (397.1) observed.
[0729] Step C:
N-(2,5-difluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(-
4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide: Charge a
100 mL round-bottomed flask with
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(0.103 g, 0.442 mmol obtained from Example 19, step C), and
CH.sub.2Cl.sub.2 (10 mL). Oxalyl chloride in DCM (2M) (2.84 ml,
5.68 mmol) and DMF (3 drops) were added. The reaction mixture was
stirred for 1 hour and concentrated. The crude material was
resuspend in DCM and
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2,5-di-
fluorobenzenamine (0.750 g, 1.89 mmol), N,N-dimethylpyridin-4-amine
(0.0231 g, 0.189 mmol) and triethylamine (0.287 g, 2.84 mmol) were
added. The reaction mixture was stirred at r ambient temperature
for 16 hours, then diluted with water and DCM. The organic layer
washed with brine, dried over sodium sulfate, filtered and
concentrated. The crude material was purified by chromatography,
eluting with EtOAc and concentrated. To the crude material in a 25
mL RBF was add TFA (3 mL). The mixture was heated to 70.degree. C.
for 2 hours, then cooled to ambient temperature and concentrated.
The residue was triturated with DCM/MeOH 1:1 (5 mL) to afford 461
mg (46%) of the desired product. LRMS M+1 (493.1) observed. .sup.1H
NMR (400 MHz, DMSOd6) .delta.12.14 (s, 1H), 8.54 (s, 1H), 8.43 (m,
1H), 8.36 (m, 1H), 8.30 (m, 1H), 7.77 (m, 1H), 7.68 (m, 2H), 7.42
(t, J=8 Hz, 2H), 6.35 (d, J=5 Hz, 1H), 2.62 (s, 3H).
Example 97
N-(2,3-difluoro-4-(3-methyl-1H-pyrazolo[34-b]pyridin-4-yloxy)phenyl)-2-(4--
fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00209##
[0731] Step A:
1-(4-methoxybenzyl)-4-(2,3-difluoro-4-nitrophenoxy)-3-methyl-1H-pyrazolo[-
3,4-b]pyridine: Prepared according to the procedure of Example 96,
substituting 1,2,3-trifluoro-4-nitrobenzene (1.51 g, 8.54 mmol) for
1,2,4-trifluoro-5-nitrobenzene to provide 2.24 g (67%) of the
desired product. LRMS M+1 (426.9) observed.
[0732] Step B:
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2,3-di-
fluorobenzenamine: Prepared by process of Example 92 Step B,
substituting
1-(4-methoxybenzyl)-4-(2,3-difluoro-4-nitrophenoxy)-3-methyl-1H-pyrazolo[-
3,4-b]pyridine (2.24 g, 5.25 mmol). The crude material was purified
by chromatography (EtOAc/Hexane 1:2) to afford 1.00 g (45%) as a
mixture of the desired product and the ortho SnAr product. The
crude material was in the next step without purification. LRMS M+1
(397.1) observed.
[0733] Step C:
N-(2,3-difluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(-
4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide: Prepared
by process of Example 9 Step C, substituting
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2,3-di-
fluorobenzenamine (15 mg, 0.0378 mmol). The crude material was
purified by preparative TLC (1.0 mm thickness, EtOAc/Hexane 3:1) to
afford 4.3 mg (20%) of the desired product. LRMS M+1 (493.3)
observed. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.14 (s, 1H),
8.54 (s, 1H), 8.43 (m, 1H), 8.36 (m, 1H), 8.30 (m, 1H), 7.68 (m,
2H), 7.42 (t, J=8 Hz, 2H), 7.15 (m, 1H), 6.35 (d, J=5 Hz, 1H), 2.62
(s, 3H).
Example 98
N-(4-(3-(4-(dimethylamino)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylox-
y)-3-fluorophenyl)-3-(4-fluorophenyl)-2-oxo-3-azabicyclo[3.1.0]hexane-1-ca-
rboxamide
##STR00210##
[0735] Step A: Preparation of N-allyl-4-fluorobenzenamine: A
suspension of 4-fluorobenzenamine (25 g, 225 mmol),
3-bromoprop-1-ene (19.0 ml, 225 mmol) and K.sub.2CO.sub.3 (31.1 g,
225 mmol) was stirred in THF (1 L) for 2 days. Water (20 mL) and
EtOAc (1 L) were added into the reaction mixture. The organic layer
was separated and washed with brine, dried with Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified by flash column
chromatography (20% EtOAc in hexane) to afford the product (16 g,
47.0% yield) as an orange oil.
[0736] Step B: Preparation of methyl
3-(allyl(4-fluorophenyl)amino)-3-oxopropanoate: Methyl
3-chloro-3-oxopropanoate (9.4 ml, 87 mmol) was added into a
solution of N-allyl-4-fluorobenzenamine (12 g, 79 mmol), DIEA (15
ml, 87 mmol) and DMAP (0.97 mg, 7.9 mmol) in CH.sub.2Cl.sub.2 (200
mL) at 0.degree. C. under nitrogen. The reaction was stirred at
0.degree. C. for 1 hour. The reaction mixture was poured into ice
and water, extracted with CH.sub.2Cl.sub.2, washed with saturated
aqueous NaHCO.sub.3 and brine. The organic layer was dried with
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash column chromatography (50% EtOAc in hexane) to
afford the product (18.3 g, 92% yield) as brown oil.
[0737] Step C: Preparation of methyl
3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylate:
A solution of methyl 3-(allyl(4-fluorophenyl)amino)-3-oxopropanoate
(10 g, 39.7 mmol) in acetic acid (50 mL) was added into a
suspension of manganese(III)acetate dihydrate (21 g, 79.7 mmol) and
copper (II) acetate monohydrate (7.9 g, 39.7 mmol) in acetic acid
(200 mL). The reaction was stirred for 3 days, then quenched with
10% aqueous sodium bisulfite solution (100 mL). The reaction
mixture was diluted with EtOAc, washed with saturated aqueous
NaHCO.sub.3, brine, dried with Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by flash column
chromatography (50% EtOAc in hexane) to afford the product (1.2 g,
12% yield) as a brown powder. LRMS (APCI pos) m/e 250.1 (M+1).
[0738] Step D: Preparation of
3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic
acid: LiOH (0.2 g, 8.4 mmol) was added into a suspension of methyl
3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylate
(1.2 g, 4.8 mmol) in THF (20 mL) and water (1 mL). The reaction was
stirred for 1 hour. The reaction mixture was poured into water and
the solution brought to pH 4 with 1M HCl. The mixture was extracted
with EtOAc, washed with brine, dry with Na.sub.2SO.sub.4, filtered
and concentrated to afford the title compound (1 g, 79% yield) as a
light brown solid. LRMS (APCI pos) m/e 235.9 (M+1).
[0739] Step E: Preparation of
N-(4-(3-(4-(dimethylamino)piperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2-oxo-3-azabicy-
clo[3.1.0]hexane-1-carboxamide: A solution of
1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)-N,N-dimethylpiperidin-4-amine (39 mg, 0.079 mmol,
obtained from Example 93, Step A),
3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic
acid (37 mg, 0.16 mmol), EDCI (91 mg, 0.48 mmol) and HOBT (64 mg,
0.48 mmol) was stirred in DMF (10 mL) for 12 hours. The reaction
mixture was poured into saturated aqueous NH.sub.4Cl and extracted
with EtOAc. The organic layer washed with NaHCO.sub.3, 10% aqueous
LiCl, dry with Na.sub.2SO.sub.4, filtered and concentrated. The
residue was purified with flash silica gel chromatography (5% MeOH
in CH.sub.2Cl.sub.2) to afford the product (30 mg, 53%) as a white
solid. LRMS (APCI pos) m/e 708.3 (M+1).
[0740] Step F: Preparation of
N-(4-(3-(4-(dimethylamino)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)-3-fluorophenyl)-3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1--
carboxamide: A solution of
N-(4-(1-(4-methoxybenzyl)-3-(4-(dimethylamino)piperidin-1-yl)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2-oxo-3-aza-bic-
yclo[3.1.0]hexane-1-carboxamide (30 mg, 0.042 mmol) was heated in
TFA (2 mL) for 4 hours. Excess TFA was evaporated and the residue
was purified on a SCX column (7N ammonia in MeOH) to afford the
product (17 mg, 68% yield) as a yellow solid. LRMS (APCI pos) m/e
588.2 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.50 (s,
1H), 9.80 (s, 1H), 8.30 (s, 1H), 7.78-7.90 (m, 1H), 7.40-7.60 (m,
2H), 7.00-7.40 (m, 4H), 6.10-6.20 (m, 1H), 4.00-4.20 (m, 4H),
3.70-3.80 (m, 1H), 2.80-3.00 (m, 4H), 2.40 (s, 6H), 1.20-2.10 (m,
5H).
Example 99
N-(3-fluoro-4-(3-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl-
)-3-(4-fluorophenyl)-2-oxo-3-azabicyclo[3.1.0]hexane-1-carboxamide
##STR00211##
[0742] Step A: Preparation of tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(3-(4-fluorophenyl)-2-oxo-3-aza-bicy-
clo[3.1.0]hexane-1-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)pip-
erazine-1-carboxylate: A solution of tert-butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperazine-1-carboxylate (100 mg, 0.182 mmol, obtained
from Example 82 Step A),
3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic
acid (85.7 mg, 0.365 mmol, obtained from Example 98 Step D), EDCI
(210 mg, 1.09 mmol) and HOBT (148 mg, 1.09 mmol) was stirred in DMF
(6 mL) for 12 hours. The reaction mixture was poured into saturated
aqueous NH.sub.4Cl and extracted with EtOAc. The organic layer was
washed with saturated aqueous NaHCO.sub.3, 10% aqueous LiCl, dry
with Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash silica gel chromatography (5% MeOH in
CH.sub.2Cl.sub.2) to afford the product (100 mg, 71.6% yield) as a
white solid. LRMS (APCI pos) m/e 766.2 (M+1).
[0743] Step B: Preparation of
N-(3-fluoro-4-(3-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)pheny-
l)-3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxamide:
A solution of tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(3-(4-fluorophenyl)-2-oxo-3-aza-bicy-
clo[3.1.0]hexane-1-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)pip-
erazine-1-carboxylate (100 mg, 0.131 mmol) was heated in TFA (4 mL)
for 12 hours. Excess TFA was removed and the residue was purified
by flash column chromatography (20% MeOH in CH.sub.2Cl.sub.2) to
afford the product
N-(3-fluoro-4-(3-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxami-
de (32 mg, 44.9% yield) as a yellow solid. LRMS (APCI pos) m/e
546.3 (M+1). .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.90 (s,
1H), 10.48 (s, 1H), 8.88 (s, br, 1H), 8.25 (d, 1H), 7.92 (d, 1H),
7.60-7.69 (m, 2H), 7.47-7.53 (m, 2H), 7.22-7.30 (m, 2H), 6.16-6.22
(d, 1H), 4.09-4.17 (m, 1H), 3.77-3.80 (m, 1H), 3.50-3.60 (m, 1H),
3.35-3.40 (m, 1H), 3.22-3.33 (m, 4H), 3.16-3.21 (m, 1H), 2.66-2.74
(m, 1H), 1.80-1.84 (m, 1H), 1.46-1.52 (m, 1H), 1.06-1.12 (m,
1H).
Example 100
N-(2-chloro-5-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-
-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00212##
[0745] Step A:
1-(4-methoxybenzyl)-4-(5-chloro-2-fluoro-4-nitrophenoxy)-3-methyl-1H-pyra-
zolo[3,4-b]pyridine: Made according to the procedure of Example 96,
Step A substituting 1-chloro-4,5-difluoro-2-nitrobenzene (0.791 g,
4.08 mmol made from US20040082784) for
1,2,4-trifluoro-5-nitrobenzene to provide the desired product
(1.59; 96%). LRMS M+1 (443.0) observed.
[0746] Step B:
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-chlo-
ro-5-fluorobenzenamine: Prepared by process from Example 92, Step
B, substituting
1-(4-methoxybenzyl)-4-(5-chloro-2-fluoro-4-nitrophenoxy)-3-methyl-1H-pyra-
zolo[3,4-b]pyridine (1.59 g, 3.59 mmol). The reaction mixture was
diluted with EtOAc (250 mL) and saturated Na.sub.2CO.sub.3 (50 mL)
was added. The solids were filtered through a celite plug and the
organic layer was dried over sodium sulfate and concentrated to
provide the desired product (1.25 g, 85%). The crude material was
used in the next step without purification. LRMS M+1 (413.0)
observed.
[0747] Step C:
N-(2,3-difluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(-
4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide: Prepared
by process from Example 9, Step C, substituting
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-chlo-
ro-5-fluorobenzenamine (0.500 g, 1.21 mmol). The crude material was
purified by reverse phase HPLC to afford 17.7 mg (3%). LRMS M+1
(508.9) observed. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 12.31
(s, 1H), 8.69 (d, J=12 Hz, 1H), 8.41 (m, 2H), 8.28 (d, J=5 Hz, 1H),
7.92 (d, J=8 Hz, 1H), 7.69 (m, 3H), 7.43 (t, J=8 Hz, 2H), 6.34 (d,
J=5 Hz, 1H), 2.62 (s, 3H)
Example 101
N-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-
-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamid-
e
##STR00213##
[0749] Step A: Preparation of
4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl-
)-1H-pyrazolo[3,4-b]pyridin-3-amine: A mixture of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (0.10 g, 0.20 mmol; prepared as in Example 7, Step B),
1-methylpiperidin-4-amine (0.070 g, 0.61 mmol),
(S)-pyrrolidine-2-carboxylic acid (9.4 mg, 0.82 mmol), CuI (7.8 mg,
0.041 mmol), and K.sub.2CO.sub.3 (0.14 g, 1.0 mmol) was heated in
DMSO (4 mL) with sealed tube at 100.degree. C. for 17 hours. The
reaction mixture was cooled to ambient temperature and treated with
CH.sub.2Cl.sub.2, washed with water, dried over MgSO.sub.4, and
concentrated to give crude material which was purified by silica
gel flash column chromatography (10% MeOH in CH.sub.2Cl.sub.2) to
afford 49 mg (50%) of the desired product. LRMS (ESI pos) m/e 477.1
(M+1).
[0750] Step B: Preparation of
N-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin--
4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxami-
de: Prepared by a 2-step process from
4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl-
)-1H-pyrazolo[3,4-b]pyridin-3-amine and
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(prepared as in Example 19, Step C) according to the procedure
described for Example 21, Steps A and B, except that the crude was
treated with aqueous NaHCO.sub.3). The crude was rinsed with
Et.sub.2O to afford 34 mg (96%) of the desired product. LRMS (ESI
pos) m/e 573.0 (M+1). .sup.1H-NMR (400 MHz, CDCl.sub.3/CD.sub.3OD)
.delta. 8.39 (d, 1H), 8.32 (d, 1H), 8.14 (d, 1H), 8.03 (dd, 1H),
7.66 (m, 2H), 7.48 (m, 1H), 7.39 (t, 1H), 7.28 (t, 2H), 6.12 (d,
1H), 3.76 (m, 1H), 3.25 (m, 2H), 2.51 (m, 2H), 2.46 (s, 3H), 2.25
(m, 2H), 1.73 (m, 2H); .sup.19F-NMR (376 MHz, CDCl3/CD3OD) .delta.
-113.8, -128.4.
Example 102
2-(benzo[d]oxazol-2-yl)-N-(4-(3-(4-(dimethylamino)piperidin-1-yl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)acetamide
##STR00214##
[0752] Prepared by a 2-step process from
1-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)-N,N-dimethylpiperidin-4-amine (prepared as in Example 93,
Step A) and 2-(benzo[d]oxazol-2-yl)acetic acid according to the
procedure of Example 21, Steps A and B, except that the crude was
treated with aqueous NaHCO.sub.3 solution to remove TFA. The crude
was rinsed with Et.sub.2O to afford 13 mg (80%) of the desired
product. LRMS (ESI pos) m/e 530.1 (M+1). .sup.1H-NMR (400 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. 8.20 (d, 1H), 7.86 (dd, 1H), 7.72
(m, 1H), 7.60 (m, 1H), 7.41 (m, 3H), 7.30 (t, 1H), 6.22 (d, 1H),
4.15 (m, 2H), 2.95 (t, 3H), 2.64 (s, 6H), 2.09 (m, 2H), 1.84 (m,
2H); .sup.19F-NMR (376 MHz, CD.sub.3OD/CDCl.sub.3) .delta.
-128.7.
Example 103
(S)--N-(4-(3-(3-(dimethylamino)pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin--
4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4--
carboxamide
##STR00215##
[0754] Step A: Preparation of
(S)-1-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]-
pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine: To a stirred solution
of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (49 mg, 0.1 mmol) (prepared in Example 7, step B) in
300 .mu.L DMSO at ambient temperature in a capped reaction vial was
added (S)--N,N-dimethylpyrrolidin-3-amine (19 uL, 0.15 mmol)
followed by K.sub.2CO.sub.3 (27 mg, 0.2 mmol), Cu(I)I (19 mg, 0.01
mmol) and L-proline (2.3 mg, 0.02 mmol). The mixture was heated
90.degree. C. overnight, then the mixture was cooled to room
temperature, diluted to 30 mL with dichloromethane and washed with
H.sub.2O. The organic layer was dried (MgSO.sub.4), filtered and
concentrated. The crude product was loaded onto a Biotage 12S
column with dichloromethane and eluted with 5/95
MeOH/dichloromethane to provide the product as a tan oil (9.5 mg,
20% yield).
[0755] Step B: Preparation of
(S)--N-(4-(3-(3-(dimethylamino)pyrrolidin-1-yl)-1-(4-methoxybenzyl)-1H-py-
razolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-
-dihydropyridazine-4-carboxamide: To a stirred suspension of
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(prepared in Example 19, step C) (7 mg, 0.03 mmol) in 300 .mu.L
dichloromethane at room temperature under nitrogen was added DIEA
(10 .mu.L, 0.06 mmol) followed by EDCI (5.7 mg, 0.03 mmol) and
HOBT-H.sub.2O (4.6 mg, 0.03 mmol). After stirring for 10 minutes, a
solution of
(S)-1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]-
pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine (9.5 mg, 0.02 mmol) in
300 .mu.L dichloromethane was added. After stirring overnight, the
reaction was diluted to 30 mL with CH.sub.2Cl.sub.2 and washed with
10% sodium carbonate solution. The organic layers were dried
(MgSO.sub.4), filtered and concentrated. The crude product was
loaded onto a Biotage 12S column with dichloromethane and eluted
with a step gradient of dichloromethane (150 mL), 2.5/97.5
MeOH/dichloromethane (150 mL) and 5/95 MeOH/dichloromethane (200
mL) to afford the desired product as a tan oil (14 mg, 100%).
[0756] Step C: Preparation of
(S)--N-(4-(3-(3-(dimethylamino)pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-
-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-
-carboxamide: To a flask containing
(S)--N-(4-(1-(4-methoxybenzyl)-3-(3-(dimethylamino)pyrrolidin-1-yl)-1H-py-
razolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-
-dihydropyridazine-4-carboxamide (14 mg, 0.02 mmol) at ambient
temperature under a drying tube was added TFA (1 mL), and the
reaction mixture was heated at 50.degree. C. overnight. After
cooling, the reaction was concentrated to dryness and then
redissolved in 5 mL dichloromethane, to which 5 mL of 10% sodium
carbonate was added. After stirring for a few minutes, the layers
were separated and the organics were washed with 10% sodium
carbonate. The organics were dried (MgSO.sub.4), filtered and
concentrated to a crude oil. Biotage 12S with step gradient of
dichloromethane (100 mL), 5/95 MeOH/dichloromethane (100 mL), and
9/1 dichloromethane/MeOH (200 mL) eluted the product. The product
containing fractions were pooled and concentrated to a yellow solid
(4.2 mg, 36%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.83 (br
s, 1H), 8.41 (d, 1H), 8.23 (m, 1H), 7.96 (m, 1H), 7.60 (m, 2H),
7.40 (m, 1H), 7.24 (m, 2H), 6.16 (d, 1H), 3.82 (m, 1H), 3.72 (m,
2H), 3.56 (m, 1H), 2.87 (m, 1H), 2.30 (s, 6H), 2.20 (m, 1H), 1.94
(m, 1H). LCMS (APCI+): m/z 573 (M+1) detected.
Example 104
(R)--N-(4-(3-(3-(dimethylamino)pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin--
4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4--
carboxamide
##STR00216##
[0758] Step A: Preparation of
(R)-1-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]-
pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine: To a stirred
suspension of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (49 mg, 0.1 mmol) (prepared according to Example 7,
step B) and (R)--N,N-dimethylpyrrolidin-3-amine (23 mg, 0.2 mmol)
in 300 .mu.L THF at ambient temperature in a capped reaction vial
was added racemic Binap (9 mg, 0.015 mmol) followed by NaOtBu (14
mg, 0.15 mmol) and 18-crown-6 (40 mg, 0.1499 mmol). The reaction
purged with nitrogen gas and then held under a balloon of nitrogen.
Pd(dba).sub.2 (6 mg, 0.01 mmol) was then added and the reaction was
sealed and heated to 40.degree. C. After stirring for 72 hours, the
reaction was cooled to ambient temperature, diluted to 30 mL with
dichloromethane and washed with 10% sodium carbonate solution. The
organics were dried (MgSO.sub.4), filtered and concentrated. The
brown residue was dissolved in a minimum of dichloromethane and
loaded onto a Biotage 12S column. The column was eluted with 95/5
dichloromethane/MeOH to provide the product as a tan foam (40 mg,
84%).
[0759] Step B: Preparation of
(R)--N-(4-(3-(3-(dimethylamino)pyrrolidin-1-yl)-1-(4-methoxybenzyl)-1H-py-
razolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-
-dihydropyridazine-4-carboxamide: Carried out according to the
procedure of Example 103, Step B, substituting
(R)-1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]-
pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine for
(S)-1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]-
pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine. The product was
isolated as a tan oil (36 mg, 99%).
[0760] Step C: Preparation of
(R)--N-(4-(3-(3-(dimethylamino)pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-
-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-
-carboxamide: Carried out according to the procedure of Example
103, Step C, substituting
(R)--N-(4-(3-(3-(dimethylamino)pyrrolidin-1-yl)-1-(4-methoxybenzyl)-1H-py-
razolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-
-dihydropyridazine-4-carboxamide for
(S)--N-(4-(3-(3-(dimethylamino)pyrrolidin-1-yl)-1-(4-methoxybenzyl)-1H-py-
razolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-
-dihydropyridazine-4-carboxamide. The crude material was purified
to provide the product as a yellow solid (11 mg, 37%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 11.83 (br s, 1H), 10.25 (br s, 1H),
8.43 (d, 1H), 8.24 (d, 1H), 8.22 (br s, 1H), 7.96 (m, 1H), 7.61 (m,
2H), 7.40 (d, 1H), 7.25 (m, 3H), 6.15 (d, 1H), 3.83 (m, 1H), 3.73
(m, 2H), 3.57 (m, 1H), 2.88 (m, 1H), 2.30 (s, 6H), 2.20 (m, 1H),
1.95 (m, 1H). LCMS (APCI+): m/z 573 (M+1) detected.
Example 105
N-(3-Fluoro-4-(3-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylox-
y)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00217##
[0762] Step A: Preparation of tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate: A 100 mL
round-bottomed flask was charged with
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (250.0 mg, 0.5099 mmol, prepared in Example 7, step B),
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (315.3 mg, 1.020 mmol),
tetrakis(triphenylphosphine)palladium (117.8 mg, 0.1020 mmol), 1M
Na.sub.2CO.sub.3 (1.275 ml, 2.550 mmol) and DME (25 mL). The
reaction mixture was stirred at 100.degree. C. overnight. The
reaction was cooled to room temperature and partitioned between
EtOAc and H.sub.2O. The phases were separated and the aqueous phase
was re-extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
product. The crude material was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 100/1 to 10/1, v/v)
to afford product (273.3 mg, 98%). LRMS (APCI pos): >99% purity,
254 nm, m/e 546 (M+1).
[0763] Step B: Preparation of tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperidine-1-carboxylate: A 100 mL round-bottomed flask
was charged with tert-butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.248 g, 0.455
mmol), 4-methylbenzenesulfonohydrazide (0.0846 g, 0.455 mmol) and
toluene (10 mL). The reaction mixture was stirred at 100.degree. C.
for 4 days. The reaction was cooled to ambient temperature and
partitioned between EtOAc and H.sub.2O. The phases were separated
and the aqueous phase was re-extracted with EtOAc. The combined
organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude material was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 100/1 to 10/1, v/v)
to afford the product (84.3 mg, 33.9%). LRMS (APCI pos): >96%
purity, 254 nm, m/e 548 (M+1).
[0764] Step C: Preparation of tert-butyl
4-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbox-
amido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidi-
ne-1-carboxylate: A round-bottomed flask was charged with
tert-butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperidine-1-carboxylate (84.3 mg, 0.1539 mmol),
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(108.1 mg, 0.4618 mmol, prepared according to Example 19, step C),
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (147.6 mg, 0.7697 mmol),
1H-benzo[d][1,2,3]triazol-1-ol (104.0 mg, 0.7697 mmol),
N-ethyl-N-isopropylpropan-2-amine (199.0 mg, 1.539 mmol) and DMF
(10 mL). The reaction mixture was stirred at room temperature
overnight. The reaction was partitioned between EtOAc and H.sub.2O.
The phases were separated and the aqueous phase was re-extracted
with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
product. The crude product was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to
afford the desired product (108.3 mg, 92.11%). LRMS (APCI pos): m/e
664 (M-99).
[0765] Step D: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(piperidin-4-yl)-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-ca-
rboxamide: A round-bottomed flask was charged with tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidi-
ne-1-carboxylate (74.3 mg, 0.0973 mmol), 2,2,2-trifluoroacetic acid
(111 mg, 0.973 mmol) and CH.sub.2Cl.sub.2 (10 mL). The reaction
mixture was stirred at ambient temperature 1 hour. The solvent was
removed and the residue was purified by silica gel chromatography
(DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to afford product
(58.8 mg, 91.1%). LRMS (APCI pos): >99% purity, 254 nm, m/e 664
(M+1).
[0766] Step E: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-yl)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridaz-
ine-4-carboxamide: A round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-ca-
rboxamide (20.0 mg, 0.0301 mmol), formaldehyde (0.905 mg, 0.0301
mmol), sodium triacetoxyborohydride (6.39 mg, 0.0301 mmol) and
CH.sub.2Cl.sub.2 (10 mL). The reaction mixture was stirred at
ambient temperature for 2 days. Then the reaction was partitioned
between EtOAc and H.sub.2O. The phases were separated and the
aqueous phase was re-extracted with EtOAc. The combined organic
layers were dried (Na.sub.2SO.sub.4), filtered and concentrated to
yield a crude product. The crude product was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 100/1 to 10/1, v/v)
to afford product (16.3 mg, 79.8%). LRMS (APCI pos): >99%
purity, 254 nm, m/e 678 (M+1).
[0767] Step F: Preparation of
N-(3-fluoro-4-(3-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
A 50 mL round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridaz-
ine-4-carboxamide (16.3 mg, 0.0241 mmol) and CF.sub.3COOH (5 mL).
The reaction mixture was stirred at 80.degree. C. overnight. The
solvent was removed and the residue was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to
afford product, which was further purified by preparative HPLC to
afford the desired product (3.2 mg, 16.9%). LRMS (APCI pos):
>99% purity, 254 nm, m/e 558 (M+1). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 11.94 (s, 1H), 8.24-8.36 (m, 3H), 8.03 (dd,
1H), 7.65 (m, 2H), 7.49 (m, 1H), 7.41 (m, 1H), 7.22-7.30 (m, 2H),
6.31 (d, 1H), 3.62 (m, 2H), 3.45 (m, 1H), 3.14-3.26 (m, 2H), 2.87
(s, 3H), 2.39-2.58 (m, 2H), 2.14-2.32 (m, 2H).
Example 106
N-(3-Fluoro-4-(3-(hexahydropyrrolo[34-c]pyrrol-2(1H)-yl)-1H-pyrazolo[3,4-b-
]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4--
carboxamide
##STR00218##
[0769] Step A: Preparation of tert-butyl
5-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: A 100 mL
round-bottomed flask was charged with
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (100 mg, 0.204 mmol, prepared in Example 7, step B),
tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (217
mg, 1.02 mmol), copper(I)iodide (15.5 mg, 0.0816 mmol),
(S)-pyrrolidine-2-carboxylic acid (18.8 mg, 0.163 mmol),
K.sub.2CO.sub.3 (141 mg, 1.02 mmol) and DMSO (10 mL). The reaction
mixture was stirred at 100.degree. C. overnight. The reaction was
cooled to ambient temperature and partitioned between EtOAc and
H.sub.2O. The phases were separated and the aqueous phase was
re-extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude product
was purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 50/1 to 10/1, v/v) to afford the desired product (44.8 mg,
38.2%). LRMS (APCI pos): m/e 575 (M+1).
[0770] Step B: Preparation of tert-butyl
5-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbox-
amido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)hexahydr-
opyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: A round-bottomed flask
was charged with tert-butyl
5-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (44.8
mg, 0.0780 mmol),
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(54.8 mg, 0.234 mmol),
N1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diamine
hydrochloride (74.7 mg, 0.390 mmol), 1H-benzo[d][1,2,3]triazol-1-ol
(52.7 mg, 0.390 mmol), N-ethyl-N-isopropylpropan-2-amine (101 mg,
0.780 mmol) and DMF (10 mL). The reaction mixture was stirred at
ambient temperature overnight. The reaction was partitioned between
EtOAc and H.sub.2O. The phases were separated and the aqueous phase
was re-extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude material
was purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 50/1 to 10/1, v/v) to afford product (42.5 mg, 68.9%). LRMS
(APCI pos): m/e 691 (M-99).
[0771] Step C: Preparation of
N-(3-fluoro-4-(3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(4-methoxyben-
zyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,-
3-dihydropyridazine-4-carboxamide: A round-bottomed flask was
charged with tert-butyl
5-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-hexahyd-
ropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (42.5 mg, 0.0537 mmol),
2,2,2-trifluoroacetic acid (123 mg, 1.07 mmol) and CH.sub.2Cl.sub.2
(10 mL). The reaction mixture was stirred at ambient temperature
for 4 hours. The solvent was removed and the residue was purified
by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to
10/1, v/v) to give product (13.8 mg, 37.2%). LRMS (APCI neg): m/e
690 (M).
[0772] Step D: Preparation of
N-(3-fluoro-4-(3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1H-pyrazolo[3,4-
-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine--
4-carboxamide: A round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1H-p-
yrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,-
3-dihydropyridazine-4-carboxamide (13.8 mg, 0.0200 mmol) and
CF.sub.3COOH (5 mL). The reaction mixture was stirred at 80.degree.
C. overnight. The solvent was removed and the residue was purified
by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to
10/1, v/v) to give product, which was further purified by
preparative HPLC to afford the desired product (2.1 mg, 13.2%).
LRMS (APCI pos): >99% purity, 254 nm, m/e 571 (M+1). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 11.92 (s, 1H), 8.34 (d, 1H), 8.29 (d,
1H), 8.21 (d, 1H), 8.03 (d, 1H), 7.65 (m, 2H), 7.48 (d, 1H), 7.41
(m, 1H), 7.26 (m, 2H), 6.26 (d, 1H), 3.74 (d, 2H), 3.57 (m, 2H),
3.08-3.38 (m, 6H).
Example 107
N-(4-(3-(1,4-Diazepan-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophe-
nyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00219##
[0774] Step A: Preparation of tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)-1,4-diazepane-1-carboxylate: A round-bottomed flask was
charged with
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-f-
luorobenzenamine (100.0 mg, 0.2040 mmol, prepared according to
Example 7, step B), tert-butyl 1,4-diazepane-1-carboxylate (204.3
mg, 1.020 mmol), copper(I)iodide (15.54 mg, 0.08159 mmol),
(S)-pyrrolidine-2-carboxylic acid (18.79 mg, 0.1632 mmol),
K.sub.2CO.sub.3 (140.9 mg, 1.020 mmol) and DMSO (10 mL). The
reaction mixture was stirred at 100.degree. C. overnight. The
reaction was partitioned between EtOAc and H.sub.2O. The phases
were separated and the aqueous phase was re-extracted with EtOAc.
The combined organic layers were dried (Na.sub.2SO.sub.4), filtered
and concentrated to yield a crude product. The crude product was
purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 50/1 to 10/1, v/v) to afford product (110.4 mg, 96.2%). LRMS
(APCI pos): m/e 563 (M+1).
[0775] Step B: Preparation of tert-butyl
4-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbox-
amido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1,4-dia-
zepane-1-carboxylate: A 100 mL round-bottomed flask was charged
with tert-butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)-1,4-diazepane-1-carboxylate (110.4 mg, 0.1962 mmol),
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(137.9 mg, 0.5887 mmol, prepared according to Example 19, step C),
N1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diamine
hydrochloride (188.1 mg, 0.9811 mmol),
1H-benzo[d][1,2,3]triazol-1-ol (132.6 mg, 0.9811 mmol),
N-ethyl-N-isopropylpropan-2-amine (253.6 mg, 1.962 mmol) and DMSO
(25 mL). The reaction mixture was stirred at room temperature
overnight. The reaction was partitioned between EtOAc and H.sub.2O.
The phases were separated and the aqueous phase was re-extracted
with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude material
was purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 100/1 to 10/1, v/v) to afford product (118.3 mg, 77.4%). LRMS
(APCI pos): m/e 679 (M-99).
[0776] Step C: Preparation of
N-(4-(3-(1,4-diazepan-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-
-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-
-carboxamide: A round-bottomed flask was charged with tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1,4-dia-
zepane-1-carboxylate (118.3 mg, 0.1519 mmol), 2,2,2-trifluoroacetic
acid (346.4 mg, 3.038 mmol) and CH.sub.2Cl.sub.2 (10 mL). The
reaction mixture was stirred at room temperature for one hour. The
solvent was removed and the residue was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to
give product (60.7 mg, 58.88%). LRMS (APCI pos): m/e 679 (M+1).
[0777] Step D: Preparation of
N-(4-(3-(1,4-diazepan-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoroph-
enyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
A 100 mL round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-(1,4-diazepan-1-yl)-1H-pyrazolo[3,4-b]pyridin-
-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-
-carboxamide (60.7 mg, 0.0894 mmol) and CF.sub.3COOH (5 mL). The
reaction mixture was stirred at 80.degree. C. overnight. The
solvent was removed and the residue was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to
afford product, which was further purified by preparative HPLC to
afford the product (0.9 mg, 1.28%). LRMS (APCI pos): >99%
purity, 254 nm, m/e 559 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.34 (m, 2H), 8.22 (d, 1H), 8.07 (d, 1H), 7.67 (m, 2H),
7.52 (d, 1H), 7.43 (t, 1H), 7.30 (m, 2H), 6.27 (d, 1H), 3.91 (m,
2H), 3.75 (m, 2H), 3.48 (m, 2H), 3.39 (m, 2H), 2.23 (m, 2H).
Example 108
N-(4-(3-(3-(dimethylamino)propylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)--
3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxami-
de
##STR00220##
[0779] Step A: Preparation of
N1-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyr-
idin-3-yl)-N3,N3-dimethylpropane-1,3-diamine: Prepared according to
the procedure of Example 82, Step A, substituting
N,N-dimethyl-1,3-propanediamine (0.13 ml, 1.02 mmol) for tert-butyl
piperazine-1-carboxylate. Purified by silica gel column
chromatography (Biotage 25S) eluting with 5-10% MeOH/CHCl.sub.3 to
afford the desired product as opaque oil. Yield: 62 mg, 65%. LRMS
(APCI pos) m/e 465.2 (M+H).
[0780] Step B: Preparation of
N-(4-(3-(3-(dimethylamino)propylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,-
4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydrop-
yridazine-4-carboxamide: Prepared according to the procedure of
Example 82, Step B, substituting
N1-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyr-
idin-3-yl)-N3,N3-dimethylpropane-1,3-diamine (60 mg, 0.129 mmol)
for tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperazine-1-carboxylate. The crude material was purified
by silica gel column chromatography (Biotage 25S) eluting with 5-7%
MeOH/CH.sub.2Cl.sub.2 to afford the desired product as yellow oil.
Yield: 55 mg at 90% purity, 56%. LRMS (APCI pos) m/e 681.2
(M+H).
[0781] Step C: Preparation of
N-(4-(3-(3-(dimethylamino)propylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-
-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxam-
ide: Prepared according to the procedure of Example 53, Step B,
substituting
N-(4-(3-(3-(dimethylamino)propylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,-
4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydrop-
yridazine-4-carboxamide (55 mg, 0.0808 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by silica gel column
chromatography (Biotage 12M) eluting with 5-10%
MeOH/CH.sub.2Cl.sub.2 to afford desired product as the di-TFA salt.
Yield 17.5 mg, 27%. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.23
(s, 1H), 11.7 (s, 1H), 9.35 (broad s, 1H), 8.39 (d, 1H), 8.26 (d,
1H), 8.15 (d, 1H), 8.04 (d, 1H), 7.68 (q, 2H), 7.61 (d, 1H), 7.49
(t, 1H), 7.42 (t, 2H), 6.04 (d, 1H), 5.87 (broad s, 2H), 3.14
(broad m, 2H), 2.79 (s, 6H), 2.01 (m, 2H). LRMS (APCI pos) m/e
561.2 (M+H).
Example 109
N-(3-fluoro-4-(3-(1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyri-
dazine-4-carboxamide
##STR00221##
[0783] Step A: Preparation of
3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methylhexahydropyrrolo[3,4-b]pyrrol--
5(1H)-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline: Prepared
according to the procedure of Example 82, Step A, substituting
1-methyl-octahydropyrrolo[3,4-b]pyrrole (129 mg, 1.02 mmol) for
tert-butyl piperazine-1-carboxylate. The crude material was
purified by silica gel column chromatography (Biotage 25S) eluting
with 5-10% MeOH/CHCl.sub.3 to afford the desired product as opaque
oil. Yield: 35 mg, 35%. LRMS (APCI pos) m/e 489.2 (M+H).
[0784] Step B: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methylhexahydropyrrolo[3,4-b]pyrr-
ol-5(1H)-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)--
3-oxo-2,3-dihydropyridazine-4-carboxamide: Prepared according to
the procedure of Example 82, Step B, substituting
3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methylhexahydropyrrolo[3,4-b]pyrrol--
5(1H)-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (35 mg, 0.072
mmol) for tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperazine-1-carboxylate. The crude material was purified
by silica gel column chromatography (Biotage 25S) eluting with 5-7%
MeOH/CH.sub.2Cl.sub.2 to afford the desired product. Yield: 22 mg,
44%. LRMS (APCI pos) m/e 705.3 (M+H).
[0785] Step C: Preparation of
N-(3-fluoro-4-(3-(1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-1H-pyra-
zolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyr-
idazine-4-carboxamide: Prepared according to the procedure of
Example 53, Step B, substituting
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methylhexahydropyrrolo[3,4-b]pyrr-
ol-5(1H)-yl)-1H-[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,-
3-dihydropyridazine-4-carboxamide (22 mg, 0.0312 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by silica gel column
chromatography (Biotage 12M) eluting with 2% MeOH/CH.sub.2Cl.sub.2
to afford desired product as 2TFA salt. Yield 14 mg, 55%. LRMS
(APCI pos) m/e 585.3 (M+H).
Example 110
N-(3-fluoro-4-(3-(piperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)p-
henyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00222##
[0787] Prepared by a 2-step process from tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-ylamino)piperidine-1-carboxylate (prepared as described in
Example 101, Step A, using tert-butyl
4-aminopiperidine-1-carboxylate) and
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
according to the procedure of Example 101, Step B. The crude
material was purified by silica gel flash column chromatography
(60% MeOH in CH.sub.2Cl.sub.2) to afford 19 mg (34%) of the desired
product. LRMS (ESI pos) m/e 559.1 (M+1). .sup.1H-NMR (400 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. 8.41 (d, 1H), 8.33 (d, 1H), 8.14 (d,
1H), 8.02 (dd, 1H), 7.65 (m, 2H), 7.47 (d, 1H), 7.37 (t, 1H), 7.28
(t, 2H), 6.12 (d, 1H), 3.80 (m, 1H), 3.16 (d, 2H), 2.79 (t, 2H),
2.24 (d, 2H), 1.53 (m, 2H); .sup.19F NMR (376 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. -113.1, -127.7.
Example 111
Preparation of
.+-.N-(3-fluoro-4-(3-((3R*,7S*)-hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)--
yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-
-dihydropyridazine-4-carboxamide
##STR00223##
[0789] Step A: Preparation of tert-butyl
1H-pyrrolo[3,2-c]pyridine-1-carboxylate: To a stirred mixture of
1H-pyrrolo[3,2-c]pyridine (2.3 g, 20 mmol) and
N,N-dimethylpyridin-4-amine (2.4 g, 20 mmol) in CH.sub.3CN (20 mL)
was added Boc-anhydride (3.9 g, 18 mmol). The mixture was stirred
for 18 hours at ambient temperature. The reaction was concentrated
in vacuo, and then purified by Biotage Flash 40S, eluting with 1:1
EtOAc/hexanes. The product was obtained as a colorless oil (4.0 g,
101%).
[0790] Step B: Preparation of .+-.(3R*,7S*)-tert-butyl
octahydropyrrolo[3,2-c]pyridine-1-carboxylate: A mixture of
tert-butyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate (0.22 g, 1.0
mmol), EtOH (10 mL), and acetic acid (5 mL) was purged with
N.sub.2, and then Adam's catalyst PtO.sub.2 (69 mg, 0.30 mmol) was
added. The reaction was shaken in a Parr apparatus under 50 psi
H.sub.2 for 3 days at ambient temperature. The mixture was filtered
through a pad of celite, washing with DCM. The filtrate was
concentrated in vacuo, then resuspended in DCM (10 mL) and basified
with saturated aqueous Na.sub.2CO.sub.3 (10 mL). The phases were
separated, and the aqueous phase was re-extracted with DCM. The
combined organic phases were dried (Na.sub.2SO.sub.4), filtered,
and concentrated. The crude was purified by preparative TLC (2 mm
thickness, Rf=0.31), eluting with 10% MeOH (containing 7N NH.sub.3)
in DCM. Yield: 95 mg (42%).
[0791] Step C: Preparation of .+-.(3R*,7S*)-tert-butyl
5-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-octahyd-
ropyrrolo[3,2-c]pyridine-1-carboxylate: A mixture of
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
(0.0706 g, 0.10 mmol, prepared according to Example 63, Step A),
.+-.(3R*,7S*)-tert-butyl
octahydropyrrolo[3,2-c]pyridine-1-carboxylate (0.0951 g, 0.420
mmol), copper(I)iodide (0.00381 g, 0.0200 mmol),
(S)-pyrrolidine-2-carboxylic acid (0.00461 g, 0.0400 mmol),
K.sub.2CO.sub.3 (0.0691 g, 0.500 mmol), and DMSO (10 mL) was
stirred at 100.degree. C. for 18 hours in a sealed vessel. The
reaction was cooled to ambient temperature, water (25 mL) was
added, and the aqueous phase was extracted with EtOAc. The combined
organic layers were dried over (Na.sub.2SO.sub.4), concentrated and
purified by preparative TLC (Rf=0.28, 1 mm thickness), eluting with
1:1 EtOAc/hexanes. The product was obtained as a waxy solid (8 mg,
9%).
[0792] Step D: Preparation of
.+-.N-(3-fluoro-4-(3-((3R*,7S*)-hexahydro-1H-pyrrolo[3,2-c]pyridin-5(6H)--
yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-
-dihydropyridazine-4-carboxamide: A mixture of
.+-.(3R*,7S*)-tert-butyl
5-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-octahyd-
ropyrrolo[3,2-c]pyridine-1-carboxylate (8 mg, 0.00994 mmol), and
2,2,2-trifluoroacetic acid (0.498 ml, 6.46 mmol) was heated to
80.degree. C. in a sealed vessel for 6 hours. After cooling to
ambient temperature, the reaction was concentrated in vacuo, using
toluene to azeotrope residual TFA (2.times.5 mL). The resulting
residue was dissolved in DCM, and purified by preparative TLC (0.5
mm thickness, Rf=0.03), eluting with 10% MeOH (containing 7N
NH.sub.3) in CHCl.sub.3. The product was obtained as a pale yellow
powder (4.5 mg, 73%). HPLC: 94% purity (220 nm); LRMS (ESI+): 100%
purity, 220 nm, m/z 585 (M+1) detected; .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.35 (d, J=4 Hz, 1H), 8.30 (d, J=4 Hz, 1H),
8.22 (d, J=5 Hz, 1H), 8.06 (m, 1H), 7.68 (m, 2H), 7.51 (m, 1H),
7.41 (t, J=9 Hz, 1H), 7.29 (t, J=9 Hz, 2H), 6.27 (d, J=5 Hz, 1H),
3.78 (m, 3H), 3.48 (m, 1H), 3.36 (m, 2H), 3.17 (m, 1H), 2.60 (m,
1H), 2.37 (m, 1H), 2.01 (m, 3H).
Example 112
.+-.N-(3-fluoro-4-(3-((3
S*,7S*)-octahydropyrrolo[2,3-c]pyridin-6-yl)-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00224##
[0794] Step A: Preparation of tert-butyl
1H-pyrrolo[2,3-c]pyridine-1-carboxylate: Prepared from
1H-pyrrolo[2,3-c]pyridine (2.3 g, 20 mmol) using the same procedure
described for Example 111, Step A. The product was obtained as a
colorless oil (4.0 g, 101%).
[0795] Step B: Preparation of .+-.(3R*,7S*)-tert-butyl
octahydropyrrolo[2,3-c]pyridine-1-carboxylate: Prepared from
tert-butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.218 g, 1.0
mmol) using the same procedure as described for Example 111, Step
B. Yield: 91 mg (40%).
[0796] Step C: Preparation of .+-.(3R*,7S*)-tert-butyl
6-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-octahyd-
ropyrrolo[2,3-c]pyridine-1-carboxylate: Prepared from
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
(0.0706 g, 0.10 mmol) and .+-.(3R*,7S*)-tert-butyl
octahydropyrrolo[2,3-c]pyridine-1-carboxylate (0.0905 g, 0.400
mmol) according to the procedure described for Example 111, Step C.
The product was obtained as a waxy solid (14 mg, 17%).
[0797] Step D: Preparation of
.+-.N-(3-fluoro-4-(3-((3S*,7S*)-octahydropyrrolo[2,3-c]pyridin-6-yl)-1H-p-
yrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydro-
pyridazine-4-carboxamide: Prepared .+-.(3R*,7S*)-tert-butyl
6-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-octahyd-
ropyrrolo[2,3-c]pyridine-1-carboxylate (14 mg, 0.0174 mmol)
according to the procedure described for Example 111, Step D. The
product was obtained as a pale yellow powder (4.5 mg, 42%). HPLC:
95% purity (220 nm); LRMS (ESI+): 100% purity, 220 nm, m/z 585
(M+1) detected; .sup.1H NMR (400 MHz, MeOD-d.sub.3) .delta. 8.31
(d, J=4 Hz, 1H), 8.26 (d, J=4 Hz, 1H), 8.18 (d, J=6 Hz, 1H), 8.02
(m, 1H), 7.64 (m, 2H), 7.45 (m, 1H), 7.37 (t, J=9 Hz, 1H), 7.25 (t,
J=9 Hz, 2H), 6.22 (d, J=6 Hz, 1H), 3.96 (m, 1H), 3.85 (m, 1H), 3.48
(m, 1H), 3.34 (m, 2H), 3.14 (m, 1H), 2.99 (m, 1H), 2.34 (m, 1H),
2.05 (m, 1H), 1.81 (m, 2H), 1.59 (m, 1H).
Example 113
1-(benzo[d]oxazol-2-yl)-N-(4-(3-(4-(dimethylamino)piperidin-1-yl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)cyclopropanecarboxamide
##STR00225##
[0799] Step A: Preparation of methyl
1-(2-hydroxyphenylcarbamoyl)cyclopropane carboxylate: To a stirred
suspension of potassium 1-(methoxycarbonyl)cyclopropanecarboxylate
(182 mg, 1 mmol) in 3 mL THF at room temperature under nitrogen was
added 15 .mu.L of DMF. Oxalyl chloride (87 .mu.L, 1 mmol) was then
added neat dropwise by syringe. After stirring at ambient
temperature for 2 hours, the reaction was cooled to 0.degree. C.
and treated with DIEA (0.497 ml, 2.85 mmol) followed by
2-aminophenol (104 mg, 0.951 mmol) neat as a solid. The cooling
bath was allowed to melt and the reaction was then stirred at
ambient temperature overnight. The reaction was diluted to 30 mL
with ethyl acetate and washed with 2N HCl, water, saturated sodium
bicarbonate and brine. The organics were dried (MgSO.sub.4),
filtered and concentrated to a yellow solid (147 mg, 68%
yield).
[0800] Step B: Preparation of methyl
1-(benzo[d]oxazol-2-yl)cyclopropanecarboxylate: To a stirred
suspension of methyl
1-((2-hydroxyphenyl)carbamoyl)cyclopropanecarboxylate (0.147 g,
0.62 mmol) in 2.5 mL THF at room temperature under nitrogen was
added triphenylphosphine (0.361 g, 1.375 mmol) followed by DIAD
(0.2663 ml, 1.375 mmol). After 2 hours, the reaction mixture was
loaded directly onto a Biotage 40S column in THF and was eluted
with 9/1 hexanes/EtOAc to provide the desired product as a yellow
oil (132 mg, 97%).
[0801] Step C: Preparation of
1-(benzo[d]oxazol-2-yl)cyclopropanecarboxylic acid: To a stirred
solution of methyl 1-(benzo[d]oxazol-2-yl)cyclopropanecarboxylate
(0.132 g, 0.6077 mmol) in 3 mL 3:2 THF:H.sub.2O at room temperature
under nitrogen was added LiOH (0.02911 g, 1.215 mmol). After
stirring at ambient temperature overnight the reaction was diluted
to 30 mL with ethyl acetate and washed with 2N HCl, water and
brine. The organics were dried (MgSO.sub.4), filtered and
concentrated to a white solid (100 mg, 81% yield).
[0802] Step D: Preparation of
1-(benzo[d]oxazol-2-yl)-N-(4-(3-(4-(dimethylamino)piperidin-1-yl)-1-(4-me-
thoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)cyclopropan-
ecarboxamide: To a stirred solution of
1-(benzo[d]oxazol-2-yl)cyclopropanecarboxylic acid (3.8 mg, 0.019
mmol) in 150 .mu.L dichloromethane at room temperature under
nitrogen was added DIEA (8 .mu.L, 0.047 mmol) followed by EDCI (4.5
mg, 0.024 mmol) and HOBT-H.sub.2O (3.6 mg, 0.024 mmol). After 15
minutes, a solution of
1-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)-N,N-dimethylpiperidin-4-amine (7.7 mg, 0.016 mmol)
(prepared in Example 93, Step A) in 150 .mu.L dichloromethane was
added. After stirring for 48 hours, the reaction was diluted to 30
mL with dichloromethane and washed with 10% sodium carbonate
solution. The organics were dried (MgSO.sub.4), filtered and
concentrated. The crude product was loaded onto a Biotage 12S
column with dichloromethane and eluted with a step gradient of
dichloromethane (100 mL), 2.5/97.5 MeOH/dichloromethane (100 mL)
and 5/95 MeOH/dichloromethane to provide the desired product as a
white foam (6.6 mg, 62% yield).
[0803] Step E: Preparation of
1-(benzo[d]oxazol-2-yl)-N-(4-(3-(4-(dimethylamino)piperidin-1-yl)-1H-pyra-
zolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)cyclopropanecarboxamide:
To a flask containing
N-(4-(1-(4-methoxybenzyl)-3-(4-(dimethylamino)piperidin-1-yl)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-1-(benzo[d]oxazol-2-yl)cyclopropan-
ecarboxamide (6.6 mg, 0.01 mmol) at room temperature under a drying
tube was added TFA (2 mL). The reaction was warmed to 50.degree. C.
overnight. The reaction was cooled to room temperature and was
concentrated. The residue was dissolved in 10 mL dichloromethane
and stirred rapidly with 10 mL 10% sodium carbonate solution. The
layers were separated and the organics dried (MgSO.sub.4). The
crude product was concentrated and the crude material was loaded
onto a Biotage 12S column with dichloromethane. The column was
eluted with a step gradient of dichloromethane (150 mL) and
94.5/5/0.5 dichloromethane/MeOH, concentrated ammonium hydroxide to
provide the desires product as a yellow glass (2.7 mg, 50% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 12.17 (br s, 1H), 9.92
(br s, 1H), 8.24 (d, 1H), 7.90 (m, 1H), 7.73 (m, 1H), 7.48 (m, 2H),
7.38 (m, 2H), 7.30 (m, 1H), 6.21 (d, 1H), 4.11 (m, 2H), 2.91 (m,
2H), 2.40 (m, 1H), 2.34 (s, 6H), 2.08 (m, 2H), 1.96 (br m, 2H),
1.90 (m, 2H), 1.74 (br m, 2H). LCMS (APCI+): m/z 556 (M+1)
detected.
Example 114
N-(3-fluoro-4-(3-(4-(pyrrolidin-1-yl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyr-
idin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carb-
oxamide
##STR00226##
[0805] Step A: Preparation of
3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)-1H--
pyrazolo[3,4-b]pyridin-4-yloxy)aniline: Prepared according to the
procedure of Example 82, Step A, substituting
4-(1-pyrrolidinyl)piperidine (315 mg, 2.04 mmol) for tert-butyl
piperazine-1-carboxylate. The crude material was purified by silica
gel column chromatography (Biotage 25S) eluting with 7%
MeOH/CHCl.sub.3 to afford the desired product as orange semi-solid.
Yield: 43 mg, 20%. LRMS (APCI pos) m/e 517.2 (M+H).
[0806] Step B: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)--
1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dih-
ydropyridazine-4-carboxamide: Prepared according to the procedure
of Example 82, Step B, substituting
3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)-1H--
pyrazolo[3,4-b]pyridin-4-yloxy)aniline (43 mg, 0.0832 mmol) for
tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperazine-1-carboxylate. The crude material was purified
by silica gel column chromatography (Biotage 25S) eluting with
5-10% MeOH/CH.sub.2Cl.sub.2 to afford the desired product as yellow
solid. Yield: 28.6 mg, 47%. LRMS (APCI pos) m/e 733.3 (M+H).
[0807] Step C: Preparation of
N-(3-fluoro-4-(3-(4-(pyrrolidin-1-yl)piperidin-1-yl)-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-car-
boxamide: Prepared according to the procedure of Example 53, Step
B, substituting
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)--
1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dih-
ydropyridazine-4-carboxamide (28 mg, 0.0382 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by silica gel column
chromatography (Biotage 12M) eluting with 5/95/0.1
MeOH/DCM/NH.sub.4OH to afford desired product as pale yellow solid.
Yield 10.4 mg, 44%. LRMS (APCI pos) m/e 613.2 (M+H).
Example 115
N-(4-(3-(2-((dimethylamino)methyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridi-
n-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine--
4-carboxamide
##STR00227##
[0809] Step A: Preparation of
4-(3-(2-((dimethylamino)methyl)piperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyr-
azolo[3,4-b]pyridin-4-yloxy)-3-fluoroaniline: Prepared according to
the procedure of Example 82, Step A, substituting
N-(2-piperidylmethyl)-dimethylamine (145 mg, 1.02 mmol) for
tert-butyl piperazine-1-carboxylate. The crude material was
purified by silica gel column chromatography (Biotage 25S) eluting
with 10% MeOH/CH.sub.2Cl.sub.2 to afford the desired product as
yellow semi-solid. Yield: 9.6 mg, 9.3%. LRMS (APCI pos) m/e 505.2
(M+H).
[0810] Step B: Preparation of
N-(4-(3-(2-((dimethylamino)methyl)piperidin-1-yl)-1-(4-methoxybenzyl)-1H--
pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2-
,3-dihydropyridazine-4-carboxamide: Prepared according to the
procedure of Example 82, Step B, substituting
4-(3-(2-((dimethylamino)methyl)piperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyr-
azolo[3,4-b]pyridin-4-yloxy)-3-fluoroaniline (10 mg, 0.0198 mmol)
for tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperazine-1-carboxylate. The crude material was purified
by silica gel column chromatography (Biotage 12S) eluting with 5%
MeOH/CH.sub.2Cl.sub.2 to afford the desired product as yellow
solid. Yield: 7.2 mg, 50%. LRMS (APCI pos) m/e 721.3 (M+H).
[0811] Step C: Preparation of
N-(4-(3-(2-((dimethylamino)methyl)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyrid-
in-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-
-4-carboxamide: Prepared according to the procedure of Example 53,
Step B, substituting
N-(4-(3-(2-((dimethylamino)methyl)piperidin-1-yl)-1-(4-methoxybenzyl)-1H--
pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2-
,3-dihydropyridazine-4-carboxamide (7.2 mg, 0.010 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by silica gel column
chromatography (Biotage 12M) eluting with 5/95/0.1
MeOH/DCM/NH.sub.4OH to afford desired product as pale yellow solid.
Yield 4.7 mg, 78%. LRMS (APCI pos) m/e 601.2 (M+H).
Example 116
N-(5-chloro-2-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-
-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00228##
[0813] Step A:
1-(4-methoxybenzyl)-4-(2-chloro-5-fluoro-4-nitrophenoxy)-3-methyl-1H-pyra-
zolo[3,4-b]pyridine: Made according to the procedure for Example
96, Step A, substituting 1-chloro-2,4-difluoro-5-nitrobenzene
(0.826 g, 4.27 mmol made from US20040082784 substituting
1-chloro-2,4-difluorobenzene for 1-chloro-4,5-difluoro-benzene) for
1,2,4-trifluoro-5-nitrobenzene. Obtained 1.01 g (52%) of the
desired product. LRMS M+1 (442.9) observed.
[0814] Step B:
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-5-chlo-
ro-2-fluorobenzenamine: Prepared by process from Example 92, Step
B, substituting
1-(4-methoxybenzyl)-4-(2-chloro-5-fluoro-4-nitrophenoxy)-3-methyl-1H-pyra-
zolo[3,4-b]pyridine (0.850 g, 1.92 mmol). The reaction mixture was
dilute with EtOAc (250 mL) and saturated Na.sub.2CO.sub.3 (50 mL)
was added. The solution was filtered through celite and the
filtrate was dried over sodium sulfate and concentrated to provide
the product (0.325 g, 35%). The crude material was used in the next
step without purification.
[0815] Step C:
N-(5-chloro-2-fluoro-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl-
)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
Prepared by process from Example 9, Step C, substituting
4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-5-chlo-
ro-2-fluorobenzenamine (0.325 g, 0.787 mmol). The crude material
was purified by reverse phase HPLC to afford 1 mg (1%) of the
desired product. LRMS M+1 (508.9) observed. 1H NMR (400 MHz,
CDCl.sub.3) .delta. 12.31 (s, 1H), 8.69 (m, 1H), 8.41 (m, 2H), 8.28
(m, 1H), 7.69 (m, 4H), 7.43 (m, 2H), 6.20 (m, 1H), 2.62 (s, 3H)
Example 117
(R)--N-(3-fluoro-4-(3-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)-1H-pyrazo-
lo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyrid-
azine-4-carboxamide
##STR00229##
[0817] Step A: Preparation of
(R)-3-fluoro-4-(1-(4-methoxybenzyl)-3-(2-(pyrrolidin-1-ylmethyl)pyrrolidi-
n-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline: Prepared
according to the procedure of Example 82, Step A, substituting
(S)-(+)-(2-pyrrolidinylmethyl)pyrrolidine (0.33 ml, 2.04 mmol) for
tert-butyl piperazine-1-carboxylate. The crude material was
purified by silica gel column chromatography (Biotage 25S) eluting
with 7% MeOH/CH.sub.2Cl.sub.2 to afford the desired product as
yellow semi-solid. Yield: 29.5 mg at 82% purity, 11.5% yield. LRMS
(APCI pos) m/e 517.2 (M+H).
[0818] Step B: Preparation of
(R)--N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(2-(pyrrolidin-1-ylmethyl)pyrro-
lidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-
-oxo-2,3-dihydropyridazine-4-carboxamide: Prepared according to the
procedure of Example 82, Step B, substituting
(R)-3-fluoro-4-(1-(4-methoxybenzyl)-3-(2-(pyrrolidin-1-ylmethyl)pyrrolidi-
n-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (25 mg, 0.048
mmol) for tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperazine-1-carboxylate. The crude material was purified
by silica gel column chromatography (Biotage 12M) eluting with 5%
MeOH/CH.sub.2Cl.sub.2 to afford the desired product. Yield: 6 mg,
17%. LRMS (APCI pos) m/e 733.3 (M+H).
[0819] Step C: Preparation of
(R)--N-(3-fluoro-4-(3-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyri-
dazine-4-carboxamide: Prepared according to the procedure of
Example 53, Step B, substituting
(R)--N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(2-(pyrrolidin-1-ylmethyl)pyrro-
lidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-
-oxo-2,3-dihydropyridazine-4-carboxamide (6 mg, 0.0082 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by silica gel column
chromatography (Biotage 12M) eluting with 5/95/0.1
MeOH/DCM/NH.sub.4OH to afford desired product as yellow semi-solid.
Yield 1.9 mg at 90% purity, 34% yield. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 11.84 (s, 1H), 8.41 (d, 1H), 8.24 (d, 1H), 8.21
(d, 1H), 7.96 (d, 1H), 7.60 (q, 2H), 7.40 (d, 1H), 7.27-7.21 (m,
2H) 6.14 (d, 1H), 4.37 (broad m, 2H), 3.95 (q, 2H), 3.51 (m, 2H),
3.04-2.74 (broad m, 6H), 2.33 (m, 2H), 2.01 (m, 2H). LRMS (APCI
pos) m/e 613.2 (M+H).
Example 118
N-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-
-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
##STR00230##
[0821] Prepared by a 2-step process from
4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl-
)-1H-pyrazolo[3,4-b]pyridin-3-amine (prepared in Example 101, step
A) and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic
acid (prepared from methyl 2-oxo-2H-pyran-3-carboxylate with
4-fluoroaniline and followed by hydrolysis using the methods
described in US Publication No. 2005/0239820) according to the
procedure of Example 101. The crude was rinsed with Et.sub.2O to
afford 14 mg (73%) of the desired product. LRMS (ESI pos) m/e 572.0
(M+1). .sup.1H-NMR (400 MHz, CD.sub.3OD/CDCl.sub.3) .delta. 8.72
(d, 1H), 8.24 (d, 1H), 8.02 (dd, 1H), 8.02 (dd, 1H), 7.87 (d, 1H),
7.47 (m, 2H), 7.41 (m, 1H), 7.38 (m, 3H), 6.72 (m, 1H), 6.12 (d,
1H), 3.70 (m, 1H), 2.88 (d, 2H), 2.35 (s, 3H), 2.24 (m, 1H), 2.21
(m, 2H), 1.62 (m, 2H); .sup.19F NMR (376 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. -112.6, -128.0.
Example 119
N-(3-fluoro-4-(3-(methyl(1-methylpiperidin-4-yl)amino)-1H-pyrazolo[3,4-b]p-
yridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-ca-
rboxamide
##STR00231##
[0823] Prepared by a 2-step process from
4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-methyl-N-(1-methylpiper-
idin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (prepared as described
in Example 101, Step A, using N,1-dimethylpiperidin-4-amine) and
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
according to the procedure of Example 101, Step B. The crude was
rinsed with Et.sub.2O to afford 5.9 mg (55%) of the desired
product. LRMS (ESI pos) m/e 587.0 (M+1). .sup.1H-NMR (400 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. 8.42 (d, 1H), 8.37 (d, 1H), 8.20 (d,
1H), 8.02 (dd, 1H), 7.64 (m, 2H), 7.46 (d, 1H), 7.26 (m, 3H), 6.20
(d, 1H), 3.70 (m, 1H), 2.98 (m, 2H), 2.90 (s, 3H), 2.28 (s, 3H),
2.08 (m, 2H), 1.93 (m, 2H), 1.81 (m, 2H); .sup.19F NMR (376 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. -112.1, -127.3.
Example 120
N-(3-fluoro-4-(3-(4-(methylamino)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-
-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxam-
ide
##STR00232##
[0825] Step A: Preparation of tert-butyl
1-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbox-
amido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidi-
n-4-yl(methyl)carbamate: A round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
(100 mg, 0.142 mmol, prepared in Example 63, step A), tert-butyl
methyl(piperidin-4-yl)carbamate (152 mg, 0.708 mmol),
copper(I)iodide (5.39 mg, 0.0283 mmol),
(S)-pyrrolidine-2-carboxylic acid (6.52 mg, 0.0566 mmol),
K.sub.2CO.sub.3 (97.8 mg, 0.708 mmol) and DMSO (10 mL). The
reaction mixture was stirred at 100.degree. C. overnight. The
reaction was cooled to ambient temperature and partitioned between
EtOAc and H.sub.2O. The phases were separated and the aqueous phase
was re-extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
product. The crude product was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 100/1 to 10/1, v/v)
to afford product (98.5 mg, 87.8%). LRMS (APCI pos): m/e 693
(M-99).
[0826] Step B: Preparation of
N-(3-fluoro-4-(3-(4-(methylamino)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridi-
n-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxa-
mide: A round-bottomed flask was charged with tert-butyl
1-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidi-
n-4-yl(methyl)carbamate (98.5 mg, 0.124 mmol) and CF.sub.3COOH (5
mL). The reaction mixture was stirred at 80.degree. C. overnight.
The solvent was removed and the residue was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to
give the product, which was not pure enough. The impure product was
further purified by preparative HPLC to afford product (17.3 mg,
24.3%). LRMS (APCI pos) m/e 573 (M+1). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 11.97 (s, 1H), 8.38 (d, 1H), 8.33 (d, 1H), 8.25
(d, 1H), 8.08 (m, 1H), 7.65 (m, 2H), 7.48 (d, 1H), 7.40 (m, 1H),
7.28 (m, 2H), 6.28 (d, 1H), 4.10 (m, 2H), 3.32 (m, 1H), 3.01 (m,
2H), 2.72 (s, 3H), 2.18 (m, 2H), 2.81 (m, 2H).
Example 121
N-(3-Fluoro-4-(3-(pyrrolidin-3-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-
phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00233##
[0828] Step A: Preparation of tert-butyl
3-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbox-
amido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)pyr-
rolidine-1-carboxylate: A round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
(100 mg, 0.142 mmol, prepared in Example 63, step A), tert-butyl
3-aminopyrrolidine-1-carboxylate (132 mg, 0.708 mmol),
copper(I)iodide (5.39 mg, 0.0283 mmol),
(S)-pyrrolidine-2-carboxylic acid (6.52 mg, 0.0566 mmol),
K.sub.2CO.sub.3 (97.8 mg, 0.708 mmol) and DMSO (10 mL). The
reaction mixture was stirred at 80.degree. C. overnight. The
reaction was cooled to ambient temperature and partitioned between
EtOAc and H.sub.2O. The phases were separated and the aqueous phase
was re-extracted with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
product. The crude product was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 100/1 to 10/1, v/v)
to afford product (61.3 mg, 56.6%). LRMS (APCI pos): m/e 765
(M+1).
[0829] Step B: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(pyrrolidin-3-ylamino)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazin-
e-4-carboxamide: A round-bottomed flask was charged with tert-butyl
3-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)pyr-
rolidine-1-carboxylate (61.3 mg, 0.08015 mmol),
2,2,2-trifluoroacetic acid (182.8 mg, 1.603 mmol) and
CH.sub.2Cl.sub.2 (5 mL). The reaction mixture was stirred at room
temperature for 4 hours. The solvent was removed and the residue
was purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 50/1 to 10/1, v/v) to give product (40.8 mg, 76.58%). LRMS
(APCI pos) m/e 665 (M+1).
[0830] Step C: Preparation of
N-(3-fluoro-4-(3-(pyrrolidin-3-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy-
)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
A 100 mL round-bottomed flask was charged with
N-(4-(1-(4-methoxybenzyl)-3-(pyrrolidin-3-ylamino)-1H-pyrazolo[3,4-b]pyri-
din-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazin-
e-4-carboxamide (40.8 mg, 0.0614 mmol) and CF.sub.3COOH (5 mL). The
reaction mixture was stirred at 80.degree. C. overnight. The
solvent was removed and the residue was purified by silica gel
chromatography (DCM/7 M NH.sub.3 in MeOH from 50/1 to 10/1, v/v) to
give product, which was further purified by preparative HPLC to
afford product (1.9 mg, 5.68%). LRMS (APCI pos): m/e 545 (M+1).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 11.96 (s, 1H), 8.36 (d,
1H), 8.31 (d, 1H), 8.19 (d, 1H), 8.04 (dd, 1H), 7.68 (m, 2H), 7.51
(d, 1H), 7.40 (t, 1H), 7.29 (m, 2H), 6.16 (d, 1H), 4.48 (m, 1H),
3.56 (m, 3H), 3.39 (m, 1H), 2.42 (m, 1H), 2.32 (m, 1H).
Example 122
N-(3-fluoro-4-(3-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-
-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxam-
ide
##STR00234##
[0832] Prepared by a 2-step process from
4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(tetrahydro-2H-pyran-4--
yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (prepared as described in
Example 101, Step A except using tetrahydro-2H-pyran-4-amine) and
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
according to the procedure of Example 101, Step B. The crude was
purified by silica gel flash column chromatography (2% MeOH in
CH.sub.2Cl.sub.2) to afford 82 mg (77%) of the desired product.
LRMS (ESI pos) m/e 560.0 (M+1). .sup.1H NMR (400 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. 8.41 (d, 1H), 8.33 (d, 1H), 8.14 (d,
1H), 8.02 (dd, 1H), 7.66 (m, 2H), 7.47 (d, 1H), 7.37 (t, 1H), 7.28
(t, 2H), 6.12 (d, 1H), 4.02 (m, 2H), 3.89 (m, 1H), 3.59 (m, 2H),
2.18 (m, 2H), 1.64 (m, 2H); .sup.19F NMR (376 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. -113.2, -127.8.
Example 123
N-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-
-yloxy)phenyl)biphenyl-3-carboxamide
##STR00235##
[0834] Step A: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyr-
azolo[3,4-b]pyridin-4-yloxy)phenyl)biphenyl-3-carboxamide: To a
stirred solution of
1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-methylpiperidin-4-yl-
)-1H-pyrazolo[3,4-b]pyridin-3-amine (12 mg, 0.026 mmol) (prepared
in Example 101, step A) in 260 .mu.L dichloromethane at 0.degree.
C. under nitrogen was added DIEA (14 .mu.L, 0.078 mmol) followed by
biphenyl-3-carbonyl chloride (7 mg, 0.031 mmol). The reaction was
allowed to warm to room temperature overnight. The reaction was
diluted to 10 mL with dichloromethane and stirred rapidly with 10%
sodium carbonate solution for 5 minutes. The organics were isolated
and dried (MgSO.sub.4). The organics were filtered and concentrated
to a residue that was loaded onto a Biotage 12S column with
dichloromethane and eluted with 4/1 EtOAc/hexanes. The product
containing fractions were pooled and concentrated to a yellow oil
(10 mg, 59% yield).
[0835] Step B: Preparation of
N-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin--
4-yloxy)phenyl)biphenyl-3-carboxamide: To a flask containing
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyr-
azolo[3,4-b]pyridin-4-yloxy)phenyl)biphenyl-3-carboxamide (10 mg,
0.015 mmol) at room temperature under a drying tube was added TFA
(1 mL). The solution was warmed to 50.degree. C. for 3 hours. After
cooling to ambient temperature, the solution was concentrated, and
the residue was redissolved in 5 mL dichloromethane and stirred
rapidly with 5 mL 10% sodium carbonate solution to provide the free
base. The organic layer was isolated, dried (MgSO.sub.4), filtered
and concentrated. The crude product was passed through a small
gravity silica cartridge with 95/5 dichloromethane/MeOH to provide
the desired product as a clear oil (2.2 mg, 27% yield). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 9.40 (br s, 1H), 8.20 (d, 1H), 8.11
(m, 1H), 8.01 (m, 1H), 7.92 (m, 1H), 7.85 (m, 1H), 7.82 (m, 1H),
7.65 (m, 2H), 7.60 (m, 1H), 7.50 (m, 2H), 7.41 (m, 2H), 7.30 (m,
1H), 6.10 (d, 1H), 4.54 (m, 1H), 3.73 (br m, 1H), 2.89 (br m, 2H),
2.34 (s, 3H), 2.24 (br m, 3H), 1.68 (br m, 2H). LCMS (APCI+): m/z
537 (M+1) detected.
Example 124
N-(3-fluoro-4-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-
-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00236##
[0837] Prepared by a 2-step process from
3-fluoro-4-(1-(4-methoxybenzyl)-3-morpholino-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)aniline (prepared as described in Example 101, Step A, except
using morpholine) and
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
according to the procedure of Example 101, Step B. The crude was
purified by silica gel flash column chromatography (2% MeOH in
CH.sub.2Cl.sub.2) to afford 7.6 mg (37%) of the desired product.
LRMS (ESI pos) m/e 546.0 (M+1). .sup.1H-NMR (400 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. 8.41 (d, 1H), 8.33 (d, 1H), 8.21 (d,
1H), 8.02 (dd, 1H), 7.65 (m, 2H), 7.46 (d, 1H), 7.34 (t, 1H), 7.28
(t, 2H), 6.25 (d, 1H), 3.89 (m, 4H), 3.47 (m, 4H); .sup.19F-NMR
(376 MHz, CD.sub.3OD/CDCl.sub.3) .delta. -113.1, -128.2.
Example 125
N-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-
-yloxy)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide
##STR00237##
[0839] Step A: Preparation of
5-chloro-1-(4-fluorophenyl)-3-methoxypyrazin-2(1H)-one:
3,5-dichloro-1-(4-fluorophenyl)pyrazin-2(1H)-one (13.0 g, 50.2
mmol; prepared by according to the general methods described by M.
Tutonda, et al., Tetrahedron, 1990, 46, 5715) dissolved in absolute
methanol (100 mL) was treated with NaOMe (6.78 g, 125 mmol). The
reaction mixture was stirred at room temperature for 1 hour,
neutralized with 2 N HCl (Et.sub.2O solution), and evaporated the
solvent under reduced pressure. The residue was treated with EtOAc,
washed with 0.5 N HCl, dried over MgSO.sub.4, and concentrated
under reduced pressure to give the desired product (12.8 g, 100%).
LRMS (ESI pos) m/e 254.9, 256.9 (M+1, Cl pattern).
[0840] Step B: Preparation of
1-(4-fluorophenyl)-3-methoxypyrazin-2(1H)-one: K.sub.2CO.sub.3
(1.09 g, 7.85 mmol) and 10% Pd/C (0.42 g, 0.39 mmol) were added to
5-chloro-1-(4-fluorophenyl)-3-methoxypyrazin-2(1H)-one (2.0 g, 7.85
mmol) in MeOH (100 mL) at room temperature under a H.sub.2
atmosphere and the reaction was stirred for 6 hours. The reaction
mixture was filtered with MeOH and concentrated under reduced
pressure. The crude was treated with CH.sub.2Cl.sub.2, washed with
water, dried over MgSO.sub.4, and concentrated to give the desired
product (1.55 g, 90%). LRMS (ESI pos) m/e 221.0 (M+1).
[0841] Step C: Preparation of
3-chloro-1-(4-fluorophenyl)pyrazin-2(1H)-one: POCl.sub.3 (5.6 mL,
61.3 mmol) was added dropwise to a solution of
1-(4-fluorophenyl)-3-methoxypyrazin-2(1H)-one in DMF (30 mL) with
stirring at 0.degree. C. followed by heating at 90.degree. C. for
1.5 hours. The residue was cooled to 0.degree. C., quenched by
adding saturated sodium acetate solution, extracted with
CH.sub.2Cl.sub.2, washed with water, dried over MgSO.sub.4, and
concentrated. The crude was purified by silica gel flash column
chromatography (0.7% MeOH in CH.sub.2Cl.sub.2) to afford 3.52 g
(64%) of the desired product. LRMS (ESI pos) m/e 224.9, 227.0 (M+1,
Cl pattern).
[0842] Step D: Preparation of
4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carbonitrile: A
mixture of 3-chloro-1-(4-fluorophenyl)pyrazin-2(1H)-one (3.52 g,
15.7 mmol), CuCN (2.81 g, 31.3 mmol) and N-methylpyrrolidone (30
mL) was heated for 5.5 hours at 150.degree. C. while being stirred.
The residue was triturated with hot CHCl.sub.3 and filtered over
charcoal. The filtrate was evaporated and concentrated under
reduced pressure. The residue was triturated with CH.sub.2Cl.sub.2
and the solution was concentrated. The crude was purified by silica
gel flash column chromatography (3:1=CH.sub.2Cl.sub.2:Hexane then
CH.sub.2Cl.sub.2) to afford 0.78 g (23%) of the desired product.
LRMS (ESI pos) m/e 215.9 (M+1).
[0843] Step E: Preparation of
4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid: A
mixture of
4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carbonitrile (0.42
g, 1.95 mmol) and H.sub.2SO.sub.4 (4.16 mL, 78.1 mmol) was stirred
at ambient temperature for 17 hours. Then the reaction mixture
(amide intermediate) was added to MeOH (50 mL), and then the
reaction was heated at 70.degree. C. for 2.5 hours. The reaction
mixture was quenched with ice-water and treated with aqueous 2N
NaOH solution at 0.degree. C. The mixture was acidified with
aqueous 1N HCl, extracted with EtOAc, dried over MgSO.sub.4, and
concentrated to afford 0.315 g of the desired product (69% for
3-step process in one pot reaction), which was rinsed with
Et.sub.2O.
[0844] Step F: Preparation of
N-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin--
4-yloxy)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide-
: Prepared by a 2-step process from
4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl-
)-1H-pyrazolo[3,4-b]pyridin-3-amine and
4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid
according to the procedure of Example 101, Step B. The crude was
rinsed with Et.sub.2O to afford 8.8 mg (53%) of the desired
product. LRMS (ESI pos) m/e 573.0 (M+1). .sup.1H NMR (400 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. 8.14 (d, 1H), 8.05 (dd, 1H), 7.86
(m, 2H), 7.57 (m, 2H), 7.51 (d, 1H), 7.34 (m, 3H), 6.12 (d, 1H),
3.71 (m, 1H), 2.92 (m, 2H), 2.35 (s, 3H), 2.29 (m, 2H), 2.22 (m,
2H), 1.65 (m, 2H); .sup.19F NMR (376 MHz, CD.sub.3OD/CDCl.sub.3)
.delta. -112.1, -129.4.
Example 126
N-(3-fluoro-4-(3-(1-(2-hydroxyethyl)piperidin-4-ylamino)-1H-pyrazolo[3,4-b-
]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4--
carboxamide
##STR00238##
[0846] Prepared by a 2-step process from
2-(4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]p-
yridin-3-ylamino)piperidin-1-yl)ethanol (prepared as described in
Example 101, Step A except using 2-(4-aminopiperidin-1-yl)ethanol)
and 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic
acid according to the procedure of Example 101, Step B. The crude
material was rinsed with Et.sub.2O to afford 11 mg (55%) of the
desired product. LRMS (ESI pos) m/e 603.1 (M+1). .sup.1H-NMR (400
MHz, CD.sub.3OD/CDCl.sub.3) .delta. 8.42 (d, 1H), 8.31 (d, 1H),
8.13 (d, 1H), 8.0 (dd, 1H), 7.63 (m, 2H), 7.45 (d, 1H), 7.33 (t,
1H), 7.28 (t, 2H), 6.10 (d, 1H), 3.72 (m, 3H), 3.03 (m, 2H), 2.65
(m, 2H), 2.40 (m, 2H), 2.25 (m, 2H), 1.67 (m, 2H); .sup.19F NMR
(376 MHz, CD.sub.3OD/CDCl.sub.3) .delta. -112.1, -126.9.
Example 127
N-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-
-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxoazepane-3-carboxamide
##STR00239##
[0848] Step A: Preparation of 1-(4-fluorophenyl)azepan-2-one: A
suspension of .epsilon.-caprolactam (10 g, 90 mmol),
1-fluoro-4-iodobenzene (10 ml, 90 mmol), L-proline (4.1 g, 36
mmol), K.sub.2CO.sub.3 (37 g, 270 mmol), and Cu(I)I (3.4 g, 18
mmol) was stirred in DMSO (50 mL) and heated to 100.degree. C. for
12 hours. Water (50 mL) was added and the reaction mixture was
extracted with EtOAc. The organic layer washed with water) and
brine, dried with Na.sub.2SO.sub.4, filtered and concentrated. The
residue was purified by silica gel chromatography (50% EtOAc in
hexane) to afford the product (1.2 g, 6.4% yield) as brown oil.
LRMS (APCI pos) m/e 208.0 (M+1).
[0849] Step B: Preparation of benzyl
1-(4-fluorophenyl)-2-oxoazepane-3-carboxylate: A solution of
1-(4-fluorophenyl)azepan-2-one (1.1 g, 5.3 mmol) was dissolved in
THF (5 mL) and was added into LDA (11 mmol) at -78.degree. C. and
stirred for 5 minutes. Benzyl chloroformate (1.6 ml, 11 mmol) was
added at -78.degree. C. and the reaction warmed to ambient
temperature. The solution was poured into ice and diluted with
EtOAc (100 mL). The organic layer washed with brine, dried with
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by column chromatography (50% EtOAc in hexane) to afford
the product (1 g, 55% yield) as brown oil.
[0850] Step C: Preparation of
1-(4-fluorophenyl)-2-oxoazepane-3-carboxylic acid: A mixture of
benzyl 1-(4-fluorophenyl)-2-oxoazepane-3-carboxylate (1 g, 3 mmol)
and Pd/C (0.1 g, 10% wet) was stirred in MeOH (5 mL) under a
H.sub.2 atmosphere. After 4 hours, the catalyst was removed by
filtration through a pad of silica gel with MeOH. Solvent was
evaporated to afford the product (0.3 g, 41% yield) as a white
solid. LRMS (APCI pos) m/e 251.8 (M+1).
[0851] Step D: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-
-b]pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxoazepane-3-carb-
oxamide: EDCI (48 mg, 0.25 mmol) was added to a mixture of the
1-(4-fluorophenyl)-2-oxoazepane-3-carboxylic acid (21 mg, 0.084
mmol) and HOBT (34 mg, 0.25 mmol) in DMF (0.5 mL) at ambient
temperature, and the reaction mixture was stirred for 10 minutes at
ambient temperature.
1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-methylpiperidin-4-yl-
)-1H-pyrazolo[3,4-b]pyridin-3-amine (20 mg, 0.042 mmol, obtained
from Example 101, Step A) and triethylamine (0.035 ml, 0.25 mmol)
were added. The resulting mixture was stirred for 12 hours at
ambient temperature. The reaction mixture was diluted with EtOAc.
The organic layer washed with 10% aqueous LiCl, dried over
Na.sub.2SO.sub.4, and concentrated. The residue was purified by
flash column chromatography (5% MeOH in CH.sub.2Cl.sub.2) to afford
the product (20 mg, 67% yield) as a white solid. LRMS (APCI pos)
m/e 710.3 (M+1).
[0852] Step E: Preparation of
N-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin--
4-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxoazepane-3-carboxamide: A
solution of
N-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[-
3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxoazepane-3-c-
arboxamide (20 mg, 0.028 mmol) was heated in TFA (1 mL) at
55.degree. C. for 3 hours. TFA was evaporated and EtOAc was added
to dilute the mixture. The mixture washed with saturated aqueous
NaHCO.sub.3, brine, dry with Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by flash column
chromatography (20% MeOH in CH.sub.2Cl.sub.2) to afford the product
(5 mg, 30% yield) as a white solid. LRMS (APCI pos) m/e 590.1
(M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 12.15 (s, 1H),
10.20 (s, 1H), 8.10 (s, 1H), 7.82 (d, 1H), 7.18-7.50 (m, 7H),
5.98-6.00 (m, 1H), 5.10-5.20 (m, 1H), 3.90-4.02 (m, 2H), 3.40-3.62
(m, 2H), 2.62-2.80 (m, 1H), 2.15 (s, 3H), 1.90-2.02 (m, 5H),
1.50-1.88 (m, 6H).
Example 128
N-(2-chloro-5-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]-
pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-c-
arboxamide
##STR00240##
[0854] Step A: Preparation of 1-chloro-4,5-difluoro-2-nitrobenzene:
To 4-chloro-1,2-difluorobenzene (25.0 g, 168.3 mmol) cooled to
0.degree. C. was added fuming nitric acid (50.0 ml, 168.3 mmol)
dropwise over 30 minutes. The solution was warmed to room
temperature and stirred for 2 hours. The solution was poured slowly
over ice and the resultant mixture extracted with diethyl ether.
The diethyl ether layers were washed with brine, dried with
Na.sub.2SO.sub.4, filtered and concentrated to afford the product
(28 g, 81% yield) as orange oil. .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 7.89 (s, 1H), 7.46 (s, 1H).
[0855] Step B: Preparation of
1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-ol: A
mixture of
1-(4-methoxybenzyl)-4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine
(7.00 g, 17.52 mmol, obtained from Example 84, Step D), cesium
acetate (33.62 g, 175.2 mmol) and DMF (175 mL) was heated to
100.degree. C. for 12 hours. The reaction was cooled to room
temperature, diluted with water (50 mL), extracted with EtOAc (100
mL), dried over sodium sulfate, filtered and concentrated. The
residue was purified by flash column chromatography (5% MeOH in
CH.sub.2Cl.sub.2) to afford the product (2.23 g, 79% yield) as a
light orange solid. LRMS (APCI pos) m/e 381.9 (M+H).
[0856] Step C: Preparation of
1-(4-methoxybenzyl)-4-(5-chloro-2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrazo-
lo[3,4-b]pyridine: A mixture of
1-chloro-4,5-difluoro-2-nitrobenzene (2.23 g, 11.5 mmol),
1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-ol (4.00 g,
10.5 mmol), K.sub.2CO.sub.3 (1.60 g, 11.5 mmol) and DMF (100 mL)
was heated to 50.degree. C. for 18 hours. The reaction was cooled
to ambient temperature, diluted with water (500 mL), extracted with
EtOAc, dry over sodium sulfate, filter and concentrate. The residue
was purified by flash column chromatography (5% MeOH in
CH.sub.2Cl.sub.2) to provide a light pink solid. The solid was
triturated with hot MeOH to afford the product (2.35 g, 40% yield)
as a white solid. LRMS (APCI pos) m/e 554.8 (M+H).
[0857] Step D: Preparation of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-chloro-
-5-fluorobenzenamine: A mixture of
1-(4-methoxybenzyl)-4-(5-chloro-2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrazo-
lo[3,4-b]pyridine (2.85 g, 5.14 mmol), SnCl.sub.2 dihydrate (4.64
g, 20.6 mmol) and EtOH (70 mL) was heated to 70.degree. C. for 8
hours. The reaction mixture was cooled to room temperature, diluted
with EtOAc, washed with saturated aqueous Na.sub.2CO.sub.3, dried
over sodium sulfate and concentrated. The residue was purified by
flash column chromatography (5% MeOH in CH.sub.2Cl.sub.2) to afford
the product (2.02 g, 64% yield) as a light yellow solid. LRMS (APCI
pos) m/e 524.9 (M+H).
[0858] Step E: Preparation of
1-(4-methoxybenzyl)-4-(4-amino-5-chloro-2-fluorophenoxy)-N-(1-methylpiper-
idin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine:
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-chloro-
-5-fluorobenzenamine (200 mg, 0.38 mmol) was added into a
suspension of 4-amino-1-methylpiperidine (131 mg, 1.14 mmol),
Cu(I)I (14.5 mg, 0.0762 mmol), K.sub.2CO.sub.3 (263 mg, 1.91 mmol)
and L-proline (17.6 mg, 0.152 mmol) in DMSO (6 mL) and the reaction
mixture was heated at 100.degree. C. for 12 hours. The reaction
with diluted with CH.sub.2Cl.sub.2 and water (10 mL) was added. The
organic layer was then washed with water (10 mL), brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by flash column chromatography (5% MeOH in
CH.sub.2Cl.sub.2) to afford the product (130 mg, 66.7% yield) as a
brown oil. LRMS (APCI pos) m/e 511.1 (M+H).
[0859] Step F: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-
-b]pyridin-4-yloxy)-2-chloro-5-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3--
dihydropyridazine-4-carboxamide: A solution of
1-(4-methoxybenzyl)-4-(4-amino-5-chloro-2-fluorophenoxy)-N-(1-methylpiper-
idin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (130 mg, 0.254 mmol)
in CH.sub.2Cl.sub.2 (1 mL) was added into a solution of
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(119 mg, 0.509 mmol, obtained from Example 19 Step C),
triethylamine (0.213 ml, 1.53 mmol), EDCI (293 mg, 1.53 mmol) and
HOBT (206 mg, 1.53 mmol) in CH.sub.2Cl.sub.2 (2 mL). The reaction
mixture was stirred for 12 hours at ambient temperature. The
reaction was diluted with CH.sub.2Cl.sub.2 and washed with
saturated aqueous NaHCO.sub.3 and brine. The organic layer obtained
was dried with Na.sub.2SO.sub.4, filtered and concentrated. The
residue was purified by flash column chromatography (5% MeOH in
CH.sub.2Cl.sub.2) to afford the product (100 mg, 54.1% yield) as a
yellow solid. LRMS (APCI pos) m/e 727.2 (M+H).
[0860] Step G: Preparation of
N-(2-chloro-5-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b-
]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4--
carboxamide: A solution of
N-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-
-b]pyridin-4-yloxy)-2-chloro-5-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3--
dihydropyridazine-4-carboxamide (100 mg, 0.138 mmol) was dissolved
in TFA (2 mL) and the solution was heated to 50.degree. C. for 1
hour. Excess TFA was evaporated and the crude material was
dissolved in EtOAc. The organic layer washed with saturated aqueous
NaHCO.sub.3, brine, dried with Na.sub.2SO.sub.4, filtered and
concentrated to afford a yellow solid. The solid washed with
diethyl ether to afford the product (35 mg, 41.9% yield) as a
yellow solid. LRMS (APCI pos) m/e 607.0 (M+H). .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. 12.32 (s, 1H), 12.22 (s, 1H), 8.70
(d, 1H), 8.42 (dd, 12H), 8.17 (d, 1H), 7.91 (d, 1H), 7.74-7.67 (m,
2H), 7.49-7.41 (m, 2H), 6.17-6.13 (m, 1H), 5.23-5.18 (m, 1H),
3.60-3.42 (m, 1H), 2.85-2.73 (m, 2H), 2.20 (s, 3H), 2.10-1.96 (m,
4H), 1.65-1.53 (m, 2H).
Example 129
N-(3-fluoro-4-(3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-car-
boxamide
##STR00241##
[0862] Step A: Preparation of tert-butyl
4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperi-
dine-1-carboxylate: A 1 L, 1-neck flask was charged with
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.0
g, 103 mmol), and DMF (250 mL). The reaction mixture was cooled to
0.degree. C. and NaH (2.73 g, 108 mmol) (95%) was added. The
reaction mixture was stirred at 0.degree. C. for 1 hour. tert-Butyl
4-(methylsulfonyloxy)piperidine-1-carboxylate (30.2 g, 108 mmol;
prepared as in WO 06/021881) was added and the reaction mixture was
heated at 100.degree. C. overnight. The reaction mixture was cooled
to ambient temperature and diluted with water. The reaction mixture
was extracted with EtOAc, and the organic layer washed with brine,
dried over sodium sulfate, filtered and concentrated. The crude
material was purified on a Biotage 40S column eluting with
EtOAc/Hexane 10% to 25% EtOAc. The product was isolated as a white
solid (11.3 g, 29%).
[0863] Step B: tert-butyl
4-(4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]p-
yridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: A 100 mL
round-bottomed flask was charged with tert-butyl
4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperi-
dine-1-carboxylate (0.289 g, 0.765 mmol),
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (0.250 g, 0.510 mmol from Example 63, Step A),
potassium carbonate (0.106 g, 0.765 mmol), Pd(PPh.sub.3).sub.4
(0.0295 g, 0.0255 mmol), degassed DMF (2 mL) and water (0.5 mL).
The reaction mixture was heated at 100.degree. C. using a CEM
microwave for 2 hours. The reaction mixture was cooled to ambient
temperature and extracted with EtOAc/water. The organic layer was
dried over sodium sulfate, filtered and concentrated. The crude
material was purified by preparative TLC (2.0 mm eluting with
EtOAc). Isolated 0.113 g (32%) of the desired product. LRMS M+1
(614.1) observed.
[0864] Step C: tert-butyl
4-(4-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-car-
boxamido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-p-
yrazol-1-yl)piperidine-1-carboxylate: A 25 mL round-bottomed flask
was charged with
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(0.0840 g, 0.358 mmol obtained from Example 19, step C), EDCI
(0.0687 g, 0.358 mmol), HOBT (0.0549 g, 0.358 mmol), and DMF (5
mL). The reaction mixture was stirred for 30 minute and tert-butyl
4-(4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]p-
yridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.110 g,
0.179 mmol) and Hunig's base (0.0463 g, 0.358 mmol) were added. The
reaction mixture was stirred for 18 hours, then diluted with water
and extracted with EtOAc. The organic layer was dried over sodium
sulfate, filtered and concentrated. The crude material was purified
by preparative TLC (0.5 mm thickness) eluting with
CHCl.sub.3/MeOH(NH.sub.3 7N) 4:1. To the isolated product was added
TFA (2 mL) and the solution was heated to 70.degree. C. for 1 hour.
The solution was concentrated and triturated with DCM/MeOH 1:1. The
solids were collected by filtration to provide 5.1 mg (5%) of the
desired product. LRMS M+1 (610.0) observed.
Example 130
2-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-
-yloxy)phenylamino)-N-(4-fluorophenyl)nicotinamide
##STR00242##
[0866] Step A: 2-amino-N-(4-fluorophenyl)nicotinamide: A 1 L
round-bottomed flask was charged with HOBT-H.sub.2O (20.37 g, 133.0
mmol), EDCI (25.50 g, 133.0 mmol), 2-aminonicotinic acid (12.25 g,
88.69 mmol), and DMF (750 mL). The reaction mixture was stirred for
30 minutes, then Hunig's base (30.90 ml, 177.4 mmol) and
4-fluorobenzenamine (10.65 ml, 110.9 mmol) were added. The reaction
mixture was stirred for 18 hours, then diluted with water. After 30
minutes the resulting precipitate was collected by filtration and
dried to provide the product. LRMS M+1 (231.9) observed.
[0867] Step B:
2-(3-fluoro-4-methoxyphenylamino)-N-(4-fluorophenyl)nicotinamide: A
1 L round-bottomed flask was charged with cesium carbonate (11.1 g,
34.1 mmol), 4-bromo-2-fluoro-1-methoxybenzene (5.00 g, 24.4 mmol),
2-amino-N-(4-fluorophenyl)nicotinamide (7.61 g, 32.9 mmol), and
dioxane (250 mL). The reaction mixture was degassed with nitrogen
for 10 minutes, and Xanphos (0.564 g, 0.975 mmol) and Pd.sub.2
dba.sub.3 (0.670 g, 0.732 mmol) were added. The reaction mixture
was heated at 90.degree. C. for 48 hours. The reaction mixture was
cooled to ambient temperature and diluted with water. The reaction
mixture was extracted with EtOAc, dried over sodium sulfate,
filtered and concentrated. The crude material was purified by
silica gel chromatography (biotage 65) eluting with DCM/MeOH (3%).
Isolated 8.50 g (93%) of the product. LRMS M+1 (365.0)
observed.
[0868] Step C:
2-(3-fluoro-4-hydroxyphenylamino)-N-(4-fluorophenyl)nicotinamide: A
250 mL round-bottomed flask was charged with
2-(3-fluoro-4-methoxyphenylamino)-N-(4-fluorophenyl)nicotinamide
(8.00 g, 22.5 mmol) and DCM (75 mL). The reaction mixture was
cooled to 0.degree. C. and BBr.sub.3 (10.9 ml, 115 mmol) was added
dropwise over 5 minutes. The reaction mixture was stirred for 2
hours, then slowly quenched by pipetting the reaction into a flask
(500 mL) containing saturated NaHCO.sub.3 (20 mL), water (150 mL).
This solution was extracted with EtOAc. The organic layer was dried
and concentrated to provide the product 6.25 g (73%). LRMS M-1
(339.9) observed.
[0869] Step D:
2-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenylamino)-N-(4-fluorophenyl)nicotinamide: A 100 mL sealable
tube was charged with
1-(4-methoxybenzyl)-4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine
(0.250 g, 0.626 mmol Example 84, Step D),
2-(3-fluoro-4-hydroxyphenylamino)-N-(4-fluorophenyl)nicotinamide
(0.427 g, 1.25 mmol), cesium carbonate (0.408 g, 1.25 mmol), and
1-bromobenzene (6.26 ml, 0.626 mmol). The reaction mixture was
heated to 160.degree. C. for 18 hours. The reaction mixture was
cooled to ambient temperature and concentrated. The residue was
dissolved in EtOAc and washed with brine. The crude material was
purified by silica gel (Biotage 40S) eluting with 4:1 Hexane/EtOAc
to provide the product (0.35 g, 71%). LRMS M-1 (704.9)
observed.
[0870] Step E:
2-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-
-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(4-fluorophenyl)nicotinamide:
A 25 mL round-bottomed flask was charged with Cu(I)I (0.0108 g,
0.0568 mmol), 1-methylpiperidin-4-amine (0.0973 g, 0.852 mmol),
K.sub.2CO.sub.3 (0.196 g, 1.42 mmol), L-Proline (0.0131 g, 0.114
mmol) and DMSO (2.5 mL). The reaction mixture was stirred for 5
minutes and
2-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenylamino)-N-(4-fluorophenyl)nicotinamide (0.200 g, 0.284
mmol) in DMSO (2.5 mL) was added. The reaction mixture was heated
to 100.degree. C. for 18 hours. The reaction mixture was cooled to
ambient temperature and DCM and water (10 mL) were added. The
organic layer washed with brine, dried over sodium sulfate,
filtered and concentrated. The crude material was purified by
silica gel chromatography, eluting with EtOAc to provide the
product (23 mg, 11%). LRMS M-1 (691.2) observed.
[0871] Step F:
2-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin--
4-yloxy)phenylamino)-N-(4-fluorophenyl)nicotinamide: A 25 mL
round-bottomed flask was charged with
2-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-
-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(4-fluorophenyl)nicotinamide
(0.023 g, 0.0333 mmol) and TFA (3 mL). The reaction mixture was
heated to 70.degree. C. for 1 hour. The reaction was concentrated
and the residue was purified by preparative TLC [0.5 mm thickness
eluting with 15% MeOH(NH.sub.3)/CHCl.sub.3] to provide the product
(9 mg, 46%). LRMS M-1 (571.1) observed. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 10.56 (s, 1H), 10.12 (br s, 1H), 8.43 (m, 1H),
8.18 (m, 1H), 8.06 (m, 2H), 7.91 (m, 1H), 7.53 (m, 2H), 7.31 (m,
1H), 7.13 (m, 3H), 6.86 (m, 1H), 6.11 (m, 1H), 4.58 (d, J=7 Hz,
1H), 3.74 (br s, 1H), 2.92 (br s, 2H), 2.37 (s, 3H), 2.27 (br s,
2H), 1.72 (br s, 2H), 1.59 (br s, 1H). .sup.19F NMR (376 MHz,
CDCl.sub.3) .delta. -76.0 (3F), -117.0 (1F), -127.6 (1F).
Example 131
3-(4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxa-
mido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)cyclohexyl
2,2,2-trifluoroacetate
##STR00243##
[0873] Step A: Preparation of
3-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-ylamino)cyclohexanol: A suspension of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (100 mg, 0.204 mmol, obtained from Example 7, Step B),
3-aminocyclohexanol (70.5 mg, 0.612 mmol), Cu(I)I (7.77 mg, 0.0408
mmol), K.sub.2CO.sub.3 (141 mg, 1.02 mmol) and L-proline (9.39 mg,
0.082 mmol) was stirred in DMSO (5 mL) and heated to 100.degree. C.
for 12 hours. Water (5 mL) was added and the reaction mixture was
extracted with CH.sub.2Cl.sub.2. The organic layer washed with
water and brine, dried with Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by flash column
chromatography (5% MeOH in CH.sub.2Cl.sub.2) to afford the product
(47 mg, 48.3% yield) as a brown oil. LRMS (APCI pos) m/e 694.2
(M+H).
[0874] Step B: Preparation of N-(4-(1
(4-methoxybenzyl)-3-(3-hydroxycyclohexylamino)-dihydropyridazine-4-carbox-
amide: A solution of
3-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-ylamino)cyclohexanol (50 mg, 0.10 mmol),
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(74 mg, 0.31 mmol, obtained from Example 19 Step C), EDCI (120 mg,
0.63 mmol), Et.sub.3N (0.1 mL) and HOBT-H.sub.2O (96 mg, 0.63 mmol)
was stirred in DMF (1 mL) for 10 hours. The reaction mixture was
poured into water and extracted with CH.sub.2Cl.sub.2. The organic
layer washed with saturated aqueous NaHCO.sub.3, 10% aqueous LiCl,
dried with Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified with flash silica gel chromatography (5% MeOH in
CH.sub.2Cl.sub.2) to afford the product (35 mg, 48% yield) as a
brown solid. LRMS (APCI pos) m/e 694.2 (M+H).
[0875] Step C: Preparation of
3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carbox-
amido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)cyclohexyl
2,2,2-trifluoroacetate: A solution of
N-(4-(1-(4-methoxybenzyl)-3-(3-hydroxycyclohexylamino)-1H-pyrazolo[3,4-b]-
pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyrid-
azine-4-carboxamide (40 mg, 0.058 mmol) in TFA (1 mL) was heated to
50.degree. C. for 1 hour. Excess TFA was evaporated and the residue
was dissolved in EtOAc. The organic layer was then washed with
saturated aqueous NaHCO.sub.3, brine, dried with Na.sub.2SO.sub.4,
filtered and concentrated to afford the product (30 mg, 78% yield)
as a yellow solid. LRMS (APCI pos) m/e 670.2 (M+H). .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 12.20 (d, 1H), 11.70 (s, 1H), 8.38
(d, 1H), 8.26 (d, 1H), 8.12 (dd, 1H), 8.02 (dd, 1H), 7.66-7.70 (m,
2H), 7.56-7.62 (m, 1H), 7.46-7.52 (m, 1H), 7.38-7.44 (m, 2H), 6.02
(d, 2H), 5.20-5.40 (m, 1H), 3.60-3.80 (m, 1H), 2.20-2.30 (m, 1H),
2.00-2.10 (m, 2H), 1.80-1.90 (m, 2H), 1.60-1.80 (m, 2H), 1.30-1.45
(m, 1H).
Example 132
N-(3-fluoro-4-(3-(3-hydroxycyclohexylamino)-1H-pyrazolo[3,4-b]pyridin-4-yl-
oxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00244##
[0877] LiOH (2M solution, 2 drops) was added into a solution of
3-(4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carbox-
amido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)cyclohexyl
2,2,2-trifluoroacetate (10 mg, 0.015 mmol, obtained from Example
131, Step C) in THF (0.5 mL) and MeOH (0.1 mL). HCl (5M, 0.1 mL).
EtOAc was added to dilute the reaction mixture. The organic layer
was separated, washed with brine, dried with Na.sub.2SO.sub.4,
filtered and concentrated to afford the product (2.5 mg, 29% yield)
as a yellow solid. LRMS (APCI pos) m/e 574.2 (M+H). .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 8.38 (d, 1H), 8.26 (d, 1H), 8.12
(d, 1H), 8.05 (dd, 1H), 7.66-7.70 (m, 2H), 7.56-7.62 (m, 1H),
7.48-7.54 (m, 1H), 7.38-7.44 (m, 2H), 6.80-7.00 (m, 1H), 6.00-6.05
(m, 1H), 3.80-4.00 (m, 2H), 3.50-3.80 (m, 1H), 1.80-2.00 (m, 1H),
1.60-1.80 (m, 2H), 1.40-1.60 (m, 1H), 1.10-1.30 (m, 2H), 0.80-0.90
(m, 2H).
Example 133
Methyl
4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-car-
boxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate
##STR00245##
[0879] Step A: Preparation of methyl
4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxami-
do)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate:
To a suspension of
N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-flu-
orophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
(1.0 g, 1.42 mmol; prepared as in Example 7, Step B) in 1:2
DMF:MeOH (60 mL) was added triethylamine (0.434 ml, 3.11 mmol) and
1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.116 g,
0.142 mmol). The mixture was purged with N.sub.2(g) and CO(g) and
then held under balloon pressure CO(g). The mixture was heated at
70.degree. C. and stirred overnight (18 hours). The heat was
removed and the excess solvent was evaporated. Diethyl ether (100
mL) was added and the resulting solid removed by filtration to
afford the desired product as white solid. Yield (735 mg, 81%).
LRMS (APCI pos) m/e 639.1 (M+H).
[0880] Step B: Preparation of methyl
4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxami-
do)phenoxy)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate: Prepared
according to the procedure of Example 53, Step B, substituting
methyl
4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxami-
do)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate
(735 mg, 1.04 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. Purified by trituration with 10% MeOH/ether to afford
desired product as pale green solid. Yield 504 mg, 94%. .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 11.69 (s, 1H), 8.41 (d, 1H), 8.38 (d,
1H), 8.26 (d, 1H), 8.04 (dd, 1H), 7.69 (q, 2H), 7.57 (d, 1H), 7.41
(m, 3H), 6.51 (d, 1H), 3.85 (s, 3H). LRMS (APCI pos) m/e 519.1
(M+H).
Example 134
N-(3-fluoro-4-(3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylox-
y)phenyl)-3-oxo-2-(pyridin-2-yl)-2,3-dihydropyridazine-4-carboxamide
##STR00246##
[0882] Step A: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)-3-fluorophenyl)-3-oxo-2-(pyridin-2-yl)-2,3-dihydropyridazin-
e-4-carboxamide:
3-Oxo-2-(pyridin-2-yl)-2,3-dihydropyridazine-4-carboxylic acid
(0.0282 g, 0.130 mmol; prepared as in Example 141, Steps A-C) was
dissolved in 5 mL of CH.sub.2Cl.sub.2 and cooled to 0.degree. C.
HOBt (0.0351 g, 0.259 mmol), EDCI (0.0497 g, 0.259 mmol), and NMM
(0.0333 ml, 0.303 mmol) were added and the reaction mixture was
stirred under N.sub.2(g) for 15 minutes.
4-(1-(4-Methoxybenzyl)-3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyrid-
in-4-yloxy)-3-fluorobenzenamine (0.020 g, 0.0432 mmol; prepared
according to Example 86, Step A) in 2 mL of 1:1
CH.sub.2Cl.sub.2/DMF was added and the reaction was stirred at
ambient temperature for 5 hours. The mixture was partitioned
between EtOAc and aqueous NaHCO.sub.3. The organic layer washed
with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by silica gel column chromatography (Flash
5 g) eluting with 3% MeOH/CH.sub.2Cl.sub.2 to afford the desired
product as yellow semi-solid. Yield: 25.8 mg, 86%. LRMS (APCI pos)
m/e 662 (M+H).
[0883] Step B: Preparation of
N-(3-fluoro-4-(3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylo-
xy)phenyl)-3-oxo-2-(pyridin-2-yl)-2,3-dihydropyridazine-4-carboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting
N-(4-(1-(4-methoxybenzyl)-3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)-3-fluorophenyl)-3-oxo-2-(pyridin-2-yl)-2,3-dihydropyridazin-
e-4-carboxamide (25.8 mg, 0.039 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The residue was purified by trituration with diethyl
ether to afford desired product as yellow solid. Yield 14.7 mg,
69%. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.78 (s, 1H), 11.6 (s,
1H), 8.67 (d, 1H), 8.39 (d, 1H), 8.30 (d, 1H), 8.22 (d, 1H), 8.12
(m, 1H), 8.03 (dd, 1H), 7.73 (d, 1H), 7.64-7.57 (m, 2H), 7.51 (t,
1H), 6.18 (d, 1H). LRMS (APCI pos) m/e 542.3 (M+H).
Example 135
N-(3-fluoro-4-(3-((1,4-trans)-4-hydroxycyclohexylamino)-1H-pyrazolo[3,4-b]-
pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-c-
arboxamide
##STR00247##
[0885] Prepared by a 2-step process from
(1,4-trans)-4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazol-
o[3,4-b]pyridin-3-ylamino)cyclohexanol (prepared as described in
Example 101, Step A except using (1,4-trans)-4-aminocyclohexanol)
and 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic
acid according to the procedure of Example 101, Step B. The crude
was rinsed with Et.sub.2O to afford 28 mg (79%) of the desired
product. LRMS (APCI pos) m/e 574.3 (M+1). .sup.1H-NMR (400 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. 8.41 (d, 1H), 8.33 (d, 1H), 8.14 (m,
1H), 8.0 (dd, 1H), 7.65 (m, 2H), 7.46 (d, 1H), 7.36 (t, 1H), 7.28
(t, 2H), 6.10 (d, 1H), 3.63 (m, 2H), 2.27 (m, 2H), 2.02 (m, 2H),
1.47 (q, 2H), 1.37 (q, 2H); .sup.19F NMR (376 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. -113.0, -127.6.
Example 136
N-(3-fluoro-4-(3-((1,4-trans)-4-hydroxycyclohexylamino)-1H-pyrazolo[3,4-b]-
pyridin-4-yloxy)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-car-
boxamide
##STR00248##
[0887] Prepared by a 2-step process from
(1,4-trans)-4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazol-
o[3,4-b]pyridin-3-ylamino)cyclohexanol (prepared as described in
Example 101, Step A except using (1,4-trans)-4-aminocyclohexanol)
and 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid
according to the procedure of Example 101, Step B. The crude was
rinsed with Et.sub.2O to afford 24 mg (81%) of the desired product.
LRMS (ESIpos) m/e 574.1 (M+1). .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. 8.14 (d, 1H), 8.04 (dd, 1H), 7.92 (d, 1H), 7.79 (d, 1H),
7.61 (m, 2H), 7.53 (d, 1H), 7.51 (t, 1H), 7.40 (t, 2H), 6.11 (d,
1H), 3.60 (m, 2H), 2.21 (m, 2H), 1.99 (m, 2H), 1.40 (m, 4H);
.sup.19F NMR (376 MHz, CD.sub.3OD/CDCl.sub.3) .delta. -113.5,
-129.3.
Example 137
N-(3-fluoro-4-(3-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-
phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00249##
[0889] Step A: Preparation of tert-butyl
4-((4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyr-
idin-3-yl)methyl)piperidine-1-carboxylate: To a 10 mL reaction
flask was added tert-butyl 4-methylenepiperidine-1-carboxylate (81
mg, 0.411 mmol) and was purged with N.sub.2(g) three times. 9-BBN
(0.821 ml, 0.411 mmol) was added and the clear solution refluxed
(72.degree. C.) for 1 hour. The reaction was cooled to ambient
temperature and then added directly to a mixture of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (181 mg, 0.370 mmol; prepared as in Example 7, Step B),
1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (10.1 mg,
0.0123 mmol) and potassium carbonate (68.1 mg, 0.493 mmol) in
DMF:H.sub.2O (1 mL:0.1 mL). The dark orange mixture was stirred at
60.degree. C. for 6 hours, then cooled to ambient temperature and
poured into water. The pH was adjusted to 11 with 1N NaOH, and the
aqueous layer was extracted with ethyl acetate. The organic layer
was washed with brine, dried over Na.sub.2SO.sub.4, and evaporated.
The residue was purified by silica gel column chromatography
(Biotage 25M) eluting with 3% MeOH/CH.sub.2Cl.sub.2 to afford the
desired product. Yield: 25 mg, 11%. LRMS (APCI pos) m/e 562.1
(M+H).
[0890] Step B: Preparation of tert-butyl
4-((4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbo-
xamido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)-
piperidine-1-carboxylate: Prepared according to the procedure of
Example 82, Step B, substituting tert-butyl
4-((4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyr-
idin-3-yl)methyl)piperidine-1-carboxylate (25 mg, 0.045 mmol) for
tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperazine-1-carboxylate. The crude material was purified
by silica gel column chromatography (Isolute 10 g) eluting with 1%
MeOH/CH.sub.2Cl.sub.2 to afford the desired product as pale yellow
semi-solid. Yield: 12 mg, 35%. LRMS (APCI pos) m/e 778.4 (M+H).
[0891] Step C: Preparation of
N-(3-fluoro-4-(3-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy-
)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting tert-butyl
4-((4-(2-fluoro-4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbo-
xamido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)-
piperidine-1-carboxylate (12 mg, 0.0154 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The crude material was purified by trituration with 10%
MeOH/ether to afford desired product as yellow solid. Yield: 7.5
mg, 87%. .sup.1H NMR (400 MHz). LRMS (APCI pos) m/e 558.3
(M+H).
Example 138
N-(3-fluoro-4-(3-(1-(2-methoxyethyl)piperidin-4-ylamino)-1H-pyrazolo[3,4-b-
]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4--
carboxamide dihydrochloride
##STR00250##
[0893] Step A: Preparation of tert-butyl
1-(2-methoxyethyl)piperidin-4-ylcarbamate: A stirred mixture of
tert-butyl piperidin-4-ylcarbamate (1.1 g, 5.5 mmol),
1-bromo-2-methoxyethane (0.69 g, 5.0 mmol), potassium iodide (0.83
g, 5.0 mmol), K.sub.2CO.sub.3 (0.69 g, 5.0 mmol) and CH.sub.3CN (10
mL) was heated to 80.degree. C. in a sealed vessel for 18 hours.
After cooling to ambient temperature, the mixture was diluted with
EtOAc (15 mL) and water (15 mL). The phases were separated, and the
organic phase washed with water, brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated. The product was obtained as a waxy
solid (1.0 g, 77%).
[0894] Step B: Preparation of 1-(2-methoxyethyl)piperidin-4-amine:
A mixture of tert-butyl 1-(2-methoxyethyl)piperidin-4-ylcarbamate
(0.842 g, 3.26 mmol) and 2,2,2-trifluoroacetic acid (2.51 ml, 32.6
mmol) was stirred for 15 minutes at ambient temperature. The
mixture was concentrated in vacuo, using toluene (2.times.10 mL) to
azeotrope residual TFA. The crude TFA salt of the product was
converted to the free base using Biotage Flash 40M flash
chromatography, eluting with 10% MeOH (containing 7N NH.sub.3) in
DCM (500 mL), followed by 20% MeOH (containing 7N NH.sub.3) in DCM
(500 mL). The product was obtained as an oil (195 mg, 37%).
[0895] Step C: Preparation of
1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-(2-methoxyethyl)pipe-
ridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine: A mixture of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (0.123 g, 0.25 mmol, prepared according to Example 7,
Step B), 1-(2-methoxyethyl)piperidin-4-amine (0.119 g, 0.750 mmol),
copper(I)iodide (0.00952 g, 0.0500 mmol),
(S)-pyrrolidine-2-carboxylic acid (0.0115 g, 0.100 mmol),
K.sub.2CO.sub.3 (0.173 g, 1.25 mmol), and DMSO (0.5 mL) was stirred
at 100.degree. C. for 3 days in a sealed vessel. The reaction was
partitioned between EtOAc and water. The phases were separated and
the aqueous phase was re-extracted with EtOAc. The combined organic
phases were washed with water, dried (Na.sub.2SO.sub.4), filtered,
and concentrated. The crude was purified by preparative TLC (1 mm
thickness) eluting with 10% MeOH/CHCl.sub.3. Yield: 42 mg (32%).
LRMS (APCI+): 100% purity, 220 nm, m/z 521 (M+1) detected.
[0896] Step D: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-(1-(2-methoxyethyl)piperidin-4-ylamino)-1H-py-
razolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-
-dihydropyridazine-4-carboxamide: EDCI (47 mg, 0.24 mmol) was added
to a stirred mixture of
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(57 mg, 0.24 mmol, prepared according to the procedure for Example
19, Step C), HOBt-hydrate (38 mg, 0.24 mmol), and DIEA (0.070 mL,
0.404 mmol) in DCM (1 mL) at ambient temperature, and the reaction
was stirred for 15 minutes at ambient temperature.
1-(4-Methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-(2-methoxyethyl)pipe-
ridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (42 mg, 0.0807 mmol)
was added, and the resulting solution was stirred for 2 days at
ambient temperature. The crude reaction mixture was loaded directly
on to a preparative TLC plate (2 mm thickness) and eluted with 10%
MeOH/DCM. The product was obtained as a waxy solid (45 mg, 76%).
LRMS (APCI+): 100% purity, 220 nm, m/z 737 (M+1) detected.
[0897] Step E: Preparation of
N-(3-fluoro-4-(3-(1-(2-methoxyethyl)piperidin-4-ylamino)-1H-pyrazolo[3,4--
b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-
-carboxamide dihydrochloride: A stirred mixture of
N-(4-(1-(4-methoxybenzyl)-3-(1-(2-methoxyethyl)piperidin-4-ylamino)-1H-py-
razolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-
-dihydropyridazine-4-carboxamide (45 mg, 0.0611 mmol) and
2,2,2-trifluoroacetic acid (0.471 ml, 6.11 mmol) were heated to
60.degree. C. in a sealed vessel for 18 hours. After cooling to
ambient temperature, the reaction was concentrated in vacuo, using
toluene to azeotrope residual TFA (2.times.5 mL). The crude was
partitioned between DCM and saturated aqueous NaHCO.sub.3. The
phases were separated, and the aqueous phase was re-extracted with
DCM. The combined organic phases were dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The resulting crude was
re-dissolved in DCM, and purified by Biotage Flash 40S, eluting
with 5% MeOH/DCM (500 mL), 10% MeOH/DCM (500 mL), and then 15%
MeOH/DCM (500 mL). The resulting free base (21 mg) was dissolved in
DCM (1 mL) and MeOH (0.2 mL) and 2N HCl in ether (0.5 mL) was
added. The mixture was concentrated in vacuo, using absolute EtOH
(3.times.5 mL) to azeotropically remove residual solvents. The
product was obtained as a pale yellow powder (23 mg, 54%). HPLC:
98% purity (220 nm); LRMS (APCI+): 100% purity, 220 nm, m/z 617
(M+1) detected; .sup.1H NMR (400 MHz, MeOD-d3) .delta. 12.0 (s,
1H), 8.36 (m, 3H), 8.12 (m, 1H), 7.68 (m, 2H), 7.55 (m, 2H), 7.29
(m, 2H), 6.38 (m, 1H), 3.94 (m, 1H), 3.75 (m, 3H), 3.42 (m, 6H),
3.22 (m, 1H), 2.42 (m, 2H), 2.26 (m, 1H), 2.07 (m, 2H).
Example 139
N-(3-fluoro-4-(3-(1-(2-fluoroethyl)piperidin-4-ylamino)-1H-pyrazolo[3,4-b]-
pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-c-
arboxamide dihydrochloride
##STR00251##
[0899] Step A: Preparation of tert-butyl
1-(2-fluoroethyl)piperidin-4-ylcarbamate: To a stirred mixture of
tert-butyl piperidin-4-ylcarbamate (1.00 g, 5.0 mmol) and
1-bromo-2-fluoroethane (0.952 g, 7.50 mmol) in DMF (10 mL) was
added NaH (0.180 g, 7.50 mmol) at ambient temperature. The mixture
was heated to 50.degree. C. for 18 hours under N.sub.2. After
cooling to ambient temperature, the mixture was diluted with EtOAc
and water. The phases were separated, and the organic phase was
washed with water, brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The product was obtained as a waxy solid (1.05 g,
84%).
[0900] Step B: Preparation of 1-(2-fluoroethyl)piperidin-4-amine:
Prepared from tert-butyl 1-(2-fluoroethyl)piperidin-4-ylcarbamate
(1.05 g, 4.26 mmol) according to the procedure described for
Example 138, Step B. The product was obtained as an oil (444 mg,
70%).
[0901] Step C: Preparation of
1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-(2-fluoroethyl)piper-
idin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine: Prepared from
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (245 mg, 0.500 mmol, prepared according to Example 7,
Step B) and 1-(2-fluoroethyl)piperidin-4-amine (219 mg, 1.50 mmol)
according to the procedure described for Example 138, Step C.
Yield: 128 mg (50%). LRMS (APCI+): 100% purity, 220 nm, m/z 509
(M+1) detected.
[0902] Step D: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-(1-(2-fluoroethyl)piperidin-4-ylamino)-1H-pyr-
azolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3--
dihydropyridazine-4-carboxamide: Prepared from
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(177 mg, 0.755 mmol, prepared according to the procedure for
Example 19, Step C) and
1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-(2-fluoroethyl)p-
iperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (128 mg, 0.252
mmol) according to the procedure for Example 138, Step D. The
product was obtained as a waxy solid (145 mg, 80%). LRMS (APCI+):
100% purity, 220 nm, m/z 725 (M+1) detected.
[0903] Step E: Preparation of
N-(3-fluoro-4-(3-(1-(2-fluoroethyl)piperidin-4-ylamino)-1H-pyrazolo[3,4-b-
]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4--
carboxamide dihydrochloride: Prepared from
N-(4-(1-(4-methoxybenzyl)-3-(1-(2-fluoroethyl)piperidin-4-ylamino)-1H-pyr-
azolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3--
dihydropyridazine-4-carboxamide (145 mg, 0.200 mmol) according to
the procedure for Example 138, Step E. The product was obtained as
a pale yellow powder (83 mg, 60%). HPLC: 98% purity (220 nm); LRMS
(APCI+): 100% purity, 220 nm, m/z 605 (M+1) detected; .sup.1H NMR
(400 MHz, MeOD-d3) .delta. 11.98 (s, 1H), 8.32 (m, 4H), 8.10 (d,
J=12 Hz, 1H), 7.67 (m, 2H), 7.54 (m, 2H), 7.29 (m, 2H), 6.38 (d,
J=6 Hz, 1H), 4.95 (m, 2H), 3.97 (m, 1H), 3.76 (m, 2H), 3.61 (m,
4H), 2.42 (m, 3H), 2.13 (m, 2H).
Example 140
N-(3-fluoro-4-(3-(4-(2-methoxyethyl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyri-
din-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbo-
xamide
##STR00252##
[0905] Step A: Preparation of tert-butyl
4-(2-methoxyethyl)piperazine-1-carboxylate: Prepared from
tert-butyl piperazine-1-carboxylate (1.02 g, 5.50 mmol) and
1-bromo-2-methoxyethane (0.695 g, 5.0 mmol) according to the
procedure described for Example 138, Step A. The product was
obtained as a waxy solid (11.10 g, 89%).
[0906] Step B: Preparation of 1-(2-methoxyethyl)piperazine:
Prepared from tert-butyl 4-(2-methoxyethyl)piperazine-1-carboxylate
(1.10 g, 4.50 mmol) according to the procedure for Example 138,
Step B. The product was obtained as an oil (246 mg, 38%).
[0907] Step C: Preparation of
4-(1-(4-methoxybenzyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)-3-fluorobenzenamine: Prepared from
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (20 mg, 0.0408 mmol, prepared according to Example 7,
Step B) and 1-(2-methoxyethyl)-piperazine (17.6 mg, 0.122 mmol)
according to the procedure described for Example 138, Step C.
Yield: 12 mg (51%).
[0908] Step D: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihy-
dropyridazine-4-carboxamide: EDCI (27 mg, 0.14 mmol) was added to a
stirred mixture of
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(11 mg, 0.047 mmol, prepared according to the procedure described
for Example 19, Step C) and HOBt-hydrate (22 mg, 0.14 mmol) in DMF
(0.3 mL) at ambient temperature, and the reaction mixture was
stirred for 15 minutes at ambient temperature.
4-(1-(4-Methoxybenzyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (12 mg, 0.024 mmol) and
triethylamine (0.020 ml, 0.14 mmol) were then added, and the
resulting mixture was stirred for 18 hours at ambient temperature.
The reaction mixture was diluted with EtOAc and washed with water.
The aqueous phase was re-extracted with EtOAc. The combined organic
phases were washed with water, dried (Na.sub.2SO.sub.4), filtered,
and concentrated in vacuo. The crude material was purified by
preparative TLC (0.5 mm) and eluted with 15% MeOH/DCM (Rf=0.74).
The product was obtained as a waxy solid (2 mg, 10%).
[0909] Step E: Preparation of
N-(3-fluoro-4-(3-(4-(2-methoxyethyl)piperazin-1-yl)-1H-pyrazolo[3,4-b]pyr-
idin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carb-
oxamide: A stirred mixture of
N-(4-(1-(4-methoxybenzyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihy-
dropyridazine-4-carboxamide (2 mg, 0.002767 mmol), and
2,2,2-trifluoroacetic acid (0.2132 ml, 2.767 mmol) was heated to
60.degree. C. in a sealed vessel for 18 hours. After cooling to
ambient temperature, the reaction was concentrated in vacuo, using
toluene to azeotrope residual TFA. The resulting residue was
dissolved in DCM, and purified by preparative TLC (0.5 mm
thickness, Rf=0.50), eluting with 10% MeOH (containing 7N NH.sub.3)
in DCM. The product was obtained as a pale yellow powder (1 mg,
48%). HPLC: 89% purity (220 nm); LRMS (APCI+): 100% purity, 220 nm,
m/z 603 (M+1) detected; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
11.87 (s, 1H), 9.81 (s, 1H), 8.44 (m, 1H), 8.26 (m, 2H), 7.98 (m,
1H), 7.63 (m, 2H), 7.42 (m, 1H), 7.28 (m, 3H), 6.22 (m, 1H), 3.75
(m, 1H), 3.61 (m, 3H), 3.39 (s, 3H), 2.73 (m, 4H), 1.5-2.2 (m,
4H).
Example 141
N-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-
-yloxy)phenyl)-3-oxo-2-(pyridin-2-yl)-2,3-dihydropyridazine-4-carboxamide
##STR00253##
[0911] Step A: Preparation of
(E)-2-(2-(pyridin-2-yl)hydrazono)acetaldehyde: A mixture of the
1-(pyridin-2-yl)hydrazine (2.00 g, 18.33 mmol), water (13 mL), and
acetic acid (10.49 ml, 183.3 mmol) was added with stirring into a
40% aqueous solution of glyoxal (10.51 ml, 91.63 mmol) over 20
minutes. Stirring was continued for 18 hours and then the aqueous
was extracted with EtOAc. The diluted aqueous layer was slowly
basified with sodium hydrogen carbonate (15.40 g, 183.3 mmol). The
resulting solids were collected by filtration and washed with water
to afford 1.65 g (85%) of the desired product and dimer. LRMS (apci
pos): 150 (M+H).
[0912] Step B: Preparation of
(E)-2,2-dimethyl-5-(2-(2-(pyridin-2-yl)hydrazono)ethylidene)-1,3-dioxane--
4,6-dione: A suspension of dioxan-dione (0.676 g, 4.69 mmol) and
(E)-2-(2-(pyridin-2-yl)hydrazono)acetaldehyde (0.700 g, 4.69 mmol)
in toluene (20 mL) was treated with acetic acid (10 drops) and
piperidine (10 drops). The reaction mixture was then stirred at
room temp for 17 hours. The precipitate was filtered and thoroughly
washed with light petroleum to afford 174.6 mg (12%) of the desired
product. LRMS (apci pos): 276 (M+H).
[0913] Step C: Preparation of
3-oxo-2-(pyridin-2-yl)-2,3-dihydropyridazine-4-carboxylic acid: A
mixture of
(E)-2,2-dimethyl-5-(2-(2-(pyridin-2-yl)hydrazono)ethylidene)-1,3-dioxa-
ne-4,6-dione (0.050 g, 0.182 mmol) and NaOMe (0.0118 g, 0.218 mmol)
in MeOH (6 mL) was heated under reflux for 15 hours. The salt was
treated with cold 1 N HCl solution, extracted with DCM, dried over
MgSO.sub.4, and concentrated to afford 17.6 mg (45%) of the desired
product. LRMS (apci pos): 218 (M+H).
[0914] Step D: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-
-b]pyridin-4-yloxy)-3-fluorophenyl)-3-oxo-2-(pyridin-2-yl)-2,3-dihydropyri-
dazine-4-carboxamide: To a 50 mL round bottom flask charged with
3-oxo-2-(pyridin-2-yl)-2,3-dihydropyridazine-4-carboxylic acid
(0.0273 g, 0.126 mmol) in 2 mL of DCM was added HOBt (0.0340 g,
0.252 mmol), EDCI (0.0483 g, 0.252 mmol), and NMM (0.0323 ml, 0.294
mmol) at 0.degree. C. The reaction mixture was stirred under
N.sub.2 for 15 minutes, and then
1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-methylpiperidin-4-yl-
)-1H-pyrazolo[3,4-b]pyridin-3-amine (0.020 g, 0.0420 mmol, prepared
according to procedure of Example 101, Step A) in 1 mL DCM was
added. The reaction was stirred for 18 hours, then diluted with DCM
and washed with NaHCO.sub.3 and brine. The organic layer was dried
over Na.sub.2SO.sub.4, filtered and concentrated. The crude
material was purified by flash silica gel chromatography, eluting
with 1-3% MeOH/DCM up to 90:9:1 DCM:MeOH:NH.sub.4OH to afford 43 mg
of a yellow residue, which was further purified on a Horizon 12M
eluting with 20-60% ACN/H.sub.2O to afford 10 mg (35%) of desired
product. LRMS (apci pos) 676 (M+H).
[0915] Step E: Preparation of
N-(3-fluoro-4-(3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin--
4-yloxy)phenyl)-3-oxo-2-(pyridin-2-yl)-2,3-dihydropyridazine-4-carboxamide-
: A stirred mixture of
N-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-
-b]pyridin-4-yloxy)-3-fluorophenyl)-3-oxo-2-(pyridin-2-yl)-2,3-dihydropyri-
dazine-4-carboxamide (0.014 g, 0.02072 mmol) and
2,2,2-trifluoroacetic acid (TFA) (0.1596 ml, 2.072 mmol) was heated
to 60.degree. C. for 18 hours under N.sub.2. The mixture was
concentrated in vacuo using toluene (3.times.5 mL) to azeotrope
residual TFA. The residue was partitioned between saturated aqueous
NaHCO.sub.3 and EtOAc. The phases were separated, and the organic
phase washed with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo. The residue was triturated with ether and
decanted to obtain the product as a brown powder (10 mg, 86%). LRMS
(apci pos): >99% purity, 220 nm, m/z 556 (M+H); .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 11.77 (s, 1H), 8.74 (m, 1H), 7.44 (d, 1H),
8.28 (d, 1H), 8.02 (m, 2H), 7.66 (d, 1H), 7.53 (t, 1H), 7.42 (m,
1H), 7.24 (m, 1H), 6.10 (br s, 1H), 4.55 (bd, 1H), 3.80 (br s, 1H),
3.16 (br s, 2H), 2.44 (m, 10H); .sup.19F NMR (376 MHz, CDCl.sub.3)
.delta. -125.2 (m).
Example 142
N-(4-(3-(1-ethylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3--
fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00254##
[0917] Prepared by a 2-step process from
4-(4-amino-2-fluorophenoxy)-N-(1-ethylpiperidin-4-yl)-1-(4-methoxybenzyl)-
-1H-pyrazolo[3,4-b]pyridin-3-amine (prepared as described in
Example 101, Step A except using 1-ethylpiperidin-4-amine) and
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
according to the procedure of Example 101, Step B. The crude was
rinsed with Et.sub.2O to afford 16 mg with HCl salt (76%) of the
desired product. LRMS (APCI pos) m/e 587.2 (M+1). .sup.1H NMR (400
MHz, CD.sub.3OD/CDCl.sub.3) .delta. 8.40 (d, 1H), 8.34 (d, 1H),
8.30 (m, 1H), 8.10 (d, 1H), 7.66 (m, 2H), 7.53 (m, 1H), 7.48 (m,
1H), 7.29 (t, 2H), 6.35 (d, 1H), 4.0 (m, 1H), 3.68 (m, 2H), 3.23
(m, 2H), 3.14 (m, 2H), 2.43 (m, 2H), 2.10 (m, 2H), 1.41 (m, 3H);
.sup.19F NMR (376 MHz, CD.sub.3OD/CDCl.sub.3) .delta. -113.7,
-128.1.
Example 143
N-(3-fluoro-4-(3-(1-isopropylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridi-
n-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxa-
mide
##STR00255##
[0919] Prepared by a 2-step process from
4-(4-amino-2-fluorophenoxy)-N-(1-isopropyl
piperidin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-amine
(prepared as described in Example 101, Step A except using
1-isopropylpiperidin-4-amine) and
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
according to the procedure of Example 101, Step B. The crude was
rinsed with Et.sub.2O to afford 14 mg with HCl salt (76%) of the
desired product. LRMS (APCI pos) m/e 601.3 (M+1). .sup.1H NMR (400
MHz, CD.sub.3OD/CDCl.sub.3) .delta. 8.41 (d, 1H), 8.33 (d, 1H),
8.15 (m, 1H), 8.01 (dd, 1H), 7.64 (m, 2H), 7.47 (m, 1H), 7.36 (t,
1H), 7.28 (t, 2H), 6.12 (d, 1H), 3.83 (m, 1H), 3.23 (m, 3H), 2.82
(m, 2H), 2.34 (m, 2H), 1.83 (m, 2H), 1.27 (m, 6H); .sup.19F NMR
(376 MHz, CD.sub.3OD/CDCl.sub.3) .delta. -112.8, -127.6.
Example 144
N-(3-fluoro-4-(3-(4-methylpiperazine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridin-
-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxam-
ide
##STR00256##
[0921] Step A: Preparation of
3-fluoro-4-(3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline:
Dissolved
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (50 mg, 0.102 mmol; prepared as in Example 7, Step B)
in excess TFA (1 mL). The dark solution was stirred at 50.degree.
C. for (20 hours. The mixture was concentrated in vacuo, using
toluene (2.times.5 mL) to azeotrope residual TFA. The crude was
partitioned between CH.sub.2Cl.sub.2 and NaHCO.sub.3. The cloudy
organic layer was evaporated and the resulting semi-solid
triturated with diethyl ether to afford the desired product. Yield:
33 mg, 87%. LRMS (APCI pos) m/e 371.1 (M+H).
[0922] Step B: Preparation of
(4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)(4-methylpipe-
razin-1-yl)methanone:
3-Fluoro-4-(3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (30
mg, 0.0811 mmol) was dissolved in DMF (1 mL), and
1-methylpiperazine (0.045 ml, 0.405 mmol) and
1,1'-bis(diphenylphosphino) ferrocenedichloropalladium(II) (6.67
mg, 0.0081 mmol) were added. The reaction mixture was purged with
N.sub.2(g) followed by CO(g) and then held under balloon pressure
of CO(g). The mixture was stirred at 70.degree. C. for 18 hours.
The crude mixture was partitioned between ethyl acetate and water.
The organic layer washed with brine, dried over Na.sub.2SO.sub.4
and evaporated to afford crude product. The residue was purified by
silica gel column chromatography (Biotage 12M) eluting with 5%
MeOH/CHCl.sub.3 to afford the desired product. Yield: 14 mg at 80%
purity, 37%. LRMS (APCI pos) m/e 371.1 (M+H).
[0923] Step C: Preparation of
N-(3-fluoro-4-(3-(4-methylpiperazine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridi-
n-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxa-
mide: Prepared according to the procedure of Example 82, Step B,
substituting
(4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)(4-methylpipe-
razin-1-yl)methanone (14 mg, 0.0302 mmol) for tert-butyl
4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperazine-1-carboxylate. The crude material was purified
by preparative TLC (1 mm thickness) eluting with 5%
MeOH/CH.sub.2Cl.sub.2. The di-HCl salt was prepared with 2N
HCl/ether to afford the desired product as white solid. Yield: 4.3
mg, 22%. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.71 (s, 1H), 8.38
(d, 1H), 8.36 (d, 1H), 8.26 (d, 1H), 8.05 (dd, 1H), 7.69 (q, 2H),
7.62 (d, 1H), 7.50 (t, 1H), 7.41 (t, 2H), 6.34 (d, 1H), 3.89 (broad
s, 8H). LRMS (APCI pos) m/e 587.1 (M+H).
Example 145
.+-.N-(3-fluoro-4-(3-((3R*,4S*)-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazin-
e-4-carboxamide dihydrochloride
##STR00257##
[0925] Step A: Preparation of .+-.(3R*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-ylamino)-3-fluoropiperidine-1-carboxylate: A mixture of
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (0.123 g, 0.25 mmol, prepared according to Example 7,
Step B), .+-.(3S*,4R*)-tert-butyl
4-amino-3-fluoropiperidine-1-carboxylate (0.164 g, 0.750 mmol,
prepared according to WO 2006/087543), copper(I)iodide (0.00952 g,
0.0500 mmol), (S)-pyrrolidine-2-carboxylic acid (0.0115 g, 0.100
mmol), K.sub.2CO.sub.3 (0.173 g, 1.25 mmol), and DMSO (1 mL) was
stirred at 100.degree. C. for 3 days. The reaction was partitioned
between EtOAc and water. The phases were separated and the aqueous
phase was re-extracted with EtOAc (5 mL). The combined organic
phases were washed with water, dried (Na.sub.2SO.sub.4), filtered,
and concentrated. The crude was purified by preparative TLC (1 mm
thickness, Rf=0.56) eluting with 10% MeOH/CHCl.sub.3. LRMS (APCI+):
m/z 581 (M+1) detected.
[0926] Step B: Preparation of .+-.(3R*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3--
fluoropiperidine-1-carboxylate: EDCI (43.6 mg, 0.227 mmol) was
added to a stirred mixture of
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(53.2 mg, 0.227 mmol, prepared according to the procedure for
Example 19, Step C), HOBt-hydrate (34.8 mg, 0.227 mmol) and DIEA
(0.0792 ml, 0.455 mmol) in DCM (1 mL) at ambient temperature, and
the reaction mixture was stirred for 15 minutes at ambient
temperature. .+-.(3R*,4S*)-tert-Butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-ylamino)-3-fluoropiperidine-1-carboxylate (66 mg, 0.114 mmol)
was then added. The resulting solution was stirred for 18 hours at
ambient temperature. To a separate 1 dram vial was added an
additional equivalent of the
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid,
HOBt, DIEA, and EDCI in DCM (0.5 mL). This mixture was stirred for
15 minutes, then added to the original reaction mixture, which was
stirred for an additional day at ambient temperature. The crude
reaction mixture was loaded directly on to a preparative TLC plate
(2 mm thickness) and eluted with 10% MeOH/DCM (Rf=0.70). A second
preparative TLC plate (1 mm thickness, Rf=0.17) eluting with 1:1
EtOAc/hexanes was utilized to obtain pure product (35 mg, 39%)
[0927] Step C: Preparation of
.+-.N-(3-fluoro-4-(3-((3R*,4S*)-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[-
3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazi-
ne-4-carboxamide dihydrochloride: A stirred mixture of
.+-.(3R*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3--
fluoropiperidine-1-carboxylate (35 mg, 0.0439 mmol), and
2,2,2-trifluoroacetic acid (0.338 ml, 4.39 mmol) was heated to
80.degree. C. in a sealed vessel for 2 hours. The reaction was
concentrated in vacuo, using toluene (2.times.5 mL) to azeotrope
residual TFA. The resulting residue was dissolved in DCM, and
purified by preparative TLC (0.5 mm thickness, Rf=0.13), eluting
with 20% MeOH/DCM. The purified product was re-dissolved in DCM (1
mL) and acidified with 2N HCl in diethyl ether (0.5 mL). The
solvent and excess HCl was removed in vacuo, using EtOH to
azeotrope (3.times.5 mL). The product was obtained as a pale yellow
powder (12 mg, 40%). HPLC: 96% purity (220 nm); LRMS (ESI+): 100%
purity, 220 nm, m/z 577 (M+1) detected; .sup.1H NMR (400 MHz,
MeOD-d.sub.3) .delta. 11.99 (s, 1H), 8.32 (m, 3H), 8.10 (d, J=12
Hz, 1H), 7.68 (m, 2H), 7.54 (m, 2H), 7.30 (m, 2H), 6.42 (d, J=6 Hz,
1H), 5.26 (m, 1H), 4.26 (m, 1H), 3.78 (m, 1H), 3.54 (m, 3H), 2.27
(m, 2H).
Example 146
.+-.N-(3-fluoro-4-(3-((3S*,4S*)-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazin-
e-4-carboxamide dihydrochloride
##STR00258##
[0929] Step A: Preparation of .+-.(3S*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-ylamino)-3-fluoropiperidine-1-carboxylate: Prepared from
4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (0.123 g, 0.25 mmol, prepared according to Example 7,
Step B), and .+-.(3S*,4S*)-tert-butyl
4-amino-3-fluoropiperidine-1-carboxylate (0.164 g, 0.750 mmol,
prepared according to the procedure described in WO 2006/087543)
according to the procedure described for Example 143, Step A. LRMS
(APCI+): m/z 581 (M+1) detected.
[0930] Step B: Preparation of .+-.(3S*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3--
fluoropiperidine-1-carboxylate: Prepared from
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(50.8 mg, 0.217 mmol, prepared according to the procedure for
Example 19, Step C) and .+-.(3S*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-ylamino)-3-fluoropiperidine-1-carboxylate (63 mg, 0.109 mmol)
according to the procedure described for Example 143, Step B.
Yield: 17 mg (20%).
[0931] Step C: Preparation of
.+-.N-(3-fluoro-4-(3-((3S*,4S*)-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[-
3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazi-
ne-4-carboxamide dihydrochloride: Prepared from
.+-.(3S*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3--
fluoropiperidine-1-carboxylate (17 mg, 0.0213 mmol) and
2,2,2-trifluoroacetic acid (0.164 ml, 2.13 mmol) according to the
procedure described for Example 143, Step C. The product was
obtained as a pale yellow powder (9 mg, 63%). HPLC: 97% purity (220
nm); LRMS (ESI+):100% purity, 220 nm, m/z 577 (M+1) detected;
.sup.1H NMR (400 MHz, MeOD-d3) .delta. 11.99 (s, 1H), 8.36 (d, J=4
Hz, 1H), 8.32 (m, 2H), 8.11 (d, J=12 Hz, 1H), 7.68 (m, 2H), 7.54
(m, 2H), 7.29 (t, J=9 Hz, 2H), 6.41 (d, J=6 Hz, 1H), 5.27 (m, 1H),
5.15 (m, 1H), 4.23 (m, 1H), 3.70 (m, 1H), 3.47 (m, 1H), 3.41 (m,
1H), 3.25 (m, 1H), 2.46 (m, 1H), 2.18 (m, 1H).
Example 147
N-(3-fluoro-4-(3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00259##
[0933] Step A: Preparation of
3-Fluoro-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)aniline:
4-(1-(4-Methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (200 mg, 0.408 mmol, prepared in Example 7, step B),
1-methyl-2-(tributylstannyl)-1H-imidazole (908.4 mg, 2.45 mmol),
tetrakis (triphenylphosphine) palladium (94.28 mg, 0.0816 mmol) and
toluene (4 mL) were charged in a 25 mL, single-neck, round-bottomed
flask. The reaction mixture was stirred at 60.degree. C. until the
starting material had been consumed (4 hours). Then the reaction
mixture was cooled to room temperature and partitioned between
EtOAc (100 mL) and H.sub.2O (50 mL). The phases were separated, and
the aqueous phase was re-extracted with EtOAc (3.times.50 mL). The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated to yield a crude product. The crude product was
purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 100/1 to 10/1, v/v) to afford product (0.143 g, 79%). LRMS
(APCI pos): >99% purity, 254 nm, m/e 445 (M+1). .sup.1H NMR (400
MHz, CDCl.sub.3).delta. 8.31 (m, 1H), 7.71 (m, 1H), 7.50 (m, 1H),
7.35 (m, 2H), 6.94 (m, 1H), 6.84 (m, 2H), 6.50 (m, 1H), 6.43 (m,
1H), 6.28 (d, 1H), 5.64 (s, 2H), 3.90 (s, 3H), 3.75 (s, 3H), 3.67
(s, 2H, NH.sub.2).
[0934] Step B: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyri-
dazine-4-carboxamide:
4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)-3-fluorobenzenamine (143.2 mg, 0.322 mmol),
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(377.3 mg, 1.61 mmol, prepared in Example 19, step C),
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (308.8 mg, 1.61 mmol), 1H-benzo[d][1,2,3]triazol-1-ol
(217.7 mg, 1.61 mmol), N-ethyl-N-isopropylpropan-2-amine (208.2 mg,
1.61 mmol) and CH.sub.2Cl.sub.2 (5 mL) were charged in a 25 mL,
single-neck, round-bottomed flask. The reaction mixture was stirred
at room temperature until the starting material had been consumed
(overnight). Then the reaction mixture was partitioned between
EtOAc (50 mL) and H.sub.2O (50 mL). The phases were separated and
the aqueous phase was re-extracted with EtOAc (3.times.50 mL). The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated to yield a crude product. The crude product was
purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 100/1 to 10/1, v/v) to afford product (127 mg, 59.67%). LRMS
(APCI pos): >99% purity, 254 nm, m/e 661 (M+1).
[0935] Step C: Preparation of
N-(3-fluoro-4-(3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide-
:
N-(4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-imidazol-2-yl)-1H-pyrazolo[3,4--
b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyr-
idazine-4-carboxamide (127 mg, 0.192 mmol) and TFA (2 mL) were
charged in a 50 mL single-neck, round-bottomed flask. The reaction
mixture was stirred at 60.degree. C. until the starting material
had been consumed (overnight). Then the reaction was cooled to room
temperature and the CF.sub.3COOH was removed under reduced
pressure. The residue was partitioned between DCM (50 mL) and
saturated NaHCO.sub.3 (50 mL). The phases were separated and the
aqueous phase was extracted with DCM (3.times.50 mL). The combined
organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated to yield a crude product. The crude product was
purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 100/1 to 10/1, v/v) to afford product (62.5 mg, 60.2%). LRMS
(APCI pos): >99% purity, 254 nm, m/e 541 (M+1). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 14.01 (s, 1H), 11.71 (s, 1H), 8.37 (m,
2H), 8.27 (d, 1H), 8.06 (m, 1H), 7.76 (d, 1H), 7.68 (m, 2H),
7.52-7.63 (m, 2H), 7.47 (d, 1H), 7.41 (m, 2H), 6.36 (d, 1H), 3.31
(s, 3H).
Example 148
.+-.N-(4-(3-((3R*,4S*)-1-ethyl-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[3,-
4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydrop-
yridazine-4-carboxamide dihydrochloride
##STR00260##
[0937] Step A: Preparation of
.+-.N-(4-(1-(4-methoxybenzyl)-3-((3R*,4S*)-3-fluoropiperidin-4-ylamino)-1-
H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-
-2,3-dihydropyridazine-4-carboxamide bis-trifluoroacetic acid salt:
A mixture of .+-.(3R*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3--
fluoropiperidine-1-carboxylate (58 mg, 0.0728 mmol) prepared
according to Example 145, Step B and 2,2,2-trifluoroacetic acid
(0.280 ml, 3.64 mmol) was stirred for 5 minutes at room temperature
under N.sub.2. The mixture was concentrated in vacuo, using toluene
to azeotrope (3.times.5 mL) residual TFA. The crude product was
carried forward as a TFA salt without purification at this step.
LRMS (APCI+): m/z 697 (M+1) detected.
[0938] Step B: Preparation of
.+-.N-(4-(1-(4-methoxybenzyl)-3-((3R*,4S*)-1-ethyl-3-fluoropiperidin-4-yl-
amino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluoropheny-
l)-3-oxo-2,3-dihydropyridazine-4-carboxamide: A mixture of
.+-.N-(4-(1-(4-methoxybenzyl)-3-((3R*,4S*)-3-fluoropiperidin-4-ylamino)-1-
H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-
-2,3-dihydropyridazine-4-carboxamide bis-trifluoroacetic acid salt
(72 mg, 0.0779 mmol), acetaldehyde (5 mg, 0.1 mmol), sodium
triacetoxyborohydride (25 mg, 0.12 mmol), and DCM (0.5 mL) was
stirred at room temperature for 18 hours. Water (5 mL) was added,
and the aqueous layer was extracted with DCM (3.times.5 mL). The
organic layers were combined and dried (Na.sub.2SO.sub.4).
Concentrated and purified by preparative TLC, eluting with 5% MeOH
(containing 7N NH.sub.3) in CHCl.sub.3. Yield: 8 mg (14%). LRMS
(APCI+): m/z 725 (M+1) detected.
[0939] Step C: Preparation of
.+-.N-(4-(3-((3R*,4S*)-1-ethyl-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydro-
pyridazine-4-carboxamide: Prepared from
.+-.N-(4-(1-(4-methoxybenzyl)-3-((3R*,4S*)-1-ethyl-3-fluoropiperidin-4-yl-
amino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluoropheny-
l)-3-oxo-2,3-dihydropyridazine-4-carboxamide (8 mg, 0.01 mmol) and
2,2,2-trifluoroacetic acid (0.43 mL, 5.5 mmol) according to the
procedure described for Example 145, Step C. The product was
obtained as a pale yellow powder (4 mg, 51%). HPLC: 95% purity (220
nm); LRMS (ESI+): 97% purity, 220 nm, m/z 605 (M+1) detected;
.sup.1H NMR (400 MHz, MeOD-d3) .delta. 11.98 (s, 1H), 8.35 (m, 3H),
8.09 (d, J=13 Hz, 1H), 7.67 (m, 2H), 7.53 (m, 2H), 7.29 (t, J=9 Hz,
2H), 6.42 (d, J=5 Hz, 1H), 5.37 (d, J=47 Hz, 1H), 4.26 (m, 1H),
3.97 (m, 1H), 3.66 (m, 1H), 3.52 (m, 1H), 3.28 (m, 2H), 2.34 (m,
2H), 1.39 (t, J=7 Hz, 3H).
Example 149
.+-.N-(4-(3-((3S*,4S*)-1-ethyl-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[3,-
4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydrop-
yridazine-4-carboxamide dihydrochloride
##STR00261##
[0941] Step A: Preparation of
.+-.N-(4-(1-(4-methoxybenzyl)-3-((3S*,4S*)-3-fluoropiperidin-4-ylamino)-1-
H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-
-2,3-dihydropyridazine-4-carboxamide bis-trifluoroacetic acid salt:
Prepared from .+-.(3S*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydr-
opyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3--
fluoropiperidine-1-carboxylate (13 mg, 0.016 mmol, obtained from
Example 146, Step B) according to the procedure for Example 148,
Step A. The crude product was carried forward as a TFA salt without
purification at this step. LRMS (APCI+): m/z 697 (M+1)
detected.
[0942] Step B: Preparation of
.+-.N-(4-(1-(4-methoxybenzyl)-3-((3S*,4S*)-1-ethyl-3-fluoropiperidin-4-yl-
amino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluoropheny-
l)-3-oxo-2,3-dihydropyridazine-4-carboxamide: Prepared from
.+-.N-(4-(1-(4-methoxybenzyl)-3-((3S*,4S*)-3-fluoropiperidin-4-ylamino)-1-
H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-
-2,3-dihydropyridazine-4-carboxamide bis-trifluoroacetic acid salt
(18 mg, 0.020 mmol) according to the procedure described for
Example 148, Step B. Yield: 5 mg (35%). LRMS (APCI+): m/z 725 (M+1)
detected.
[0943] Step C: Preparation of
.+-.N-(4-(3-((3S*,4S*)-1-ethyl-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydro-
pyridazine-4-carboxamide dihydrochloride: Prepared from
.+-.N-(4-(1-(4-methoxybenzyl)-3-((3S*,4S*)-1-ethyl-3-fluoropiperidin-4-yl-
amino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluoropheny-
l)-3-oxo-2,3-dihydropyridazine-4-carboxamide (5 mg, 0.007 mmol) and
2,2,2-trifluoroacetic acid (0.27 mL, 3.5 mmol) according to the
procedure for Example 145, Step C. The product was obtained as a
pale yellow powder (3 mg, 58%). HPLC: 91% purity (220 nm); LRMS
(ESI+): 93% purity, 220 nm, m/z 605 (M+1) detected; .sup.1H NMR
(400 MHz, MeOD-d3) .delta. 11.97 (s, 1H), 8.36 (m, 2H), 8.28 (m,
1H), 8.06 (m, 1H), 7.67 (m, 2H), 7.52 (m, 2H), 7.29 (t, J=9 Hz,
2H), 6.34 (d, J=6 Hz, 1H), 5.47 (d, J=47 Hz, 1H), 4.26 (m, 1H),
3.86 (m, 1H), 3.47 (m, 2H), 3.26 (m, 2H), 2.47 (m, 2H), 1.37 (t,
J=7 Hz, 3H).
Example 150
N-(3-fluoro-4-(3-(1-isopropylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridi-
n-4-yloxy)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxami-
de
##STR00262##
[0945] Prepared by a 2-step process from
4-(4-amino-2-fluorophenoxy)
N-(1-isopropylpiperidin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrid-
in-3-amine (prepared as described in Example 101, Step A except
using 1-isopropylpiperidin-4-amine) and
4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid
(Example 125, Step E) according to the procedure of Example 101,
Step B. The crude was rinsed with Et.sub.2O to afford 4.6 mg (64%)
of the desired product. The desired product was treated with 2N HCl
(Et.sub.2O solution) in a solution of MeOH and EtOAc to afford HCl
salt compound. LRMS (APCIpos) m/e 601.3 (M+1). .sup.1H-NMR (400
MHz, CD.sub.3OD/CDCl.sub.3) .delta. 8.17 (d, 1H), 8.06 (dd, 1H),
7.91 (d, 1H), 7.84 (d, 1H), 7.55 (m, 2H), 7.49 (d, 1H), 7.34 (t,
3H), 6.14 (d, 1H), 3.93 (m, 1H), 3.52 (m, 2H), 3.17 (m, 2H), 2.47
(m, 2H), 1.96 (m, 2H), 1.40 (d, 6H); .sup.19F NMR (376 MHz,
CD.sub.3OD/CDCl.sub.3) .delta. -111.0, -127.6.
Example 151
N-(3-fluoro-4-(3-(1-methyl-1H-imidazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-y-
loxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00263##
[0947] Step A: Preparation of
3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-imidazol-5-yl)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)aniline:
4-(1-(4-Methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluoro-
benzenamine (300 mg, 0.612 mmol, prepared in Example 7, step B),
1-methyl-5-(tributylstannyl)-1H-imidazole (681 mg, 1.84 mmol) (Org.
Proc. Res. & Dev., 2003, 7(5), 676-683), tetrakis
(triphenylphosphine) palladium (0) (141 mg, 0.122 mmol) and toluene
(5 mL) were charged in a 25 mL, single-neck, round-bottomed flask.
The reaction mixture was stirred at 100.degree. C. until the
starting material had been consumed (2 days). Then the reaction was
cooled to room temperature and then partitioned between EtOAc (50
mL) and water (50 mL). The phases were separated and the aqueous
phase was extracted with EtOAc (3.times.50 mL). The combined
organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated to yield a crude product. The crude product was
purified by silica gel chromatography (DCM/7 M NH.sub.3 in MeOH
from 100/1 to 10/1, v/v) to afford product (213 mg, 78.3%). LRMS
(APCI pos): >95% purity, 254 nm, m/e 445 (M+1). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.32 (d, 1H), 7.71 (m, 1H), 7.50 (m, 1H),
7.36 (m, 2H), 6.96 (m, 1H), 6.83 (m, 2H), 6.52 (m, 1H), 6.46 (m,
1H), 6.28 (d, 1H), 5.65 (s, 2H), 3.92 (s, 3H), 3.77 (s, 3H), 3.67
(s, 2H, NH.sub.2),
[0948] Step B: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(1-methyl-1H-imidazol-5-yl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyri-
dazine-4-carboxamide:
4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-imidazol-5-yl)-1H-pyrazolo[3,4-b]py-
ridin-4-yloxy)-3-fluorobenzenamine (0.213 g, 0.479 mmol),
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(0.561 g, 2.40 mmol, prepared in Example 19, step C),
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (0.459 g, 2.40 mmol), 1H-benzo[d][1,2,3]triazol-1-ol
hydrate (0.367 g, 2.40 mmol), N-ethyl-N-isopropylpropan-2-amine
(0.310 g, 2.40 mmol) and CH.sub.2Cl.sub.2 (5 mL) were charged in a
50 mL single-neck, round-bottomed flask. The reaction mixture was
stirred at room temperature until LC-MS shows that the starting
material had been consumed (overnight). Then the reaction was
partitioned between EtOAc (50 mL) and water (50 mL). The phases
were separated and the aqueous phase was extracted with EtOAc
(3.times.50 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to yield a crude
product. The crude product was purified by silica gel
chromatography (CH.sub.2Cl.sub.2/MeOH from 100/1 to 50/1, v/v) to
afford product (0.201 g, 63.5%). LRMS (APCI pos): >95% purity,
254 nm, m/e 661 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
11.75 (s, 1H), 8.31 (d, 1H), 8.25 (d, 1H), 8.14 (d, 1H), 7.87 (dd,
1H), 7.60 (s, 1H), 7.52 (m, 2H), 7.42 (s, 1H), 7.28 (m, 3H), 7.13
(m, 3H), 6.75 (m, 2H), 6.20 (d, 1H), 5.56 (s, 2H), 3.83 (s, 3H),
3.67 (s, 3H).
[0949] Step C: Preparation of
N-(3-fluoro-4-(3-(1-methyl-1H-imidazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4--
yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide-
:
N-(4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-imidazol-5-yl)-1H-pyrazolo[3,4--
b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyr-
idazine-4-carboxamide (0.201 g, 0.3043 mmol) and CF.sub.3COOH (2
mL) were charged in a 25 mL, single-neck, round-bottomed flask. The
reaction mixture was stirred at 100.degree. C. until the starting
material had been consumed (7 days). Then the CF.sub.3COOH was
removed under reduced pressure. The residue was partitioned between
DCM (50 mL) and saturated NaHCO.sub.3 (50 mL). The phases were
separated and the aqueous phase was extracted with DCM (3.times.50
mL). The combined organic layers were dried (Na.sub.2SO.sub.4),
filtered and concentrated to yield a crude product. The crude
product was purified by silica gel chromatography (DCM/7 M NH.sub.3
in MeOH from 100/1 to 10/1, v/v) to afford product (133.5 mg,
81.18%). LRMS (APCI pos): >98% purity, 254 nm, m/e 541 (M+1).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.74 (s, 1H), 9.31 (s,
1H), 8.46 (d, 1H), 8.39 (d, 1H), 8.26 (d, 1H), 8.10 (s, 1H), 8.07
(d, 1H), 7.68 (m, 2H), 7.62 (m, 2H), 7.42 (m, 2H), 6.46 (d, 1H),
4.07 (s, 3H).
Example 152
N-(3-fluoro-4-(3-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-
phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide
##STR00264##
[0951] Step A: Preparation of tert-butyl
4-((4-(2-fluoro-4-(4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxa-
mido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)pi-
peridine-1-carboxylate: Prepared according to the procedure of
Example 137, Step B, substituting
4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (40
mg, 0.17 mmol) for
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid.
Title compound was purified by Si column chromatography (Biotage
25M) loading with DCM and eluting with 3% MeOH in DCM to afford
desired product as yellow foam. Yield: 43 mg, 65%. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 11.82 (s, 1H), 8.28 (d, 1H), 7.99 (d, 1H),
7.94 (d, 1H), 7.51 (d, 2H), 7.45 (m, 3H), 7.32 (t, 3H), 7.21 (t,
1H), 6.82 (d, 2H), 6.21 (d, 1H), 5.59 (s, 2H), 3.76 (s, 3H), 3.02
(d, 2H), 2.66 (br m, 2H), 2.03 (br m, 1H), 1.64 (br m, 4H), 1.44
(s, 9H), 1.25 (br m, 3H). LRMS (APCI pos) m/e 778.0 (M+H).
[0952] Step B: Preparation of
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(piperidin-4-ylmethyl)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine--
2-carboxamide: Dissolved tert-butyl
4-((4-(2-fluoro-4-(4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxa-
mido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)pi-
peridine-1-carboxylate (43 mg, 0.055 mmol) in DCM (1 mL) and added
excess TFA (d 1.48) (0.100 ml). The mixture was stirred at room
temperature for 18 hours. The solvent was removed, and the crude
was partitioned between DCM (15 mL) and aqueous 10%
Na.sub.2CO.sub.3 (20 mL). The organic layer was washed with brine,
dried over sodium sulfate and evaporated to afford title compound
as free-base. Yield 41 mg, 89% purity by HPLC, 97%. LRMS (APCI pos)
m/e 678.3 (M+H).
[0953] Step C: Preparation of
N-(3-fluoro-4-(3-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy-
)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide:
Prepared according to the procedure of Example 53, Step B,
substituting tert-butyl
4-((4-(2-fluoro-4-(4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxa-
mido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)pi-
peridine-1-carboxylate (10 mg, 0.015 mmol) for
N-(3-fluoro-4-(1-(4-methoxybenzyl)-3-(3-(methylcarbamoyl)phenyl)-1H-pyraz-
olo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicar-
boxamide. The solvent was removed, and the crude was partitioned
between DCM (15 mL) and aqueous 10% Na.sub.2CO.sub.3 (20 mL). The
organic layer was washed with brine, dried over sodium sulfate and
evaporated to afford crude free-base. Di-HCl salt was prepared by
dissolution in MeOH and added 2N HCl/ether. The solution was
stirred for 10 minutes. The solvent was evaporated, and the residue
was triturated with 20% MeOH/ether to afford title compound as
yellow solid. Yield 4.2 mg, 90% purity by HPLC, 41%. LRMS (APCI
pos) m/e 558.3 (M+H).
Example 153
N-(4-(3-((1-ethylpiperidin-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-
-3-fluorophenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamid-
e
##STR00265##
[0955] Step A: Preparation of
N-(4-(1-(4-methoxybenzyl)-3-((1-ethylpiperidin-4-yl)methyl)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydro-
pyrazine-2-carboxamide:
N-(4-(1-(4-methoxybenzyl)-3-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyri-
din-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine--
2-carboxamide (17 mg, 0.025 mmol; prepared as in Example 152, Step
B) was added to a small round bottom flask and dissolved in dry THF
(1.5 mL). Acetaldehyde (5.56 mg, 0.126 mmol) and a drop of acetic
acid (d 1.049) were added. The reaction mixture was stirred for 10
minutes under N.sub.2(g) at room temperature. NaBH(OAc).sub.3 (53.5
mg, 0.252 mmol) was added and stirred at room temperature for 1
hour. The reaction mixture was partitioned between water and DCM
and extracted with a second portion of DCM (10 mL). The combined
organics were dried over sodium sulfate and evaporated to afford
desired product, used as crude in next step. Yield 18.6 mg, 90%
purity by HPLC, 94%. LRMS (APCI pos) m/e 706.3 (M+H).
[0956] Step B: Preparation of
N-(4-(3-((1-ethylpiperidin-4-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy-
)-3-fluorophenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxami-
de:
N-(4-(1-(4-methoxybenzyl)-3-((1-ethylpiperidin-4-yl)methyl)-1H-pyrazol-
o[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihy-
dropyrazine-2-carboxamide (18 mg, 0.025 mmol) was added to a small
round bottom flask and dissolved in excess TFA (d 1.48) (0.2 ml,
2.550 mmol). The mixture was stirred at 70.degree. C. overnight.
The solvent was evaporated, and the crude was chromatographed on Si
(preparative TLC) 0.5 mm thickness, eluting with 10% MeOH/DCM w/1%
NH.sub.4OH. Product isolated and determined to by mono-TFA salt by
.sup.19F-NMR. Yield 1.4 mg, 8%. .sup.1H NMR (400 MHz, MeOD) .delta.
8.29 (d, 1H), 8.08 (d, 1H), 7.93 (d, 1H), 7.79 (d, 2H), 7.60 (m,
2H), 7.54 (br d, 1H), 7.41 (t, 1H), 7.35 (t, 2H), 6.33 (d, 1H),
3.10 (d, 2H), 2.75 (br s, 2H), 2.43 (br s, 2H), 2.11 (br m, 1H),
1.88 (d, 2H), 1.55 (m, 2H), 1.19 (t, 3H). LRMS (APCI pos) m/e 586.3
(M+H).
Example 154
N-(3-fluoro-4-((2-morpholinoethyl)(1H-pyrazolo[3,4-b]pyridin-4-yl)amino)ph-
enyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide
##STR00266##
[0958] Step A: Preparation of
1-(4-methoxybenzyl)-N-(2-morpholinoethyl)-1H-pyrazolo[3,4-b]pyridin-4-ami-
ne: 1-(4-methoxybenzyl)-4-chloro-1H-pyrazolo[3,4-b]pyridine (0.200
g, 0.731 mmol) was charged to a pressure tube in 5 mL of NMP.
2-morpholinoethanamine (0.144 ml, 1.10 mmol) was added and the
reaction was heated to 150.degree. C. for 72 hours. After cooling,
the reaction mixture was diluted with 25 mL of EtOAc and washed
with water (2.times.15 mL) and then dried with brine and
Na.sub.2SO.sub.4. Purification via flash Si 10 g eluting with 1-5%
MeOH/DCM with NH.sub.4OH to afford 151 mg (55%) of product as a
yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.20 (d, 1H),
7.92 (s, 1H), 7.30 (t, 2H), 6.83 (m, 2H), 6.14 (d, 1H), 5.56 (s,
2H), 5.41 (s, 1H), 3.75 (m, 7H), 3.44 (m, 2H), 2.73 (t, 2H), 2.51
(bs, 4H).
[0959] Step B: Preparation of
1-(4-methoxybenzyl)-N-(2-fluoro-4-nitrophenyl)-N-(2-morpholinoethyl)-1H-p-
yrazolo[3,4-b]pyridin-4-amine:
1-(4-Methoxybenzyl)-N-(2-morpholinoethyl)-1H-pyrazolo[3,4-b]pyridin-4-ami-
ne (0.025 g, 0.06804 mmol) was charged to a pressure tube in DMF (1
mL). NaH (0.004082 g, 0.1021 mmol) was added, and the reaction was
allowed to stir at room temperature for 15 minutes.
1,2-difluoro-4-nitrobenzene (0.009389 ml, 0.08505 mmol) was added,
and the reaction was stirred at room temperature for 3 hours. The
reaction mixture was diluted with EtOAc (25 mL) and washed with
water (15 mL). The organics were then dried with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. Purification via flash
Si 5 g eluting with 1-5% MeOH/DCM to afford 28 mg (80%) of product
as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.32 (d,
1H), 8.14 (m, 2H), 7.61 (t, 1H), 7.30 (m, 2H), 6.82 (d, 3H), 6.43
(d, 1H), 5.54 (s, 2H), 4.05 (t, 2H), 3.75 (s, 3H), 3.59 (t, 4H),
2.76 (t, 2H), 2.44 (m, 4H); .sup.19F NMR (376 MHz, CDCl.sub.3)
-113.92 (s, 1F); LRMS (apci pos): 307.1 (M+H).sup.+.
[0960] Step C: Preparation of
N1-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-fluoro-N1-(2-mo-
rpholinoethyl)benzene-1,4-diamine:
1-(4-methoxybenzyl)-N-(2-fluoro-4-nitrophenyl)-N-(2-morpholinoethyl)-1H-p-
yrazolo[3,4-b]pyridin-4-amine (0.024 g, 0.0474 mmol) and
SnCl2-dihydrate (0.0535 g, 0.237 mmol) were stirred in EtOH (2 mL)
for 2 hours at reflux. The reaction was cooled to room temperature
and then concentrated under reduced pressure and dried in vacuo.
The residue was diluted with EtOAc and washed with saturated
Na.sub.2CO.sub.3 (20 mL). The organics were dried over
Na.sub.2SO.sub.4. The organics were filtered and concentrated to
give 21 mg (92%) of product as a light yellow oil. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.21 (d, 1H), 7.27 (m, 2H), 7.11 (m, 1H),
6.558 (bs, 1H), 6.49 (m, 2H), 6.29 (d, 1H), 5.48 (s, 2H), 4.12 (m,
4H), 3.73 (s, 3H), 3.69 (m, 4H), 2.73 (t, 2H), 2.48 (m, 4H); F NMR
(400 MHz, CDCl.sub.3) -120.43 (s, 1F); LRMS (apci pos): 477.3
(M+H).sup.+.
[0961] Step D: Preparation of
N-(4-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(2-morpholinoet-
hyl)amino)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine--
4-carboxamide:
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid
(0.0310 g, 0.132 mmol) (prepared according to the procedure of
Example 19, Step C) was taken up in DMF (1 mL). EDCI (0.0422 g,
0.220 mmol), HOBt (0.0298 g, 0.220 mmol), and DIEA (0.0384 ml,
0.220 mmol) were then added. After stirring under N.sub.2 for 15
minutes,
N1-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-2-fluoro-N1-(2-mo-
rpholinoethyl)benzene-1,4-diamine (0.021 g, 0.0441 mmol) was added
in DMF (1 mL). After stirring for 5.5 hours, DCM was removed. The
product was taken up into EtOAc and washed with diluted NaHCO.sub.3
and brine. The product was dried over Na.sub.2SO.sub.4, filtered
and concentrated. Purification via Flash Si 5 g eluting with 1-5%
MeOH/DCM with NH.sub.4OH to obtain 15.7 mg (51%) of product as a
yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.88 (s,
1H), 8.41 (d, 1H), 8.24 (m, 2H), 7.93 (dd, 1H), 7.63 (m, 2H), 7.43
(m, 1H), 7.35 (m, 1H), 7.27 (m, 4H), 6.80 (m, 2H), 6.61 (br s, 1H),
6.31 (d, 1H), 5.48 (s, 2H), 3.94 (t, 2H), 3.75 (s, 3H), 3.65 (t,
3H), 2.88 (s, 1H), 2.75 (t, 2H), 2.47 (t, 4H); .sup.19F NMR (376
MHz, CDCl.sub.3) -111.41 (s, 1F), -117.59 (s, 1F); LRMS (apci pos):
693.3 (M+H).sup.+.
[0962] Step E: Preparation of
N-(3-fluoro-4-((2-morpholinoethyl)(1H-pyrazolo[3,4-b]pyridin-4-yl)amino)p-
henyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide:
N-(4-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(2-morpholinoet-
hyl)amino)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine--
4-carboxamide (0.015 g, 0.02165 mmol) was dissolved in TFA (0.1668
ml, 2.165 mmol) and stirred at 60.degree. C. for 18 hours. Excess
TFA was evaporated, and the crude product was then resuspended in
toluene and reconcentrated to remove trace TFA. The crude solid was
then partitioned between EtOAc and NaHCO.sub.3. The organic layer
was separated and dried over sodium sulfate. After filtration to
remove sodium sulfate and concentration, the residual crude solid
was taken up in a small amount of DCM and treated with 2N HCl in
ether. The suspension was evaporated to dryness to give 14 mg (95%)
of product as a brown solid. LRMS (apci pos): 573.3
(M+H).sup.+.
Example 155
N-(3-fluoro-4-((2-morpholinoethyl)(1H-pyrazolo[3,4-b]pyridin-4-yl)amino)ph-
enyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide
##STR00267##
[0964] Step A: Preparation of
N-(3-fluoro-4-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(2-mor-
pholinoethyl)amino)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2--
carboxamide: Prepared according to the procedure of Example 154,
Step D substituting
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyrazine-4-carboxylic acid for
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic
acid.
[0965] Step B: Preparation of
N-(3-fluoro-4-((2-morpholinoethyl)(1H-pyrazolo[3,4-b]pyridin-4-yl)amino)p-
henyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxamide:
Prepared according to the procedure of Example 154, step E using
N-(3-fluoro-4-((1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)(2-mor-
pholinoethyl)amino)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2--
carboxamide. LRMS (apci pos): 573.2 (M+H).sup.+.
Example 156
N-(3-fluoro-4-(3-(4-isopropylpiperazine-1-carbonyl)-1H-pyrazolo[3,4-b]pyri-
din-4-yloxy)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxa-
mide
##STR00268##
[0967] Step A: Preparation of
N-(3-fluoro-4-(3-(4-isopropylpiperazine-1-carbonyl)-1H-pyrazolo[3,4-b]pyr-
idin-4-yloxy)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carbox-
amide: Prepared according to the procedure of Example 158, Step B,
substituting
4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid
(18.5 mg, 0.0791 mmol) for
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid.
The crude product isolated was the double addition product with
amide formation at both the aniline NH.sub.2 and pyrazole NH. The
crude was dissolved in MeOH (1 mL) and treated with triethylamine
(5 eq.) at 50.degree. C. to affect hydrolysis of pyrazole amide.
Title compound was purified by preparative TLC (0.5 mm thickness)
eluting with 90/10 DCM/MeOH to afford desired product as pale
yellow solid. Yield: 3.4 mg, 20%. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 14.04 (s, 1H), 11.32 (s, 1H), 8.39 (d, 2H), 8.00 (m, 1H),
7.99 (s, 1H), 7.96 (s, 1H), 7.65 (m, 2H), 7.56 (d, 1H), 7.45 (m,
3H), 6.42 (d, 1H), 3.64 (br s, 2H), 2.67 (m, 1H), 2.39 (br s, 2H),
2.33 (br s, 2H), 0.91 (d, 6H). LRMS (APCI pos) m/e 615.3 (M+H).
Example 157
N-(3-fluoro-4-(3-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)-1H-pyrazolo-
[3,4-b]pyridin-4-yloxy)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazin-
e-2-carboxamide
##STR00269##
[0969] Prepared by a 2-step process from
4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(8-methyl-8-azabicyclo[-
3.2.1]octan-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (prepared as
described in Example 101, Step A except using
8-methyl-8-azabicyclo[3.2.1]octan-3-amine) and
4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid
(Example 125, Step E) according to the procedure of Example 101,
Step B. The crude was rinsed with Et.sub.2O to afford 7 mg (18%) of
the desired product. The desired product was treated with 2N HCl
(Et.sub.2O solution) in a solution of MeOH and EtOAc to afford HCl
salt compound. LRMS (ESIpos) m/e 599.2 (M+1). .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. 8.36 (m, 1H), 8.14 (d, 1H), 7.94 (m, 1H), 7.80
(m, 1H), 7.60 (m, 4H), 7.35 (t, 2H), 6.54 (d, 1H), 4.07 (m, 1H),
3.93 (m, 2H), 2.81 (s, 3H), 2.35-2.58 (m, 8H); .sup.19F NMR (376
MHz, CD.sub.3OD) .delta. -113.5, -129.6.
Example 158
N-(3-fluoro-4-(3-(4-isopropylpiperazine-1-carbonyl)-1H-pyrazolo[3,4-b]pyri-
din-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carbo-
xamide
##STR00270##
[0971] Step A: Preparation of
(4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)(4-isopropylp-
iperazin-1-yl)methanone: Prepared according to the procedure of
Example 144, Step B, substituting 1-isopropylpiperazine (346 mg,
2.70 mmol) for 1-methylpiperazine. Purified by preparative TLC (0.5
mm thickness) eluting with 90/10/1 DCM/MeOH/NH.sub.4OH to afford
the desired product as pale yellow solid. Yield: 30 mg, 28%. LRMS
(APCI pos) m/e 399.2 (M+H).
[0972] Step B: Preparation of
N-(3-fluoro-4-(3-(4-isopropylpiperazine-1-carbonyl)-1H-pyrazolo[3,4-b]pyr-
idin-4-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carb-
oxamide: Prepared according to the procedure of Example 82, Step B,
substituting
(4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)(4-isopropylp-
iperazin-1-yl)methanone (30 mg, 0.075 mmol) for tert-butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-yl)piperazine-1-carboxylate. Purified by preparative TLC (0.5
mm thickness) eluting with 90/10/1 DCM/MeOH/NH.sub.4OH to afford
the desired product as pale yellow solid. Yield: 16 mg, 35%.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.69 (s, 1H), 8.39 (m, 2H),
8.27 (s, 1H), 8.03 (d, 1H), 7.68 (m, 2H), 7.57 (d, 1H), 7.41 (t,
3H), 6.43 (d, 1H), 3.62 (br s, 2H), 2.64 (m, 1H), 2.40 (br d, 4H),
0.90 (d, 6H). LRMS (APCI pos) m/e 615.3 (M+H).
Example 159
.+-.N-(3-fluoro-4-(3-((3R*,4S*)-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine--
2-carboxamide dihydrochloride
##STR00271##
[0974] Step A: Preparation of .+-.(3R*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydr-
opyrazine-3-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fl-
uoropiperidine-1-carboxylate: Prepared from
4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (190
mg, 0.811 mmol, prepared according to the procedure for Example
125, Step E) and .+-.(3R*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-ylamino)-3-fluoropiperidine-1-carboxylate (157 mg, 0.270
mmol, obtained from Example 145, Step A) according to the procedure
described for Example 145, Step B. Yield: 138 mg (51%).
[0975] Step B: Preparation of
.+-.N-(3-fluoro-4-(3-((3R*,4S*)-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[-
3,4-b]pyridin-4-yloxy)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-
-2-carboxamide dihydrochloride: Prepared from
.+-.(3R*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydr-
opyrazine-3-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fl-
uoropiperidine-1-carboxylate (138 mg, 0.173 mmol) and
2,2,2-trifluoroacetic acid (1.33 mL, 17.3 mmol) according to the
procedure described for Example 145, Step C. The product was
obtained as a pale yellow powder (30 mg, 25%). HPLC: 94% purity
(254 nm); LRMS (ESI+): 577 m/z (M+1) detected; .sup.1H NMR (400
MHz, CDCl.sub.3, free base) .delta. 11.83 (s, 1H), 10.22 (br s,
1H), 8.22 (d, J=5 Hz, 1H), 8.01 (d, J=12 Hz, 1H), 7.94 (d, J=4 Hz,
1H), 7.52 (d, J=4 Hz, 1H), 7.46 (m, 4H), 7.32 (t, J=8 Hz, 2H), 7.27
(m, 3H), 6.10 (d, J=5 Hz, 1H), 4.95 (d, J=42 Hz, 1H), 4.88 (s, 1H),
4.06 (m, 1H), 3.39 (m, 1H), 3.17 (m, 1H), 2.92 (m, 1H), 2.77 (m,
1H), 2.03 (m, 1H), 1.76 (m, 1H).
Example 160
.+-.N-(3-fluoro-4-(3-((3S*,4S*)-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[3-
,4-b]pyridin-4-yloxy)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine--
2-carboxamide dihydrochloride
##STR00272##
[0977] Step A: Preparation of .+-.(3S*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydr-
opyrazine-3-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fl-
uoropiperidine-1-carboxylate: Prepared from
4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (60
mg, 0.26 mmol, prepared according to the procedure for Example 125,
Step E) and .+-.(3S*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyri-
din-3-ylamino)-3-fluoropiperidine-1-carboxylate (50 mg, 0.086 mmol,
obtained from Example 146, Step A) according to the procedure
described for Example 145, Step B. Yield: 42 mg (58%).
[0978] Step B: Preparation of
.+-.N-(3-fluoro-4-(3-((3S*,4S*)-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[-
3,4-b]pyridin-4-yloxy)phenyl)-4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-
-2-carboxamide dihydrochloride: Prepared from
.+-.(3S*,4S*)-tert-butyl
4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydr-
opyrazine-3-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fl-
uoropiperidine-1-carboxylate (42 mg, 0.053 mmol) and
2,2,2-trifluoroacetic acid (0.41 ml, 5.3 mmol) according to the
procedure described for Example 145, Step C. The product was
obtained as a pale yellow powder (19 mg, 55%). HPLC: 99% purity
(254 nm); LRMS (ESI+): 577 m/z (M+1) detected; .sup.1H NMR (400
MHz, CDCl.sub.3, free base) .delta. 11.84 (s, 1H), 9.92 (br s, 1H),
8.21 (d, J=5 Hz, 1H), 8.02 (m, 1H), 7.94 (d, J=4 Hz, 1H), 7.52 (d,
J=4 Hz, 1H), 7.46 (m, 3H), 7.32 (t, J=8 Hz, 2H), 7.26 (m, 1H), 6.11
(d, J=5 Hz, 1H), 4.82 (d, J=6 Hz, 1H), 4.58 (m, 1H), 4.01 (m, 1H),
3.39 (m, 1H), 3.02 (m, 1H), 2.82 (m, 2H), 2.46 (m, 1H), 1.60 (m,
1H).
Example A
c-Met Enzyme Assay
[0979] The assay for the determination of cMet kinase activity is
based on an enzyme linked immunosorbant assay (ELISA). A compound
of Formula I, 50 pM cMet (His-tagged recombinant human Met (amino
acids 974-end), expressed by baculovirus), and 5 .mu.M ATP in assay
buffer (25 mM MOPS, pH 7.4, 5 mM MgCl.sub.2, 0.5 mM MnCl.sub.2, 100
.mu.M Sodium Orthovanadate, 0.01% Triton X-100, 1 mM DTT, final
DMSO concentration 1% (v/v)) are incubated on a 0.25 mg/mL PGT
coated plates for 20 minutes at room temperature. The reaction
mixture is removed by washing and the phosphorylated polymer
substrate is detected with 0.2 .mu.g/mL phosphotyrosine specific
monoclonal antibody (PY20) conjugated to horseradish peroxidase
(HRP). After the addition of 1M phosphoric acid to stop the
development, the chromogenic substrate (TMB) color is quantitated
by spectrophotometry at 450 nm. Certain compounds of this invention
had IC.sub.50's of less than 1 .mu.M in this assay.
Example B
[0980] The cellular activity of the compounds of the present
invention may be determined by the following procedure. MKN45 cells
were plated in Costar 3904 96-well plates in growth media (RPMI,
10% FBS) at a density of 15000 cells/well and incubated at
37.degree. C., 5% CO.sub.2 overnight. The following day, one-tenth
volume of a 10.times. concentration of compounds was added to the
wells in a 11-point dilution series. The dilutions series was
composed of an initial 1:3 dilution in DMSO, followed by a 1:20
dilution in HBSS, for a final DMSO concentration on cells of 0.5%.
Control wells were treated with 0.5% DMSO. The typical range of
dilution was 5 .mu.M to 0.3 nM, which was expanded to 25 .mu.M
depending on the potency of the compound. Once compound was added
to the cells, plates were incubated for one hour at 37.degree. C.,
5% CO.sub.2. Plates were then washed in PBS, fixed in 4%
formaldehyde and rehydrated with a 10% methanol solution. The
plates were then blocked with Licor blocking buffer. The total
phosphorylated cMet levels were measured by incubating with a
rabbit polyclonal antibody against phosphorylated cMet followed by
an anti-rabbit antibody conjugated to Alexa Fluor 680. Signal was
normalized for differences in cell number by reference to the
levels of the housekeeping protein GAPDH. Cells were incubated with
a mouse monoclonal antibody against GAPDH followed by an anti-mouse
antibody labeled with IRdye 800. Signal was measured on the Licor.
The overall fluorescent signal from the Alexa Fluor 680 is
normalized by dividing the value by the fluorescent value of the
IRdye 800 signal. The fluorescent signal of the control wells was
defined as 100% and the percent of inhibition of phosphorylated
cMet was expressed as percent of control. IC.sub.50 values were
determined from the percent of control data using a standard
4-parameter logistical model.
[0981] The foregoing description is considered as illustrative only
of the principles of the invention. Further, since numerous
modifications and changes will be readily apparent to those skilled
in the art, it is not desired to limit the invention to the exact
construction and process shown as described above. Accordingly, all
suitable modifications and equivalents may be considered to fall
within the scope of the invention as defined by the claims that
follow.
[0982] The words "comprise," "comprising," "include," "including,"
and "includes" when used in this specification and in the following
claims are intended to specify the presence of stated features,
integers, components, or steps, but they do not preclude the
presence or addition of one or more other features, integers,
components, steps, or groups thereof.
* * * * *