U.S. patent number RE43,878 [Application Number 13/374,053] was granted by the patent office on 2012-12-25 for amidophenoxyindazoles useful as inhibitors of c-met.
This patent grant is currently assigned to Eli Lilly and Company. Invention is credited to Tiechao Li, Mark Andrew Pobanz, Chuan Shih, Zhipei Wu, Wei Jennifer Yang, Boyu Zhong.
United States Patent |
RE43,878 |
Li , et al. |
December 25, 2012 |
Amidophenoxyindazoles useful as inhibitors of c-Met
Abstract
The present invention provides amidophenoxyindazole compounds
useful in the treatment of cancer.
Inventors: |
Li; Tiechao (Indianapolis,
IN), Pobanz; Mark Andrew (Indianapolis, IN), Shih;
Chuan (Indianapolis, IN), Wu; Zhipei (Indianapolis,
IN), Yang; Wei Jennifer (Indianapolis, IN), Zhong;
Boyu (Indianapolis, IN) |
Assignee: |
Eli Lilly and Company
(Indianapolis, IN)
|
Family
ID: |
41010247 |
Appl.
No.: |
13/374,053 |
Filed: |
December 8, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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61083294 |
Jul 24, 2008 |
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61085082 |
Jul 31, 2008 |
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61108659 |
Oct 27, 2008 |
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Reissue of: |
12503223 |
Jul 15, 2009 |
8030302 |
Oct 4, 2011 |
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Current U.S.
Class: |
514/232.5;
514/234.5 |
Current CPC
Class: |
A61P
35/00 (20180101); A61P 43/00 (20180101); C07D
401/14 (20130101); C07D 403/12 (20130101); C07D
405/14 (20130101); C07D 401/12 (20130101); C07D
403/14 (20130101) |
Current International
Class: |
A61K
31/416 (20060101); C07D 401/14 (20060101); A61K
31/501 (20060101); A61K 31/444 (20060101); A61K
31/4439 (20060101); C07D 403/12 (20060101); C07D
413/14 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2006/116713 |
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Nov 2006 |
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WO |
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WO 2007/075567 |
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May 2007 |
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WO |
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2007/103308 |
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Sep 2007 |
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WO |
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WO 2008/008539 |
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Jan 2008 |
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WO |
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WO 2008/051808 |
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May 2008 |
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WO |
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2009/003084 |
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Mar 2009 |
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WO |
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Primary Examiner: Saeed; Kamal
Attorney, Agent or Firm: Tucker; Tina M.
Parent Case Text
.Iadd.This application claims the priority of U.S. provisional
patent application 61/083,294 filed Jul. 24,2008, U.S. provisional
patent application 61/085,082 filed Jul. 31, 2008, and U.S.
provisional patent application 61/108,659 filed Oct. 27,
2008..Iaddend.
Claims
We claim:
1. A compound of the formula: ##STR00072## wherein: R.sup.1 is H or
methyl; R.sup.2 is amino, dimethylamino, fluoro, cyclopropyl,
pyridyl optionally substituted with an amino substituent or 1-2
methyl substituents, pyrazolyl optionally substituted with two
methyl substituents, 2-methoxy-pyrimidin-5-yl,
4-methylsulfonylphenyl, tetrahydro-2H-pyran-4-ylamino,
(tetrahydro-2H-pyran-4-yl)amino carbonyl, or a morpholin-4-yl
substituent: ##STR00073## where R.sup.a, R.sup.b and R.sup.c are
independently selected from H or methyl; R.sup.3 is H or F; R.sup.4
is H, methyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, or
pyrazol-1-ylmethyl; R.sup.5 is H or F; and X is CH.dbd.N,
CH.dbd.CH, CH.dbd.C(CH.sub.3), C(CH.sub.3).dbd.CH,
C(CH.sub.3).dbd.N, N(CH.sub.3), or
.[.C(morpholin-4ylmethyl).dbd.CH.].
.Iadd.C(morpholin-4-ylmethyl).dbd.CH.Iaddend.; or a
pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.2 is amino, dimethylamino,
cyclopropyl, pyridyl optionally substituted with an amino
substituent or 1-2 methyl substituents, pyrazol-4-yl, or a
morpholin-4-yl.
3. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.2 is amino, dimethylamino,
pyrazol-4-yl, or a morpholin-4-yl.
4. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.2 is pyrazol-4-yl.
5. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4 is H, methyl, or
morpholin-4-ylmethyl.
6. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.4 is H.
7. The compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein X is CH.dbd.CH or
CH.dbd.C(CH.sub.3).
8. .[.The compound according to claim 1 which is .].
N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1--
(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 which is
N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-6--
methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide or a
pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 wherein the pharmaceutically
acceptable salt is a methanesulfonate salt.
11. The compound according to claim 1 wherein the particle size is
less than 10 microns.
12. A pharmaceutical composition comprising a compound of .[.claim
1 or a pharmaceutically acceptable salt thereof.]. .Iadd.the
formula: ##STR00074## wherein: R.sup.1 is H or methyl; R.sup.2 is
amino, dimethylamino, fluoro, cyclopropyl, pyridyl optionally
substituted with an amino substituent or 1-2 methyl substituents,
pyrazolyl optionally substituted with two methyl substituents,
2-methoxy-pyrimidin-5-yl, 4-methylsulfonylphenyl,
tetrahydro-2H-pyran-4-ylamino, (tetrahydro-2H-pyran-4-yl)amino
carbonyl, or a morpholin-4-yl substituent; ##STR00075## where
R.sup.a, R.sup.b and R.sup.c are independently selected from H or
methyl; R.sup.3 is H or F; R.sup.4 is H, methyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl, or pyrazol-1-ylmethyl;
R.sup.5 is H or F; and X is CH.dbd.N, CH.dbd.CH,
CH.dbd.C(CH.sub.3), C(CH.sub.3).dbd.CH, C(CH.sub.3).dbd.N,
N(CH.sub.3), or C(morpholin-4-ylmethyl).dbd.CH; or a
pharmaceutically acceptable salt thereof.Iaddend., and a
pharmaceutically acceptable carrier, diluent or excipient.
13. A method of treating cancer selected from the group consisting
of lung cancer, breast cancer, colorectal cancer, renal cancer,
pancreatic cancer, head cancer, neck cancer, hereditary papillary
renal cell carcinoma, childhood hepatocellular carcinoma, and
gastric cancer in a mammal comprising administering to a mammal in
need of such treatment an effective amount of a compound of
.[.claim 1 or a pharmaceutically acceptable salt thereof.].
.Iadd.the formula: ##STR00076## wherein: R.sup.1 is H or methyl;
R.sup.2 is amino, dimethylamino, fluoro, cyclopropyl, pyridyl
optionally substituted with an amino substituent or 1-2 methyl
substituents, pyrazolyl optionally substituted with two methyl
substituents, 2-methoxy-pyrimidin-5-yl, 4-methylsulfonylphenyl,
tetrahydro-2H-pyran-4-ylamino, (tetrahydro-2H-pyran-4-yl)amino
carbonyl, or a morpholin-4-yl substituent; ##STR00077## where
R.sup.a, R.sup.b and R.sup.c are independently selected from H or
methyl; R.sup.3 is H or F; R.sup.4 is H, methyl,
piperidin-1-ylmethyl, morpholin-4-ylmethyl, or pyrazol-1-ylmethyl;
R.sup.5 is H or F; and X is CH.dbd.N, CH.dbd.CH,
CH.dbd.C(CH.sub.3), C(CH.sub.3).dbd.CH, C(CH.sub.3).dbd.N,
N(CH.sub.3), or C(morpholin-4-ylmethyl).dbd.CH; or a
pharmaceutically acceptable salt thereof.Iaddend..
.Iadd.14. The pharmaceutical composition according to claim 12
wherein the compound is
N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1--
(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
or a pharmaceutically acceptable salt thereof..Iaddend.
.Iadd.15. The method according to claim 13 wherein the compound is
N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1--
(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
or a pharmaceutically acceptable salt thereof..Iaddend.
Description
c-Met is a member of the tyrosine kinase growth factor receptor
family. c-Met expression occurs in endothelial, epithelial, and
mesenchymal cells. Binding to c-Met of the endogenous ligand,
hepatocyte growth factor (HGF), promotes cell migration,
proliferation, and invasion.
c-Met is implicated in the progression of certain tumors. c-Met
overexpression has been shown in numerous tumor types including
colon, breast, renal, lung, hemangiomas, squamous cell myeloid
leukemia, melanomas, glioblastomas, and astrocytomas. Activation of
tumor cell c-Met receptors enhances tumor cell proliferation,
invasion/metastasis, and resistance to apoptosis and cytotoxic
therapies.
Various amidophenoxyheteroaryl c-Met inhibitors have been reported.
See for example, US2005/0288290, US2006/0211695, US2006/0004006,
and WO 2007103308.
However, there is still a need for further compounds that inhibit
c-Met. The present invention provides novel amidophenoxyindazole
compounds believed to have clinical use for treatment of cancer
through inhibiting c-Met. Preferred compounds of the present
invention are also believed to provide an improvement in potency
over certain other c-Met inhibitor compounds found in the art.
The present invention provides compounds of Formula I:
A compound of the formula:
##STR00001## wherein:
R.sup.1 is H or methyl;
R.sup.2 is amino, dimethylamino, fluoro, cyclopropyl, pyridyl
optionally substituted with an amino substituent or 1-2 methyl
substituents, pyrazolyl optionally substituted with two methyl
substituents, 2-methoxy-pyrimidin-5-yl, 4-methylsulfonylphenyl,
tetrahydro-2H-pyran-4-ylamino, (tetrahydro-2H-pyran-4-yl)amino
carbonyl, or a morpholin-4-yl substituent:
##STR00002## where R.sup.a, R.sup.b and R.sup.c are independently
selected from H or methyl;
R.sup.3 is H or F;
R.sup.4 is H, methyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl,
or pyrazol-1-ylmethyl;
R.sup.5is H or F; and
X is CH.dbd.N, CH.dbd.CH, CH.dbd.C(CH.sub.3), C(CH.sub.3).dbd.CH,
C(CH.sub.3).dbd.N, N(CH.sub.3), or
.[.C(morpholin-4ylmethyl).dbd.CH.].
.Iadd.C(morpholin-4-ylmethyl).dbd.CH.Iaddend.;
or a pharmaceutically acceptable salt thereof.
The present invention provides a method of treating cancer selected
from the group consisting of lung cancer, breast cancer, colorectal
cancer, renal cancer, pancreatic cancer, head cancer, neck cancer,
hereditary papillary renal cell carcinoma, childhood hepatocellular
carcinoma, and gastric cancer in a mammal comprising administering
to a mammal in need of such treatment an effective amount of a
compound of Formula I or a pharmaceutically acceptable salt
thereof.
The present invention also provides a pharmaceutical composition
comprising a compound of Formula I or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier, diluent or
excipient.
This invention also provides a compound of Formula I or a
pharmaceutically acceptable salt thereof for use as a medicament.
Additionally, this invention provides use of a compound of Formula
I or a pharmaceutically acceptable salt thereof in the manufacture
of a medicament for treating cancer. In particular these cancers
are selected from the group consisting of lung cancer, breast
cancer, colorectal cancer, renal cancer, pancreatic cancer, head
cancer, neck cancer, hereditary papillary renal cell carcinoma,
childhood hepatocellular carcinoma, and gastric cancer.
Furthermore, this invention provides a pharmaceutical composition
for treating cancer selected from the group consisting of lung
cancer, breast cancer, colorectal cancer, renal cancer, pancreatic
cancer, head cancer, neck cancer, hereditary papillary renal cell
carcinoma, childhood hepatocellular carcinoma, and gastric cancer
comprising a compound of Formula I or a pharmaceutically acceptable
salt thereof as an active ingredient.
It will be understood by the skilled reader that most or all of the
compounds of the present invention are capable of forming salts.
The compounds of the present invention are amines, and accordingly
react with any of a number of inorganic and organic acids to form
pharmaceutically acceptable acid addition salts. Such
pharmaceutically acceptable acid addition salts and common
methodology for preparing them are well known in the art. See,
e.g., P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS:
PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2002); L. D.
Bighley, S. M. Berge, D. C. Monkhouse, in "Encyclopedia of
Pharmaceutical Technology`. Eds. J. Swarbrick and J. C. Boylan,
Vol. 13, Marcel Dekker, Inc., New York, Basel, Hong Kong 1995, pp.
453-499; S. M. Berge, et al., "Pharmaceutical Salts," Journal of
Pharmaceutical Sciences, Vol 66, No. 1, January 1977. Preferred
pharmaceutically acceptable salts of the compounds of the present
invention are the methanesulfonate salts.
Preferred are compounds of Formula I wherein:
(a) R.sup.1 is H;
(b) R.sup.1 is methyl;
(c) R.sup.2 is amino, dimethylamino, cyclopropyl,
6-methyl-pyridin-3-yl, pyrazol-4-yl, or a morpholin-4-yl of the
formula:
##STR00003##
(d) R.sup.2 is amino, dimethylamino, pyrazol-4-yl, or
morpholin-4-yl;
(e) R.sup.2 is pyrazo-4-yl;
(f) R.sup.1 is methyl and R.sup.2 is pyrazol-4-yl;
(g) R.sup.3 is F;
(h) R.sup.1 is methyl, R.sup.2 is pyrazol-4-yl, and R.sup.3 is
F;
(i) R.sup.4 is H, methyl, or morpholin-4-ylmethyl;
(j) R.sup.4is H;
(k) R.sup.1 is methyl, R.sup.2 is pyrazol-4-yl, R.sup.3 is F, and
R.sup.4 is H;
(l) R.sup.5 is H;
(m) R.sup.5 is F;
(n) R.sup.1 is methyl, R.sup.2 is pyrazol-4-yl, R.sup.3 is F,
R.sup.4 is H, and R.sup.5 is H;
(o) R.sup.1 is methyl, R.sup.2 is pyrazol-4-yl, R.sup.3 is F,
R.sup.4 is H, and R.sup.5 is F;
(p) X is CH.dbd.CH or CH.dbd.C(CH.sub.3);
(q) R.sup.1 is methyl, R.sup.2 is pyrazol-4-yl, R.sup.3 is F,
R.sup.4 is H, R.sup.5 is H, and X is CH.dbd.CH or
CH.dbd.C(CH.sub.3);
(r) R.sup.1 is methyl, R.sup.2 is pyrazol-4-yl, R.sup.3 is F,
R.sup.4 is H, R.sup.5 is F, and X is CH.dbd.CH or
CH.dbd.C(CH.sub.3);
(s) R.sup.1 is methyl, R.sup.2 is pyrazol-4-yl, R.sup.3 is F,
R.sup.4 is H, R.sup.5 is H or F, and X is CH.dbd.C(CH.sub.3);
(t) R.sup.1 is methyl, R.sup.2 is pyrazol-4-yl, R.sup.3 is F,
R.sup.4 is H, R.sup.5 is H, and X is CH.dbd.C(CH.sub.3); and
(u) R.sup.1 is methyl, R.sup.2 is pyrazol-4-yl, R.sup.3 is F,
R.sup.4 is H, R.sup.5 is F, and X is CH.dbd.C(CH.sub.3).
The compounds of the present invention can be prepared according to
the following synthetic schemes by methods well known and
appreciated in the art. Suitable reaction conditions for the steps
of these schemes are well known in the art and appropriate
substitutions of solvents and co-reagents are within the skill of
the art. Likewise, it will be appreciated by those skilled in the
art that synthetic intermediates may be isolated and/or purified by
various well known techniques as needed or desired, and that
frequently, it will be possible to use various intermediates
directly in subsequent synthetic steps with little or no
purification. Furthermore, the skilled artisan will appreciate that
in some circumstances, the order in which moieties are introduced
is not critical. The particular order of steps required to produce
the compounds of the present invention is dependent upon the
particular compound being synthesized, the starting compound, and
the relative liability of the substituted moieties, as is well
appreciated by the skilled chemist. All substituents, unless
otherwise indicated, are as previously defined, and all reagents
are well known and appreciated in the art.
Compounds of the present invention may be synthesized as
illustrated in the following Scheme I, where X, R.sup.3, R.sup.4,
and R.sup.5 are as previously defined, and R.sup.1' and R.sup.2'
are equal to or precursors of R.sup.1 and R.sup.2.
##STR00004##
The compounds of the present invention can be made by standard
peptide coupling conditions well known to the skilled artisan. A
suitably substituted indazole aniline of formula (a) is reacted
with an acid compound of formula (b), in the presence of a peptide
coupling reagent such as
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),
1-hydroxybenzotriazole hydrate (HOBt), an appropriate base such as
N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), or
triethylamine (TEA), in a suitable solvent such as dichloromethane
(DCM), N,N-dimethylformamide (DMF) or tetrahydrofuran (THF) to
provide the desired amide of the present invention. If R.sup.1' is
a suitable nitrogen protecting group such as tetrahydropyran (THP),
or if R.sup.2' is a functional group protected by a
nitrogen-protecting group, a de-protection step is needed to obtain
the desired compound of the present invention.
##STR00005##
The compound of formula (a) can be prepared as illustrated in
Scheme II, where R.sup.1', R.sup.2', and R.sup.3 are as previously
defined.
The compound of formula (f) can react with a properly substituted
compound of formula (g) at elevated temperature, in the presence of
a suitable base such as sodium bicarbonate in a proper solvent such
as DMF to provide the compound of formula (e). The compound of
formula (e) can be methylated with a proper methylation reagent
such as methyl iodide in a suitable solvent such as THF with a
suitable base such as potassium tert-butoxide to provide the
compound of formula (d), where R.sup.1' is a methyl. The compound
of formula (e) can also be protected with a suitable protecting
reagent such as 2,3-dihydropyran (DHP) in a appropriate solvent
such as THF, in the presence of an acid such as CH.sub.3SO.sub.3H
to provide the compound of formula (d), where R.sup.1' is a
protecting group such as 2-tetrahydropyranyl. [Methods for
introducing or removing protecting groups are well known in the
art; see, for example, Greene and Wuts, Protective Groups in
Organic Synthesis, 3.sup.rd Ed., John Wiley and Sons, New York,
(1999)].
The compound of formula (d) can react under various
transition-metal facilitated coupling conditions to provide the
desired compound of formula (c) with a properly substituted
R.sup.2' as previously defined. More specifically, if it is a
carbon-carbon coupling, the compound of formula (c) can be made
under coupling conditions such as a Suzuki coupling with a suitable
boronic acid, an appropriate catalyst such as
1,1'-bis(diphenylphosphino)ferrocene palladium (II) chloride
(PdCl.sub.2(dppf)), and a proper base such as CsF in a suitable
solvent such as 1,4-dioxane at elevated temperature. If it is a
carbon-nitrogen coupling, the compound of formula (c) can be made
under coupling conditions such as a Buchwald-Hartwig coupling with
a proper nitrogen-containing reactant such as morpholine, a
suitable ligand such as 2-di-tert-butylphosphino-2'-methylbiphenyl,
a base such as KOH, and a catalyst such as
tris(dibenzylideneacetone)-dipalladium (0) (Pd.sub.2(dba).sub.3),
in an appropriate solvent such as tert-butanol at elevated
temperature. The coupling reaction can be carried out under
conventional heating conditions or under microwave reaction
conditions well known to the skilled artisan.
The compound of formula (c) can be reduced to an amino compound
under various reduction conditions well known to the skilled
artisan. More specifically, the compound of formula (c) can react
with stannous chloride in a suitable solvent such as ethyl acetate
(EtOAc)/ethanol (EtOH) at an elevated temperature to give the
desired compound of formula (a). If R.sup.1' is a
nitrogen-protecting group such as 2-tetrohydropyranyl, the
protecting group will be cleaved. R.sup.1' will be a proton after
the reduction.
The compound of formula (c) can also be reduced by reacting with
N,N-dimethylhydrazine and FeCl.sub.3 in a proper solvent such as
methanol (MeOH), or H.sub.2/palladium on carbon (Pd/C) in proper
solvent such as EtOH. Both reduction conditions will only reduce
the nitro group to an amino group, and will leave the
nitrogen-protecting group, R.sup.1', untouched.
It is well known to the skilled artisan that reactions on nitrogen
of some nitrogen-containing heterocycles such as indazole compounds
could generate tautomers. The ratio of tautomers depends
essentially on the mode of performing reactions and different
conditions. Intermediates disclosed in this invention with nitrogen
protecting groups such as THP may exist as regioisomers. In the
compounds of the present invention, when R.sup.1 is a proton, it
may exist as a pair of fast exchanging tautomers as illustrated in
Scheme III.
##STR00006##
The following preparations and examples are named using
ChemDraw.RTM. Ultra version 10.0.
Preparation 1
N-(4-Methoxy-2-methylphenyl)acetamide
To a solution of 4-methoxy-2-methylaniline (120 g, 0.88 mol) in DCM
(400 mL) is added acetic acid anhydride (120 mL, 1.2 mol) dropwise.
The reaction mixture is stirred at room temperature (RT) for 3
hours. After petroleum ether (PE) (1.6 L) is added, the slurry is
stirred for another one hour. The precipitate is collected by
filtration and is washed with PE to give the product as a pink
solid (130 g, 82% yield). MS (m/z): 180.0 (M+H).
Preparation 2
N-(5-Bromo-4-methoxy-2-methylphenyl)acetamide
To a solution of N-(4-methoxy-2-methylphenyl)acetamide (130 g, 0.73
mol) in acetic acid (800 mL) is added bromine (42 mL, 0.8 mol)
dropwise at 0.degree. C. After addition, the resulting mixture is
stirred at RT overnight. Saturated aqueous NaHSO.sub.3 is added
until a clear solution is obtained, and then a large amount of
water (2.0 L) is added forming a precipitate. The precipitated
solid is collected and washed with water to give the crude product
(thin layer chromatography (TLC) solvent: DCM:EtOAc=10:1). The
solid is dissolved in minimum amount of refluxing DCM, and then PE
(about 10-20% volume of DCM used) is added. The resulting solution
is cooled to RT. After 2 hours, the precipitated solid is collected
and washed with PE to give a white product (108 g, 57% yield). MS
(m/z): 260.0 (M+H).
Preparation 3
5-Bromo-4-methoxy-2-methylaniline
To a solution of N-(5-bromo-4-methoxy-2-methylphenyl)acetamide (108
g, 0.42 mol) in MeOH (400 mL) is added concentrated HCl (160 mL, 2
mol). After being heated at reflux overnight, the mixture is
neutralized with aqueous NaHCO.sub.3, and extracted with EtOAc
(1200 mL). The organic phase is dried and concentrated to afford
the product (76 g, 84% yield). MS (m/z): 216.0 (M+H).
Preparation 4
1-(5-Bromo-4-methoxy-2-methylphenyl)diazonium tetrafluoroborate
To a solution of 5-bromo-4-methoxy-2-methylaniline (76 g, 0.35 mol)
in HBF.sub.4 (48% wt, 140 mL) and H.sub.2O (280 mL) is added a
solution of NaNO.sub.2 (27.6 g, 0.4 mol) in H.sub.2O (60 mL) at
0.degree. C. After the addition is completed, the reaction mixture
is stirred at 0.degree. C. for 30 minutes (min). The precipitate is
filtered, washed with a small amount of ice water several times and
dried to give the product (110 g, 99% yield). MS (m/z): 229.0
(M+H).
Preparation 5
6-Bromo-5-methoxy-1H-indazole
1-(5-Bromo-4-methoxy-2-methylphenyl)diazonium tetrafluoroborate
(110 g, 0.35 mol) is added in one portion to a stirred mixture of
KOAc (140.5 g, 1.43 mol) and 18-crown-6-ether (9.3 g, 0.035 mol) in
CHCl.sub.3 (800 mL) and stirred at RT overnight. The mixture is
filtered and the solid is washed with DCM. The combined filtrate is
concentrated and the residue is purified by silica gel column
chromatography (DCM:MeOH=50:1) to give the product (10 g). The cake
is added to THF (1600 mL) and the mixture is stirred at RT for one
hour. The mixture is filtered and the filtrate is concentrated to
give 10 g of the crude product (total yield 88%). MS (m/z): 229.0
(M+H).
Preparation 6
6-Bromo-5-hydroxy-1H-indazole
To a solution of 6-bromo-5-methoxy-1H-indazole (60 g, 0.265 mol) in
DCM (1300 mL) is added a solution of BBr.sub.3 (105 g, 0.42 mol) in
DCM (200 mL) at 0.degree. C. The reaction mixture is warmed to RT
and stirred overnight. Then the reaction solution is quenched with
MeOH at 0.degree. C. The solvent is removed in vacuo and the
residue is neutralized with NaHCO.sub.3 solid. The mixture is
partitioned by water (1500 mL) and EtOAc (1500 mL). The aqueous
layer is extracted with EtOAc (1500 mL) two times. The combined
organic layers are dried and concentrated to give crude product,
which is purified by silica gel column chromatography (PE:THF=2:1)
to give the desired product (42.5 g, 75% yield). MS (m/z): 215.0
(M+H).
Preparation 7
6-Bromo-5-(2-fluoro-4-nitrophenoxy)-1H-indazole
A mixture of 6-bromo-5-hydroxy-1H-indazole (7.0 g, 33.0 mmol),
3,4-difluoronitrobenzene (4.98 mg, 31.0 mmol), NaHCO.sub.3 (2.5 g,
31.0 mmol) in DMF (100 mL) is stirred at 80.degree. C. for 4 hours.
Then LiCl (10% aqueous solution) is added and the solution is
extracted with EtOAc. The organic phase is dried over anhydrous
MgSO.sub.4, filtered and concentrated. The residue is purified by
silica gel column chromatography eluting with PE:DCM (1:1) to give
the desired product (5.5 g, 46.6% yield). MS (m/z): 354.0
(M+H).
The following compound is prepared essentially by the method of
Preparation 7:
TABLE-US-00001 Prep. Physical data No. Chemical name MS (m/z) (M +
H) 8 6-Bromo-5-(4-nitrophenoxy)-1H-indazole 336
Preparation 9
6-Bromo-5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazo-
le
To a solution of 6-bromo-5-(2-fluoro-4-nitrophenoxy)-1H-indazole
(5.0 g, 14.2 mmol) in THF (50 mL) is added DHP (2.4 g, 28.5 mmol)
and CH.sub.3SO.sub.3H (1.0 g, 10.4 mmol). The resulting mixture is
stirred at RT for 1 hour. Then EtOAc and aqueous NaHCO.sub.3
solutions are added. The organic phase is separated, dried over
anhydrous MgSO.sub.4, filtered and concentrated. The residue is
purified by silica gel column chromatography eluting with PE:EtOAc
(5:1) to give the desired product (5.5 g, 89.0% yield). MS (m/z):
436.0 (M+H).
The following compound is prepared essentially by the method of
Preparation 9:
TABLE-US-00002 Prep. Physical data No. Chemical name MS (m/z) (M +
H) 10 6-Bromo-5-(4-nitrophenoxy)-1-(tetrahydro- 418.0
2H-pyran-2-yl)-1H-indazole
Preparation 11
6-Bromo-1-methyl-5-(4-nitrophenoxy)-1H-indazole
To a mixture of 6-bromo-5-(4-nitrophenoxy)-1H-indazole (2.68 g,
8.02 mmol) and KOH (600 mg, 10.69 mmol) in acetone (100 mL) cooled
with an ice-water bath is added dropwise methyl iodide (0.55 mL,
8.83 mmol). After the reaction mixture is stirred at 0.degree. C.
for 2 hours, it is stirred at RT overnight. The solvent is removed,
and the residue is purified by silica gel column chromatography
eluting with PE:EtOAc (3:1) to give the product (1.50 g, 53.7%
yield). MS (m/z): 348.0 (M+H).
The following compound is prepared essentially by the method of
Preparation 11:
TABLE-US-00003 Prep. Physical data No. Chemical name MS (m/z) (M +
H) 12 6-Bromo-5-(2-fluoro-4-nitrophenoxy)-1- 365.9
methyl-1H-iadazole
Alternatively,
6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole
(Preparation 12) may also be prepared in the following 3 step
process:
2,4-Dibromo-5-hydroxy-benzaldehyde (50 g, 178.6 mmol),
1,2-difluoro-4-nitrobenzene (28.4 g, 178.6 mmol) and potassium
carbonate (49.0 g, 357.2 mmol) are stirred in DMF (500 mL) at
60.degree. C. for 2 hours. The reaction is quenched with water
(1000 mL) and extracted with methyl tert-butylether (MTBE)
(2.times.500 mL). The organic layer is washed with saturated sodium
chloride aqueous solution (2.times.500 mL), dried with anhydrous
sodium sulfate, and concentrated to obtain a yellow solid. The
crude solid is recrystallized in EtOAc/PE (1:5) to give
2,4-dibromo-5-(2-fluoro-4-nitrophenoxy)benzaldehyde as a yellow
solid (52.8 g, 70.6% yield).
2,4-Dibromo-5-(2-fluoro-4-nitrophenoxy)benzaldehyde (13.0 g, 31.0
mmol) is refluxed with methylhydrazine (4.3 g, 93 mmol) in THF (130
mL) for 2 hours. The reaction is quenched with water (150 mL) and
extracted with MTBE (2.times.150 mL). The organic layer is washed
with saturated sodium chloride aqueous solution (2.times.150 mL),
dried with anhydrous sodium sulfate, and concentrated to obtain a
solid. The crude solid is recrystallized in EtOAc/hexane to obtain
1-(2,4-dibromo-5-(2-fluoro-4-nitrophenoxy)benzylidene)-2-methylhydrazine
as a yellow solid (10.6 g, 76.7% yield). MS (m/z): 447.9 (M+H).
1-(2,4-Dibromo-5-(2-fluoro-4-nitrophenoxy)benzylidene)-2-methylhydrazine
(1.0 g, 2.2 mmol), cuprous chloride (22 mg, 0.2 mmol), potassium
carbonate (0.638 g, 7.2 mmol), DMF (10 mL), and a stir bar are
combined in a pressure tube under nitrogen. The cap is sealed and
the tube is placed in an oil bath with stirring. The bath is heated
to 100.degree. C. over 30 min and held at 100.degree. C. for 6
hours and then cooled to RT. The reaction mixture is poured into a
separatory funnel containing MTBE (10 mL) and water (10 mL). The
layers are separated and the aqueous layer is extracted with an
additional portion of MTBE (10 mL). The organic layers are
combined, and washed with water followed by saturated sodium
chloride aqueous solution. The organic layer is dried over
magnesium sulfate and concentrated to yield 0.70 g of crude
product. The crude solid is dissolved in DCM and heptane, and then
concentrated to remove DCM resulting in the formation of a slurry.
The product is collected by filtration and dried under vacuum to
give 6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole as a
solid (0.65 g, 79% yield). MS (m/z): 367.8 (M+H).
Preparation 13
6-Bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-5-ol
To a solution of 6-bromo-5-hydroxy-1H-indazole (725.0 g, 3.4 mol)
in THF (10.2 L) is added DHP (336.5 mL, 3.57 mol) and
CH.sub.3SO.sub.3H (65.4 g, 0.68 mol) at RT. The resulting mixture
is stirred at RT for 22 hours. The reaction mixture is quenched
with distilled water (6 L) and extracted with EtOAc (6 L).
Saturated aqueous NaHCO.sub.3 solution (1100 mL) is added to adjust
the pH to 8. After phase separation, the organic phase is washed
with water (4 L) and then saturated aqueous sodium chloride (3 L),
dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated
to give the product as a solid (1.64 kg, 99.3% yield). MS (m/z):
299.0 (M+H).
Preparation 14
6-Bromo-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazo-
le
To a solution of
6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-5-ol (1.475 kg,
4.96 mol) in DMF (5.3 L) is added 3,4-difluoronitrobenzene (1.18
kg, 7.45 mol) and NaHCO.sub.3 (625.5 g, 7.45 mol) at RT. The
reaction mixture is heated at 70.degree. C. for 10 hours and then
cooled to less than 20.degree. C. Deionized (DI) water (7.9 L) is
slowly added to the solution and the resulting slurry is stirred at
15.degree. C. for one hour. The solid is collected by vacuum
filtration, and the solid cake is washed with water (8 L). It is
then air dried under vacuum on filter and is triturated with methyl
MTBE (18.6 L) at reflux conditions for two hours. The slurry is
then cooled to RT and the solid is collected by vacuum filtration.
The solid cake is washed with MTBE (4 L.times.2) and dried in a
vacuum oven at 35.degree. C. to give the desired product (1.405 kg,
64.9% yield). MS (m/z): 436.0 (M+H).
Preparation 15
5-(2-Fluoro-4-nitrophenoxy)-6-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-
-1H-indazole
A mixture of
6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indaz-
ole (5.0 g, 11.5 mmol), 4-pyridineboronic acid (3.0 g, 24.3 mmol),
PdCl.sub.2(dppf) (1.8 g, 2.25 mmol) and CsF (5.0 g, 33.0 mmol) in
1,4-dioxane (100 mL) is stirred at 110.degree. C. overnight. Then,
aqueous NH.sub.4Cl and EtOAc are added. The organic phase is
separated, dried over anhydrous MgSO.sub.4 and concentrated. The
residue is purified by silica gel column chromatography eluting
with PE:EtOAc (3:1) to give the desired product (2.8 g, 56% yield).
MS (m/z): 435.1 (M+H).
The following compounds are prepared essentially by the method of
Preparation 15:
TABLE-US-00004 Physical data MS (m/z) Prep. No. Chemical name (M +
H) 16 5-(2-Fluoro-4-nitrophenoxy)-6-(4-(methyl- 512.1
sulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole 17
tert-Butyl 4-(5-(2-fluoro-4-nitrophenoxy)-1- 524.1
(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-1H-
pyrazole-1-carboxylate
5-(2-Fluoro-4-nitrophenoxy)-6-(1H-pyrazol-4-yl)-1- 424.1
(tetrahydro-2H-pyran-2-yl)-1H-indazole 18
5-(2-Fluoro-4-nitrophenoxy)-6-(pyridin-3-yl)-1- 435.1
(tetrahydro-2H- pyran-2-yl)-1H-indazole 19
6-(1,3-Dimethyl-1H-pyrazol-5-yl)-5-(2-fluoro-4- 452.1
nitrophenoxy)-1-(tetrahydropyran-2-yl)-1H-indazole 20
5-(2-Fluoro-4-nitrophenoxy)-6-(2-methoxypyrimi- 466.1
din-5-yl)-1-(tetrahydropyran-2-yl)-1H-indazole 21
5-(2-Fluoro-4-nitrophenoxy)-6-(2-methylpyridin-4- 449.1
yl)-1-(tetrahydropyran-2-yl)-1H-indazole 22*
6-Cyclopropyl-5-(2-fluoro-4-nitrophenoxy)-2- 398
(tetrahydro-2H-pyran-2-yl)-2H-indazole 23 tert-Butyl
4-(1-methyl-5-(4-nitrophenoxy)-1H- 436.0
indazol-6-yl)-1H-pyrazole-1-carboxylate
1-Methyl-5-(4-nitrophenoxy)-6-(1H-pyrazol-4-yl)- 336.0 1H-indazole
24 5-(2-Fluoro-4-nitrophenoxy)-1-methyl-6-(2- 379.1
methylpyridin-4-yl)-1H-indazole 25
5-(2-Fluoro-4-nitrophenoxy)-1-methyl-6-(pyridin-3- 365.1
yl)-1H-indazole 26 (tert-Butyl
4-(5-(2-fluoro-4-nitrophenoxy)-1-methyl- 454.0
1H-indazol-6-yl)-1H-pyrazole-1-carboxylate 27 tert-Butyl
4-(5-(2-fluoro-4-nitrophenoxy)-1-methyl- 454.1
1H-indazol-6-yl)-1H-pyrazole-1-carboxylate
5-(2-Fluoro-4-nitrophenoxy)-1-methyl-6-(1H- 354.1
pyrazo1-4-yl)-1H-indazole *Reaction is carried out under microwave
conditions at 95.degree. C. for about 90 min.
Preparation 28
6-(2,6-Dimethylpyridin-4-yl)-5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydropyra-
n-2-yl)-1H-indazole
To a solution of
6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydropyran-2-yl)-1
1H-indazole (1.31 g, 3.0 mmol) in 1,4-dioxane (20 mL) is added
bis(pinacolato)diboron (0.91 g, 3.6 mmol), Pd.sub.2(dba).sub.3
(0.14 g, 0.2 mmol), tricyclohexylphosphine (0.1 g, 0.4 mmol),
potassium acetate (KOAc) (0.59 g, 6.0 mmol) under N.sub.2. After
the reaction mixture is heated to reflux for 3 hours under N.sub.2,
it is cooled to RT. 4-Bromo-2,6-dimethylpyridine hydrobromide (0.8
g, 3.0 mmol), PdCl.sub.2(dppf) (0. 16 g, 0.2 mmol), CsF (1.38 g,
9.0 mmol) are added under N.sub.2. The resulting mixture is heated
at reflux overnight under N.sub.2. The solid is filtered off and
the filtrate is concentrated. The residue is purified by silica gel
column chromatography eluting with PE:EtOAc (from 5:1 to 1:1) to
give the product (0.67 g, 48.3% yield). MS (m/z): 463.1 (M+H).
Preparation 29
4-(5-(2-Fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-y-
l)morpholine
To a solution of
6-bromo-5-(2-fluoro-4-nitro-phenoxy)-1-(tetrahydropyran-2-yl)-1
H-indazole (8.0 g, 18 mmol) in tert-butanol (150 mL) and H.sub.2O
(3.2 mL) is added Pd.sub.2(dba).sub.3 (320 mg, 0.35 mmol),
2-di-tert-butylphosphino-2'-methylbiphenyl (480 mg, 1.54 mmol), KOH
(3.2 g, 57 mmol) and morpholine (3.2 g, 36.7 mmol) under N.sub.2.
After the mixture is stirred at 70.degree. C. for 2 hours under a
N.sub.2 atmosphere, it is filtered and the filtrate is
concentrated. The residue is partitioned with EtOAc (100 mL) and
saturated aqueous NH.sub.4Cl (30 mL). The organic layer is
separated, dried over MgSO.sub.4, and concentrated. The residue is
purified by silica gel column chromatography eluting with PE:EtOAc
(3:1) to give the product (4.5 g, 56.5% yield). MS (m/z): 443.1
(M+H).
The following compounds are prepared essentially by the method of
Preparation 29:
TABLE-US-00005 Physical data Prep. MS (m/z) No. Chemical name (M +
H) 30 5-(2-Fluoro-4-nitrophenoxy)-N,N-dimethyl-1- 401.2
(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine 31
N,N-Dimethyl-5-(4-nitrophenoxy)-1-(tetrahydro- 383.1
2H-pyran-2-yl)-1H-indazol-6-amine
Preparation 32
4-(5-(2-Fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H
-indazol-6-yl)-2-methylmorpholine(racemic)
To a 25 mL microwave vial is added
6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indaz-
ole (0.8 g, 1.8 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (98 mg, 165
.mu.mol) and Pd.sub.2(dba).sub.3 (50 mg, 55 .mu.mol). The mixture
is suspended in toluene (12 mL, 113 mmol) and then
2-methylmorpholine hydrochloride (278 mg, 2.02 mmol) and sodium
tert-butoxide (454 mg, 4.58 mmol) are added. The reaction mixture
is heated at 150.degree. C. for 25 min in a microwave reactor. The
reaction mixture is then concentrated and the residue is purified
on a silica gel column eluting with hexanes (A) and EtOAc (B),
gradient from 90% (A): 10%(B) to 60%(A):40%(B) over 60 min then to
50%(A):50%(B) for 20 min to give an orange solid as the desired
product (410 mg, 39% yield). MS (m/z): 457 (M+H).
The following compounds are prepared essentiallyby the method of
Preparation 32:
TABLE-US-00006 Physical data Prep. MS (m/z) No. Chemical name (M +
H) 33 (2R)-4-(5-(2-Fluoro-4-nitrophenoxy)-2-(tetrahydro-2H- 456.8
pyran-2-yl)-2H-indazol-6-yl)-2-methyhmorpholine 34
(2S,6R)-4-(5-(2-Fluoro-4-nitrophenoxy)-2-(tetrahydro- 470.8
2H-pyran-2-yl)-2H-indazol-6-yl)-2,6- dimethylmorpholine
Preparation 35
4-(5-(2-Fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-6-y-
l)-2,2-dimethylmorpholine
6-Bromo-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indaz-
ole (1.5 g, 3.4 mmol) is added to a 50 mL Genevac Carousel.RTM.
tube and is suspended into the amylene hydrate (10 mL, 91.4 mmol)
and N.sub.2 is bubbled in suspension. To the mixture is added
2-(di-tert-butylphosphino)-2'-methylbiphenyl (97.7 mg, 309
.mu.mol), Pd.sub.2(dba).sub.3 (94.5 mg, 103 .mu.mol) and DI water
(0.3 mL), and N.sub.2 bubbling is continued for 10 min. To this
mixture is added 2,2-dimethylmorpholine hydrochloride (1.04 g, 6.9
mmol) and a solution of KOH (617 mg, 11.0 mmol) dissolved in 0.3 mL
of distilled water. The reaction mixture is heated at 80.degree. C.
for 2 hours and then cooled to RT. The mixture is then poured into
EtOAc (300 mL), washed with distilled water (1.times.100 mL) and
then saturated aqueous sodium chloride (100 mL). The combined
aqueous layers are extracted with EtOAc (100 mL). The combined
organic solution is dried with Na.sub.2SO.sub.4, filtered, and
concentrated to dryness to give a gold solid. The solid is purified
on a silica gel column eluting with hexanes (A) and EtOAc (B),
gradient from 95%(A):5%(B) to 75%(A):25%(B) over 70 min to give a
light yellow solid as the desired product (410 mg, 25% yield). MS
(m/z): 470.8 (M+H).
Preparation 36
5-(2-Fluoro-4-nitrophenoxy)-6-(pyridine-4-yl)-1H-indazole
To a solution of
5-(2-fluoro-4-nitrophenoxy)-6-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl-
)-1H-indazole (2.8 g, 6.45 mmol) in EtOH (30 mL) is added HCl
(concentrated 5.0 mL). The mixture is stirred at 80.degree. C. for
2 hours. Then aqueous NaHCO.sub.3 and EtOAc are added. The organic
phase is dried over anhydrous MgSO.sub.4 and concentrated. The
residue is purified by silica gel column chromatography eluting
with PE:EtOAc (3:1) to give the desired product (1.95 g, 86.0%
yield). MS (m/z): 351.0 (M+H).
Preparation 37
3-Fluoro-4-(6-(pyridine-4-yl)-1H-indazole-5-yloxy)aniline
A mixture of
5-(2-fluoro-4-nitrophenoxy)-6-(pyridine-4-yl)-1H-indazole (1.95 g,
4.5 mmol) and SnCl.sub.2.2H.sub.2O (10.2 g, 45.3 mmol) in
EtOAc/EtOH (200 mL/10 mL) is stirred at 80.degree. C. for 2 hours.
Then aqueous NaHCO.sub.3 and EtOAc are added. The organic phase is
dried over anhydrous MgSO.sub.4 and concentrated. The residue is
purified by silica gel column chromatography eluting with PE:EtOAc
(2:1) to give the desired product (1.10 g, 61.0% yield). MS (m/z):
321.0 (M+H).
Preparation 38
3-Fluoro-4-(6-(4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-i-
ndazol-5-yloxy)aniline
To a solution of
5-(2-fluoro-4-nitrophenoxy)-6-(4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-
-pyran-2-yl)-1H-indazole (320 mg, 0.63 mmol) in EtOAc (50 mL) is
added Pd/C (10%, 100 mg). The resulting mixture is degassed by
evacuation and backfilled with H.sub.2 three times. It is stirred
under an atmosphere of H.sub.2 at RT overnight. The solid is
removed by filtration and the filtrate is concentrated. The residue
is purified by silica gel column chromatography eluting with
DCM:MeOH (20:1) to give the desired product (250 mg, 83% yield). MS
(m/z): 482.1 (M+H).
The following compounds are prepared essentially by the method of
Preparation 38:
TABLE-US-00007 Physical data Prep. MS (m/z) No. Chemical name (M +
H) 39 3-Fluoro-4-(1-methyl-6-(2-methylpyridin-4-yl)-1H- 349.1
indazol-5-yloxy)aniline 40 tert-Butyl
4-(5-(4-amino-2-fluorophenoxy)-1-methyl- 424
1H-indazol-6-yl)-1H-pyrazole-1-carboxylate
Preparation 41
4-(6-(1H-Pyrazol-4-yl)-1H-indazol-5-yloxy)-3-fluoroaniline
To a solution of
5-(2-fluoro-4-nitrophenoxy)-6-(1H-pyrazol-4-yl)-1-(tetrahydropyran-2-yl)--
1H-indazole (900 mg, 2.13 mmol) and
4-[5-(2-fluoro-4-nitro-phenoxy)-1-(tetrahydropyran-2-yl)-1H-indazol-6-yl]-
-pyrazole-1-carboxylic acid tert-butyl ester (3.1 g, 5.92 mmol) in
EtOAc/EtOH (75 mL/75 mL) is added stannous chloride dihydrate (10
g, 52.74 mmol). The reaction mixture is stirred at reflux
overnight. After it is cooled and basified with saturated aqueous
NaHCO.sub.3 to pH 8-9, the mixture is extracted with EtOAc (100
mL). The organic phase is separated, dried over MgSO.sub.4, and
concentrated. The residue is purified by silica gel column
chromatography eluting first with PE:EtOAc (1:1) and then with
EtOAc to give the product (1.75 g, 71.0% yield). MS (m/z): 310.0
(M+H).
The following compounds are prepared essentially by the method of
Preparation 41:
TABLE-US-00008 Physical data Prep. MS (m/z) No. Chemical name (M +
H) 42 3-Fluoro-4-(6-(pyridin-3-yl)-1H-indazol-5- 321.1
yloxy)aniline 43 4-(6-(1,3-Dimethyl-1H-pyrazol-5-yl)-1H-indazol-5-
338.1 yloxy)-3- fluoroaniline 44
3-Fluoro-4-(6-morpholino-1H-indazol-5-yloxy)aniline 329.1 45
4-[6-(2,6-Dimethylpyridin-4-yl)-1H-indazol-5-yloxy]- 349.1
3-fluoroaniline 46 3-Fluoro-4-[6-(2-methoxypyrimidin-5-yl)-1H-
352.1 indazol-5-yloxy]-aniline 47
5-(4-Amino-2-fluorophenoxy)-N,N-dimethyl-1H- 287.1 indazol-6-amine
48 3-Fluoro-4-(6-(2-methylpyridin-4-yl)-1H-indazol-5- 335.1
yloxy)aniline 49 5-(4-Aminophenoxy)-N,N-dimethyl-1H-indazol-6-
269.1 amine 50 4-(1-Methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5- 306.0
yloxy)aniline 51 3-Fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H- 324.1
indazol-5-yloxy)aniline 52
3-Fluoro-4-(1-methyl-6-(pyridin-3-yl)-1H-indazol-5- 335.1
yloxy)aniline
Preparation 53
4-(6-Cyclopropyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-5-yloxy)-3-fluoro-
aniline
To a 25 mL glass vial is added
6-cyclopropyl-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-
-indazole (395 mg, 994 .mu.mol) and MeOH (20 mL, 494 mmol). To the
suspension is added N,N-dimethylhydrazine (756 .mu.L, 9.94 mmol)
and FeCl.sub.3 (163 mg, 994 .mu.mol). The vial is capped, and
heated to 60.degree. C. and stirred for 2 hours and then stirred at
50.degree. C. overnight. The mixture is filtered over a Buchner
funnel and the solid washed with MeOH (100 mL). The filtrate is
collected and concentrated to give a brown/orange solid. The
residue is purified on a silica gel column eluting with DCM (A) and
a 10% MeOH in a DCM solution (B), gradient from 100% (A) to 85%(A):
15%(B) over 50 min to give a yellow solid as the title compound
(358 mg, 98% yield). MS (m/z): 368 (M+H).
The following compounds are prepared essentially by the method of
Preparation 53:
TABLE-US-00009 Physical data Prep. MS (m/z) No. Chemical name (M +
H) 54 3-Fluoro-4-(6-(2-methylmorpholino)-2-(tetrahydro-2H- 427
pyran- 2-yl)-2H-indazol-5-yloxy)aniline 55
4-(6-(2,2-Dimethylmorpholino)-2-(tetrahydro-2H- 441
pyran-2-yl)-2H-indazol-5-yloxy)-3-fluoroaniline 56
3-Fluoro-4-(6-((R)-2-methylmorpholino)-2-(tetrahydro- 427
2H-pyran-2-yl)-2H-indazol-5-yloxy)aniline 57
4-(6-((2S,6R)-2,6-dimethylmorpholimo)-2-(tetrahydro- 441
2H-pyran-2-yl)-2H-indazol-5-yloxy)-3-fluoroaniline 58
3-Fluoro-4-(6-morpholino-2-(tetrahydro-2H-pyran-2- 413 yl)-2H-
indazol-5-yloxy)aniline
Preparation 59
N-(Diphenylmethylene)-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazol-6-am-
ine
To a 10 mL microwave vial is added
6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole (500 mg,
1.37 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (73 mg,
123 .mu.mol) and Pd.sub.2(dba).sub.3 (38 mg, 41 .mu.mol). The
mixture is suspended in toluene (5 mL, 47 mmol) and benzophenone
imine (272 mg, 1.5 mmol) and sodium tert-butoxide (203 mg, 2.05
mmol) are added. The mixture is heated at 150.degree. C. for 20 min
in a microwave reactor. After cooling, the reaction solution is
concentrated to give a brown oil which is dissolved in DCM (150 mL)
and washed with saturated aqueous sodium chloride (2.times.50 mL).
The aqueous layers are combined and extracted with DCM (1.times.50
mL), dried with Na.sub.2SO.sub.4, filtered and concentrated to give
a brown residue. The residue is purified on a silica gel column
eluting with hexanes (A) and EtOAc (B), gradient from 85%(A):
15%(B) to 50%(A):50%(B) over 50 min to give a yellow solid material
as the title compound (574 mg, 90.1% yield). MS (m/z): 467.2
(M+H).
Preparation 60
5-(4-Amino-2-fluorophenoxy)-N-benzhydryl-1-methyl-1H-indazol-6-amine
To a 100 mL round bottom flask is added
N-(diphenylmethylene)-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazol-6-a-
mine (424 mg, 909 .mu.mol) and EtOH (35 mL, 601 mmol). To the
mixture is added ammonium formate (1000 mg, 15.9 mmol) followed by
the addition of 10% Pd/C (300 mg, 141 .mu.mol) and the reaction
mixture is stirred at RT for 1 hour and heated at 45.degree. C. for
15 min. The solvent is removed and the residue is dissolved in DCM
(150 mL) and distilled water (100 mL). The organic layer is washed
with distilled water (1 x 100 mL), and the combined aqueous layers
are extracted with DCM (1 x 50 mL). The combined organic solution
is dried with Na.sub.2SO.sub.4, filtered, and concentrated. The
crude is purified on a silica gel column eluting with hexanes (A)
and EtOAc (B), gradient from 90% (A)10% (B) to 40% (A):60% (B) over
90 min to give an off-white solid material as the title compound
(204 mg, 51% yield). MS (m/z): 438.8 (M+H).
Preparation 61
1-Acetyl-6-bromo-1H-indazol-5-yl acetate
A mixture of 6-bromo-5-hydroxy-1H-indazole (25 g, 117 mmol) in
acetic acid anhydride (75 mL) is heated at 110.degree. C. with
stirring for 2 hours. After it is cooled, diethyl ether (100 mL) is
added. The precipitate is collected by filtration, washed with
diethyl ether (30 mL), and dried under vacuum to afford the product
(34 g, 98% yield). MS (m/z): 297.0 (M+H).
Preparation 62
Ethyl 5-hydroxy-1H-indazole-6-carboxylate
An autoclave is charged with 1-acetyl-6-bromo-1H-indazol-5-yl
acetate (25 g, 84 mmol), TEA (25 g, 252 mmol), dichloro bis
(benzonitrile) palladium (Pd(PhCN).sub.2Cl.sub.2) (1.6 g, 4.2
mmol), 1,1 '-bis(diphenylphosphino)ferrocene (dppf) (4.7 g, 8.4
mmol) and EtOH (500 mL) is stirred at 130.degree. C. under an
atmosphere of CO for 8 hours. The reaction mixture is concentrated,
and the residue is purified by silica gel column chromatography to
afford the product (15.5 g, 90% yield). MS (m/z): 207.0 (M+H).
Preparation 63
Ethyl
5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carboxylate
To a solution of ethyl 5-hydroxy-1H-indazole-6-carboxylate (15.5 g,
75 mmol) in DCM (100 mL) and THF (100 mL) containing
methanesulfonic acid (721 mg, 7.5 mmol) is added a solution of
3,4-dihydro-2H-pyran (6.6 g, 79 mmol) in DCM (20 mL) dropwise at
RT. The resulting solution is stirred at RT overnight. After the
solvent is removed, EtOAc (500 mL), saturated aqueous sodium
chloride (500 mL) and NaHCO.sub.3 (5 g) are added. The organic
layer is separated, dried and concentrated. The residue is purified
by silica gel column chromatography to afford the product (16.8 g,
77% yield). MS (m/z): 291.1 (M+H).
Preparation 64
Ethyl-5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-
-6-carboxylate
A mixture of ethyl
5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carboxylate
(10.8 g, 37 mmol), 1,2-difluoro-4-nitrobenzene (7.1 g, 44 mmol),
NaHCO.sub.3 (7.4 g, 88 mmol) and DMF (100 mL) is stirred at
80.degree. C. for 2 hours. After it is cooled to RT, water (400 mL)
and PE (50 mL) are added and the mixture is stirred for 20 min. The
precipitate is collected and dried under vacuum at 50.degree. C. to
afford the product (15 g, 95% yield). MS (m/z): 430.1 (M+H).
Preparation 65
5-(2-Fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-car-
boxylic acid
To a solution of
ethyl-5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-
e-6-carboxylate (22 g, 51.2 mmol) in THF (60 mL) and MeOH (60 mL)
and H.sub.2O (10 mL) is added LiOH (3 g, 125 mmol). The resulting
solution is stirred at RT for 1.5 hours and the organic solvents
are removed. The aqueous residue is acidified with cold 6N HCl to
pH 2, and extracted with EtOAc (150 mL). The organic phase is
separated, dried, and concentrated. The residue is purified by
silica gel column chromatography eluting with PE:EtOAc:acetic acid
(100:100:1) to afford the product (19.5 g, 95% yield). MS (m/z):
402.1 (M+H).
Preparation 66
tert-Butyl
5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-ind-
azol-6-ylcarbamate
A mixture of
5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-ca-
rboxylic acid(590 mg, 1.47 mmol), diphenylphosphoryl azide (485 mg,
1.76 mmol), TEA (179 mg, 1.76 mmol), 4 .ANG. molecular sieves (3 g)
in tert-butanol (40 mL) is stirred at 80.degree. C. overnight. The
mixture is filtered and the filtrate is concentrated. The residue
is purified by silica gel column chromatography eluting with
PE/EtOAc (10:1) to give the desired product (400 mg, 65% yield). MS
(m/z): 473.1 (M+H).
Preparation 67
tert-Butyl
5-(4-amino-2-fluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-ind-
azol-6-ylcarbamate
To a solution of tert-butyl
5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-ylc-
arbamate (400 mg, 0.85 mmol) in EtOAc (50 mL) is added Pd/C (10%,
50 mg). The resulting mixture is degassed by evacuation and
backfilled with H.sub.2 three times. The mixture is stirred under
an atmosphere of H.sub.2 at RT overnight. The solid is removed by
filtration and the filtrate is concentrated. The residue is
purified by silica gel column chromatography eluting with DCM:MeOH
(10:1) to give the desired product (300 mg, 80% yield). MS (m/z):
443.2 (M+H).
Preparation 68
5-(2-Fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-N-(tetrahydro-2H--
pyran-4-yl)-1H-indazole-6-carboxamide
The solution of
5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-ca-
rboxylic acid (0.5 g, 1.25 mmol), tetrahydropyran-4-ylamine (0.13
g, 1.25 mmol), EDCI (0.24 g, 1.25 mmol), HOBT (0.17 g, 1.25 mmol),
N-methylmorpholine (0.5 mL) in DMF (5 mL) is stirred at RT
overnight. Then the reaction mixture is partitioned with saturated
aqueous NH.sub.4Cl (20 mL) and EtOAc (50 mL). The organic phase is
separated, dried over MgSO.sub.4, and concentrated. The residue is
purified by silica gel column chromatography eluting with PE:EtOAc
(1:1) to provide the product (0.49 g, 81.2% yield). MS (m/z): 485.1
(M+H).
Preparation 69
5-(4-Amino-2-fluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-N-(tetrahydro-2H--
pyran-4-yl)-1H-indazole-6-carboxamide
To a solution of
5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-N-(tetrahydro-2H-
-pyran-4-yl)-1H-indazole-6-carboxamide (0.49 g, 1.0 mmol) in MeOH
(50 mL) is added Pd/C (100 mg, 10% wt) under N.sub.2. The resulting
mixture is degassed by evacuation and backfilled with nitrogen.
Then the reaction mixture is stirred at RT under H.sub.2 atmosphere
overnight. The solid is removed by filtration and the filtrate is
concentrated to give a crude product (0.42 g, 91.4% yield). MS
(m/z): 455.1 (M+H).
Preparation 70
5-(Benzyloxy)-6-bromo-1H-indazole
To a solution of 6-bromo-5-hydroxy-1H-indazole (5 g, 23.5 mmol) in
THF (50 mL) is added benzyl alcohol (3.05 g, 28.2 mmol), PPh.sub.3
(7.39 g, 28.2 mmol) and diethylazodicarboxylate (4.46 mL, 28.2
mmol). After the reaction mixture is stirred at RT overnight, EtOAc
(50 mL) and saturated aqueous NH.sub.4Cl (30 mL) are added. The
organic phase is separated, dried over MgSO.sub.4, and
concentrated. The residue is purified by silica gel column
chromatography eluting with PE:EtOAc (4:1) to provide the product
(5.0 g, 70.2% yield). MS (m/z): 303.0 (M+H).
Preparation 71
5-(Benzyloxy)-6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
To a solution of 5-(benzyloxy)-6-bromo-1H-indazole (5 g, 16.5 mmol)
in THF (30 mL) and DCM (30 mL) is added 3,4-dihydro-2H-pyran (3 mL,
32.8 mmol) and methanesulfonic acid (1 mL, 15.3 mmol). After the
reaction mixture is stirred at RT for 2 hours, EtOAc (50 mL) and
saturated aqueous NaHCO.sub.3 are added. The organic phase is
separated, dried over MgSO.sub.4, and concentrated. The residue is
purified by silica gel column chromatography eluting with PE:EtOAc
(4:1) to give the desired product (2.7 g, 42.2% yield). MS (m/z):
387.0 (M+H).
Preparation 72
5-(Benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-
-indazol-6-amine
To a solution of
5-(benzyloxy)-6-brome-1-(tetrahydri-2H-pyran-2-yl)-1H-indazole (2
g, 5.16 mmol) in toluene (30 mL) is added tetrahydropyran-4-ylamine
(800 mg, 7.91 mmol), palladium acetate (60 mg, 267 .mu.mol),
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (200 mg, 508
.mu.mol) and sodium tert-butoxide (700 mg, 7.28 mmol) under
N.sub.2. After the reaction is stirred at 100.degree. C. under
N.sub.2 for 1 hour, EtOAc (30 mL) is added and the reaction mixture
is filtered. The filtrate is concentrated and the residue is
purified by silica gel column chromatography eluting first with
EtOAc:PE (1/1) and then EtOAc to give the desired product (1.87 g,
88.8% yield). MS (m/z): 408.2 (M+H).
Preparation 73
N-(5-(Benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(tetrahyd-
ro-2H-pyran-4-yl)acetamide
To a solution of
5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-N-(tetrahydro-2H-pyran-4-yl)-1-
H-indazol-6-amine (1.87 g, 4.59 mmol) in THF (30 mL) is added
acetyl chloride (0.39 mL, 5.48 mmol) and K.sub.2CO.sub.3 (760 mg,
5.50 mmol). After the reaction mixture is heated to reflux for 30
min, H.sub.2O (20 mL) and EtOAc (30 mL) are added. The organic
phase is separated, washed with saturated aqueous NH.sub.4Cl, dried
and concentrated to give the product (1.7 g, 82.4% yield). MS
(m/z): 450.2 (M+H).
Preparation 74
N-(5-Hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(tetrahydro-2-
H-pyran-4-yl)acetamide
To a solution of
N-(5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(tetrahy-
dro-2H-pyran-4-yl)acetamide (1.7 g, 3.78 mmol) in EtOH (100 mL) and
EtOAc (100 mL) is added Pd/C (1 g, 10% wt). After the reaction
mixture is stirred at RT under H.sub.2 overnight, it is filtered
and the filtrate is concentrated. The residue is purified by silica
gel column chromatography eluting first with PE:EtOAc (1:1) and
then EtOAc to give the product (1.2 g, 88.2% yield). MS (m/z):
360.2 (M+H).
Preparation 75
N-(5-(2-Fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-y-
l)-N-(tetrahydro-2H-pyran-4-yl)acetamide
To a solution of
N-(5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-tetrahydro-2-
H-pyran-4-yl)acetamide (1.2 g, 3.34 mmol) in DMF (30 mL)is added
1,2-difluoro-4-nitrobenzene (0.64 g, 4.02 mmol) and
Cs.sub.2CO.sub.3 (1.63 g, 5.00 mmol). After the reaction mixture is
stirred at 100.degree. C. for 2 hours, EtOAc (60 mL) and saturated
aqueous NH.sub.4Cl are added. The organic phase is separated, dried
over MgSO.sub.4 and concentrated. The residue is purified by silica
gel column chromatography eluting first with PE:EtOAc (1:1) and
then EtOAc to give the product (1.44 g, 86.5% yield). MS (m/z):
499.2 (M+H).
Preparation 76
5-(4-Amino-2-fluorophenoxy)-N-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-amin-
e
The title compound is prepared essentially by the method of
Preparation 41. MS (m/z): 343.1 (M+H).
Preparation 77
5-(Benzyloxy)-6-(6-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-ind-
azole
To a solution of
5-(benzyloxy)-6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4
g, 10.3 mmol) in 1,4-dioxane (25 mL) is added
bis(pinacolato)diboron (3 g, 11.8 mmol), dppf (0.3 g, 541 .mu.mol),
PdCl.sub.2(dppf) (0.42 g, 514 .mu.mol) and KOAc (2 g, 20.4 mmol)
under N.sub.2. After the reaction mixture is stirred at reflux for
5 hours, 5-bromo-2-methylpyridine (2.1 g, 12.2 mmol),
tetrakis(triphenylphosphine)palladium (Pd(PPh.sub.3).sub.4) (0.6 g,
519 .mu.mol) and Cs.sub.2CO.sub.3 (4 g, 12.3 mmol) are added and
the mixture is stirred at reflux overnight. The reaction mixture is
cooled and filtered, the filtrate is concentrated. The residue is
purified by silica gel column chromatography eluting with PE:EtOAc
(2:1) to give the product (1.9 g, 46.0% yield). MS (m/z): 400.1
(M+H).
Preparation 78
6-(6-Methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol
To a solution of
5-(benzyloxy)-6-(6-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-in-
dazole (1.44 g, 3.60 mmol) in EtOH (50 mL) and EtOAc (50 mL) is
added Pd/C (500 mg, 10% wt) under N.sub.2. The resulting mixture is
degassed by evacuation and backfilled with nitrogen. Then the
reaction mixture is stirred at RT under H.sub.2 atmosphere
overnight. The reaction mixture is filtered. The filtrate is
concentrated to give the product (982 mg, 88.0% yield). MS (m/z):
310.1 (M+H).
Preparation 79
5-(2-Fluoro-4-nitrophenoxy)-6-(6-methylpyridin-3-yl)-1-(tetrahydro-2H-pyra-
n-2-yl)-1H-indazole
The title compound is essentially made by the same method of
Preparation 75. MS (m/z): 449.2 (M+H).
Preparation 80
3-Fluoro-4-(6-(6-methylpyridin-3-yl)-1H-indazol-5-yloxy)aniline
The title compound is prepared essentially by the method of
Preparation 41. MS (m/z): 335.1 (M+H).
Preparation 81
1-(4-Bromo-2-fluorophenoxy)-2-fluoro-5-methyl-4-nitrobenzene
The title compound is prepared essentially by the same method of
Preparation 75. .sup.1H NMR (d.sub.6-dimethylsulfoxide (DMSO))
.delta. 8.20 (d, 1H), 7.80 (d, 1H), 7.42 (d, 1H), 7.30(d, 1H),
7.10(d, 1H).
Preparation 82
4-(4-Bromo-2-fluorophenoxy)-5-fluoro-2-methylaniline
The title compound is prepared essentially by the method of
Preparation 53. MS (m/z): 315.8 (M+H).
Preparation 83
5-(4-Bromo-2-fluorophenoxy)-6-fluoro-1H-indazole
To a suspension of
4-(4-bromo-2-fluorophenoxy)-5-fluoro-2-methylaniline (5.2 g, 16.6
mmol) in water (100 mL) is added fluoroboric acid (6.06 g, 33.1
mmol) at RT. The solution is cooled to 0.degree. C. and NaNO.sub.2
(1.71 g, 24.8 mmol) in water (2 mL) is added. The reaction is
stirred at 0.degree. C. for 40 min. CHCl.sub.3 (200 mL) is added.
The organic phase is separated, dried over Na.sub.2SO.sub.4, and
filtered. To the filtrate is added KOAc (7.31 g, 74.5 mmol) and
18-crown-6-ether (0.218 g, 0.82 mmol). The reaction is stirred at
RT for 1 hour. The reaction mixture is washed with saturated
aqueous sodium chloride, dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue is washed with DCM and filtered to offer
the desired product as a light yellow solid. The filtrate is
purified by chromatography eluting with DCM then EtOAc:hexane (1:1)
to give additional desired product. Both portions of the solid are
combined to offer the desired product (3.2 g, 59% yield). MS (m/z):
324.8 (M+H).
Preparation 84
5-(4-Bromo-2-fluorophenoxy)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indaz-
ole
The title compound is prepared essentially by the method of
Preparation 9. MS (m/z): 410.8 (M+H).
Preparation 85
N-(Diphenylmethylene)-3-fluoro-4-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-
-indazol-5-yloxy)aniline
The mixture of
5-(4-bromo-2-fluorophenoxy)-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-inda-
zole (0.97 g, 2.37 mmol), benzophenone imine (0.64 g, 3.56 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.10 g, 0.075
mol), Cs.sub.2CO.sub.3 (1.16 g, 3.56 mmol), Pd.sub.2(dba).sub.3
(0.11 g, 0.12 mmol) in 1,4-dioxane (20 mL) is purged with nitrogen,
heated to 100.degree. C. and stirred overnight. The reaction
mixture is cooled to RT, extracted with EtOAc, washed with
saturated aqueous sodium chloride, dried over Na.sub.2SO.sub.4,
filtered and concentrated (1.45 g). MS (m/z): 510 (M+H).
Preparation 86
3-Fluoro-4-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yloxy)
aniline
To a solution of
N-(diphenylmethylene-3-fluoro-4-(6fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H--
indazol-5-yloxy)aniline (1.45 g, 2.85 mmol) in THF (30 mL) and
water (5 mL) is added 1N aqueous HCl (5.69 mL, 5.69 mmol). The
reaction is stirred at RT for 2 hours. EtOAc is added and the
mixture is washed with saturated aqueous NaHCO.sub.3 solution,
saturated aqueous sodium chloride, dried over Na.sub.2SO.sub.4,
filtered and evaporated. The residue is purified by chromatography
eluting with DCM then EtOAc:hexane (1:1) to offer the desired
product as a pale gel (0.53 g, 54% yield). MS (m/z): 346 (M+H).
Preparation 87
Ethyl
5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-
-6-carboxylate
The title compound is essentially made by the same method of
Preparation 75. MS (m/z): 430.1 (M+H).
Preparation 88
Ethyl 5-(2-fluoro-4-nitrophenoxy)-1H-indazole-6-carboxylate
To a solution of ethyl
5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-ca-
rboxylate (15 g, 35 mmol) in DCM (300 mL) is added trifluoroacetic
acid (TFA) (30 mL), and stirred at RT overnight. DCM is evaporated.
The residue is partitioned between EtOAc (800 mL) and 5% aqueous
NaHCO.sub.3 (400 mL). The organic layer is washed with saturated
aqueous sodium chloride, dried over MgSO.sub.4, and concentrated.
The residue is purified by silica gel column chromatography eluting
with PE:acetone (5:1) to afford the product (10.4 g, 86% yield). MS
(m/z): 346.1 (M+H).
Preparation 89
Ethyl
5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole-6-carboxylate
The title compound is prepared essentially by the method of
Preparation 11: MS (m/z): 360.1 (M+H).
Preparation 90
5-(2-Fluoro-4-nitrophenoxy)-1-methyl-1H-indazole-6-carboxylic
acid
To a solution of ethyl
5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole-6-carboxylate
(1.19 g, 3.5 mmol) in THF/H.sub.2O (15 mL/5 mL) is added LiOH (0.2
g, 8.3 mmol). After the reaction is stirred at RT for 2 hours, the
solvents are removed. The residue is acidified with 2N HCl to pH 5,
and extracted with EtOAc (50 mL). The organic phase is washed with
saturated aqueous sodium chloride, dried and concentrated to give
the product (1.1 g, 100% yield). MS (m/z): 332.0 (M+H).
Preparation 91
tert-Butyl
5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazol-6-ylcarbamate
The suspension of
5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole-6-carboxylic acid
(1.1 g, 3.3 mmol), diphenyl phosphoryl azide (0.91 g, 3.3 mmol),
TEA (0.33 g, 3.3 mmol) and 4 .ANG. molecular sieve (2.5 g) in
tert-butanol (50 mL) is heated at reflux overnight. Then the solid
is filtered off and the filtrate is concentrated. The residue is
partitioned between saturated aqueous sodium chloride (40 mL) and
EtOAc (100 mL). The organic phase is separated, dried and
concentrated and the residue is purified by silica gel column
chromatography eluting with PE:acetone (4:1) to give the product
(0.64 g, 47.9% yield). MS (m/z): 403.1 (M+H).
Preparation 92
tert-Butyl
5-(4-amino-2-fluorophenoxy)-1-methyl-1H-indazol-6-ylcarbamate
The title compound is prepared essentially by the method of
Proparation 38. MS (m/z): 373.1 (M+H).
Preparation 93
5-(5-(Benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)pyridin-2-am-
ine
to a solution of
5-(benzyloxy)-6-bromo-1-(tetrahydri-2H-pyran-2yl)-1H-indazole (1.5
g, 3.87 mmol) in 1,4-dioxane (50 mL) is added
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1
g, 4.54 mmol), Pd(PPh.sub.3).sub.4 (200 mg, 173 .mu.mol) and
Cs.sub.2CO.sub.3 (5 g, 10.6 mmol). After the reaction mixture is
stirred at reflux overnight, it is partitioned between EtOAc (100
mL) and saturated aqueous NH.sub.4Cl (50 mL). The organic phase is
separated, dried and concentrated. The residue is purified by
silica gel column chromatography eluting with DCM:MeOH (15:1) to
give the product (0.80 g, 51.5% yield). MS (m/z): 401.1 (M+H).
Preparation 94
tert-Butyl
5-(5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)p-
yridin-2-ylcarbamate
To a solution of
5-(5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)pyridin-2-a-
mine (310 mg, 774 .mu.mol) in THF (20 mL) is added
di-tert-butyldicarbonate (250 mg, 1.13 mmol) and TEA (1 mL, 7.17
mmol). After the reaction mixture is stirred at RT for 3 hours, it
is partitioned between EtOAc (50 mL) and saturated aqueous
NH.sub.4Cl (20 mL). The organic phase is separated, dried and
concentrated. The residue is purified by silica gel column
chromatography eluting with PE:EtOAc (3:1) to give the product (260
mg, 67.1% yield). MS (m/z): 501.2 (M+H).
Preparation 95
tert-Butyl
5-(5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)pyrid-
in-2-ylcarbamate
To a solution of tert-butyl
5-(5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)pyridin-2-y-
lcarbamate (260 mg, 519 .mu.mol) in EtOH (25 mL) and EtOAc (25 mL)
is added Pd/C (100 mg, 10% wt) under N.sub.2. The resulting mixture
is degassed by evacuation and backfilled with nitrogen. Then the
reaction mixture is stirred at RT under H.sub.2 atmosphere for 6
hours. The reaction mixture is filtered. The filtrate is
concentrated to give the product (200 mg, 93.8% yield). MS (m/z):
411.1 (M+H).
Preparation 96
tert-Butyl
5-(5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H--
indazol-6-yl)pyridin-2-ylcarbamate
The title compound is essentially made by the same method of
Preparation 75. MS (m/z): 550.2 (M+H).
Preparation 97
tert-Butyl
5-(5-(4-amino-2-fluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H--
indazol-6-yl)pyridin-2-ylcarbamate
The title compound is prepared essentially by the method of
Preparation 38. MS (m/z): 520.2 (M+H).
Preparation 98
tert-Butyl
4-(5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyr-
azole-1-carboxylate
5-(2-Fluoro-4-nitrophenoxy)-1-methyl-6-(1
H-pyrazol-4-yl)-1H-indazole (1.56 g, 4.42 mmol) in DCM (15.6 mL) is
added di-tert-butyldicarbonate (1.09 mL, 4.83 mmol). The mixture is
stirred for 30 min. HPLC shows the reaction is complete. The
solvent is removed under reduced pressure. Then MTBE (5 mL) is
added. The solution is cooled with ice water bath and stirred for
15 min, then filtered to give the title compound as a solid (0.764
g, 48.9%).
Preparation 99
6-Bromo-5-(2-fluoro-4-nitrophenoxy)-1H-indazole
To a 3000 mL flask is added
6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indaz-
ole (250 g, 573.1 mmol) followed by MeOH (1000 mL) and MeSO.sub.3H
(1 12.71 mL,1.72 mol) and heated to 50.degree. C. for 14 hours.
Solid crystallizes out of solution. The mixture is then cooled to
RT. The reaction mixture is concentrated under vacuum at 45.degree.
C. to dryness to get solid. The solid is diluted with DCM (2000 mL)
and treated with water (1000 mL) and 5N NaOH (about 350 mL) until
the pH is 8-9. The organic layer is separated and the solvent is
removed followed by azeotrope with toluene to give 195.6 g of the
yellow solid material. MS (m/z): 354.0 (M+H).
Preparation 100
6-Bromo-5-(2-fluoro-4-nitrophenoxy)-1-methyl-i H-indazole
To a 4000 mL flask is added
6-bromo-5-(2-fluoro-4-nitrophenoxy)-1H-indazole (230 g, 653.2
mmol), DMF (3000 mL), and K.sub.2CO.sub.3 (135.41 g, 979.78 mmol).
The reaction mixture is cooled to 4.5.degree. C. with an ice bath.
To the mixture is added methyl iodide (92.71 g, 653.19 mmol) and
the reaction is allowed to stir for 20 min at the same temperature.
The reaction is allowed to warm to RT and stir for 13 hours. The
reaction mixture is monitored by liquid chromatography mass
spectrometry. Additional methyl iodide (50 g) and NaHCO.sub.3 (33
g) are added and the reaction mixture is stirred at RT until the
reaction is completed. The reaction mixture is divided into two
portions labeled (A) and (B), and each one is quenched with water
(1 L) followed by extraction with EtOAc (1 L) causing some solids
to form. The combined solids from (A) and (B) are collected by
vacuum filtration to give 70 g of crude weight having about 90%
6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole (which is
the desired isomer) and 8%
6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-methyl-2H-indazole isomers.
This solid is then triturated with 1000 mL of DCM and 750 mL of
MeOH overnight (about 14 hours). The solid is collected by
filtration and rinsed with fresh DCM (100 mL) to give 55.5 g of
desired material labeled (C). The mother liquor is concentrated and
labeled (D). The organic layer from (A) and (B) are separated and
concentrated. The residues from (A) and (B) are combined to give
185 g of crude as an orange solid labeled (E).
The crude compound (E) is dissolved in MeOH and DCM, and then the
solution is divided into 3 portions. 600 g of silica gel is mixed
with each portion of solution, and then the silica gel mixture is
loaded into seven 270 g size empty cartridges. Seven 1.5 kg
ISCO.RTM. columns are used with solvent system starting with 25%
EtOAc in hexanes, then it is switched to 50% EtOAc in hexanes to
give 62 g of the desired compound as a yellow powder labeled (F).
After 7 runs, there are some mixed fractions of
6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole and
6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-methyl-2H-indazole isomers.
The fractions are combined and combined with mother liquor (D) from
the procedure described above to give 17 g of the mixture. The
mixture is dissolved in MeOH and DCM, mixed with 170 g of silica
into the solution, and run on a 1.5 kg column to give 10 g of a
yellow powder as the desired product labeled (G). Total yield (55.5
g (C), 62 g (F), and 10 g (G)) is 127.5 g.
Preparation 101
tert-Butyl
4-(5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyr-
azole-1-carboxylate
To a 12 L round bottom flask equipped with overhead agitation, a
thermocouple, heating mantle, condenser, and subsurface nitrogen
sparge is added 1,4-dioxane (7.44 L) and water (1.67 L). The
solution is purged with N.sub.2 (inlet tube). Next
6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole (595 g,
1.63 mol) is added and the solution is purged with N.sub.2 again.
tert-Butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
(717.02 g, 2.44 mol), potassium phosphate tribasic N-hydrate (689.8
g, 3.25 mol), and 1,1'-Bis(di-tert-butylphosphino)ferrocene (7.71
g, 16.25 mmol) are added. Finally, Pd.sub.2(dba).sub.3 (7.44 g,
8.13 mmol) is added. The solution is purged for 15 min and then
heated at 60.degree. C. for 12 hours. The reaction is not complete
and more Pd.sub.2(dba).sub.3 (7.44 g, 8.13 mmol) is added. The
solution is again heated at 60.degree. C. for 3 additional hours
and the reaction is complete. 1,4-Dioxane is then removed
(Buchi.RTM. bath temp 60.degree. C.) and the residue is
re-dissolved in 10 volumes (6 L) of DCM. Water (3 L) is added and
then the layers are separated. The organic solution is dried over
Na.sub.2SO.sub.4, filtered and concentrated to a dark oil (835 g).
The material is not purified and is forward processed to the next
step. The material is about 60% desired product and about 40%
5-(2-fluoro-4-nitrophenoxy)-1-methyl-6-(1H-pyrazol-4-yl)-1H-indazole.
The crude obtained is reprotected in the next step. It is assumed
that 50% of the crude product is the
5-(2-fluoro-4-nitrophenoxy)-1-methyl-6-(1H-pyrazol-4-yl)-1H-indazole.
To a 22 L round bottom flask with overhead agitation, thermocouple,
1 L addition funnel, N.sub.2 purge, and cooling bath is added a
solution of crude
5-(2-fluoro-4-nitro-phenoxy)-1-methyl-6-(1H-pyrazol-4-yl)-1H-indazo-
le (835 g, 1. 18 mol) in DCM (6 L) of. di-tert-butyldicarbonate
(283.69 g, 1.30 mol) dissolved in DCM (350 mL) of is added to an
addition funnel. The solution is added dropwise over 48 min. After
the reaction is complete, DCM is removed by rotary evaporation to
give a dark oil. To the dark oil is added MTBE (2.5 L) and the oily
solution is cooled to about 0-5.degree. C. The solution is seeded
with material obtained in Preparation 98. After seeding,
crystallization is observed and the resulting slurry is stirred for
30-40 min. The pale yellow slurry is filtered over a polypropylene
pad and the cake is washed with cold (0-5.degree. C.) MTBE (1.5 L).
The solids are dried in a 40.degree. C. vacuum oven overnight to
give the desired product (443 g, 60% crude yield). MS (m/z): 354.0
(M+H). The material is shown to be about 93-95% pure by HPLC and is
therefore forward processed.
Preparation 102
tert-Butyl
4-(5-(4-amino-2-fluorophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyr-
azole-1-carboxylate
To a 3 gallon tank is added tert-butyl
4-(5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-ca-
rboxylate (433.0 g, 952.8 mmol) followed by THF (6.5 L) and Pd/C
(21.65 g, 10% Pd/C and 21.65 g, 5% Pd/C). The mixture is heated to
35.degree. C. under hydrogen gas for 2 hours. The reaction is then
cooled to RT and allowed to stir under hydrogen gas overnight, then
is heated to 40.degree. C. under hydrogen gas for seven hours. An
additional 2 g Pd/C (1 g, 10% Pd/C and 1 g, 5% Pd/C) is added and
stirred under hydrogen gas for another hour and cooled to RT. The
mixture is again stirred under hydrogen gas overnight and the
reaction is completed. The mixture is filtered over a combination
of GFF.RTM. and Watman.RTM. paper. The filtrate is concentrated to
a slightly yellow solid (446 g, 110% recovery).
Preparation 103
Methyl 2-oxo-1,2-dihydropyridine-3-carboxylate
To a flask is added 2-hydroxynicotinic acid (10 g, 72 mmol),
concentrated H.sub.2SO.sub.4 (2 mL) and MeOH (400 mL), followed by
toluene (80 mL). The reaction mixture is heated to reflux overnight
with a Dean-Stark trap. After cooling to RT, the mixture is
filtered and the filtrate is concentrated. The residue is dissolved
in DCM (200 mL), neutralized with saturated aqueous NaHCO.sub.3 to
pH 7 and extracted with DCM (200 mL) for three times. The combined
organic phases are dried and concentrated to give the desired
product (8.2 g, 74% yield). MS (m/z): 153.9 (M+H).
Preparation 104
Methyl
1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate
To a mixture of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (6.0
g, 39 mmol), 4-fluorophenylboronic acid (16.3 g, 116 mmol), cupric
acetate (14 g, 78 mmol) and pyridine (12 g, 0.156 mol) in DCM (300
mL) is added 4 .ANG. molecular sieves (5 g). The reaction mixture
is stirred at RT overnight open to air. After the solids are
filtered and washed with water, the filtrate is extracted with DCM
(100 mL). The organic layer is dried over MgSO.sub.4 and
concentrated. The residue is purified by silica gel column
chromatography eluting with PE:DCM (2:1 to 0:1) to give the product
(9.6 g, 100% yield). MS (m/z): 248.0 (M+H).
Preparation 105
Ethyl 2-(4-fluorophenyl)hydrazinecarboxylate
To a solution of 4-fluorophenylhydrazine hydrochloride (2 g, 12.05
mmol) in THF (60 mL) is added DIPEA (6 mL, 34.40 mmol), ethyl
chloroformate (1.2 mL, 12.55 mmol) and 4-dimethylaminopyridine
(0.16 g, 1.31 mmol). The mixture is stirred at RT for 4 hours. The
reaction is diluted with water and extracted with EtOAc, the
organic phase is washed with saturated aqueous sodium chloride,
dried over Na.sub.2SO.sub.4 and concentrated. The residue is
purified by column chromatography on silica gel, eluting with DCM
then DCM:MeOH (80:1) to afford the title compound (1.92 g, 80.5%
yield). MS (m/z): 199 (M+H).
Preparation 106
1-(4-Fluorophenyl)-2-methylhydrazine
To a mixture of LiAlH.sub.4 (1.1 g) in THF (15 mL) is added a
solution of ethyl 2-(4-fluorophenyl)hydrazinecarboxylate (1.9 g,
9.59 mmol) in THF (10 mL) dropwise under nitrogen in an ice-salt
bath. After the addition, the ice bath is removed and the mixture
is heated to 60.degree. C. overnight. The reaction is cooled and
quenched with water. The precipitate is filtered and washed with
EtOAc. The organic phase is separated, dried over Na.sub.2SO.sub.4,
and concentrated. The residue is purified by flash chromatography,
eluting with PE:EtOAc (80:1 to 60:1) to afford the title compound
(1 g, 74% yield). MS (m/z): 141 (M+H).
Preparation 107
Ethyl
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carb-
oxylate
A mixture of 1-(4-fluorophenyl)-2-methylhydrazine (0.6 g, 4.28
mmol), diethyl 2-acetylmalonate (0.96 g, 4.75 mmol), and acetic
acid (0.51 g, 8.49 mmol) in water (15 mL) is heated at 115.degree.
C. for 3 hours. The reaction is cooled and extracted with EtOAc
twice. The organic phase is washed with saturated aqueous sodium
chloride, dried over Na.sub.2SO.sub.4 and concentrated. The residue
is purified by column chromatography on silica gel, eluting with
DCM:MeOH (from 150:1 to 60:1) to afford the title compound (0.59 g,
49.5% yield). MS (m/z): 279 (M+H).
Preparation 108
(E)-2-(2-(4-Fluorophenyl)hydrazono)acetaldehyde
A solution of 4-fluorophenylhydrazine hydrochloride (1 g, 6 mmol)
in THF (20 mL) is treated with DIPEA (3 mL, 18 mmol). Then
oxalaldehyde (40% in water, 0.89 g, 6.0 mmol) in THF (10 mL) is
added dropwise in an ice-bath. After the addition, the mixture is
stirred at RT for 30 min, quenched with water, and extracted with
EtOAc. The organic phase is washed with saturated aqueous sodium
chloride, dried over Na.sub.2SO.sub.4 and concentrated to afford
the crude title compound (0.97 g, 97% yield). MS (m/z): 167
(M+H).
Preparation 109
Ethyl
2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate
Crude (E)-2-(2-(4-fluorophenyl)hydrazono)acetaldehyde (0.97 g, 5.8
mmol) is dissolved in EtOH (50 mL), and diethyl malonate (0.93 g,
5.8 mmol) and piperidine (0.2 mL, 2.0 mmol) are added. The mixture
is heated at reflux overnight. The reaction mixture is then cooled
and concentrated. The residue is diluted with water and extracted
with EtOAc twice. The combined organic extracts are dried over
Na.sub.2SO.sub.4 and concentrated. The residue is purified by
column chromatography on silica gel, eluting with PE:EtOAc (from
3:1 to 1:1), to afford title compound (0.26 g, 17% yield of two
steps) MS (m/z): 263 (M+H).
Preparation 110
Methyl 3-(4-fluorophenylamino)-3-oxopropanoate
To a solution of 4-fluoroaniline (4.4 mL, 45 mmol) in acetone is
added TEA (8.5 mL, 67 mmol) and methyl malonyl chloride (7.2 mL, 67
mmol). The mixture is stirred at RT for 5 hours and then
concentrated. After water (20 mL) is added, the residue is
acidified with concentrated HCl to pH 3. The precipitate is
collected by filtration and washed with PE to give the product
(14.1 g, 100% yield). MS (m/z): 212.1 (M+H).
The following compounds are prepared essentially by the method of
Preparation 110:
TABLE-US-00010 Physical data Prep. MS (m/z) No. Chemical name (M +
H) 111 Ethyl 3-oxo-3-(phenylamino)propanoate 208 112 Ethyl
3-(4-fluorophenylamino)-3-oxopropanoate 226.1
Preparation 113
Ethyl
1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate
To a solution of methyl
3-(4-fluorophenylamino)-3-oxopropanoate(10.1 g, 48 mmol) in EtOH
(100 mL) is added trans-4-methoxy-3-buten-2-one (5.7 g, 57 mmol)
and CH.sub.3ONa (3.1 g, 57 mmol). The mixture is heated at reflux
overnight and then concentrated. The residue is purified by silica
gel column chromatography eluting with PE:EtOAC (from 5:1 to 2:1)
to give the product (2.1 g, 16% yield). MS (m/z): 276.1 (M+H).
The following compounds are prepared essentially by the method of
Preparation 113:
TABLE-US-00011 Physical data Prep. MS (m/z) No. Chemical name (M +
H) 114 Ethyl 1-(4-fluorophenyl)-5-methyl-2-oxo-1,2- 276.1
dihydropyridine-3-carboxylate 115 Ethyl
5-methyl-2-oxo-1-phenyl-1,2- 258.1
dihydropyridine-3-carboxylate
Preparation 116
(Z)-4-Aminopent-3-en-2-one
To a solution of 2,4-pentanedione (20.0 g, 0.2 mol) in water (20
mL) is added 25% aqueous ammonia (13.2 mL, 0.2 mol) dropwise at RT.
The mixture is stirred at RT for 2 hours. Then the solvent is
removed to give the product (20.0 g, 100% yield) as a solid. 1H NMR
(Acetone-d.sub.6, 300 MHz): 1.88 (s, 3H), 1.88 (s, 3H), 2.8 (br s,
1H), 6.54 (br s, 1H), 9.7 (brs, 1H).
Preparation 117
Ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate
A solution of (Z)-4-aminopent-3-en-2-one (20.0 g, 0.2 mol) in dry
THF (20 mL) is added to a solution of ethyl cyanoacetate (22.6 g,
0.2 mol) and TEA (20.2 g, 0.2 mol) in dry THF (200 mL). The
reaction mixture is heated at reflux for 56 hours and then
concentrated. The residue is kept standing at RT for 5 hours and
the precipitate is filtered and washed with EtOAc to afford the
title compound (7.3 g, 19.9% yield). MS (m/z): 196.0 (M+H).
Preparation 118
Ethyl
1-(4-fluorophenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxyl-
ate
A suspension of ethyl
4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (5.0 g, 0.025
mol), 4-fluorophenylboronic acid (10.7 g, 0.077 mol), cupric
acetate (1.33 g, 0.007 mol), pyridine (6.86 mL), and 4 A molecular
sieves (5.0 g) in 1,4-dioxane (80 mL) is heated at 80.degree. C.
for 68 hours. The solids are filtered off and the filtrate is
concentrated. The residue is partitioned with EtOAc (50 mL) and 2N
HCl (70 mL). The precipitated solid is collected by filtration and
washed with EtOAc to give the title product (1.2 g). The EtOAc
filtrate is separated, dried and concentrated. The residue is
purified by silica gel column chromatography eluting with
PE:EtOAc:MeOH (40:20:1) to give another portion of product (0.12
g), (1.32 g total, 17.8% yield). MS (m/z): 290.1 (M+H).
Preparation 119
Ethyl
4,6-dimethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate
A suspension of ethyl
4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (7.5 g, 0.038
mol), phenylboronic acid (14.1 g, 0.115 mol), cupric acetate (1.38
g, 0.008 mol), pyridine (7.5 mL) in 1,4-dioxane (80 mL) is heated
at 80.degree. C. for 96 hours. The solid is filtered off and the
filtrate is concentrated. The residue is partitioned with EtOAc (50
mL) and 2N HCl (70 mL), and the precipitate is collected by
filtration and washed with EtOAc to give the title product (2.95
g). The EtOAc solution is separated, dried and concentrated. The
residue is purified by silica gel column chromatography eluting
with PE:acetone (2:1) to give another portion of (0.3 g). (3.25 g,
31.2% yield). MS (m/z): 272.0 (M+H).
Preparation 120
Ethyl
5-(bromomethyl)-2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyr-
azole-4-carboxylate
To a solution of ethyl
2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxyla-
te (1.2 g, 4.3 mmol) and azobisisobutyronitrile (AIBN) (0.09 g,
0.06 mmol) in DCM is added N-bromosuccinimide (NBS) (0.9 g, 4.3
mmol) in three portions at RT. The resulting reaction mixture is
stirred at RT overnight. The mixture is concentrated and the
residue is purified by silica gel column chromatography eluting
with PE:EtOAc (4:1) to give the product as a white solid (1.3 g,
84% yield). MS (m/z) 357.0 (M+H).
Preparation 121
Ethyl
5-((1H-pyrazol-1-yl)methyl)-2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-di-
hydro-1H-pyrazole-4-carboxylate
To a solution of ethyl
5-(bromomethyl)-2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-
-4-carboxylate (1.3 g, 3.6 mmol) and 1H-pyrazole (0.25 g, 3.6 mmol)
in THF (50 mL) and H.sub.2O (1 mL) cooled in an ice-water bath is
added solid KOH (0.2 g, 3.6 mmol) in three portions. After the
reaction mixture is stirred at RT overnight, the solvent is
removed. The residue is purified by silica gel column
chromatography eluting with PE:EtOAc (4:1) to give the product
(0.87 g, 70% yield). MS (m/z): 345.1 (M+H).
The following compounds are prepared essentially by the method of
Preparation 121:
TABLE-US-00012 Physical data MS (m/z) Prep. No. Chemical name (M +
H) 122 Ethyl 2-(4-fluorophenyl)-1-methyl-5- 364.1
(morpholinomethyl)-3-oxo-2,3-dihydro-1H- pyrazole-4-carboxylate 123
Ethyl 2-(4-fluorophenyl)-1-methyl-3-oxo-5- 362.1
(piperidin-1-ylmethyl)-2,3-dihydro-1H-pyrazole- 4-carboxylate
Preparation 124
Ethyl
1-(4-fluorophenyl)-5-(morpholinomethyl)-2-oxo-1,2-dihydropyridine-3--
carboxylate
A mixture of ethyl
1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate
(0.275 g, 1 mmol), NBS (0.2 g, 1.1 mmol), AIBN (40 mg, 0.2 mmol) in
CCl.sub.4 (20 mL) is heated at reflux for 3 hours. After the
reaction is cooled down, morpholine (0.088 mL, 1 mmol) and
K.sub.2CO.sub.3 (0.14 g, 1 mmol) are added. The reaction is stirred
at RT for another 2 hours. The solvent is removed, and the residue
is diluted with water (10 mL) and extracted with EtOAc (20 mL)
twice. The combined organic phases are washed with saturated
aqueous sodium chloride, dried, and concentrated. The residue is
purified by silica gel column chromatography eluting with DCM:MeOH
(from 100:1 to 50:1, containing 0.5% 2 N NH.sub.3 in MeOH), to
afford the title compound (0.17 g, 47% yield). MS (m/z): 361.1
(M+H).
Preparation 125
Ethyl 2-(4-fluorophenylcarbamoyl)-3-methylbut-2-enoate
To a solution of 4-fluoroaniline (2 g, 18 mmol) in diethyl
isopropylidenemalonate (10 g, 50 mmol) is added 1H-imidazole (0.25
g, 3.67 mmol). The reaction mixture is stirred at 200.degree. C.
under N.sub.2 for 3 hours. After the reaction is cooled, silica gel
is added. The mixture is loaded onto a silica gel column, and
eluted first with PE and then PE:EtOAc (3:1) to give the product
(1.85 g, 39% yield). MS (m/z): 266.1 (M+H).
Preparation 126
Ethyl
1-(4-fluorophenyl)-4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate
A mixture of ethyl 2-(4-fluorophenylcarbamoyl)-3-methylbut-2-enoate
(1.85 g, 6.97 mmol) and N,N-dimethylformamide dimethyl acetal (5
mL, 37.45 mmol) is stirred at 90.degree. C. for 90 min. After the
reaction is cooled, EtOAc (30 mL) and saturated NH.sub.4Cl solution
(20 mL) are added. The organic phase is separated, dried and
concentrated. The residue is purified by silica gel column
chromatography eluting with DCM:MeOH (10:1). The fractions
containing product are concentrated, and the residue is mixed with
ether to give 1.2 g of yellow solid which is filtered and
discarded. The filtrate is concentrated and purified again by
silica gel column chromatography eluting with DCM:MeOH (20:1) to
give the product (500 mg, 26% yield). MS (m/z): 276.1 (M+H).
Preparation 127
Ethyl
2-(4-fluorophenyl)-6-methyl-3-oxo-2,3-dihydropyridazine-4-carboxylat-
e
To a suspension of 1-triphenylphosphoranylidene-2-propanone (3.18
g, 9.99 mmol) in THF (50 mL) is added diethyl ketomalonate (1.74 g,
9.99 mmol). The resulting mixture is stirred at RT for 30 min to
give a clear solution. Then this solution is added to a solution of
4-fluorophenylhydrazine hydrochloride (1.62 g, 9.96 mmol) in
EtOH:H.sub.2O (30 mL:30 mL). After the resulting mixture is
refluxed for 1 hour, TEA (3 mL) is added and the mixture is stirred
at reflux for another 1 hour. Then it is concentrated and the
residue is partitioned with saturated aqueous NH.sub.4Cl (30 mL)
and EtOAc (30 mL). The organic phase is separated, dried and
concentrated. The residue is purified by silica gel column
chromatography eluting with PE:EtOAc (3:1) to give the product
(1.20 g, 43% yield). MS (m/z): 277.1 (M+H).
Preparation 128
1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
To a solution of methyl
1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (10.0 g,
0.04 mol) in MeOH (150 mL) and water (50 mL) is added LiOH (1.9 g,
0.08 mol). The resulting reaction mixture is stirred at RT for 0.5
hour. After most of the MeOH is removed, the mixture is acidified
with concentrated aqueous HCl until a white solid precipitates. The
solid is collected by filtration and washed with water (5 mL) to
give the desired product (8.7 g, 93% yield). MS (m/z): 234.0
(M+H).
The following compounds are prepared essentially by the method of
Preparation 128:
TABLE-US-00013 Physical data Prep. MS (m/z) No. Chemical name (M +
H) 129 2-(4-Fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro- 251
1H-pyrazole-4-carboxylic acid 130
2-(4-Fluomphenyl)-3-oxo-2,3-dihydropyridazine-4- 235 carboxylic
acid 131 1-(4-Fluorophenyl)-6-methyl-2-oxo-1,2-dihydro- 248.1
pyridine-3-carboxylic acid 132
1-(4-Fluorophenyl)-4,6-dimethyl-2-oxo-1,2-dihydro-
pyridine-3-carboxylic acid 133
4,6-Dimethyl-2-oxo-1-phenyl-1,2-dihydro-pyridine- 244.0
3-carboxylic acid 134*
5-((1H-Pyrazol-1-yl)methy1)-2-(4-fluorophenyl)-1-
methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid 135**
2-(4-Fluorophenyl)-1-methyl-5-(morpholinomethyl)- 336.1 3-oxo-2,3-
dihydro-1H-pyrazole-4-carboxylic acid 136
2-(4-Fluorophenyl)-1-methyl-3-oxo-5-(piperidin-1- 334.1
ylmethyl)-2,3-dihydro-1H-pyrazole-4-carboxylic acid 137
1-(4-Fluorophenyl)-5-methyl-2-oxo-1,2-dihydro- 248.0
pyridine-3-carboxylic acid 138
5-Methyl-2-oxo-l-phenyl-1,2-dihydropyridine-3- 230.1 carboxylic
acid 139 1-(4-Fluorophenyl)-5-(morpholinomethyl)-2-oxo-1,2- 333.1
dihydropyridine-3-carboxylic acid l40**
1-(4-Fluorophenyl)-4-methyl-2-oxo-1,2- 248.1
dihydropyridine-3-carboxylic acid 141
2-(4-Fluorophenyl)-6-methyl-3-oxo-2,3- 249.0
dihydropyridazine-4-carboxylic acid *KOH is used as the base.
**NaOH is used as the base.
Preparation 142
6-Methyl-2-oxo-1-phenyl-1,2-dihydro-pyridine-3-carboxylic acid
To a solution of sodium ethoxide in EtOH (prepared from sodium (0.5
g, 21.75 mmol) dissolved in EtOH (40 mL)) is added ethyl
3-oxo-3-(phenylamino)propanoate (4 g, 19.30 mmol) and
trans-4-methoxy-3-buten-2-one (2 g, 19.98 mmol). After the reaction
is stirred at reflux overnight, the mixture is concentrated. The
residue is partitioned between H.sub.2O (50 mL) and EtOAc (50 mL).
The aqueous layer is acidified with concentrated HCl to a pH
3.about.4 and then it is extracted with EtOAc. The organic extracts
are dried and concentrated. The residue is purified by silica gel
column chromatography eluting with DCM:MeOH (25:1) to give the
product (1.20 g, 27% yield). MS (m/z): 230.0 (M+H).
Preparation 143
1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic
acid
To a mixture of
1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde
(2 g, 9.25 mmol) in water (100 mL) at 75.degree. C. is added a
solution of KMnO.sub.4 (1.5 g, 9.49 mmol) in water (200 mL) slowly.
After the addition is complete, the reaction mixture is stirred at
75.degree. C. for another 1 hour. Solid KOH is added to make the
solution alkaline and the mixture is filtered while it is hot. To
the filtrate is added EtOH (10 mL) and EtOAc (50 mL). The organic
phase is separated and discarded. The aqueous phase is acidified
with concentrated HCl to pH 5 and extracted with EtOAc (60 mL) and
DCM (60 mL). The organic phases are combined, dried, and
concentrated to give the title product (1.9 g, 88.46%yield). MS
(m/z): 233.1 (M+H).
Preparation 144
Ethyl 3-(4-fluorophenylamino)-3-oxopropanoate
To a 4-necked 10 L round bottom flask, is added DCM (5000 mL),
4-fluoroaniline (111 g, 1.0 mol) and TEA (166 mL, 1.2 mol). Ethyl
malonyl chloride (196 g, 1.3 mol) in DCM (500 mL) is added dropwise
under N.sub.2 at 0-5.degree. C. (under ice bath) during 4 hours.
After addition, the mixture is stirred for 30 min at this
temperature. Water (2 L) is added into the mixture with stirring at
this temperature. The organic phase is washed with saturated
NaHCO.sub.3, saturated aqueous sodium chloride and dried over
anhydrous Na.sub.2SO.sub.4. The aqueous phase is extracted with
EtOAc (2.times.1 L). The organic phase is washed with saturated
aqueous sodium chloride and dried over anhydrous Na.sub.2SO.sub.4.
After filtration, the residue is washed with PE (1 L) to give ethyl
3-(4-fluorophenylamino)-3-oxopropanoate (230 g, crude yield 102%)
as a yellow solid. MS (m/z): 226.1 (M+H).
Preparation 145
1-(4-Fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic
acid
To a 4-necked 3 L round bottom flask, is added EtOH (1500 mL),
ethyl 3-(4-fluorophenylamino)-3-oxopropanoate (139 g, 617 mmol),
sodium ethoxide (65.6 g, 925 mmol) and 4-methoxy-3-buten-2-one (103
g, 925 mmol). The mixture is refluxed for 3 hours. After the
solution is cooled to RT, the reaction mixture is concentrated
under reduced pressure to remove the EtOH. The residue is diluted
with DCM (700 mL) and 1 M HCl (1500 mL). The aqueous phase is
extracted with DCM (3.times.500 mL). The combined organic extracts
are washed with saturated aqueous sodium chloride (1000 mL), dried
over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue is triturated with EtOAc (150 mL) at RT
(10-15.degree. C.) for 1 hour. After filtration and washing with
EtOAc (50 mL),
1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic
acid is obtained as a yellow solid (85.3 g, 56% yield). MS (m/z):
248 (M+H).
Example 1
N-(3-Fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(-
4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
##STR00007##
To a 100 mL round bottom flask is added tert-butyl
4-(5-(4-amino-2-fluorophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-ca-
rboxylate (1.43 g, 3.38 mmol),
1-(4-flurorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic
acid (1.25 g, 5.07 mmol), EDCI (1.48 g, 7.6 mmol) and HOBt (776 mg,
5.07 mmol) followed by DMF (15 mL, 193.99 mmol) and then DIPEA
(1.47 mL, 8.44 mmol). The mixture is allowed to stir at RT
overnight. The reaction mixture is diluted into EtOAc (300 mL) and
washed with saturated aqueous sodium chloride (5.times.100 mL). The
combined aqueous solution is extracted with EtOAc (1.times.100 mL)
and then the combined organic solutions are dried over
N.sub.2SO.sub.4, filtered, and concentrated to dryness. The solid
is purified on a silica gel column eluting with DCM (A) and a 10%
MeOH in a DCM solution (B), gradient from 100% (A) to 80% (A):20%
(B) over 70 min to give tert-butyl
4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-
-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate
as a gold solid (2.20 g, 87% yield). MS (m/z): 653. (M+H), 675
(M+Na).
To a round bottom flask is added tert-butyl
4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-
-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate
(1.92 g, 2.94 mmol) and DCM (50 mL) followed by triethylsilane
(1.88 mL, 11.77 mmol) and TFA (17.8 mL, 235.35 mmol). The reaction
mixture is allowed to stir at RT for 1.5 hours. The solvent is
removed and diluted into DCM (150 mL) and washed with saturated
aqueous NaHCO.sub.3 solution (2.times.100 mL). The organic solution
is dried with Na.sub.2SO.sub.4, and concentrated under reduced
pressure to give a solid material. The solid is purified on a
silica gel column eluting with DCM (A) and a 10% MeOH in DCM
solution (B), gradient from 100% (A) to 75%(A):25%(B) over 70 min,
held at this 75:25 ratio for 15 min to give the title compound as
an off-white solid. The solid is dissolved in hot EtOH (50 mL)
followed by a portion-wise addition of distilled water (250 mL)
causing a white solid to precipitate. The solid is filtered over a
Buchner funnel and washed with distilled water (3.times.15 mL), air
dried, and vacuum dried at 60.degree. C. for 15 hours to give the
title compound as an off-white solid (1.27 g, 78% yield). MS (m/z):
552.8 (M+H).
Example 2
N-(3-Fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(-
4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
##STR00008##
A 12 L round bottom flask is equipped with overhead agitation, a
thermocouple, and a N.sub.2 purge. tert-Butyl
4-(5-(4-amino-2-fluorophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-ca-
rboxylate (404 g, 954.08 mmol) is dissolved in DMF (2 L) and
charged to the flask. DMF (1 L) is used to rinse the flask.
1-(4-Fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic
acid (259.46 g, 1.05 mol) and EDCI (228.63 g, 1.19 mol) are added
and it is rinse in with DMF (500 mL). Then HOBt (189.94 g, 1.24
mol) is added and it is again rinsed in with DMF (500 mL). Finally,
DIPEA is slowly added (184.97 g, 1.43 mol). The dark solution is
then stirred at RT over the weekend. To a 20 L bottom outlet flask
is added DI water (3 L) and DCM (5 L). The reaction mixture is
poured in and it is rinsed in with DCM (1 L). The organic layer is
separated, washed with DI water (3.times.3 L), dried over
Na.sub.2SO.sub.4, filtered, rinsed solids with DCM and concentrated
the filtrate. EtOAc (2 L) is added to the residue and the solution
is stirred for 1 hour. The product crystallizes out. The mixture is
concentrated. Another portion of EtOAc (2 L) is added and
concentrated to remove all of the DCM. EtOAc (650 mL) and MTBE (3
L) are added to the residue and the solution is stirred in an ice
bath for 1 hour. The tan slurry is filtered using a polypropylene
pad. The cake is rinsed with MTBE (2.times.500 mL). The light tan
solid is dried overnight in the vacuum oven at 40.degree. C. to
give the crude product (553 g). The crude product is purified by
silica gel column chromatography eluting with (50% EtOAc (50%):35%
DCM (35%): n-heptane (15%)) to give the pure desired product
tert-butyl
4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-
-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate
(424 g, 68%). MS (m/z): 651.0 (M-H).
tert-Butyl
4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-
-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate
(423.9 g, 649.50 mmol) is dissolved in DCM (4.24 L). HCl in MeOH
(5.74 N, 799.99 mL, 4.59 mol) is added and the solution is heated
at 30.degree. C. for 1 hour. Then the reaction mixture is heated to
45.degree. C. and DCM (1.5 L) is added. After two hours, the
solution is heated to 50.degree. C. and DCM (2 L) is added. After 3
hours, DCM (2 L) is added followed by HCl in MeOH (4.5 N, 721.67
mL, 3.25 mol). After another 45 min, DCM (1 L), HCl in MeOH (4.5 N,
288.67 mL, 1.30 mol), and MeOH (1.5 L) are added. The reaction
solution is then heated to 60.degree. C. After 4 hours, MeOH (2 L)
is added and 10 min later DCM (1 L) is added followed by HCl in
MeOH (4.5 N, 200 mL). After 5 hours, the reaction is complete. The
reaction mixture is concentrated to about 1/3 volume. MeOH (2 L) is
added and the solution is concentrated to a thick slurry. Again,
MeOH (2 L) is added and the mixture is concentrated to a thick
slurry. The slurry is cooled to about 10-15.degree. C. and then
filtered. The solids are washed with MeOH. The solids are placed in
a 55.degree. C. vacuum oven for 2 days to give the desired product
N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1--
(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
hydrochloride (377 g, 92.8%). MS (m/z): 551.0 (M-H).
To a 22 L round bottom flask equipped with mechanical stirring
under nitrogen is added
N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1--
(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
hydrochloride (367 g, 0.62 mol) followed by DCM (7.34 L) and water
(7.34 L). Na.sub.2CO.sub.3 (181.6 g, 1.71 mol) is added and the
mixture is stirred at RT for 30 min. The pH is checked and found to
be about 9.4. The mixture is filtered over polypropylene. The
solids are collected and placed into a 5 L round bottom flask. A
20% water/MeOH solution (2.6 L) is added and the slurry is stirred
for 30 min. The slurry is filtered and the solids are washed with
20% water/MeOH (600 mL). The solids are placed in a vacuum oven at
35.degree. C. overnight. The first weighing indicates 394 g
(theoretical yield 324.8 g, about 121% mass recovery). TGA
(Thermogravimetric analysis)/DSC (differential scanning
calorimetry) shows about 17 wt % free water and 10-11 wt% volatile
loss at the melt. The solids are dried at 55.degree. C. in a vacuum
oven with a N.sub.2 sweep for 3.5 hours (354.7 g, about 109% mass
recovery, NMR shows about 9.3 wt % DCM). No free water is present
according to TGA/DSC. The material is sent for milling.
The jet mill (Aljet.TM. 0101) in a glove bag is assembled inside a
walk in hood and hooked up to N.sub.2 to a 100 lb header. The inlet
pusher nozzle is adjusted for maximum draw and max nitrogen flow is
introduced into the mill. Pressure readings are noted as 90 psi on
pusher nozzle and 85 psi on both grind nozzles. The starting
material (353.4 g) is slowly fed to the mill inlet, stopping to
empty the receiver sock as needed. The total milling time is 22 min
and 25 second. The calculated feed rate is 15.8 g/min (353.4 grams
divided by 22.42 min). The milled material (335.7 g, 95%) is
obtained with 17.7 g loss. Particle size analysis result of the
milled material is d90 of 4.6 microns.
TGA/DSC indicates about 11.4 wt % volatiles at the melt and NMR
(DMSO) shows about 9.3 wt % DCM. .sup.1H NMR (DMSO) .delta. 12.94
(br s, 1 H), 11.88 (s, 1H), 8.44 (d,J=7.47 Hz, 1 H), 8.12 (br s, 1
H), 8.00 (br s, 1 H), 7.96 (s, 1 H), 7.94 (d,J=2.2 Hz, 1 H), 7.91
(d,J=2.6 Hz, 1 H), 7.87 (s, 1H), 7.47-7.37 (m, 5 H), 6.82 (t,J=9.26
Hz, 8.82 Hz, 1 H), 6.65 (d,J=7.49 Hz, 1 H), 4.04 (s, 3 H), 2.03 (s,
3 H). LC/MS: (M+H) 553.1.
Anhydrous Crystal Form Preparation
To 10 mL of EtOH is added 120 mg of the above compound into a 20 mL
vial. The sample is heated to 70.degree. C. with stirring.
Initially the solids start to dissolve and then a suspension forms
followed by a white precipitate. The sample is cooled to RT while
being stirred. A small sample of the slurry is taken by pipette and
allowed to air dry. This material is highly crystalline and proves
to be an ethanol solvate by TGA. To the remaining suspension, 10 mL
of heptane is added and then heated to boiling. The measured
temperature is monitored at 70.8.degree. C. until the volume has
been reduced to 10 mL. When the temperature starts to rise, the
heat is removed and the slurry stirred at RT overnight. The solid
is isolated by vacuum filtration and dried in a vacuum oven at
45.degree. C. for 3 hours, resulting in 77% recovery. The
crystalline form shows a weight loss of 0.17% from 25-238.degree.
C. by TGA. The form's onset of melting is 247.8.degree. C.
Example 3
N-(3-Fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(-
4-fluorophenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide
methanesulfonate
##STR00009##
To a solution of
3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)aniline
(300 mg, 927.8 .mu.mol) and
1-(4-fluorophenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylic
acid (300 mg, 1. 15 mmol) in DMF (5 mL) is added HOBt (130 mg,
0.962 mmol), EDCI (180 mg, 0.939 mmol) and N-methylmorpholine (0.5
mL). After the reaction mixture is stirred at 60.degree. C.
overnight, it is partitioned between EtOAc (50 mL) and saturated
aqueous NH.sub.4Cl (30 mL). The organic phase is separated, dried
and concentrated. The residue is triturated with EtOAc (5 mL) and
the solids are collected by filtration to give
N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1--
(4-fluorophenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide
as the desired product (230 mg, 43.7% yield.) MS (m/z): 567.2
(M+H).
To a solution of
N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1--
(4-fluorophenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide
(230 mg, 0.406 mmol) in acetone (10 mL) is added MeSO.sub.3H (39
mg, 0.406 mmol). After the reaction is stirred at RT for 0.5 hour,
it is concentrated. The residue is washed with ether and dried to
give
N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1--
(4-fluorophenyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxamide
methanesulfonate (250 mg, 92.9% yield.) MS (m/z): 567.2 (M+H).
The following compounds are prepared essentially by the method of
Example 3 with the exception that in certain cases the freebase is
generated and not the salt:
TABLE-US-00014 Physical data Ex. MS (m/z) No. Chemical name
Structure (M + H) 4 1-(4-Fluorophenyl)-6- methyl-N-(4-(1-methyl-6-
(1H-pyrazol-4-yl)-1H- indazol-5-yloxy)phenyl)-2-
pxp-1,2-dihydropyridine- 3-carboxamide methanesulfonate
##STR00010## 535.2 5 N-(3-Fluoro-4-(1-methyl-6-
(1H-pyrazol-4-yl)-1H- indazol-5-yloxy)phenyl)-6-
methyl-2-oxo-1-phenyl-1,2- dihydropyridine-3- carboxamide
methanesulfonate ##STR00011## 535.1 6 N-(3-Fluoro-4-(1-methyl-6-
(1H-pyrazol-4-yl)-1H- indazol-5-yloxy)phenyl)-4,6-
dimethyl-2-oxo-1-phenyl-1,2- dihydropyridine-3- carboxamide
methanesulfonate ##STR00012## 549.1 7 N-(3-Fluoro-4-(1-methyl-6-
(1H-pyrazol-4-yl)-1H- indazol-5-yloxy)phenyl)-2-(4-
fluorophenyl)-1,5-dimethyl-3- oxo-2,3-dihydro-1H-pyrazole-
4-carboxamide methanesulfonate ##STR00013## 556.2 8
N-(3-Fluoro-4-(1-methyl-6- (1H-pyrazol-4-yl)-1H-
indazol-5-yloxy)phenyl)-2-(4- fluorophenyl)-3-oxo-2,3-
dihydropyridazine-4- carboxamide methanesulfonate ##STR00014##
540.2 9 N-(3-Fluoro-4-(1-methyl-6- (2-methylpyridin-4-yl)-1H-
indazol-5-yloxy)phenyl)-1-(4- fluorophenyl)-6-methyl-2-
oxo-1,2-dihydropyridine-3- carboxamide methanesulfonate
##STR00015## 578.1 10 6-Methyl-N-(4-(1-methyl-6-
(1H-pyrazol-4-yl)-1H- indazol-5-yloxy)phenyl)-2- oxo-1-phenyl-1,2-
dihydropyridine-3- carboxamide methanesulfonate ##STR00016## 517.2
11 5-((1H-Pyrazol-1-yl)methyl)- N-(3-fluoro-4-(6-morpholino-
1H-indazol-5-yloxy)phenyl)- 2-(4-fluorophenyl)-1-methyl-
3-oxo-2,3-dihydro-1H- pyrazole-4-carboxamide ##STR00017## 627.2 12
N-(3-Fluoro-4-(6-morpholino- 1H-indazol-5-yloxy)phenyl)-
1-(4-fluorophenyl)-6-methyl- 2-oxo-1,2-dihydropyridine-3-
carboxamide ##STR00018## 558.1 13 N-(4-(6-(Dimethylamino)-
indazol-5-yloxy)-3- fluorophenyl)-6-methyl-2- oxo-1-phenyl-1,2-
dihydropyridine-3- carboxamide methanesulfonate ##STR00019## 498.2
14 N-(3-Fluoro-4-(1-methyl-6- (1H-pyrazol-4-yl)-1H-
indazol-5-yloxy)phenyl)-1-(4- fluorophenyl)-5-methyl-2-
oxo-1,2-dihydropyridine-3- carboxamide methanesulfonate
##STR00020## 553.1 15 N-(3-Fluoro-4-(6-(pyridin-3-
yl)-1H-indazol-5- yloxy)phenyl)-1-(4- fluorophenyl)-6-methyl-2-
oxo-1,2-dihydropyridine-3- carboxamide ##STR00021## 550.2 16
5-((1H-Pyrazol-1-yl)methyl)- N-(4-(6-(dimethylamino)-1H-
indazol-5-yloxy)-3- fluorophenyl)-2-(4- fluorophenyl)-1-methyl-3-
oxo-2,3-dihydro-1H-pyrazole- 4-carboxamide methanesulfonate
##STR00022## 585.1 17 l-(4-Fluorophenyl)-4,6-
dimethyl-N-(4-(1-methyl-6- (1H-pyrazol-4-yl)-1H-
indazol-5-yloxy)phenyl)-2- oxo-1,2-dihydropyridine-3- carboxamide
methanesulfonate ##STR00023## 549.2 18 N-(3-Fluoro-4-(6-morpholino-
1H-indazol-5-yloxy)phenyl)- 1-(4-fluorophenyl)-2-oxo-1,2-
dihydropyridine-3- carboxamide methanesulfonate ##STR00024## 544.2
19 N-(3-Fluoro-4-(6-(tetrahydro- 2H-pyran-4-ylamino)-1H-
indazol-5-yloxy)phenyl)-1-(4- fluorophenyl)-4,6-dimethyl-2-
oxo-1,2-dihydropyridine-3- carboxamide methanesulfonate
##STR00025## 586.1 20 N-(4-(6-(Dimethylamino)-1H-
indazol-5-yloxy)-3- fluorophenyl)-2-(4- fluorophenyl)-3-oxo-2,3-
dihydropyridazine-4- carboxamide ##STR00026## 503.1 21
N-(4-(6-(Dimethylamino)-1H- indazol-5-yloxy)-3- fluorophenyl)-1-(4-
fluorophenyl)-4,6-dimethyl-2- oxo-1,2-dihydropyridine-3-
carboxamide ##STR00027## 530.2 22 N-(4-(6-(Dimethylamino)-1H-
indazol-5-yloxy)phenyl)-6- methyl-2-oxo-1-phenyl-1,2-
dihydropyridine-3- carboxamide methanesulfonate ##STR00028## 480.2
23 N-(3-Fluoro-4-(6-(6- methylpyridin-3-yl)-1H-
indazol-5-yloxy)phenyl)-1-(4- fluorophenyl)-6-methyl-2-
oxo-1,2-dihydropyridine-3- carboxamide ##STR00029## 564.1 24
4,6-Dimethyl-N-(4-(1-methyl- 6-(1H-pyrazol-4-yl)-1H-
indazol-5-yloxy)phenyl)-2- oxo-1-phenyl-1,2- dihydropyridine-3-
carboxamide methanesulfonate ##STR00030## 531.2 25
N-(3-Fluoro-4-(1-methyl-6- (pyridin-3-yl)-1H-indazol-5-
yloxy)phenyl)-2-(4- fluorophenyl)-1,5-dimethyl-3-
oxo-2,3-dihydro-1H-pyrazole- 4-carboxamide methanesulfonate
##STR00031## 567.1 26 N-(3-Fluoro-4-(6-morpholino-
1H-indazol-5-yloxy)phenyl)- 1-(4-fluorophenyl)-2-oxo-1,2-
dihydropyridine-3- carboxamide ##STR00032## 544.1 27
5-Methyl-N-(4-(1-methyl-6- (1H-pyrazol-4-yl)-1H-
indazol-5-yloxy)phenyl)-2- oxo-1-phenyl-1,2- dihydropyridine-3-
carboxamide methanesulfonate ##STR00033## 517.1 28
N-(3-Fluoro-4-(6-morpholino- 1H-indazol-5-yloxy)phenyl)-
2-(4-fluorophenyl)-1-methyl- 5-(morpholinomethyl)-3-oxo-
2,3-dihydro-1H-pyrazole-4- carboxamide methanesulfonate
##STR00034## 646.2 29 N-(3-Fluoro-4-(6-(pyridin-3-
yl)-1H-indazol-5- yloxy)phenyl)-1-(4- fluorophenyl)-2-oxo-1,2-
dihydropyridine-3- carboxamide ##STR00035## 535.5 30
N-(3-Fluoro-4-(6-(pyridin-3- yl)-1H-indazol-5- yloxy)phenyl)-2-(4-
fluorophenyl)-1-methyl-5- (morpholinomethyl)-3-oxo-
2,3-dihydro-1H-pyrazole-4- carboxamide ##STR00036## 638.2 31
N-(3-Fluoro-4-(6-(pyridin-4- yl)-1H-indazol-5- yloxy)phenyl)-2-(4-
fluorophenyl)-3-oxo-2,3- dihydropyridazine-4- carboxamide
methanesulfonate ##STR00037## 537.1 32 N-(3-Fluoro-4-(6-(pyridin-4-
yl)-1H-indazol-5- yloxy)phenyl)-2-(4- fluorophenyl)-1,5-dimethyl-3-
oxo-2,3-dihydro-1H-pyrazole- 4-carboxamide methanesulfonate
##STR00038## 553.2 33 N-(3-Fluoro-4-(6-(pyridin-3-
yl)-1H-indazol-5- yloxy)phenyl)-2-(4- fluorophenyl)-1,5-dimethyl-3-
oxo-2,3-dihydro-1H-pyrazole- 4-carboxamide methanesulfonate
##STR00039## 553.1 34 N-(4-(6-(1H-Pyrazol-4-yl)-
1H-indazol-5-yloxy)-3- fluorophenyl)-2-(4-
fluorophenyl)-6-methyl-3- oxo-2,3-dihydropyridazine-4- carboxamide
methanesulfonate ##STR00040## 540.1 35 N-(4-(6-Dimethylamino)-1H-
indazol-5-yloxy)-3- fluorophenyl)-1-(4- fluorophenyl)-6-methyl-2-
oxo-1,2-dihydropyridine-3- carboxamide ##STR00041## 516.2 36
N-(3-Fluoro-4-(6-morpholino- 1H-indazol-5-yloxy(phenyl)-
1-(4-fluorophenyl)-5- (morpholinomethyl)-2-oxo-
1,2-dihydropyridine-3- carboxamide ##STR00042## 643.2 37
N-(3-Fluoro-4-(6-morpholino- 1H-indazol-5-yloxy)phenyl)-
1-(4-fluorophenyl)-4-methyl- 2-oxo-1,2-dihydropyridine-3-
carboxamide methanesulfonate ##STR00043## 558.1 38
N-(3-Fluoro-4-(6-(6- methylpyridin-3-yl)-1H-
indazol-5-yloxy(phenyl)-1-(4- fluorophenyl)-4,6-dimethyl-2-
oxo-1,2-dihydropyridine-3- carboxamide methanesulfonate
##STR00044## 578.1 39 N-(3-Fluoro-4-(6-morpholino-
1H-indazol-5-yloxy)phenyl)- 2-(4-fluorophenyl)-6-methyl-
3-oxo-2,3-dihydropyridazine- 4-carboxamide ##STR00045## 559.2 40
N-(4-(6-(1,3-Dimethyl-1H- pyrazol-5-yl)-1H-indazol-5-
yloxy)-3-fluorophenyl)-2-(4- fluorophenyl)-3-oxo-2,3-
dihydropyridazine-4- carboxamide ##STR00046## 554.2 41
N-(3-Fluoro-4-(6-(pyridin-4- yl)-1H-inadazol-5-
yloxy(phenyl)-1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazole-4-carboxamide methanesulfonate ##STR00047## 535.2 42
N-(3-Fluoro-4-(6-morpholino- 1H-indazol-5-yloxy)phenyl)-
2-(4-fluorophenyl)-2-oxo-2,3- dihydropyridazine-4- carboxamide
##STR00048## 545.1 43 N-(4-(6-(1,3-Dimethyl-1H-
pyrazol-5-yl)-1H-indazol-5- yloxy)-3-fluorophenyl)-1-(4-
fluorophenyl)-4,6-dimethyl-2- oxo-1,2-dihydropyridine-3-
carboxamide methanesulfonate ##STR00049## 581.1 44 N-(4-(6-(2,6-
Dimethylpyridin-4-yl)-1H- indazol-5-yloxy)-3- fluorophenyl)-2-(4-
fluorophenyl)-1,5-dimethyl-3- oxo-2,3-dihydro-1H-pyrazole-
4-carboxamide methanesulfonate ##STR00050## 581.2 45
N-(3-Fluoro-4-(6-(2- methylpyridin-4-yl)-1H-
indazol-5-yloxy)phenyl)-2-(4- fluorophenyl)-1-methyl-3-
oxo-5-(piperidin-1-ylmethyl)- 2,3-dihydro-1H-pyrazole-4-
carboxamide ##STR00051## 650.1 46 N-(3-Fluoro-4-(6-(2-
methoxypyrimidin-5-yl)-1H- indazol-5-yloxy)phenyl)-1-(4-
fluorophenyl)-2-oxo-1,2- dihydropyridine-3- carboxamide
##STR00052## 567.2 47 N-(3-Fluoro-4-(6-(2- methylpyridin-4-yl)-1H-
indazol-5-yloxy)phenyl)-2-(4- fluorophenyl)-3-oxo-2,3-
dihydropyridazine-4- carboxamide ##STR00053## 551.2
Example 48
N-(4-(6-Amino-1-methyl-1H-indazol-5-yloxy)-3-fluorophenyl)-1-(4-fluorophen-
yl)-6-methyl1-2-oxo-1,2-dihydropyridine-3-carboxamide
methanesulfonate
##STR00054##
To a 10 mL screw-cap vial is added
5-(4-amino-2-fluorophenoxy)-N-benzhydryl-1-methyl-1H-indazol-6-amine
(91 mg, 208 .mu.mol),
1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic
acid (66.7 mg, 269.78 .mu.mol), EDCI (90.9 mg, 466.9 .mu.mol) and
HOBt (47.7 mg, 311.3 .mu.mol) followed by DMF (2 mL, 25.9 mmol). To
the mixture is added DIPEA (90.5 .mu.L, 518.8 .mu.mol) and the
mixture is stirred at RT for 12 hours. Additional EDCI (50 mg),
HOBt (25 mg), DIPEA (0.02 mL), and
1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic
acid (40 mg) are added and the mixture is stirred for an additional
24 hours. The reaction is diluted into EtOAc (100 mL) and washed
with saturated aqueous sodium chloride (3.times.25 mL). The
combined aqueous solution is extracted with EtOAc (1.times.25 mL).
The combined organic solution is dried over Na.sub.2SO.sub.4,
filtered, and concentrated to dryness. The residue is purified on a
silica gel column eluting with DCM (A) and a 10% MeOH in DCM
solution (B), gradient from 100% (A) to 90%(A): 10%(B) over 60 min
to give a clear wax material as the desired product (114 mg, 82%
yield). MS (m/z) 667.8 (M+H).
To a 25 mL round bottom flask is added
N-(4-(6-(benzhydrylamino)-1-methyl-1H-indazol-5-yloxy)-3-fluorophenyl)-1--
(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
(100 mg, 149.7 .mu.mol) and DCM (15 mL, 15.6 mmol) followed by the
addition of triethylsilane (0.3 mL, 1.8 mmol) and TFA (2 mL, 26.9
mmol). The reaction mixture is stirred at RT for 3 hours. The
solvent is removed and then the residue is diluted in DCM (50 mL)
and washed with a saturated NaHCO.sub.3 solution (1.times.25 mL).
The aqueous layer is extracted with DCM (1.times.25 mL) and the
combined organic solution is dried with Na.sub.2SO.sub.4, filtered
and concentrated. The residue is purified on a silicas gel column
eluting wiht DCM (A) and a 10% MeOH in a DCM solution (B), gradient
from 100% (A) to 80%(A):20%(B) over 50 min, held at 80:20 ratio for
5 min then gradient to 70%(A):30%(B) over 5 min to give a white
solid material as the desired product (67 mg, 90% yield). MS (m/z):
501.8 (M+H).
to a round bottom flask is added
N-(4-(6-amino-1-methyl-1H-indazol-5-yloxy)-3-fluorophenyl)-1-(4-fluorophe-
nyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (47.5 mg,
94.7 .mu.mol) in DCM (2 mL, 31.2 mmol) and MeOH (2 mL, 49.4 mmol).
MeSO.sub.3H (6.2 .mu.L, 94.7 .mu.mol) in MeOH is added. The
solution is concentrated to give a light yellow solid (54 mg, 96%
yield). MS (m/z): 501.8 (M+H).
The following compounds are prepared essentially by the method of
Example 48:
TABLE-US-00015 Physical data Ex. MS (m/z) No. Chemical name
Structure (M + H) 49 N-(4-(6-Amino-1-methyl-1H- indazol-5-yloxy)-3-
fluorophenyl)- 1-(4- fluorophenyl)-2-oxo-1,2- dihydropyridine-3-
carboxamide methanesulfonate ##STR00055## 487.8
Example 50
N-(4-(6-Amino-1H-indazol-5-yloxy)-3-fluorophenyl)-6-methyl-2-oxo-1-phenyl--
1,2-dihydropyridine-3-carboxamide methanesulfonate
##STR00056##
To a solution of tert-butyl
5-(4-amino-2-fluorophenoxy)-1H-indazol-6-ylcarbamate (170 mg, 474
.mu.mol) and
6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (120
mg, 0.52 mmol) in DMF (5 mL) is added HOBt (60 mg, 0.44 mmol), EDCI
(90 mg, 0.47 mmol) and N-methylmorpholine (0.5 mL). After the
reaction mixture is stirred at 60.degree. C. overnight, it is
partitioned between EtOAc (50 mL) and saturated aqueous NH.sub.4Cl
(30 mL). The organic phase is separated, dried and concentrated,
and the residue is purified by silica gel column chromatography
eluting with PE:EtOAc (1:1) to give the product (65 mg, 24. 1%
yield) MS (m/z): 570.2 [M+H]).
To a solution of tert-butyl
5-(2-fluoro-4-(6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamido)-
phenoxy)-1H-indazol-6-ylcarbamate (65 mg, 0.114 mmol) in DCM (10
mL) is added TFA (1 mL, 13.5 mmol). After the reaction is stirred
at RT overnight, it is concentrated. The residue is partitioned
with saturated aqueous NaHCO.sub.3 (30 mL) and DCM (50 mL), and the
organic phase is separated, dried and concentrated. The residue is
purified by silica gel column chromatography eluting with DCM:MeOH
(20:1) to give the product (35 mg, 65.3% yield). MS (m/z): 470.1
(M+H).
To a solution of
N-(4-(6-amino-1H-indazol-5-yloxy)-3-fluorophenyl)-6-methyl-2-oxo-1-phenyl-
-1,2-dihydropyridine-3-carboxamide (35 mg, 74.6 .mu.mol) in acetone
(10 mL) is added MeSO.sub.3H (7.16 mg, 74.6 .mu.mol). After the
reaction mixture is stirred at RT for 0.5 hour, it is concentrated.
The residue is washed with ether and dried to give
N-(4-(6-amino-1H-indazol-5-yloxy)-3-fluorophenyl)-6-methyl-2-oxo-1-phenyl-
-1,2-dihydropyridine-3-carboxamide methanesulfonate (39 mg, 92.5%
yield). MS (m/z): 470.1 (M+H).
The following compounds are prepared essentially by the method of
Example 50:
TABLE-US-00016 Physical data Ex. MS (m/z) No. Chemical name
Structure (M + H) 51 N-(4-(6-Amino-1H-indazol-5-yloxy)-3-
fluorophenyl)-1-(4-fluorophenyl)-2- oxo-1,2-dihydropyridine-3-
carboxamide ##STR00057## 474.1 52
N-(4-(6-Amino-1H-indazol-5-yloxy)-3-
fluorophenyl)-1-(4-fluorophenyl)-4,6-
dimethyl-2-oxo-1,2-dihydropyridine-3- carboxamide methanesulfonate
##STR00058## 502.2 53 N-(4-(6-Amino-1H-indazol-5-yloxy)-3-
fluorophenyl)-1-(4-fluorophenyl)-6-
methyl-2-oxo-1,2-dihydropyridine-3- carboxamide ##STR00059## 488.1
54 N-(4-(6-(6-Aminopyridin-3-yl)-1H-
indazol-5-yloxy)-3-fluorophenyl)-2-(4- fluorophenyl)-3-oxo-2,3-
dihydropyridazine-4-carboxamide ##STR00060## 552.1
Example 55
N-(3-Fluoro-4-(6-(2-methylmorpholino)-1H-indazol-5-yloxy)phenyl)-1-(4-fluo-
rophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
##STR00061##
To a 10 mL screw-cap vial is added
3-fluoro-4-(6-(2-methylmorpholino)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazo-
l-5-yloxy)aniline (44 mg, 103.17 .mu.mol),
1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (42
mg, 0.18 mmol), EDCI (45.177 mg, 232.13 .mu.mol), HOBT (23.699 mg,
154.75 .mu.mol) followed by DMF (5 mL, 64.66 mmol) and DIPEA
(44.980 .mu.L, 257.92 .mu.mol). The reaction mixture is stirred at
RT overnight. The reaction is diluted into EtOAc (50 mL) and washed
with saturated aqueous sodium chloride (5.times.25 mL). Organic
layers are dried over Na.sub.2SO.sub.4, filtered, and concentrated
to dryness. The residue is purified on a silica gel column eluting
with hexanes (A) and EtOAc (B), gradient from 80% (A): 20% (B) to
30% (A): 70% (B) over 40 min, hold at 30:70 ratio for 15 min to
give a yellow solid as desired product
N-(3-fluoro-4-(6-(2-methylmorpholino)-2-(tetrahydro-2H-pyran-2-yl)-2H-ind-
azol-5-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbox-
amide (70 mg, 99% yield). MS (m/z): 641.8 (M+H).
To a round bottom flask is added
N-(3-fluoro-4-(6-(2-methylmorpholino)-2-(tetrahydro-2H-pyran-2-yl)-2H-ind-
azol-5-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbox-
amide (66 mg, 102.86 .mu.mol) and MeOH (5 mL, 123.54 mmol). To the
resulting mixture is added MeSO.sub.3H (20.229 .mu.L, 308.57
.mu.mol) and the reaction mixture is heated to 40.degree. C. for 6
hours. The reaction mixture is concentrated and dissolved in DCM
(100 mL). The solution is washed with a mixture of saturated
aqueous sodium chloride (20 mL) and saturated aqueous sodium
bicarbonate solution (1.times.20 mL). The organic solution is
extracted with DCM (1.times.25 mL) and dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue is purified on a silica gel
column eluting with DCM (A) and a 10% MeOH in DCM solution (B),
gradient from 100% (A) to 70%(A):30%(B) over 60 min to give a light
yellow solid as the desired product (40 mg, 62% yield). MS (m/z):
557.8 (M+H).
The following compounds are prepared essentially by the method of
Example 55:
TABLE-US-00017 Physical data Ex. MS (m/z) No. Chemical name
Structure (M + H) 56 (R)-N-(3-Fluoro-4-(6-(2- methylmorpholino)-1H-
indazol-5-yloxy)phenyl)- 1-(4-fluorophenyl)-2- oxo-1,2-
dihydropyridine-3- carboxamide ##STR00062## 558.2 57
(R)-N-(3-Fluoro-4-(6-(2- methylmorpholino)-1H-
indazol-5-yloxy)phenyl)- 1-(4-fluorophenyl)-6- methyl-2-oxo-1,2-
dihydropyridine-3- carboxamide ##STR00063## 572.2 58
N-(4-(6-Cyclopropyl- 1H-indazol-5-yloxy)-3- fluorophenyl)-1-(4-
fluorophenyl)-2-oxo-1,2- dihydropyridine-3- carboxamide
##STR00064## 499 59 N-(4-(6-Cyclopropyl- 1H-indazol-5-yloxy)-3-
fluorophenyl)-1-(4- fluorophenyl)-6-methyl- 2-oxo-1,2-
dihydropyridine-3- carboxamide ##STR00065## 512.8 60
N-(4-(6-((2S,6R)-2,6- Dimethylmorpholino)- 1H-indazol-5-yloxy)-3-
fluorophenyl)-1-(4- fluorophenyl)-2-oxo-1,2- dihydropyridine-3-
carboxamide ##STR00066## 572.2 61 N-(4-(6-(2,2-
Dimethylmorpholino)- 1H-indazol-5-yloxy)-3- fluorophenyl)-1-(4-
fluorophenyl)-2-oxo-1,2- dihydropyridine-3- carboxamide
##STR00067## 572.2 62 N-(3-Fluoro-4-(6- morpholino-1H-indazol-
5-yloxy(phenyl)-1-(4- fluorophenyl)-4,6- dimethyl-2-oxo-1,2-
dihydropyridine-3- carboxamide ##STR00068## 571.8 63
N-(3-Fluoro-4-(6-(4- (methylsulfonyl)phenyl)- 1H-indazol-5-
yloxy)phenyl)-1-(4- fluorophenyl)-2-oxo-1,2- dihydropyridine-3-
carboxamide ##STR00069## 613.1 64* N-(3-Fluoro-4-(6-fluoro-
1H-indazol-5- yloxy(phenyl)-1-(4- fluorophenyl)-6-methyl-
2-oxo-1,2- dihydropyridine-3- carboxamide methanesulfonate
##STR00070## 491.2 65 5-(2-Fluoro-4-(1-(4- fluorophenyl)-6-methyl-
2-oxo-1,2- dihydropyridine-3- carboxamido)phenoxy)-
N-(tetrahydro-2H-pyran- 4-yl)-1H-indazole-6- carboxamide
##STR00071## 600.2 *Methanesulfonate salt is prepared essentially
by the same method of salt formation step in Example 3.
The following assays demonstrate that certain compounds of the
present invention potently inhibit c-Met phosphorylation in cells,
potently inhibit c-Met in vivo, and demonstrate dose dependent
anti-tumor activity in certain xenograft models.
c-Met Protein Expression and Purification
The kinase domain (KD) of human c-Met (from Gly 966 to Ser 1390,
NCBI NM.sub.--000245) is cloned into a pFastBac.RTM. RHT vector
(Invitrogen, Carlsbad, Calif.). The His-c-Met KD construct is
transposed into Baculovirus DNA using a Bac-to-Bac.RTM. system
(Invitrogen). SF9 cells are infected with the recombinant
baculovirus. The infected cells are harvested by centrifugation and
the cell pellet is collected and stored at -80.degree. C. Cells are
lysed in buffer A (40 mM tris(hydroxymethyl)aminomethane (Tris), pH
7.5, 500 mM NaCl, 20% glycerol, and 10 mM imidazole). Cell lysates
are homogenized and centrifuged. Supernatants are incubated with
nickel-nitrilotriacetic (Ni--NTA) resin and loaded onto a column.
Proteins are eluted with buffer B (buffer A plus 0.3 M imidazole)
and c-Met containing fractions are pooled together, loaded onto a
Superdex.RTM.200 column (Amershan Bioscience, Piscataway, N.J.),
eluted with buffer C (40 mM Tris, pH 7.5, 250 mM NaCl, and 10%
glycerol).
HGF Stimulated Met (pY1349) NCI-H460 Cell-based ELISA
NCI-H460 cells (purchased from ATCC) are cultured in RPMI 1640
media (Invitrogen) supplemented with 10% Fetal Bovine Serum (FBS)
and plated (prior to becoming 70% confluent) in 96-well flat-bottom
plates at a density of 20,000 cells per well in 80 .mu.L volume.
The cells are then incubated overnight in a cell culture incubator
(5% CO.sub.2, 95% Relative Humidity (RH) and 37.degree. C.) and
allowed to attach to the plate. The following morning the cells are
washed with 2 volumes of a Reduced Serum Media (RSM) (RPMI 1640
media supplemented with 0.5% FBS). After removal of the last wash,
80 .mu.L of RSM is added to each well of the cell plates. The cell
plates are incubated for 2.5 hours in a cell culture incubator, and
then dosed with compounds. Compound inhibitors are first
solubilized at 10 mM in 100% DMSO and then diluted to 100 .mu.M
with 2% DMSO RSM. Subsequently compound serial dilutions (1:3) are
prepared over a 100 .mu.M to 0.005 .mu.M range. Cells are dosed
with the addition of 20 .mu.L of compound stock to produce a final
DMSO concentration of 0.4% and a final compound concentration dose
range between 20 and 0.001 .mu.M. After dosing with compounds the
cells plates are gently agitated to mix and then allowed to
incubate for 30 min in a cell culture incubator. After dose
completion, the cells are stimulated with the addition of 20 .mu.L
per well of Hepatocyte Growth Factor (HGF) at a final concentration
of 100 ng/mL in RSM (all wells except MIN wells are stimulated, MIN
wells are dosed with 20 .mu.L RSM). After 10 min incubation in a
cell culture incubator, the liquid is removed from the cell plate
wells, and the cells are lysed by the addition of 50 .mu.L of
ice-cold Meso Scale Discovery.RTM. (MSD, Gaithersburg, Md.)
1.times. Lysis Buffer (150 mM NaCl, 20 mM Tris, pH 7.5, 1 mM EDTA,
1 mM ethylene glycol tetraacetic acid, and 1% TRITON.RTM. X-100)
supplemented with Phosphatase I and II and Protease inhibitors
(Sigma, St. Louis, Mo.). After lysis at RT for 30 min the lysates
are transferred to and captured on a MSD.RTM. Multi-Spot 96-well
4-spot PhosphoMet plate that is BSA-blocked (at 30 mg/mL Block A in
1.times. Tris Wash Buffer) and then washed one time with Tris Wash
Buffer. After 2 hours capture (at RT) the lysates are removed from
the MSD.RTM. plate and the plate is washed with 1X Tris Wash
Buffer. After blotting, 25 .mu.L of 5 nM Sulfo-Tag Anti-Total Met
antibody (detection antibody, MSD.RTM. prepared in 1.times. Tris
Wash Buffer supplemented with 10 mg/mL BSA and 0.1% Blocker D-R
(MSD.RTM.)) is added to the wells of the MSD.RTM. plate. After 1
hour capture (at RT) the MSD.RTM. plate wells are washed with
1.times. Tris Wash Buffer, and then 150 .mu.L of 1.times. Read
Buffer T (with surfactant, MSD.RTM.) is added. Immediately after
the addition of the Read Buffer, the plates are analyzed with a
SECTOR 6000 MSD.RTM. Imager plate reader. Relative IC.sub.50 values
are determined using MSD activity units by calculating percent
inhibition with respect to on-plate "MIN" and "MAX" controls and
then fitting the percent inhibition values and ten-point dose
response data to a four-parameter logistic equation. This assay has
a Minimum Significant Ratio (MSR) of 2.06. For all exemplified
compounds the IC.sub.50 values are less than 0.2 .mu.M. For
example, the average (n=6) IC.sub.50 value (50% inhibitory
concentration ) of Example 1 in this assay is 0.0352 .mu.M,
indicating it potently inhibits c-Met phosphorylation in cells.
c-Met In Vivo Target Inhibition Assay
S114 cells (licensed from PHS, over-express both human HGF and
human c-Met) are cultured in a growth media (Dulbecco's Modified
Eagle Medium) supplemented with 10% fetal calf serum and expanded.
Cells are harvested and washed twice with phosphate buffered saline
and 2.times.10.sup.6 cells are mixed with equal volume of BD
Matrigel.TM. matrix (BD Bioscience, Franklin, N.J.), and injected
subcutaneously into the flank of nude mice (athymic nude, from
Harlan, Indianapolis, Ind.). At day 8 after implant, compounds
(formulated in 10% acacia or 1% carboxymethylcellulose/0.5% sodium
lauryl sulfate/0.05% antifoam as suspension) are administered to
animals by oral gavage at 50 mg/kg. Animals are sacrificed at 2
hours post dose, and tumors are harvested and stored frozen until
needed.
Frozen tumors are pulverized using motar-pastel. The pulverized
tissues are transferred to a tube containing Lysing Matrix D beads
(MP Biomedicals, Solon, Ohio) and 600 .mu.L lysis buffer (RIPA
buffer, containing 50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1% NP-40,
0.5% sodium deoxycholate, 0.1% SDS, from Boston Bioproducts). A
FastPrep.RTM. Cell Disrupter (MP Biomedicals) is used to disrupt
the tissue and lyse the cells. Lysates are passed through a 20
gauge needle and transferred to a clean tube. Protein concentration
is determined by Bradford method.
Tumor lysates are loaded onto MSD.RTM. phosphor-Met ELISA plates
and phosphor-c-Met level is determined using the same protocol as
H460 cell-based ELISA. For all exemplified compounds the S114 in
vivo inhibition values are equal or greater than 50% at the dose of
50 mg/kg. For example, Example 1 is a potent inhibitor of c-Met
phosphorylation with an ED.sub.50 value (dose that produces 50%
inhibition in tumor of 2.9 mg/kg, indicating it is a potent c-Met
inhibitor in vivo.
Xenograft Tumor Models
Human glioblastoma cells U87MG, human gastric cancer cells MKN45,
human non small cell lung cancer cells H441, and human renal
carcinoma cells Caki-1 are expanded in culture, harvested, and
injected subcutaneously onto the rear flank of athymic nude mice.
Testing compound is prepared in an appropriate vehicle and is
administered by oral gavage when tumors are established (7-21 days
after implant). Tumor response is determined by tumor volume
measurement performed twice a week during the course of treatment.
Tumor volume inhibition (% growth inhibition) is calculated by
comparing treated groups to a vehicle control group. Body weight is
taken as a general measurement of toxicity. The Compound of Example
1 demonstrates excellent dose dependent anti-tumor activity in
these models. For example, when dosed at 1.3 mg/kg (oral (PO),
bi-daily (BID).times.35), Example 1 is able to cause 59% growth
inhibition of U87MG tumors. At 4 mg/kg dose (PO, BID.times.35), 82%
growth inhibition is achieved. At 12 mg/kg dose (PO, BID.times.3
5), 92% growth inhibition reaches.
c-Met Relevant Tumors and Xenograft Models
c-Met overexpression is a common feature for many human tumors,
including lung, breast, colorectal, gastric, renal, pancreatic,
head and neck (1,2). c-Met activating mutations in the kinase
domain are implicated as the cause for several tumors, such as
hereditary papillary renal cell carcinoma, childhood hepatocellular
carcinoma, and gastric cancer (3-7). c-Met inhibitors from Pfizer
demonstrated antitumor efficacy in many human xenograft tumors,
including U87MG, GTL16, H441, Caki-1, and PC3 (8). 1. Christinsen,
J G., Burrows, J., and Salgia, R. Cancer Letters 225:1-26, 2005. 2.
Birchmeier, C., Birchmeier, W., Gherardi, E., and Vande Woude, GF.
Nat Rev Mol Cell Biol 4: 915-925, 2003. 3. Di Renzo, M F., Olivero,
M., Martone, T. Et al. Oncogene 19:1547-1555, 2000. 4. Lee, J H.,
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The compounds of the present invention are preferably formulated as
pharmaceutical compositions administered by a variety of routes.
Most preferably, such compositions are for oral administration.
Such pharmaceutical compositions and processes for preparing the
same are well known in the art. See, e.g., REMINGTON: THE SCIENCE
AND PRACTICE OF PHARMACY (A. Gennaro, et al., eds., 19.sup.th ed.,
Mack Publishing Co., 1995).
The compounds of Formula I are generally effective over a wide
dosage range. For example, dosages per day normally fall within the
range of about 1 mg to about 200 mg total daily dose, preferably 1
mg to 150 mg total daily dose, more preferably 1 mg to 50 mg total
daily dose. In some instances dosage levels below the lower limit
of the aforesaid range may be more than adequate, while in other
cases still larger doses may be employed. The above dosage range is
not intended to limit the scope of the invention in any way. It
will be understood that the amount of the compound actually
administered will be determined by a physician, in the light of the
relevant circumstances, including the condition to be treated, the
chosen route of administration, the actual compound or compounds
administered, the age, weight, and response of the individual
patient, and the severity of the patient's symptoms.
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