Title of Invention

METHODS FOR SYNTHESIZING QUINOLINONE COMPOUNDS

Abstract The invention discloses a method of synthesizing a substituted or unsubstituted benzimidazolyl quinolinone compound by reacting a first compound of formula I with a second compound of formula II in a suitable solvent in the presence of a sodium or potassium salt of a base wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as described in the specification.
Full Text METHODS FOR SYNTHESIZING QUINOLINONE COMPOUNDS
FIELD OF THE INVENTION
[0001] This invention pertains generally to methods of synthesizing
quinolinone compounds. More specifically, the invention described herein
pertains to improved methods of synthesizing amino quinolinone compounds,
and to methods for synthesizing amino quinolinone compounds and
compositions that contain low quantities of lithium.
BACKGROUND OF THE INVENTION
[0002] A variety of chemical compounds and compositions have been
reported as having activity against one or more vascular endothelial growth
factor receptor tyrosine kinase (VEGF-RTK). Examples include quinoline
derivatives such as described in WO 98/13350, aminonicotinamide derivatives
(see, e.g. WO 01/55114), antisense compounds (see, e.g. WO 01/52904),
peptidomimetics (see, e.g. WO 01/52875), quinazoline derivatives (see, e.g.
U.S. Patent No. 6,258,951) monoclonal antibodies (see, e.g. EP 1 086 705
A1), various 5,10,15,20-tetraaryl-porphyrins and 5,10,15-triaryl-corroles (see,
e.g. WO 00/27379), heterocyclic alkanesulfonic and alkane carboxylic acid
derivatives (see, e.g. DE19841985), oxindolylquinazoline derivatives (see,
e.g. WO 99/10349), 1,4-diazaanthracine derivatives (see, e.g. U.S. Patent No.
5,763,441), and cinnoline derivatives (see, e.g. WO 97/34876), and various
indazole compounds (see, e.g. WO 01/02369 and WO 01/53268).
[0003] The synthesis of 4-hydroxy quinolone and 4-hydroxy quinoline
derivatives is disclosed in a number of references. For example, Ukrainets et
al. have disclosed the synthesis of 3-(benzimidazol-2-yl)-4-hydroxy-2-oxo-1,2-
dihydroquinoline. Ukrainets, I. et al., Tetrahedron Lett. 42, 7747-7748 (1995);
Ukrainets, I. et al., Khimiya Geterotsiklicheskikh Soedinii, 2, 239-241(1992).
Ukrainets has also disclosed the synthesis, anticonvulsive and antithyroid

activity of other 4-hydroxy quinolones and thio analogs such as 1H-2-oxo-3-
(2-benzimidazolyl)-4-hydroxyquinoline. Ukrainets, I. et al., Khimiya
Geterotsiklicheskikh Soedinii, 1,105-108 (1993); Ukrainets, l. et al., Khimiya
Geterotsiklicheskikh Soedinii, 8, 1105-1108 (1993); Ukrainets, I. et al., Chem.
Heterocyclic Comp. 33, 600-604, (1997).
[0004] The synthesis of various quinoline derivatives is disclosed in
WO 97/48694. These compounds are disclosed as capable of binding to
nuclear hormone receptors and being useful for stimulating osteoblast
proliferation and bone growth. The compounds are also disclosed as being
useful in the treatment or prevention of diseases associated with nuclear
hormone receptor families.
[0005] Various quinoline derivatives in which the benzene ring of the
quinoline is substituted with a sulfur group are disclosed in WO 92/18483.
These compounds are disclosed as being useful in pharmaceutical
formulations and as medicaments.
[0006] Quinolone and coumarin derivatives have been disclosed as
having use in a variety of applications unrelated to medicine and
pharmaceutical formulations. References that describe the preparation of
quinolone derivatives for use in photopolymerizable compositions or for
luminescent properties include: U.S. Patent No. 5,801,212 issued to Okamoto
et al.; JP 8-29973; JP 7-43896; JP 6-9952; JP 63-258903; EP 797376; and
DE 23 63 459.
[0007] A plethora of substituted quinolinone compounds including
quinolinone benzimidazolyl compounds and 4-amino substituted quinolinone
benzimidazolyl compounds such as 4-amino-5-fluoro-3-[5-(4-methylpiperazin-
1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one have recently been disclosed in
references such as WO 02/22598 and WO 2004/043389. Such compounds
are disclosed as inhibiting VEGF-RTKs. Such compounds are also disclosed
in published United States patent applications U.S. 2002/0107392 and U.S.

2003/0028018 and U.S. Patent Nos. 6,605,617, 6,774,237, and 6,762,194.
Heterocyclic compounds related to benzimidazolyl quinolinones have recently
been disclosed in WO 02/18383, U.S. 2002/0103230, and U.S. Patent No.
6,756,383. Other such compounds are disclosed along with new uses of such
compounds in inhibiting serine/threonine kinases and tyrosine kinases are
disclosed in WO 2004/018419, and U.S. 2004/0092535, filed on August 19,
2003, and claiming priority to each of the following provisional applications:
U.S. Provisional Application No. 60/405,729 filed on August 23, 2002; U.S.
Provisional Application No. 60/426,107 filed on November 13, 2002; U.S.
Provisional Application No. 60/426,226 filed on November 13, 2002; U.S.
Provisional Application No. 60/426,282 filed on November 13, 2002; U.S.
Provisional Application No. 60/428,210 filed on November 21, 2002; U.S.
Provisional Application No. 60/460,327 filed on April 3, 2003; U.S. Provisional
Application No. filed on April 3, 2003; U.S. Provisional Application No.
60/460,493 filed on April 3, 2003; U.S. Provisional Application No. 60/478, 916
filed on June 16, 2003; and U.S. Provisional Application No. 60/484,048 filed
on July 1, 2003. Each of the references in this paragraph is hereby
incorporated by reference in its entirety and for all purposes as if fully set forth
herein.
[0008] Although various methods have been disclosed for synthesizing
quinolinone compounds, new methods which optimize yields of these
compounds are needed because of their important applications in
pharmaceutical formulations and applications.
SUMMARY OF THE INVENTION
[0009] The present invention provides methods of synthesizing
quinolinone compounds such as amino substituted benzimidazolyl
quinolinone compounds. The invention further provides amino substituted
benzimidazolyl quinolinone compounds and formulations with reduced
quantities of lithium and methods for synthesizing such compounds and
formulations that do not require the use of or include lithium salts.

[0010] In one aspect, the present invention provides a method of
synthesizing a substituted or unsubstituted 4-amino-3~benzimidazolyl
quinolinone compound and compositions that include such a compound. The
method includes reacting a first compound having the formula I with a second
compound having the formula II in a suitable solvent in the presence of a
potassium or sodium salt of a base. The reaction of the first compound with
the second compound produces the substituted or unsubstituted 4-amino-3-
benzimidazolyl quinolinone compound. In some embodiments, the method
includes reacting the first compound with the second compound in a suitable
solvent in the presence of the potassium salt of the base. Formula I and
formula II have the following structures:

where:
R1, R2, R3, and R4 may be the same or different and are
independently selected from H, CI, Br, F, I, -OR10 groups, -NR11R12 groups,
substituted or unsubstituted primary, secondary, or tertiary alkyl groups,
substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl
groups, substituted or unsubstituted alkynyl groups, substituted or
unsubstituted heterocyclyl groups, or substituted or unsubstituted
heterocyclylalkyl groups;
R5, R6, R7, and R8 may be the same or different and are
independently selected from H, CI, Br, F, I, -OR13 groups, -NR14R15 groups,
-SR16 groups, substituted or unsubstituted primary, secondary, or tertiary alkyl
groups, substituted or unsubstituted aryl groups, substituted or unsubstituted
alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or

unsubstituted heterocyclyl groups, substituted or unsubstituted
heterocyclylalkyl groups, substituted or unsubstituted alkoxyalkyl groups,
substituted or unsubstituted aryloxyalkyl groups, or substituted or
unsubstituted heterocyclyloxyalkyl groups;
Z is selected from -OR9a groups or -NR9bR9c groups;
R9a is an unsubstituted aikyl group having from 1 to 8 carbon
atoms and is absent if Z is a -NR9bR9c group;
R9b and R9c are independently selected from unsubstituted alkyl
groups having from 1 to 8 carbon atoms or are both absent if Z is a -OR9a
group;
R10 and R13 may be the same or different and are independently
selected from substituted or unsubstituted alkyl groups, substituted or
unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups,
substituted or unsubstituted heterocyclylalkyl groups, substituted or
unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl
groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R11 and R14 may be the same or different and are independently
selected from substituted or unsubstituted alkyl groups, substituted or
unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R12 and R15 may be the same or different and are independently
selected from substituted or unsubstituted alkyl groups, substituted or
unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
and
R16 is selected from substituted or unsubstituted alkyl groups,
substituted or unsubstituted aryl groups, or substituted or unsubstituted
heterocyclyl groups.

[0011] In some embodiments, the substituted or unsubstituted 4-amino-
3-benzimidazolyl quinolinone compound is a compound having the formula Hi
or a tautomer of the compound. Formula III has the following structure.

where R1 through R8 and R10 through R16 have the values
described above.
[0012] In some embodiments, the method further includes reacting the
substituted or unsubstituted 4-amino-3-benzimidazolyl quinolinone compound
or a tautomer of the compound with lactic acid, wherein the lactic acid salt of
the 4-amino-3-benzimidazolyl quinolinone compound or the tautomer is
obtained.
[0013] Further objects, features and advantages of the invention will be
apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention provides methods for synthesizing amino
substituted quinolinone compounds. Such compounds act as antagonists of
receptor tyrosine kinases, and, more particularly, as inhibitors of PDGFRa and
PDGFRp, bFGF and/or VEGF-RTK function. Such compounds also have
potent activity with respect to other tyrosine kinases and also with respect to
various serine/threonine kinases. The compounds provided herein can be
formulated into pharmaceutical formulations that are useful, for example, in
treating patients with a need for an inhibitor of VEGF-RTK, especially, for use
in compositions and methods for reducing capillary proliferation and in the
treatment of cancer. The methods for synthesizing amino substituted
quinolinone compounds allows for the synthesis of formulations and
compounds that have reduced amounts of lithium.
[0015] The following abbreviations and definitions are used throughout
this application:
[0016] "bFGF" is an abbreviation that stands for basic fibroblast growth
factor.
[0017] "bFGFR", also referred to as FGFR1, is an abbreviation that
stands for a tyrosine kinase that interacts with the fibroblast growth factor
FGF.
[0018] "PDGF" is an abbreviation that stands for platelet derived growth
factor. PDGF interacts with tyrosine kinases PDGFRa and PDGFRp.
[0019] "RTK" is an abbreviation that stands for receptor tyrosine kinase.
[0020] "VEGF" is an abbreviation that stands for vascular endothelial
growth factor.
[0021] "VEGF-RTK" is an abbreviation that stands for vascular
endothelial growth factor receptor tyrosine kinase.

[0022J Generally, reference to a certain element such as hydrogen or H
is meant to include all isotopes of that element. For example, if an R group is
defined to include hydrogen or H, it also includes deuterium and tritium.
[0023] The phrase "unsubstituted alkyl" refers to alkyl groups that do
not contain heteroatoms. Thus the phrase includes straight chain alkyl groups
such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
undecyl, dodecyl and the like. The phrase also includes branched chain
isomers of straight chain alkyl groups, including but not limited to, the
following which are provided by way of example: -CH(CH3)2,
-CH(CH3)(CH2CH3), -CH(CH2CH3)2, -C(CH3)3, -C(CH2CH3)3, -CH2CH(CH3)2,
-CH2CH(CH3)(CH2CH3), -CH2CH(CH2CH3)2, -CH2C(CH3)3, -CH2C(CH2CH3)3,
-CH(CH3)CH(CH3)(CH2CH3),-CH2CH2CH(CH3)2, -CH2CH2CH(CH3)(CH2CH3),
-CH2CH2CH(CH2CH3)2, -CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3,
-CH(CH3)CH2CH(CH3)2,-CH(CH3)CH(CH3)CH(CH3)2,
-CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3), and others. The phrase also
includes cyclic alkyl groups such as cycloalkyl groups such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings
substituted with straight and branched chain alkyl groups as defined above.
The phrase also includes polycyclic alkyl groups such as, but not limited to,
adamantyl norbornyl, and bicyclo[2.2.2]octyl and such rings substituted with
straight and branched chain alkyl groups as defined above. Thus, the phrase
unsubstituted alkyl groups includes primary alkyl groups, secondary alkyl
groups, and tertiary alkyl groups. Unsubstituted alkyl groups may be bonded
to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or
sulfur atom(s) in the parent compound. Preferred unsubstituted alkyl groups
include straight and branched chain alkyl groups and cyclic alkyl groups
having 1 to 20 carbon atoms. More preferred such unsubstituted alkyl groups
have from 1 to 10 carbon atoms while even more preferred such groups have
from 1 to 5 carbon atoms. Most preferred unsubstituted alkyl groups include
straight and branched chain alkyl groups having from 1 to 3 carbon atoms and
include methyl, ethyl, propyl, and -CH(CH3)2.

[0024] The phrase "substituted alkyl" refers to an unsubstituted alky!
group as defined above in which one or more bonds to a carbon(s) or
hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atoms
such as, but not limited to, a halogen atom in halides such as F, CI, Br, and I;
an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy
groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl
and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups;
a nitrogen atom in groups such as amines, amides, alkylamines,
dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides,
and enamines; a silicon atom in groups such as in trialkylsilyl groups,
dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other
heteroatoms in various other groups. Substituted alkyl groups also include
groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is
replaced by a bond to a heteroatom such as oxygen in carbonyl, carboxyl,
and ester groups; nitrogen in groups such as imines, oximes, hydrazones,
and nitriles. Preferred substituted alkyl groups include, among others, alkyl
groups in which one or more bonds to a carbon or hydrogen atom is/are
replaced by one or more bonds to fluorine atoms. One example of a
substituted alkyl group is the trifluoromethyl group and other alkyl groups that
contain the trifluoromethyl group. Other alkyl groups include those in which
one or more bonds to a carbon or hydrogen atom is replaced by a bond to an
oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy,
aryloxy group, or heterocyclyloxy group. Still other alkyl groups include alkyl
groups that have an amine, alkylamine, dialkylamine, arylamine,
(alkyl)(aryl)amine, diarylamine, heterocyclylamine, (alkyl)(heterocyclyl)amine,
(aryl)(heterocyclyl)amine, or diheterocyclylamine group.
[0025] The phrase "unsubstituted aryl" refers to aryl groups that do not
contain heteroatoms. Thus, by way of example, the phrase includes, but is
not limited to, groups such as phenyl, biphenyl, anthracenyl, and naphthyl.
Although the phrase "unsubstituted aryl" includes groups containing
condensed rings such as naphthalene, it does not include aryl groups that

have other groups such as alkyl or halo groups bonded to one of the ring
members, as aryl groups such as tolyl are considered herein to be substituted
aryl groups as described below. A preferred unsubstituted aryl group is
phenyl, in some embodiments, unsubstituted aryl groups have from 6 to 14
carbon atoms. Unsubstituted aryl groups may be bonded to one or more
carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the
parent compound.
[0026] The phrase "substituted aryl group" has the same meaning with
respect to unsubstituted aryl groups that substituted alkyl groups had with
respect to unsubstituted alkyl groups. However, a substituted aryl group also
includes aryl groups in which one of the aromatic carbons is bonded to one of
the non-carbon or non-hydrogen atoms described above and also includes
aryl groups in which one or more aromatic carbons of the aryl group is bonded
to a substituted or unsubstituted alkyl, alkenyl, or alkynyl group as defined
herein. This includes bonding arrangements in which two carbon atoms of an
aryl group are bonded to two atoms of an alkyl, alkenyl, or alkynyl group to
define a fused ring system (e.g. dihydronaphthyl or tetrahydronaphthyl).
Thus, the phrase "substituted aryl" includes, but is not limited to groups such
as tolyl, and hydroxyphenyl among others.
[0027] The phrase "unsubstituted alkenyl" refers to straight and
branched chain and cyclic groups such as those described with respect to
unsubstituted alkyl groups as defined above, except that at least one double
bond exists between two carbon atoms. Examples include, but are not limited
to vinyl, -CH=C(H)(CH3), -CH=C(CH3)2, -C(CH3)=C(H)2, -C(CH3)=C(H)(CH3),
-C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl,
pentadienyl, and hexadienyl among others. In some embodiments,
unsubstituted alkenyl groups have from 2 to 8 carbon atoms.
[0028] The phrase "substituted alkenyl" has the same meaning with
respect to unsubstituted alkenyl groups that substituted alkyl groups had with
respect to unsubstituted alkyl groups. A substituted alkenyl group includes

alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a
carbon double bonded to another carbon and those in which one of the non-
carbon or non-hydrogen atoms is bonded to a carbon not involved in a double
bond to another carbon.
[0029] The phrase "unsubstituted alkynyl" refers to straight and
branched chain groups such as those described with respect to unsubstituted
alkyl groups as defined above, except that at least one triple bond exists
between two carbon atoms. Examples include, but are not limited to -C≡C(H),
-C≡C(CH3), -C=C(CH2CH3), -C(H2)C≡C(H), -C(H)2C≡C(CH3), and
-C(H)2C≡C(CH2CH3) among others. In some embodiments, unsubstituted
alkynyl groups have from 2 to 8 carbon atoms.
[0030] The phrase "substituted alkynyl" has the same meaning with
respect to unsubstituted alkynyl groups that substituted alkyl groups had with
respect to unsubstituted alkyl groups. A substituted alkynyl group includes
alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a
carbon triple bonded to another carbon and those in which a non-carbon or
non-hydrogen atom is bonded to a carbon not involved in a triple bond to
another carbon.
[0031] The phrase "unsubstituted heterocyclyl" refers to both aromatic
and nonaromatic ring compounds including monocyclic, bicyclic, and
polycyclic ring compounds such as, but not limited to, quinuclidyl, containing 3
or more ring members of which one or more is a heteroatom such as, but not
limited to, N, O, and S. Although the phrase "unsubstituted heterocyclyl"
includes condensed heterocyclic rings such as benzimidazolyl, it does not
include heterocyclyl groups that have other groups such as alkyl or halo
groups bonded to one of the ring members as compounds such as 2-
methylbenzimidazolyl are substituted heterocyclyl groups. Examples of
heterocyclyl groups include, but are not limited to: unsaturated 3 to 8
membered rings containing 1 to 4 nitrogen atoms such as, but not limited to
pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, dihydropyridinyl, pyrimidyl,

pyrazinyl, pyridazinyl, triazolyi (e.g. 4H-1)2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-
1,2,3-triazolyl etc.), tetrazolyl, (e.g. 1H-tetrazolyl, 2H tetrazolyl, etc.);
saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as,
but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl;
condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms
such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; unsaturated 3
to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen
atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-
oxadiazolyl, 1,3,4-oxadiazoIyl, 1,2,5-oxadiazolyl, etc.); saturated 3 to 8
membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms
such as, but not limited to, morpholinyl; unsaturated condensed heterocyclic
groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; for
example, benzoxazoiyl, benzoxadiazolyl, benzoxazinyl (e.g. 2H-1,4-
benzoxazinyl etc.); unsaturated 3 to 8 membered rings containing 1 to 3 sulfur
atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl,
isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-
thiadiazolyl, 1,2,5-thiadiazolyl, etc.); saturated 3 to 8 membered rings
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not
limited to, thiazolodinyl; saturated and unsaturated 3 to 8 membered rings
containing 1 to 2 sulfur atoms such as, but not limited to, thienyl,
dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran;
unsaturated condensed heterocyclic rings containing 1 to 2 sulfur atoms and 1
to 3 nitrogen atoms such as, but not limited to, benzothiazolyl,
benzothiadiazolyl, benzothiazinyl (e.g. 2H-1,4-benzothiazinyl, etc.),
dihydrobenzothiazinyl (e.g. 2H-3,4-dihydrobenzothiazinyl, etc.), unsaturated 3
to 8 membered rings containing oxygen atoms such as, but not limited to furyl;
unsaturated condensed heterocyclic rings containing 1 to 2 oxygen atoms
such as benzodioxolyl (e.g. 1,3-benzodioxoyl, etc.); unsaturated 3 to 8
membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as,
but not limited to, dihydrooxathiinyl; saturated 3 to 8 membered rings
containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1,4-

oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such
as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings
containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyi.
Heterocyclyl group also include those described above in which one or more
S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides
and sulfones). For example, heterocyclyl groups include tetrahydrothiophene
oxide, and tetrahydrothiophene 1,1-dioxide. Preferred heterocyclyl groups
contain 5 or 6 ring members. More preferred heterocyclyl groups include
morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1,2,3-
triazole, 1,2,4-triazole, tetrazole, thiophene, thiomorpholine, thiomorpholine in
which the S atom of the thiomorpholine is bonded to one or more O atoms,
pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazole,
quinuclidine, thiazole, isoxazole, furan, and tetrahydrofuran.
[0032] The phrase "substituted heterocyclyl" refers to an unsubstituted
heterocyclyl group as defined above in which one or more of the ring
members is bonded to a non-hydrogen atom such as described above with
respect to substituted alkyl groups and substituted aryl groups. Examples,
include, but are not limited to, 2-methylbenzimidazolyl, 5-
methylbenzimidazolyl, 5-chlorobenzthiazolyl, N-alkyl piperazinyl groups such
as 1-methyl piperazinyl, piperazine-N-oxide, N-alkyl piperazine N-oxides, 2-
phenoxy-thiophene, and 2-chloropyridinyl among others. In addition,
substituted heterocyclyl groups also include heterocyclyl groups in which the
bond to the non-hydrogen atom is a bond to a carbon atom that is part of a
substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, or
unsubstituted heterocyclyl group. Examples include but are not limited to 1-
benzylpiperidinyl, 3-phenythiomorpholinyl, 3-(pyrrolidin-1-yl)-pyrrolidinyl, and
4-(piperidin-1-yl)-piperidinyl. Groups such as N-alkyl substituted piperazine
groups such as N-methyl piperazine, substituted morpholine groups, and
piperazine N-oxide groups such as piperazine N-oxide and N-alkyl piperazine
N-oxides are examples of some substituted heterocyclyl groups. Groups such
as substituted piperazine groups such as N-alkyl substituted piperazine

groups such as N-methyl piperazine and the like, substituted morpholine
groups, piperazine N-oxide groups, and N-alkyl piperazine N-oxide groups are
examples of some substituted heterocyclyl groups that are especially suited
as R6 or R7 groups.
[0033] The phrase "unsubstituted heterocyclylalkyl" refers to
unsubstituted alkyl groups as defined above in which a hydrogen or carbon
bond of the unsubstituted alkyl group is replaced with a bond to a heterocyclyl
group as defined above. For example, methyl (-CH3) is an unsubstituted alkyl
group. -If a hydrogen atom of the methyl group is replaced by a bond to a
heterocyclyl group, such as if the carbon of the methyl were bonded to carbon
2 of pyridine (one of the carbons bonded to the N of the pyridine) or carbons 3
or 4 of the pyridine, then the compound is an unsubstituted heterocyclylalkyl
group.
[0034] The phrase "substituted heterocyclylalkyl" has the same
meaning with respect to unsubstituted heterocyclylalkyl groups that
substituted aralkyl groups had with respect to unsubstituted aralkyl groups.
However, a substituted heterocyclylalkyl group also includes groups in which
a non-hydrogen atom is bonded to a heteroatom in the heterocyclyl group of
the heterocyclylalkyl group such as, but not limited to, a nitrogen atom in the
piperidine ring of a piperidinylalkyl group. In addition, a substituted
heterocyclylalkyl group also includes groups in which a carbon bond or a
hydrogen bond of the alkyl part of the group is replaced by a bond to a
substituted and unsubstituted aryl or substituted and unsubstituted aralkyl
group. Examples include but are not limited to phenyl-(piperidin-1-yl)-methyl
and phenyl-(morpholin-4-yl)-methyl.
[0035] The phrase "unsubstituted alkoxy" refers to a hydroxyl group
(-OH) in which the bond to the hydrogen atom is replaced by a bond to a
carbon atom of an otherwise unsubstituted alkyl group as defined above.

[0036] The phrase "substituted alkoxy" refers to a hydroxy! group (-OH)
in which the bond to the hydrogen atom is replaced by a bond to a carbon
atom of an otherwise substituted alkyl group as defined above.
[0037] The phrase "unsubstituted heterocyclyloxy" refers to a hydroxyl
group (-OH) in which the bond to the hydrogen atom is replaced by a bond to
a ring atom of an otherwise unsubstituted heterocyclyl group as defined
above.
[0038] The phrase "substituted heterocyclyloxy" refers to a hydroxyl
group (-OH) in which the bond to the hydrogen atom is replaced by a bond to
a ring atom of an otherwise substituted heterocyclyl group as defined above.
[0039] The phrase "unsubstituted aryloxyalkyl" refers to an
unsubstituted alkyl group as defined above in which a carbon bond or
hydrogen bond is replaced by a bond to an oxygen atom which is bonded to
an unsubstituted aryl group as defined above.
[0040] The phrase "substituted aryloxyalkyl" refers to an unsubstituted
aryloxyalkyl group as defined above in which a bond to a carbon or hydrogen
group of the alkyl group of the aryloxyalkyl group is bonded to a non-carbon
and non-hydrogen atom as described above with respect to substituted alkyl
groups or in which the aryl group of the aryloxyalkyl group is a substituted aryl
group as defined above.
[0041] The phrase "unsubstituted heterocyclyloxyalkyl" refers to an
unsubstituted alkyl group as defined above in which a carbon bond or
hydrogen bond is replaced by a bond to an oxygen atom which is bonded to
an unsubstituted heterocyclyl group as defined above.
[0042] The phrase "substituted heterocyclyloxyalkyl" refers to an
unsubstituted heterocyclyloxyalkyl group as defined above in which a bond to
a carbon or hydrogen group of the alkyl group of the heterocyclyloxyalkyl
group is bonded to a non-carbon and non-hydrogen atom as described above

with respect to substituted alkyl groups or in which the heterocyclyl group of
the heterocyclyloxyalkyl group is a substituted heterocyclyl group as defined
above.
[0043] The phrase "unsubstituted heterocyclylalkoxy" refers to an
unsubstituted alkyl group as defined above in which a carbon bond or
hydrogen bond is replaced by a bond to an oxygen atom which is bonded to
the parent compound, and in which another carbon or hydrogen bond of the
unsubstituted alkyl group is bonded to an unsubstituted heterocyclyl group as
defined above.
[0044] The phrase "substituted heterocyclylalkoxy" refers to an
unsubstituted heterocyclylalkoxy group as defined above in, which a bond to a
carbon or hydrogen group of the alkyl group of the heterocyclylalkoxy group is
bonded to a non-carbon and non-hydrogen atom as described above with
respect to substituted alkyl groups or in which the heterocyclyl group of the
heterocyclylalkoxy group is a substituted heterocyclyl group as defined above.
Further, a substituted heterocyclylalkoxy group also includes groups in which
a carbon bond or a hydrogen bond to the alkyl moiety of the group may be
substituted with one or more additional substituted and unsubstituted
heterocycles. Examples include but are not limited to pyrid-2-ylmorpholin-4-
ylmethyl and 2-pyrid-3-yl-2-morpholin-4-ylethyl.
[0045] The phrase "unsubstituted alkoxyalkyl" refers to an
unsubstituted alkyl group as defined above in which a carbon bond or
hydrogen bond is replaced by a bond to an oxygen atom which is bonded to
an unsubstituted alkyl group as defined above.
[0046] The phrase "substituted alkoxyalkyl" refers to an unsubstituted
alkoxyalkyl group as defined above in which a bond to a carbon or hydrogen
group of the alkyl group and/or the alkoxy group of the alkoxyalkyl group is
bonded to a non-carbon and non-hydrogen atom as described above with
respect to substituted alkyl groups.

[0047] The term "protected" with respect to hydroxyl groups, amine
groups, and sulfhydryl groups refers to forms of these functionalities which are
protected from undesirable reaction with a protecting group known to those
skilled in the art such as those set forth in Protective Groups in Organic
Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY,
(3rd Edition, 1999) which can be added or removed using the procedures set
forth therein. Examples of protected hydroxyl groups include, but are not
limited to, silyl ethers such as those obtained by reaction of a hydroxyl group
with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane,
trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted
methyl and ethyl ethers such as, but not limited to methoxymethyl ether,
methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-
methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether,
allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate,
formate, acetate, trichloroacetate, and trifluoracetate. Examples of protected
amine groups include, but are not limited to, amides such as, formamide,
acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide,
and dithiosuccinimide; and others. Examples of protected sulfhydryl groups
include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-
picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and
aminothio acetals; and others.
[0048] A "pharmaceutically acceptable salt" includes a salt with an
inorganic base, organic base, inorganic acid, organic acid, or basic or acidic
amino acid. As salts of inorganic bases, the invention includes, for example,
alkali metals such as sodium or potassium; alkaline earth metals such as
calcium and magnesium or aluminum; and ammonia. As salts of organic
bases, the invention includes, for example, trimethylamine, triethylamine,
pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine. As
salts of inorganic acids, the instant invention includes, for example,
hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric
acid. As salts of organic acids, the instant invention includes, for example,

formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric
acid, maleic acid, lactic acid, citric acid, succinic acid, malic acid,
methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. As
salts of basic amino acids, the instant invention includes, for example,
arginine, lysine and ornithine. Acidic amino acids include, for example,
aspartic acid and glutamic acid.
[0049] Generally, the invention provides methods for synthesizing
benzimidazolyl quinolinone compounds such as amino substituted
benzimidazolyl quinolinone compounds. The invention further provides amino
substituted benzimidazolyl quinolinone compounds and formulations that have
reduced amounts of lithium and methods of synthesizing such compounds
and compositions.
[0050] In one aspect, the present invention provides a method for
synthesizing a substituted or unsubstituted 4-amino-3-benzimidazolyl
quinolinone compound and compositions that include such a compound. The
method includes reacting a first compound having the formula I with a second
compound having the formula II in a suitable solvent in the presence of a
sodium or potassium salt of a base. In some embodiments, the method
includes reacting the first compound with the second compound in the
suitable solvent in the presence of the potassium salt of the base. The
reaction of the first compound with the second compound produces the
substituted or unsubstituted 4-amino-3-benzimidazolyl quinolinone compound.
Formula I and formula II have the following structures:

where:

R1, R2, R3, and R4 may be the same or different and are
independently selected from H, CI, Br, F, I, -OR10 groups, -NR11R12 groups,
substituted or unsubstituted primary, secondary, or tertiary alkyl groups,
substituted or unsubstituted aryl groups, substituted or unsubstituted aikenyl
groups, substituted or unsubstituted alkynyl groups, substituted or
unsubstituted heterocyclyl groups, or substituted or unsubstituted
heterocyclylalkyl groups;
R5, R6, R7, and R8 may be the same or different and are
independently selected from H, CI, Br, F, I, -OR13 groups, -NR14R15 groups,
-SR16 groups, substituted or unsubstituted primary, secondary, or tertiary alkyl
groups, substituted or unsubstituted aryl groups, substituted or unsubstituted
alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or
unsubstituted heterocyclyl groups, substituted or unsubstituted
heterocyclylalkyl groups, substituted or unsubstituted alkoxyalkyl groups,
substituted or unsubstituted aryloxyalkyl groups, or substituted or
unsubstituted heterocyclyloxyalkyl groups;
Z is selected from -OR9a groups or -NR9bR9c groups;
R9a is an unsubstituted alkyl group having from 1 to 8 carbon
atoms and is absent if Z is a -NR9bR9c group;
R9b and R90 are independently selected from unsubstituted alkyl
groups having from 1 to 8 carbon atoms or are both absent if Z is a -OR9a
group;
R10 and R13 may be the same or different and are independently
selected from substituted or unsubstituted alkyl groups, substituted or
unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups,
substituted or unsubstituted heterocyclylalkyl groups, substituted or
unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl
groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;

R11 and R14 may be the same or different and are independently
selected from substituted or unsubstituted alkyl groups, substituted or
unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R12 and R15 may be the same or different and are independently
selected from substituted or unsubstituted alkyl groups, substituted or
unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
and
R16 is selected from substituted or unsubstituted alkyl groups,
substituted or unsubstituted aryl groups, or substituted or unsubstituted
heterocyclyl groups.
[0051] In some embodiments, the substituted or unsubstituted 4-amino-
3-benzimidazolyl quinolinone compound is a compound having the formula III,
is a tautomer of the compound having the formula III, is a salt of the
compound having the formula III, or is a salt of the tautomer of the compound
having the formula III. Formula III has the following structure:

where R1 through R8 and R10 through R16 have the values described above.
[0052] In some embodiments of the method, R1 is selected from H, CI,
Br, F, or I. In some such embodiments, R1 is F. In some specific
embodiments, R1 is F and each of R2, R3 and R4 is H such that the first

compound is a compound having the formula IA which has the following
structure

[0053] In other embodiments, at least one of R6 or R7 is a substituted or
unsubstituted heterocyclyl group. In some such embodiments, one of R6 or
R7 is a heterocyclyl group and the other of R6 or R7 is a H. In some
embodiments, one of R6 or R7 is a heterocyclyl group selected from a
substituted or unsubstituted piperidinyl group, piperazinyl group, or
morpholinyl group. In some such embodiments one of R6 or R7 is an N-alkyl
piperazinyl group such as an N-methyl piperazinyl group or the like and, in
some such embodiments, the other of R6 or R7 is a H. In other such
embodiments, Z is an -OR9a group. Therefore, in some embodiments, the
second compound is a compound having the formula HA or JIB and has one of
the following structures where R5, R8, and R9a have the values described
above for compounds having the formula II.

[0054] In some further embodiments, the second compound is a
compound having the formula HA or HB and both R5 and R8 are H such that

the second compound is a compound having the formula IIC or IID and has
one of the following structures.

[0055] In some embodiments of the method, R9a, R9b, and R9c are
straight chain alkyl groups selected from methyl, ethyl, propyl, butyl, or pentyl
groups or are branched chain alkyl groups selected from i-propyl, s-butyl, or t-
butyl groups. In some embodiments, R9a, R9b, or R9c are methyl, ethyl, or
propyl groups and in yet other embodiments, R9a, R9b, or R9c are ethyl groups.
[0056] In some embodiments of the method, the method includes
reacting the first compound with the second compound in a solvent such as a
dialkyl ether such as, but not limited to, diethyl ether or the like; a cyclic ether
such as, but not limited to, dioxane, tetrahydrofuran or the like; an aromatic
solvent such as toluene, o-xylene, m-xylene, p-xylene, mixtures thereof, or the
like; or combinations of these solvents. Other suitable solvents include polar
aprotic solvents such as DMF (N,N-Dimethylformamide) and the like. In some
such embodiments, the solvent is tetrahydrofuran. In other embodiments, the
solvent is toluene. In some embodiments, the concentration of the first
compound is greater than or about 0.10 M or is greater than or about 0.15 M
based on the amount of the solvent when the first compound and the second
compound are reacted. In some such embodiments, the concentration of the
first compound ranges from 0.10 M to 0.30 M based on the amount of solvent
when the first compound and the second compound are reacted. In some
such embodiments, the concentration of the first compound ranges from 0.15
M to 0.25 M based on the amount of solvent when the first compound and the
second compound are reacted. In some such embodiments, the

concentration of the first compound ranges from 0.17 M to 0.22 M based on
the amount of solvent when the first compound and the second compound are
reacted. In some such embodiments, the concentration of the first compound
is about 0.19 M based on the amount of solvent when the first compound and
the second compound are reacted. In some such embodiments, the
concentration of the first compound and/or the second compound ranges from
0.15 M to 0.50 M based on the amount of solvent when the first compound
and the second compound are reacted. In some such embodiments, the
concentration of the first compound and/or the second compound ranges from
0.20 M to 0.45 M based on the amount of solvent when the first compound
and the second compound are reacted. In some such embodiments, the
concentration of the first compound and/or the second compound ranges from
0.25 M to 0.45 M based on the amount of solvent when the first compound
and the second compound are reacted. In some embodiments, the
concentration of the second compound is greater than 0.10 M based on the
amount of the solvent when the first compound and the second compound are
reacted. In other such embodiments, the concentration of the second
compound is greater than about 0.15 M, whereas in other embodiments, the
concentration of the second compound is greater than about 0.20 M based on
the amount of solvent when the first compound and the second compound are
reacted. In some embodiments, the concentration of the second compound
ranges from 0.15 M to 0.30 M based on the amount of solvent when the first
compound and the second compound are reacted. In some embodiments,
the concentration of the second compound ranges from 0.18 M to 0.26 M
based on the amount of solvent when the first compound and the second
compound are reacted. In some embodiments, the concentration of the
second compound ranges from 0.20 M to 0.24 M based on the amount of
solvent when the first compound and the second compound are reacted. In
some embodiments, the concentration of the second compound is about 0.22
M based on the amount of solvent when the first compound and the second
compound are reacted. In some embodiments, the solvent is dried prior to
use in the reaction. In some such embodiments, the solvent of the reaction

comprises, less than 0.5 percent water, less than 0.25 percent water, less
than 0.1 percent water, or is less than 0.05 percent water by weight. In still
other such embodiments, the solvent comprises less than 0.01 percent water,
or is less than 0.005 percent water based on the weight. In some
embodiments, the solvent is dried prior to use in the reaction. In some
embodiments, a mixture of the solvent and the second compound is dried
prior to addition of the potassium or sodium salt of the base. In some such
embodiments, the mixture of the solvent and the second compound
comprises, less than 0.5 percent water, less than 6.25 percent water, less
than 0.2 percent water, less than 0.1 percent water, or less than 0.05 percent
water which may be determined by Karl Fischer analysis.
[0057] In some embodiments of the method, the method includes
reacting the first compound with the second compound in the suitable solvent
using the sodium or potassium salt of a base that may be used to generate an
enolate anion, which, in some embodiments, may be a sterically-hindered
base. As used herein, the term "base" refers to a chemical compound that
deprotonates another compound when reacted with it. In some such
embodiments, the sodium or potassium salt of the base that may be used to
generate an enolate anion is a base such as, for example, NaH, KH, Na2CO3,
K2CO3, sodium and potassium alkoxides such as, but not limited to, sodium
and potassium t-butoxide, propoxide, i-propoxide, ethoxide, methoxide, and
the like, sodium amide (NaNH2), potassium amide (KNH2), and the like. In
some embodiments, the base is sodium or potassium t-butoxide, and in some
such embodiments, the base is potassium t-butoxide in a solvent such as
THF. In some of these embodiments the base is potassium t-butoxide (20%
in THF). In some embodiments, the sterically hindered base is an amide
anion and in some such embodiments, the amide nitrogen is bonded to two
trialkylsilyl groups. In some such embodiments, the sodium or potassium salt
of the base is selected from a sodium or potassium bis(triaikylsilyl)amide. In
some such embodiments, the sodium or potassium bis(trialkylsilyl)amide is
sodium bis(trimethylsilyl)amide (NaHMDS) or potassium

bis(trimethylsilyl)amide (KHMDS). In some embodiments, the method further
includes adding the sodium or potassium salt of the base to a mixture of the
first compound and the second compound in the suitable solvent. In some
embodiments, the sodium or potassium salt of the base is present in an
amount of from 2 to 4 equivalents, and in some such embodiments in an
amount of from 2.5 to 3 equivalents, with respect to the first compound. In still
other embodiments, the sodium or potassium salt of the base is present in an
amount of 2 to 4 equivalents, and in some such embodiments in an amount of
from 2.5 to 3 equivalents, with respect to the second compound. In some
embodiments, the second compound is present in an amount of from 1 to 2
equivalents with respect to the first compound. In some such embodiments,
the second compound is present in an amount of from 1 to 1.5 equivalents
with respect to the first compound.
[0058] In some embodiments of the method for synthesizing a
substituted or unsubstituted 4-amino-3-benzimidazole quinolinone compound
and compositions that include such compounds, the method includes adding
the potassium salt of the base to a mixture comprising the first compound, the
second compound, and the suitable solvent at a temperature of from 20°C to
50°C. In some such embodiments, the potassium salt of the base is added to
the mixture and the temperature of the mixture is from 25°C to 45°C, from
35°C to 45°C, or from 38°C to 42°C when the potassium salt of the base is
first added to the mixture. In some embodiments, the internal temperature is
40°C or about 40°C when the potassium salt of the base is first added to the
mixture. The internal reaction temperature generally increases, for example
up to 62°C or 65°C upon addition of the potassium salt of the base to the
reaction mixture. However, in some embodiments, the internal temperature is
maintained at 30°C to 52°C, 36°C to 52°C, or in some embodiments from
38°C to 50°C during addition of the potassium salt of the base. In some such
embodiments, the potassium salt of the base is added to the mixture over a
period of from 2 to 20 minutes. In some such embodiments, the potassium
salt of the base is added to the mixture over a period of from 3 to 10 minutes

and in some such embodiments, the potassium salt of the base is added to
the mixture over a period of from 5 to 10 minutes or in some embodiments
over a period of 5 minutes.
[0059] In some embodiments of the method for synthesizing a
substituted or unsubstituted 4-amino-3-benzimidazole quinolinone compound
and compositions that include such compounds, the method includes adding
the sodium or potassium salt of the base to a mixture comprising the first
compound, the second compound, and the suitable solvent at a temperature
of from -15°C to 50°C. In some such embodiments, the potassium salt of the
base is added to the mixture and the temperature of the mixture is from 15°C
to 25°C, from 15°C to 20°C, or from 17°C to 20°C when the potassium salt of
the base is first added to the mixture. In some embodiments, the internal
temperature is 17°C to 20°C when the potassium salt of the base is first
added to the mixture. In some embodiments, the internal temperature is
maintained at a temperature of less than or about 25°C during addition of the
base. In some such embodiments, the internal temperature of the reaction is
raised to 30°C and the reaction is monitored for completion using HPLC.
[0060] In some embodiments, the method further includes (a) adding
an aromatic solvent such as toluene to a reaction flask to provide a reaction
mixture comprising the first compound and the second compound; (b) distilling
at least a portion of the aromatic solvent from the reaction flask, and (c)
repeating (a) and (b) until the water content is less than 0.1 percent, 0.05,
0.04 percent, or 0.03 percent which may be determined using Karl Fischer
analysis. In some embodiments, the distillation may be conducted under
reduced pressure. In some embodiments, the second compound is dried by
(a) mixing the second compound with a suitable organic solvent such as THF,
toluene, ethanol, or the like to form a solution, (b) concentrating the second
compound by removing at least a portion of the solvent, and (c) optionally
repeating steps (a) and (b) one or more additional times. In some such
embodiments, (a) and (b) are repeated until the water content of the solution
is less than 0.5%, less than 0.4%, less than 0.3%, less than 0.25%, less than

0.20%, less than 0.10%, less than 0.05%, or less than 0.03% which may be
determined by Karl Fischer analysis. In some embodiments, steps (a) and (b)
are accomplished at least four times. In some embodiments, the second
compound may be dried in a reaction vessel and when the desired quantity of
drying is achieved, such as a water level of less than 0.25% or less than
0.20%, the first compound and the potassium or sodium salt of the base are
added to the reaction vessel. In such embodiments, solvents such as those
suitable for use in the reaction of the first compound with the second
compound may be used to dry the second compound. Such solvents include
ethereal solvents such as diethyl ether, dioxane, THF, and the like and
aromatic solvents such as toluene.
[0061] In some embodiments of the method for synthesizing a
substituted or unsubstituted 4-amino-3-benzimidazolyl quinolinone compound
and compositions that include such a compound, the method includes drying
the second compound to a water level of less than 5.5 percent by weight prior
to reacting it with the first compound or adding it to a reaction vessel
containing the first compound or the suitable solvent. In some such
embodiments, the second compound is dried to a water level of less than 5
percent by weight, less than 4 percent by weight, less than 3 percent by
weight, less than 2.5 percent by weight, less than 2 percent by weight, less
than 1 percent by weight, or less than 0.5 percent by weight. In some such
embodiments, the second compound may be dried by mixing the hydrated
second compound with an organic solvent such as THF, toluene, or ethanol to
form a solution, concentrating the solution by solvent removal, and drying the
resulting composition under vacuum with heating. In some such
embodiments, the second compound is dried by: (a) mixing the hydrated
second compound with an organic solvent such as THF, toluene, or ethanol to
form a solution, (b) concentrating the second compound by removing at least
a portion of the solvent, (c) optionally repeating steps (a) and (b) one or more
additional times, and then (d) drying the resulting composition under vacuum
with heating.

[0062] In some embodiments of the method for synthesizing a
substituted or unsubstituted 4-amino-3-benzimidazolyl quinolinone compound
and compositions that include such a compound, the method includes
reacting the first compound with the second compound in the presence of the
sodium or potassium salt of the base for a period of time ranging from 30
minutes to 360 minutes, from 120 minutes to 300 minutes, from 180 to 300
minutes, from 180 minutes to 270 minutes, from 210 minutes to 270 minutes,
or from 210 minutes to 240 minutes at a temperature suitable to provide the
desired benzimidazolyl quinolinone compound. In some embodiments, the
reaction product mixture of the substituted or unsubstituted 4-amino-3-
benzimidazolyl quinolinone compound produced by the reaction of the first
compound with the second compound is quenched by pouring the reaction
product mixture into water. In other embodiments, water is added to the
reaction mixture which, in some embodiments, is cooled to a temperature of
from 20°C to 35°C or from 20°C to 35°C prior to adding the water. In some
embodiments, solvent may be removed under vacuum after water is added
and then additional water is added prior to collection of the solid by filtration.
The quenched reaction product mixture is typically filtered and washed with
water providing the 4-amino-3-benzimidazolyl quinolinone compound, and in
some embodiments, the quenched reaction product may be cooled to a
temperature of 5°C to 10°C prior to filtration although this is not necessary. In
some embodiments, the collected product may be dried under vacuum to
produce a yield of greater than 30 percent, greater than 40 percent, greater
than 50 percent, greater than 60 percent, greater than 70 percent, or greater
than 80 percent of the 4-amino-3-benzimidazolyl quinolinone compound.
Some embodiments of the method may further include: (a) mixing the
collected product with ethanol; (b) heating the ethanolic mixture for a period of
from 10 minutes to 180 minutes, of from 30 minutes to 120 minutes, or of
about 60 minutes at a temperature of from 40°C to 78°C, of from 45°C to
78°C, of from 60°C to 78°C, or a reflux temperature; (c) cooling the mixture to
a temperature of less than 40°C, less than 35°C, less than 30°C, or less than
20°C; (d) and filtering the cooled mixture. However, it is not necessary that

the mixture be cooled prior to filtration. In some such embodiments the
filtered product may be washed with a solvent such as ethanol or water. The
resulting product may be dried under vacuum with heating such as in a
vacuum oven, a drying pistol, a rotary evaporator, or the like.
[0063] In some embodiments of the method for synthesizing a
substituted or unsubstituted 4-amino-3-benzimidazolyl quinolinone compound
and compositions that include such a compound, the method includes
reacting a compound having the formula IV with a compound having the
formula V to provide the second compound where the variables R5, R6, R7, R8,
and R9a have the values set forth above with respect to the second compound
having the formula II and X is a halogen atom such as F, CI, Br, or I, or is the
conjugate base of an acid.

In some such embodiments, the compound having the formula IV has the
formula IVA.

In some such embodiments, the compound having the formula V has the
formula VA.


In some embodiments, the compound having the formula IV is reacted with
the compound having the formula V in a solvent such as an alcohol such as,
but not limited to, ethanol at an internal temperature of from 30°C to 70°C, of
from 35°C to 60°C, or of from 40°C to 50°C for a period of time of from 45
minutes to 240 minutes, of from 60 minutes to 180 minutes, or of from 60
minutes to 120 minutes. In some embodiments, the reaction product from the
reaction of the compound having the formula IV with the compound having the
formula V is cooled, for example to 25°C or the like, and is filtered. In other
embodiments, the reaction product is still warm when it is filtered through a
filter medium such as Celite. In some embodiments, the filter medium may be
washed with a solvent such as ethanol, and the filtrate may be concentrated
by solvent removal. The concentrated product may then be mixed with an
aqueous HCl solution, in some embodiments, a 0.37 percent HCI solution and
in other embodiments a 1M HCI solution. A base such as NaOH, for example
a 30% NaOH solution, may then be added in one portion or gradually such
that a precipitate forms. In some embodiments, the reaction product may be
mixed or dissolved with water, in some embodiments deionized water, that is
neutral with respect to pH. In such embodiments, the resulting mixture is
typically cooled to about 0°C and then is made basic by addition of a base
such as NaOH. In some such embodiments, the pH is brought to about 9.2
by addition of 20% NaOH. In some embodiments, the resulting mixture is
stirred for a period of about 1 to 5 hours, for example, for 4 hours or the like,
and is then filtered, washed with water and dried in a vacuum oven or the like.
[0064] In some embodiments of the method for synthesizing a
substituted or unsubstituted 4-amino-3-benzimidazolyl quinolinone compound
and compositions that include such a compound, a compound having the
formula VIA, VIB, or mixtures thereof is reduced, typically catalytically as

described below, with H2 to produce the compound having the formula IV
where the variables R5, R6, R7, and R8 have the values set forth above with
respect to the second compound having the formula II.

In some such embodiments, the compound having the formula VIA is a
compound having the formula VIC or VID and/or the compound having the
formula VIB is a compound having the formula VIE or VIF. In some such
embodiments, R6 or R7 is a substituted or unsubstituted heterocyclyl group,
that, in some embodiments is selected from substituted or unsubstituted
piperidinyl groups, piperazinyl groups, or morpholinyl groups. In some such
embodiments, one of R6 or R7 is an N-alkyl piperazinyl group such as an N-
methyl piperazinyl group such that the compounds having the formula VIC,
VID, VIE, and VIF have the formula VIG or VIH.



In some embodiments, the compound reduced by H2 is a compound having
the formula VIH. In other embodiments, the compound reduced by H2 is a
compound having the formula VIG. In some embodiments, the compound
having the formula VIA, VIB, or mixtures thereof is reduced with H2 in an
alcohol solvent such as ethanol using a transition metal hydrogenation
catalyst such as palladium on carbon (Pd/C). In some embodiments, the
Pd/C is 5 percent Pd/C and in some embodiments, the Pd/C is 5 percent Pd/C
with 50 percent water on a weight by weight basis. In some embodiments,
the reaction is conducted at an internal temperature of from 25°C to 70°C,
from 30°C to 60°C, or in some embodiments from 40°C to 55°C or from 45°C
to 55°C for a period of time of from 1 to 12 hours, of from 3 to 10 hours, of
from 4 to 8 hours, or of 6 hours. In some embodiments, the reduced
compound having the formula IV is directly reacted with the compound having
the formula V in the same reaction vessel without further purification.
[0065] In some embodiments of the method for synthesizing a
substituted or unsubstituted 4-amino-3-benzimidazolyl quinolinone compound
and compositions that include such a compound, a compound having the
formula VII is reacted with a compound having the formula HR7 or a salt
thereof to produce the compound having the formula VIA where the variables
R5, R6, and R8 have the values set forth above with respect to the second
compound having the formula II and Y is selected from CI or F.


In some such embodiments, the compound having the formula VII is a
compound having the formula VIIA or VIIB. In some such embodiments, R7 is
a substituted or unsubstituted heterocyclyl group, that, in some embodiments
is selected from substituted or unsubstituted piperidinyl groups, piperazinyl
groups, or morpholinyl groups. In some such embodiments, R7 is an N-alkyl
piperazinyl group such as an N-methyl piperazinyl group such that HR7 has
the formula HR7(a) shown below.

In some embodiments, the compound having the formula VII is reacted with
the compound having the formula HR7, such as N-methylpiperazine at a
temperature of from 70°C to 120°C or of 80°C to 110°C, of from 85°C to
105°C, or of 100°C for a period of from 2 hours to 24 hours, of from 4 hours to
12 hours, or of from 6 hours to 10 hours. A variety of suitable solvents such
as, but not limited to, ethanol may be employed in the reaction of the
compound having the formula HR7 with the reaction of the compound having

the formula VII. Addition of a solvent such as ethanol to the reaction helps to
prevent solidification of the reaction, in some embodiments, any of the
reactions of the method are followed by HPLC and are conducted for a period
of time until the starting materials are observed to no longer be present in any
appreciable amounts.
[0066] In some embodiments, the substituted or unsubstituted 4-amino-
3-benzimidazolyl quinolinone compound is a compound having the formula
1IIA, is a tautomer of the compound having the formula IIIA, is a salt of the
compound having the formula IIIA, or is a salt of the tautomer of the
compound having the formula IIIA and R7 is a substituted or unsubstituted
heterocyclyl group

In some such embodiments, R7 is a substituted or unsubstituted heterocyclyl
group that is selected from a substituted or unsubstituted piperidinyl group,
piperazinyl group, or morpholinyl group. In some such embodiments, R7 is a
substituted or unsubstituted N-alkyl piperazinyl group such as an N-methyl
piperazinyl group, an N-ethyl piperazinyl group, or a N-propyl piperazinyl
group.
[0067] In some embodiments, the substituted or unsubstituted 4-amino-
3-benzimidazoly! quinolinone compound is a compound having the formula
IIIB, is a tautomer of the compound having the formula 1I1B, is a salt of the
compound having the formula IIIB, or is a salt of the tautomer of the
compound having the formula IIIB


[0068] In some embodiments, the method further includes reacting the
substituted or unsubstituted 4-amino-3-benzimidazolyl quinolinone compound
or a tautomer of the compound with lactic acid, wherein the lactic acid salt of
the 4-amino-3-benzimidazolyl quinolinone compound or the tautomer is
obtained. In some such embodiments, the compound having the formula IIIB
or a tautomer thereof is reacted with lactic acid to produce the lactic acid salt
of the compound or tautomer. In some such embodiments, the compound or
tautomer is reacted with D,L-lactic acid in water and ethanol and the
monolactate salt is produced as a crystalline solid.
[0069] The use of a sodium or potassium salt of a base such as, but
not limited to, NaHMDS, KHMDS, sodium t-butoxide, or potassium t-butoxide,
rather than a lithium salt such as LiHMDS in the reaction of the first compound
with the second compound provides a method of producing compositions that
include reduced amounts of lithium and in some embodiments may not
include any lithium. Furthermore, the use of a base such as potassium t-
butoxide results in increased yields of the benzimidazolyl quinolinone
compound. Consequently, in some embodiments, the invention provides a
composition that includes a benzimidazolyl quinolinone compound having the
formula III, a tautomer of the benzimidazolyl quinolinone compound, a salt of
the benzimidazolyl quinolinone compound, a salt of the tautomer of the
benzimidazolyl compound, or mixtures thereof, wherein the benzimidazolyl
quinolinone compound is a compound having the formula III,


wherein:
R1, R2, R3, and R4 may be the same or different and are
independently selected from H, CI, Br, F, I, -OR10 groups, -NR11R12 groups,
substituted or unsubstituted primary, secondary, or tertiary alkyl groups,
substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl
groups, substituted or unsubstituted alkynyl groups, substituted or
unsubstituted heterocyclyl groups, or substituted or unsubstituted
heterocyclylalkyl groups;
R5, R6, R7, and R8 may be the same or different and are
independently selected from H, CI, Br, F, I, -OR13 groups, -NR14R15 groups,
-SR16 groups, substituted or unsubstituted primary, secondary, or tertiary alkyl
groups, substituted or unsubstituted aryl groups, substituted or unsubstituted
alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or
unsubstituted heterocyclyl groups, substituted or unsubstituted
heterocyclylalkyl groups, substituted or unsubstituted alkoxyalkyl groups,
substituted or unsubstituted aryloxyalkyl groups, or substituted or
unsubstituted heterocyclyloxyalkyl groups;
R10 and R13 may be the same or different and are independently
selected from substituted or unsubstituted alkyl groups, substituted or
unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups,
substituted or unsubstituted heterocyclylalkyl groups, substituted or

unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl
groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R11 and R14 may be the same or different and are independently
selected from substituted or unsubstituted alkyl groups, substituted or
unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R12 and R15 may be the same or different and are independently
selected from substituted or unsubstituted alkyl groups, substituted or
unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R16 is selected from substituted or unsubstituted alkyl groups,
substituted or unsubstituted aryl groups, or substituted or unsubstituted
heterocyclyl groups; and further wherein,
the amount of lithium in the composition is less than 1 percent
by weight based on the weight of the benzimidazolyl quinolinone compound in
the composition.
[0070] In some embodiments of the compositions provided herein, the
amount of lithium in the composition is less than 0.5 percent, is less than 0.1
percent, is less than 0.05 percent, is less than 0.01 percent, is less than 0.005
percent, or is less than 0.001 by weight based on the weight of the
benzimidazolyl quinolinone compound, the tautomer of the benzimidazolyl
quinolinone compound, the salt of the benzimidazolyl quinolinone compound,
the salt of the tautomer of the benzimidazolyl compound, or the mixtures
thereof in the composition. In some such embodiments of the compositions
provided herein, lithium is completely absent from the composition. In some
embodiments, the composition has less than 1 percent, less than 0.05
percent, or less than 0.01% of the uncyclized intermediate shown in Scheme
1 based on the weight of the benzimidazolyl quinolinone compound.

[0071] In some embodiments of the compositions provided herein, the
benzimidazolyl quinolinone compound having the formula III is a compound
having the formula 1MB

[0072] In various groups that include heterocyclyl groups, the
heterocyclyl group may be attached in various ways. For example, in an
-OCH2(CH2)q(heterocyclyl) group, where q is selected from 0, 1, 2, 3, or 4, the
heterocyclyl group may be bonded to a methylene carbon of the -OCH2(CH2)q
group of the -OCH2(CH2)q(heterocyclyl) through various ring members. By
way of non-limiting example, where q is 1 and the heterocyclyl group is
tetrahydrofuran, the group could be represented by the formula
-OCH2CH2(tetrahydrofuranyl) which corresponds to the following two
structures:

where structure VIII represents the group that can be referred to as the
-OCH2CH2(2-tetrahydrofuranyl) group and structure IX represents the group
that can be referred to as the -OCH2CH2(3-tetrahydrofuranyl) group. When
the heterocyclyl group is a N-containing heterocycle, such as, but not limited
to piperidine, piperazine, morpholine, or pyrrolidine, the heterocycle can be
bonded to the methylene carbon through a ring carbon atom or through a

nitrogen atom in the ring of the N-containing heterocycle. Both of these are
preferred. Where the heterocyclyl group is a piperidine and q is 2 for an
-OCH2(CH2)q(heterocyclyl) group, the following structures are possible and
preferred:

[0073] Structure X is an example of a -O(CH2)3(N-piperidinyl) or
-O(CH2)3(1-piperidinyl) group. Structure XI is an example of a -O(CH2)3-(2-
piperidinyl) group. Structure XII is an example of a -O(CH2)3(3-piperidinyl)
group. Structure XIII is an example of a -O(CH2)3(4-piperidinyl) group. Where
the heterocyclyi group is a piperazine and q is 1 for an
-OCH2(CH2)q(heterocyclyl) group, the following structures are possible and
preferred:

[0074] Structure XIV is an example of a -O(CH2)2(2-piperazinyl) group,
and structure XV is an example of a -O(CH2)2(1-piperazinyl) or -O(CH2)2(N-
piperazinyl)group. Where the heterocyclyi group is a morpholine and q is 1
for an -OCH2(CH2)q(heterocyclyl) group, the following structures are possible
and preferred:


[0075] Structure XVI is an example of a -O(CH2)2(3-morpholinyl) group,
structure XVII is an example of a -O(CH2)2(4-morpholinyl) or -O(CH2)2(N-
morpholinyl) group, and structure XVIII is an example of a -O(CH2)2(2-
morpholinyl) group. It will be observed that where the group is a pyrrolidine,
and q is 1, the structures available include -O(CH2)2(1-pyrrolidinyl) or
-O(CH2)2(N-pyrrolidinyl), -O(CH2)2(2-pyrrolidinyl), and -O(CH2)2(3-pyrrolidinyl).
[0076] Scheme 1 depicts one exemplary synthetic route for the
synthesis of a compound of a benzimidazolyl quinolinone compound and
should not be interpreted to limit the invention in any manner. As shown
below, the reaction of a first compound with a second compound is believed
to proceed via an uncyclized intermediate. However, this will be understood
to not limit the invention in any manner. The potassium salt of the resulting
compound having the formula III produced on cyclization of the intermediate
has been found to have reduced solubility resulting in precipitation of the
product from the reaction. This was surprising and unexpected given that
precipitation was not observed when a lithium salt such as LiHMDS was used
rather than a potassium salt such as KHMDS. The use of the potassium salt
rather than a lithium salt provides a greatly enhanced yield of compounds
having the formula ill such as compounds having the formula IIIB as shown in
Scheme 1 especially when a base such as a potassium alkoxide such as
potassium t-butoxide is employed. The reaction of the first compound with the
second compound was also found to provide significantly higher yields of
compounds having the formula HI when the reaction was conducted with

solvents and reactants with low water contents. For example, the yield was
found to improve significantly when the second compound was dried as
described herein such as by azeotropic evaporation from absolute ethanol or
in the reaction vessel by repeated addition of THF followed by distillation. The
yield of the compound having the formula VI, such as a compound having the
formula VIH, produced by the reaction of an N-alkyl piperazine such as N-
methyl piperazine with the compound having the formula VII, was increased
when the temperature was lowered and the amount of the compound having
the formula HR7 was increased with respect to the compound having the
formula VI. The temperatures of the reaction were lowered and the reaction
was diluted with ethanol during scale up. For example, good yields were
obtained when the reaction was conducted at a temperature of 90°C to
100°C, and the compound having the formula HR7, such as N-methyl
piperazine, was present in an amount of greater than 2.5 equivalents with
respect to the amount of the compound having the formula VI, such as 5-
chloro-2-nitroaniline. In some such embodiments, the compound having the
formula HR7 is present in an amount of greater than 2.8, greater than 2.9,
greater than 3.0, or from 2.5 to 5 equivalents with respect to the amount of the
compound having the formula VI.


[0077] Scheme 2 depicts a method for synthesizing a compound
having the formula VA and shows the general application of the method of the
invention. Those skilled in the art will understand that the selection of a
substituted or unsubstituted diaminobenzene and a substituted or
unsubstituted anthranilonitrile allows for the synthesis of a wide variety of
compounds having the formula III. Those skilled in the art will also recognize
that certain groups may need protection using standard protecting groups for
the final cyclization reaction. The extremely versatile synthetic route allows a
plethora of compounds having the formula III to be readily prepared by a
highly convergent and efficient synthetic route.


[0078] The present invention, thus generally described, will be
understood more readily by reference to the following examples, which are
provided by way of illustration and are not intended to be limiting of the
present invention. The following documents including the examples in the
documents are hereby incorporated by reference for all purposes as if fully set
forth herein in their entirety: U.S. Patent No. 6,605,617; U.S. Patent
Publication No. 2004/0092535, filed on August 19, 2003; U.S. Provisional
Application No. 60/405,729 filed on August 23, 2002; U.S. Provisional
Application No. 60/426,107 filed on November 13, 2002; U.S. Provisional
Application No. 60/426,226 filed on November 13, 2002; U.S. Provisional
Application No. 60/426,282 filed on November 13, 2002; U.S. Provisional
Application No. 60/428,210 filed on November 21, 2002; U.S. Provisional
Application No. 60/460,327 filed on April 3, 2003; U.S. Provisional Application
No. filed on April 3, 2003; U.S. Provisional Application No. 60/460,493 filed on
April 3, 2003; U.S. Provisional Application No. 60/478,916 filed on June 16,
2003; U.S. Provisional Application No. 60/484,048 filed on July 1, 2003, and
U.S. Provisional Application No. 60/517,915 filed on November 7, 2003.

EXAMPLES
[0079] The following abbreviations are used in the Examples:
EtOH: Ethanol
H2O: Water
HCI: Hydrochloric acid
HPLC: High Performance Liquid Chromatography
KHMDS: Potassium bis(trimethylsilyl)amide
LiHMDS: Lithium bis(trimethylsilyl)amide
NaHMDS: Sodium bis(trimethylsilyl)amide
NaOH: Sodium hydroxide
N2: Nitrogen
TBME: t-Butyl methyl ether
THF: Tetrahydrofuran
[0080] Nomenclature for the Example compounds was provided using
ACD Name version 5.07 software (November 14, 2001) available from
Advanced Chemistry Development, Inc., Chemlnnovation NamExpert +
Nomenclator™ brand software available from Chemlnnovation Software, Inc.,
and AutoNom version 2.2 available in the ChemOffice® Ultra software
package version 7.0 available from CambridgeSoft Corporation (Cambridge,
MA). Some of the compounds and starting materials were named using
standard IUPAC nomenclature,
[0081] Various starting materials may be obtained from commercial
sources and prepared by methods known to one of skill in the art.

Example 1
Synthesis of 5-(4-Methyl-piperazin-1-yl)-2-nitroaniline
Procedure A

[0082] 5-Chloro-2-nitroaniline (500 g, 2.898 mol) and 1-methyl
piperazine (871 g, 8.693 mol) were placed in a 2000 mL flask fitted with a
condenser and purged with N2. The flask was placed in an oil bath at 100°C
and heated until the 5-chloro-2-nitroaniline was completely reacted (typically
overnight) as determined by HPLC. After HPLC confirmed the disappearance
of the 5-chloro-2-nitroaniline, the reaction mixture was poured directly (still
warm) into 2500 mL of room temperature water with mechanical stirring. The
resulting mixture was stirred until it reached room temperature and then it was
filtered. The yellow solid thus obtained was added to 1000 mL of water and
stirred for 30 minutes. The resulting mixture was filtered, and the resulting
solid was washed with TBME (500 mL, 2X) and then was dried under vacuum
for one hour using a rubber dam. The resulting solid was transferred to a
drying tray and dried in a vacuum oven at 50°C to a constant weight to yield
670 g (97.8%) of the title compound as a yellow powder.
Procedure B
[0083] 5-Chloro-2-nitroaniline (308.2 g, 1.79 mol) was added to a 4-
neck 5000 mL round bottom flask fitted with an overhead stirrer, condenser,
gas inlet, addition funnel, and thermometer probe. The flask was then purged
with N2. 1-Methylpiperazine (758.1 g, 840 mL, 7.57 mol) and 200 proof
ethanol (508 mL) were added to the reaction flask with stirring. The flask was
again purged with N2, and the reaction was maintained under N2. The flask
was heated in a heating mantle to an internal temperature of 97°C (+/- 5°C)
and maintained at that temperature until the reaction was complete (typically

about 40 hours) as determined by HPLC. After the reaction was complete,
heating was discontinued and the reaction was cooled to an internal
temperature of about 20°C to 25°C with stirring, and the reaction was stirred
for 2 to 3 hours. Seed crystals (0.20 g, 0.85 mmol) of 5-(4-methyl-piperazin-1-
yl)-2-nitroaniline were added to the reaction mixture unless precipitation had
already occurred. Water (2,450 mL) was added to the stirred reaction mixture
over a period of about one hour while the internal temperature was
maintained at a temperature ranging from about 20°C to 30°C. After the
addition of water was complete, the resulting mixture was stirred for about one
hour at a temperature of 20°C to 30°C. The resulting mixture was then
filtered, and the flask and filter cake were washed with water (3 x 2.56 L). The
golden yellow solid product was dried to a constant weight of 416 g (98.6%
yield) under vacuum at about 50°C in a vacuum oven.
Procedure C
[0084] 5-Chloro-2-nitroaniline (401 g, 2.32 mol) was added to a 4-neck
12 L round bottom flask fitted with an overhead stirrer, condenser, gas inlet,
addition funnel, and thermometer probe. The flask was then purged with N2.
1-MethyIpiperazine (977 g, 1.08 L, 9.75 mol) and 100% ethanol (650 mL)
were added to the reaction flask with stirring. The flask was again purged
with N2, and the reaction was maintained under N2. The flask was heated in a
heating mantle to an internal temperature of 97°C (+/- 5°C) and maintained at
that temperature until the reaction was complete (typically about 40 hours) as
determined by HPLC. After the reaction was complete, heating was
discontinued and the reaction was cooled to an internal temperature of about
80°C with stirring, and water (3.15 L) was added to the mixture via an addition
funnel over the period of 1 hour while the internal temperature was maintained
at 82°C (+/- 3°C). After water addition was complete, heating was
discontinued and the reaction mixture was allowed to cool over a period of no
less than 4 hours to an internal temperature of 20-25°C. The reaction mixture
was then stirred for an additional hour at an internal temperature of 20-30°C.
The resulting mixture was then filtered, and the flask and filter cake were

washed with water (1 x 1 L), 50% ethanol (1 x 1L), and 95% ethanol (1 x 1L).
The golden yellow solid product was placed in a drying pan and dried to a
constant weight of 546 g (99% yield) under vacuum at about 50°C in a
vacuum oven.
Example 2
Synthesis of [6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic
acid ethyl ester
Procedure A

[0085] A 5000 mL, 4-neck flask was fitted with a stirrer, thermometer,
condenser, and gas inlet/outlet. The equipped flask was charged with 265.7 g
(1.12 mol. 1.0 eq) of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline and 2125 mL of
200 proof EtOH. The resulting solution was purged with N2 for 15 minutes.
Next, 20.0 g of 5% Pd/C (50% H2O w/w) was added. The reaction was
vigorously stirred at 40-50°C (internal temperature) while H2 was bubbled
through the mixture. The reaction was monitored hourly for the
disappearance of 5-(4-methyl-piperazin-1-yl)-2-nitroaniline by HPLC. The
typical reaction time was 6 hours.
[0086] After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had
disappeared from the reaction, the solution was purged with N2 for 15

minutes. Next, 440.0 g (2.25 mol) of ethyl 3-ethoxy-3-iminopropanoate
hydrochloride was added as a solid. The reaction was stirred at 40-50°C
(internal temperature) until the reaction was complete. The reaction was
monitored by following the disappearance of the diamino compound by HPLC.
The typical reaction time was 1-2 hours. After the reaction was complete, it
was cooled to room temperature and filtered through a pad of Celite filtering
material. The Celite filtering material was washed with absolute EtOH (2 x
250 mL), and the filtrate was concentrated under reduced pressure providing
a thick brown/orange oil. The resulting oil was taken up in 850 mL of a 0.37%
HCl solution. Solid NaOH (25 g) was then added in one portion, and a
precipitate formed. The resulting mixture was stirred for 1 hour and then
filtered. The solid was washed with H2O (2 x 400 mL) and dried at 50°C in a
vacuum oven providing 251.7 g (74.1%) of [6-(4-methyl-piperazin-1-yl)-1H-
benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder.
Procedure B
[0087] A 5000 mL, 4-neck jacketed flask was fitted with a mechanical
stirrer, condenser, temperature probe, gas inlet, and oil bubbler. The
equipped flask was charged with 300 g (1.27 mol) of 5-(4-methyl-piperazin-1-
yl)-2-nitroaniline and 2400 mL of 200 proof EtOH (the reaction may be and
has been conducted with 95% ethanol and it is not necessary to use 200
proof ethanol for this reaction). The resulting solution was stirred and purged
with N2 for 15 minutes. Next, 22.7 g of 5% Pd/C (50% H2O w/w) was added
to the reaction flask. The reaction vessel was purged with N2 for 15 minutes.
After purging with N2, the reaction vessel was purged with H2 by maintaining a
slow, but constant flow of H2 through the flask. The reaction was stirred at
45-55°C (internal temperature) while H2 was bubbled through the mixture until
the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline was completely consumed as
determined by HPLC. The typical reaction time was 6 hours.
[0088] After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had
disappeared from the reaction, the solution was purged with N2 for 15

minutes. The diamine intermediate is air sensitive so care was taken to avoid
exposure to air. 500 g (2.56 mol) of ethyl 3-ethoxy-3-iminopropanoate
hydrochloride was added to the reaction mixture over a period of about 30
minutes. The reaction was stirred at 45-55°C (internal temperature) under N2
until the diamine was completely consumed as determined by HPLC. The
typical reaction time was about 2 hours. After the reaction was complete, the
reaction was filtered while warm through a pad of Celite. The reaction flask
and Celite were then washed with 200 proof EtOH (3 x 285 mL). The filtrates
were combined in a 5000 mL flask, and about 3300 mL of ethanol was
removed under vacuum producing an orange oil. Water (530 mL) and then
1M HCL (350 mL) were added to the resulting oil, and the resulting mixture
was stirred. The resulting solution was vigorously stirred while 30% NaOH
(200 mL) was added over a period of about 20 minutes maintaining the
internal temperature at about 25-30°C while the pH was brought to between 9
and 10. The resulting suspension was stirred for about 4 hours while
maintaining the internal temperature at about 20-25°C. The resulting mixture
was filtered, and the filter cake was washed with H2O (3 x 300 mL). The
collected solid was dried to a constant weight at 50°C under vacuum in a
vacuum oven providing 345.9 g (90.1%) of [6-(4-methyl-piperazin-1-yl)-1H-
benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder. In an
alternative work up procedure, the filtrates were combined and the ethanol
was removed under vacuum until at least about 90% had been removed.
Water at a neutral pH was then added to the resulting oil, and the solution
was cooled to about 0°C. An aqueous 20% NaOH solution was then added
slowly with rapid stirring to bring the pH up to 9.2 (read with pH meter). The
resulting mixture was then filtered and dried as described above. The
alternative work up procedure provided the light tan to light yellow product in
yields as high as 97%.

Example 3
Method for Reducing Water Content of [6-(4-Methyl-piperazin-1-yl)-1H-
benzoimidazol-2-yl]-acetic acid ethyl ester
[0089] [6-(4-Methyl-piperazin-1-yl)-1 H-benzimidazol-2-yl]-acetic acid
ethyl ester (120.7 grams) that had been previously worked up and dried to a
water content of about 8-9% H2O was placed in a 2000 mL round bottom flask
and dissolved in absolute ethanol (500 mL). The amber solution was
concentrated to a thick oil using a rotary evaporator with heating until all
solvent was removed. The procedure was repeated two more times. The
thick oil thus obtained was left in the flask and placed in a vacuum oven
heated at 50°C overnight. Karl Fisher analysis results indicated a water
content of 5.25%. The lowered water content obtained by this method
provided increased yields in the procedure of Example 4. Other solvents such
as toluene and THF may be used in place of the ethanol for this drying
process.
Example 4
Synthesis of 4-Amino-5-fluoro-3-[6-(4-methyl-piperazin-1 -yl)-1H-
benzimidazol-2-yl]-1H-quinolin-2-one
Procedure A

[0090] [6-(4-Methyl-piperazin-1-yl)-1 H-benzimidazoi-2-yl]-acetic acid
ethyl ester (250 g, 820 mmol) (dried with ethanol as described above) was
dissolved in THF (3800 mL) in a 5000 mL flask fitted with a condenser,
mechanical stirrer, temperature probe, and purged with argon. 2-Amino-6-
fluoro-benzonitrile (95.3 g, 700 mmol) was added to the solution, and the
internal temperature was raised to 40°C. When all the solids had dissolved
and the solution temperature had reached 40°C, solid KHMDS (376.2 g, 1890

mmol) was added over a period of 5 minutes. When addition of the potassium
base was complete, a heterogeneous yellow solution was obtained, and the
internal temperature had risen to 62°C. After a period of 60 minutes, the
internal temperature decreased back to 40°C, and the reaction was
determined to be complete by HPLC (no starting material or uncyclized
intermediate was present). The thick reaction mixture was then quenched by
pouring it into H2O (6000 mL) and stirring the resulting mixture until it had
reached room temperature. The mixture was then filtered, and the filter pad
was washed with water (1000 mL 2X). The bright yellow solid was placed in a
drying tray and dried in a vacuum oven at 50°C overnight providing 155.3 g
(47.9%) of the desired 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-
benzimidazol-2-yl]-1H-quinolin-2-one.
Procedure B
[0091] A 5000 mL 4-neck jacketed flask was equipped with a distillation
apparatus, a temperature probe, a N2 gas inlet, an addition funnel, and a
mechanical stirrer. [6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic
acid ethyl ester (173.0 g, 570 mmol) was charged into the reactor, and the
reactor was purged with N2 for 15 minutes. Dry THF (2600 mL) was then
charged into the flask with stirring. After all the solid had dissolved, solvent
was removed by distillation (vacuum or atmospheric (the higher temperature
helps to remove the water) using heat as necessary. After 1000 mL of solvent
had been removed, distillation was stopped and the reaction was purged with
N2. 1000 mL of dry THF was then added to the reaction vessel, and when all
solid was dissolved, distillation (vacuum or atmospheric) was again conducted
until another 1000 mL of solvent had been removed. This process of adding
dry THF and solvent removal was repeated at least 4 times (on the 4th
distillation, 60% of the solvent is removed instead of just 40% as in the first 3
distillations) after which a 1 mL sample was removed for Karl Fischer analysis
to determine water content. If the analysis showed that the sample contained
less than 0.20% water, then reaction was continued as described in the next
paragraph. However, if the analysis showed more than 0.20% water, then the

drying process described above was continued until a water content of less
than 0.20% was achieved.
[0092] After a water content of less than or about 0.20% was achieved
using the procedure described in the previous paragraph, the distillation
apparatus was replaced with a reflux condenser, and the reaction was
charged with 2-amino-6-fluoro-benzonitrile (66.2 g, 470 mmol)( in some
procedures 0.95 equivalents is used). The reaction was then heated to an
internal temperature of 38-42°C. When the internal temperature had reached
38-42°C, KHMDS solution (1313 g, 1.32 mol, 20% KHMDS in THF) was
added to the reaction via the addition funnel over a period of 5 minutes
maintaining the internal temperature at about 38-50°C during the addition.
When addition of the potassium base was complete, the reaction was stirred
for 3.5 to 4.5 hours (in some examples it was stirred for 30 to 60 minutes and
the reaction may be complete within that time) while maintaining the internal
temperature at from 38-42°C. A sample of the reaction was then removed
and analyzed by HPLC. If the reaction was not complete, additional KHMDS
solution was added to the flask over a period of 5 minutes and the reaction
was stirred at 38-42°C for 45-60 minutes (the amount of KHMDS solution
added was determined by the following: If the IPC ratio is mL was added; if 10.0 ≥ IPC ratio ≥ 3.50, then 56 mL was added; if 20.0 ≥ IPC
ratio ≥ 10, then 30 mL was added. The IPC ratio is equal to the area
corresponding to 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-
benzimidazol-2-yl]-1H-quinolin-2-one) divided by the area corresponding to
the uncyclized intermediate). Once the reaction was complete (IPC ratio >
20), the reactor was cooled to an internal temperature of 25-30°C, and water
(350 mL) was charged into the reactor over a period of 15 minutes while
maintaining the internal temperature at 25-35°C (in one alternative, the
reaction is conducted at 40°C and water is added within 5 minutes. The
quicker quench reduces the amount of impurity that forms over time). The
reflux condenser was then replaced with a distillation apparatus and solvent
was removed by distillation (vacuum or atmospheric) using heat as required.

After 1500 mL of solvent had been removed, distillation was discontinued and
the reaction was purged with N2. Water (1660 mL) was then added to the
reaction flask while maintaining the internal temperature at 20-30°C. The
reaction mixture was then stirred at 20-30°C for 30 minutes before cooling it to
an internal temperature of 5-10°C and then stirring for 1 hour. The resulting
suspension was filtered, and the flask and filter cake were washed with water
(3 x 650 mL). The solid thus obtained was dried to a constant weight under
vacuum at 50°C in a vacuum oven to provide 103.9 g (42.6% yield) of 4-
amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1 H-benzimidazol-2-yl]-1H-
quinolin-2-one as a yellow powder.

[0093] [6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid
ethyl ester (608 g, 2.01 mol) (dried) and 2-amino-6-fluoro-benzonitrile (274 g,
2.01 mol) were charged into a 4-neck 12 L flask seated on a heating mantle
and fitted with a condenser, mechanical stirrer, gas inlet, and temperature
probe. The reaction vessel was purged with N2, and toluene (7.7 L) was
charged into the reaction mixture while it was stirred. The reaction vessel was
again purged with N2 and maintained under N2. The internal temperature of
the mixture was raised until a temperature of 63°C (+/- 3°C) was achieved.
The internal temperature of the mixture was maintained at 63°C (+/- 3°C)
while approximately 2.6 L of toluene was distilled from the flask under
reduced pressure (380 +/- 10 torr, distilling head t = 40°C (+/- 10°C) (Karl
Fischer analysis was used to check the water content in the mixture. If the
water content was greater than 0.03%, then another 2.6 L of toluene was
added and distillation was repeated. This process was repeated until a water
content of less than 0.03% was achieved). After a water content of less than

0.03% was reached, heating was discontinued, and the reaction was cooled
under N2 to an internal temperature of 17-19°C. Potassium t-butoxide in THF
(20% in THF; 3.39 kg, 6.04 moles potassium t-butoxide) was then added to
the reaction under N2 at a rate such that the internal temperature of the
reaction was kept below 20°C. After addition of the potassium t-butoxide was
complete, the reaction was stirred at an internal temperature of less than 20°C
for 30 minutes. The temperature was then raised to 25°C, and the reaction
was stirred for at least 1 hour. The temperature was then raised to 30°C, and
the reaction was stirred for at least 30 minutes. The reaction was then
monitored for completion using HPLC to check for consumption of the starting
materials (typically in 2-3 hours, both starting materials were consumed (less
than 0.5% by area % HPLC)). If the reaction was not complete after 2 hours,
another 0.05 equivalents of potassium t-butoxide was added at a time, and
the process was completed until HPLC showed that the reaction was
complete. After the reaction was complete, 650 mL of water was added to the
stirred reaction mixture. The reaction was then warmed to an internal
temperature of 50°C and the THF was distilled away (about 3 L by volume)
under reduced pressure from the reaction mixture. Water (2.6 L) was then
added dropwise to the reaction mixture using an addition funnel. The mixture
was then cooled to room temperature and stirred for at least 1 hour. The
mixture was then filtered, and the filter cake was washed with water (1.2 L),
with 70% ethanol (1.2 L), and with 95% ethanol (1.2 L). The bright yellow
solid was placed in a drying tray and dried in a vacuum oven at 50°C until a
constant weight was obtained providing 674 g (85.4%) of the desired 4-amino-
5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1 H-benzimidazol-2-yl]-1 H-quinolin-2-
one.

Example 5
Purification of 4-Amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-
benzimidazol-2-yl]-1H-quinolin-2-one
[0094] A 3000 mL 4-neck flask equipped with a condenser,
temperature probe, N2 gas inlet, and mechanical stirrer was placed in a
heating mantle. The flask was then charged with 4-amino-5-fluoro-3-[6-(4-
methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one (101.0 g, 0.26
mol), and the yellow solid was suspended in 95% ethanol (1000 mL) and
stirred. In some cases ah 8:1 solvent ratio is used. The suspension was then
heated to a gentle reflux (temperature of about 76°C) with stirring over a
period of about 1 hour. The reaction was then stirred for 45-75 minutes while
refluxed. At this point, the heat was removed from the flask and the
suspension was allowed to cool to a temperature of 25-30°C. The suspension
was then filtered, and the filter pad was washed with water (2 x 500 mL). The
yellow solid was then placed in a drying tray and dried in a vacuum oven at
50°C until a constant weight was obtained (typically 16 hours) to obtain 97.2 g
(96.2%) of the purified product as a yellow powder.

Example 6
Preparation of Lactic Acid salt of 4-Amino-5-fluoro-3-[6-(4-methyl-
piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinoIin-2-one

[0095] A 3000 mL 4-necked jacketed flask was fitted with a condenser,
a temperature probe, a N2 gas inlet, and a mechanical stirrer. The reaction
vessel was purged with N2 for at least 15 minutes and then charged with 4-
amino-5-fluoro-3-[6-(4-methyl-piperazin-1 -yl)-1 H-benzimidazol-2-yl]-1 H-
quinolin-2-one (484 g, 1.23 mol). A solution of D,L-Lactic acid (243.3 g, 1.72
mol of monomer-see the following paragraph), water (339 mL), and ethanol
(1211 mL) was prepared and then charged to the reaction flask. Stirring was
initiated at a medium rate, and the reaction was heated to an internal
temperature of 68-72°C. The internal temperature of the reaction was
maintained at 68-72°C for 15-45 minutes and then heating was discontinued.
The resulting mixture was filtered through a 10-20 micron frit collecting the
filtrate in a 12 L flask. The 12 L flask was equipped with an internal
temperature probe, a reflux condenser, an addition funnel, a gas inlet an
outlet, and an overhead stirrer. The filtrate was then stirred at a medium rate
and heated to reflux (internal temperature of about 78°C). While maintaining
a gentle reflux, ethanol (3,596 mL) was charged to the flask over a period of
about 20 minutes. The reaction flask was then cooled to an internal

temperature ranging from about 64-70°C within 15-25 minutes and this
temperature was maintained for a period of about 30 minutes. The reactor
was inspected for crystals. If no crystals were present, then crystals of the
lactic acid salt of 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-
benzimidazol-2-yl]-1H-quinolin-2-one (484 mg, 0.1 mole %) were added to the
flask, and the reaction was stirred at 64-70°C for 30 minutes before again
inspecting the flask for crystals. Once crystals were present, stirring was
reduced to a low rate and the reaction was stirred at 64-70°C for an additional
90 minutes. The reaction was then cooled to about 0°C over a period of
about 2 hours, and the resulting mixture was filtered through a 25-50 micron
fritted filter. The reactor was washed with ethanol (484 mL) and stirred until
the internal temperature was about 0°C. The cold ethanol was used to wash
the filter cake, and this procedure was repeated 2 more times. The collected
solid was dried to a constant weight at 50°C under vacuum in a vacuum oven
yielding 510.7 g (85.7%) of the crystalline yellow lactic acid salt of 4-amino-5-
fluoro-3-[6-(4-methyl-piperazin-1 -yl)-1 H-benzimidazol-2-yl]-1 H-quinolin-2-one.
A rubber dam or inert conditions were typically used during the filtration
process. While the dry solid did not appear to be very hygroscopic, the wet
filter cake tends to pick up water and become sticky. Precautions were taken
to avoid prolonged exposure of the wet filter cake to the atmosphere.
[0096] Commercial lactic acid generally contains about 8-12% w/w
water, and contains dimers and trimers in addition to the monomeric lactic
acid. The mole ratio of lactic acid dimer to monomer is generally about
1.0:4.7. Commercial grade lactic acid may be used in the process described
in the preceding paragraph as the monolactate salt preferentially precipitates
from the reaction mixture.
[0097] It should be understood that the organic compounds according
to the invention may exhibit the phenomenon of tautomerism. As the
chemical structures within this specification can only represent one of the
possible tautomeric forms at a time, it should be understood that the invention

encompasses any tautomeric form of the drawn structure. For example, the
compound having the formula 1MB is shown below with one tautomer,
Tautomer IIIBa:

Other tautomers of the compound having the formula IIIB, Tautomer IIIIBb
and Tautomer IIIIBc, are shown below:


[0098] The contents of each of the patents, patent applications and
journal articles cited above are hereby incorporated by reference herein and
for all purposes as if fully set forth in their entireties.
[0099] It is understood that the invention is not limited to the
embodiments set forth herein for illustration, but embraces all such forms
thereof as come within the scope of the following claims.

We Claim :
1. A method of synthesizing a substituted or unsubstituted benzimidazolyl quinolinone
compound, comprising: reacting a first compound having the formula I with a second compound
having the formula II in a suitable solvent in the presence of a sodium or potassium salt of a base to
provide a reaction product comprising the benzimidazolyl quinolinone compound, wherein the first
compound and the second compound have the following structures

wherein
R1, R2, R3, and R4 may be the same or different and are independently selected from H, Cl, Br, F, I,
-OR10 groups, -NR11R12 groups, substituted or unsubstituted primary, secondary, or tertiary alkyl
groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups,
substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, or
substituted or unsubstituted heterocyclylalkyl groups;
R5, R6, R7, and R8 may be the same or different and are independently selected from H, Cl, Br, F, I,
-OR13 groups, -NR14R15 groups, -SR16 groups, substituted or unsubstituted primary, secondary, or
tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl
groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups,
substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkoxyalkyl
groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted
heterocyclyloxyalkyl groups;
Z is selected from -OR9a groups or -NR9bR9c groups;

R9a is an unsubstituted alkyl group having from 1 to 8 carbon atoms and is absent if Z is a -NR9bR9c
group;
R9b and R9c are independently selected from unsubstituted alkyl groups having from 1 to 8 carbon
atoms or are both absent if Z is a -OR9a group;
R10 and R13 may be the same or different and are independently selected from substituted or
unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted
heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or
unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or
unsubstituted heterocyclyloxyalkyl groups;
R11 and R14 may be the same or different and are independently selected from substituted or
unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted
heterocyclyl groups;
R12 and R15 may be the same or different and are independently selected from substituted or
unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted
heterocyclyl groups; and
R16 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl
groups, or substituted or unsubstituted heterocyclyl groups; and further wherein the substituted or
unsubstituted benzimidazolyl compound is a compound having the formula III, is a tautomer of the
compound having the formula III, is a salt of the compound having the formula III, or is a salt of the
tautomer of the compound having the formula III


2. The method of claim 1, wherein R1 is selected from H, Cl, Br, F, or I.
3. The method of claim 1, wherein R1 is F.
4. The method of claim 1, wherein R2, R3, and R4 are all H.
5. The method of claim 1, wherein the first compound is a compound having the formula IA
having the following structure

6. The method of claim 1, wherein at least one of R6 or R7 is a substituted or unsubstituted
heterocyclyl group.
7. The method of claim 1, wherein one of R6 or R7 is a substituted or unsubstituted heterocyclyl
group and the other of R6 or R7 is a H.

8. The method of claim 1, wherein one of R6 or R7 is a substituted or unsubstituted heterocyclyl
group selected from a substituted or unsubstituted piperidinyl group, piperazinyl group, or
morpholinyl group.
9. The method of claim 8, wherein one of R6 or R7 is a substituted or unsubstituted piperazinyl
group.
10. The method of claim 9, wherein one of R6 or R7 is an N-alkyl piperazinyl group.
11. The method of claim 10, wherein one of R6 or R7 is an N-methyl piperazinyl group and the
other of R6 or R7 is an H.
12. The method of claim 1, wherein the second compound is a compound having the formula IIA
or IIB

and R5, R8, and R9a have the values defined in claim 1.

13. The method of claim 1, wherein the second compound is a compound having the formula IIC
or IID

where R9a has the values defined in claim 1.
14. The method of claim 13, wherein R9a is a straight or branched chain alkyl group selected
from methyl, ethyl, propyl, butyl, pentyl, i-propyl, s-butyl, or t-butyl groups.
15. The method of claim 14, wherein R9a is an ethyl group.
16. The method of claim 1, wherein the suitable solvent is selected from a dialkyl ether, a cyclic
ether, an aromatic solvent, or a combination thereof.
17. The method of claim 16, wherein the solvent is tetrahydrofuran or toluene.
18. The method of claim 1, wherein the sodium or potassium salt of the base is a sodium or
potassium alkoxide.
19. The method of claim 18, wherein the sodium or potassium salt of the base is potassium t-
butoxide.
20. The method of claim 1, wherein the sodium or potassium salt of the base is a sodium or
potassium bis(trialkylsilyl)amide.

21. The method of claim 20, wherein the sodium or potassium bis(trialkylsilyl)amide is sodium
bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide.
22. The method of claim 16, further comprising adding the sodium or potassium salt of the base
to a mixture of the first compound and the second compound in the suitable solvent.

23. The method claim 1, wherein the sodium or potassium salt of the base is present in an
amount of from 2 to 4 equivalents with respect to the molar quantity of the first compound.
24. The method of claim 1, wherein the sodium or potassium salt of the base is present in an
amount of from 2 to 4 equivalents with respect to the molar quantity of the second compound.
25. The method of claim 1, wherein the second compound is present in an amount of from 1 to 2
equivalents with respect to the molar quantity of the first compound.
26. The method of claim 1, further comprising adding the sodium or potassium salt of the base to
a mixture comprising the first compound, the second compound, and the suitable solvent at a
temperature of from 15°C to 50°C.
27. The method of claim 1, further comprising (a) adding an aromatic solvent to a reaction flask
to provide a reaction mixture comprising the solvent, the first compound, and the second compound,
(b) distilling a portion of the aromatic solvent from the reaction flask, and (c) repeating (a) and (b)
until the water content of the reaction mixture is less than 0.05%.
28. The method of claim 1, wherein the second compound is placed in a reaction flask and dried
by (a) adding THF to the reaction flask to create a reaction mixture, (b) distilling a portion of the
THF from the reaction flask, and (c) repeating (a) and (b) until the water content of the reaction
mixture is less than 0.5%.
29. The method of claim 28, further comprising repeating (a) and (b) until the water content of
the reaction mixture is less than or equal to 0.2%.
30. The method of claim 1, wherein the second compound is dried by: (a) mixing the second
compound with an organic solvent to form a solution; (b) removing a portion of the organic solvent
to provide the dried second compound; (c) optionally repeating (a) and (b) one or more additional
times; and (d) additionally drying the dried second compound by heating it under a vacuum.
31. The method of claim 1, wherein the first compound is reacted with the second compound in
the presence of the sodium or potassium salt of the base for a period of from 30 to 360 minutes.

32. The method of claim 1, further comprising reacting a compound having the formula IV with
a compound having the formula V to prepare the second compound, wherein the compound having
the formula IV and the compound having the formula V have the following structures,
wherein the variables R5, R6, R7, R8, and R9a have the values defined in claim 1 and X is a halogen
atom selected from F, Cl, Br, or I, or is the conjugate base of an acid.
33. The method of claim 32, wherein the compound having the formula IV is a compound having
the formula IVA

34. The method of claim 32, wherein the compound having the formula V is a compound having
the formula VA

35. The method of claim 32, wherein the compound having the formula IV is reacted with the
compound having the formula V in an alcohol solvent at an internal temperature of from 30°C to
70°C for a period of time of from 45 minutes to 240 minutes to prepare the second compound.

36. The method of claim 32, further comprising reducing a compound having the formula VIA,
VIB, or a mixture thereof to produce the compound having the formula IV

and the variables R5, R6, R7, and R8 have the values defined in claim 1.
37. The method of claim 36, wherein H2 and a hydrogenation catalyst are used to reduce the
compound having the formula VIA, the compound having the formula VIB, or the mixture thereof.
38. The method of claim 37, wherein the hydrogenation catalyst comprises palladium on carbon.
39. The method of claim 36, wherein the compound having the formula VIA is a compound
having the formula VIC or VID and/or the compound having the formula VIB is a compound having
the formula VIE or VIF

40. The method of claim 39, wherein R6 and R7 are selected from substituted or unsubstituted
heterocyclyl groups.

41. The method of claim 40, wherein R6 and R7 are selected from substituted or unsubstituted
piperidinyl groups, piperazinyl groups, or morpholinyl groups.
42. The method of claim 41, wherein one of R6 or R7 is an N-alkyl piperazinyl group.
43. The method of claim 42, wherein one of R6 or R7 is an N-methyl piperazinyl group such that
the compound having the formula VIC, VID, VIE, or VIF is a compound having the formula VIG or
VIH

44. The method of claim 43, wherein the compound reduced to provide the compound having the
formula IV is the compound having the formula VIH.
45. The method of claim 36, further comprising reacting a compound having the formula VII
with a compound having the formula HR7 or a salt thereof to prepare the compound having the
formula VIA,
wherein the variables R5, R6, R7, and R8 have the values defined in claim 1 and Y is selected from Cl
or F.

46. The method of claim 45, wherein the compound having the formula VII is a compound
having the formula VIIA or VIIB

47. The method of claim 45, wherein R7 is a substituted or unsubstituted heterocyclyl group.
48. The method of claim 47, wherein R7 is an N-alkyl piperazinyl group.
49. The method of claim 47, wherein R7 is an N-methyl piperazinyl group and HR7 is a
compound having the formula HR7(a)

50. The method of claim 47, wherein the compound having the formula VII and the compound
having the formula HR7 are reacted at a temperature of from 70°C to 120°C for a period of from 2
hours to 24 hours to prepare the compound having the formula VIA.

51. The method of claim 1, wherein the benzimidazolyl quinolinone compound is a compound
having the formula IIIA, is a tautomer of the compound having the formula IIIA, is a salt of the
compound having the formula IIIA, or is a salt of the tautomer of the compound having the formula
IIIA and R7 is a substituted or unsubstituted heterocyclyl group

52. The method of claim 51, wherein R7 is a substituted or unsubstituted heterocyclyl group
selected from a substituted or unsubstituted piperidinyl group, piperazinyl group, or morpholinyl
group.
53. The method of claim 52, wherein R7 is a substituted or unsubstituted N-alkyl piperazinyl
group.
54. The method of claim 1, wherein the benzimidazolyl quinolinone compound is a compound
having the formula IIIB, is a tautomer of the compound having the formula IIIB, is a salt of the
compound having the formula IIIB, or is a salt of the tautomer of the compound having the formula
IIIB


55. The method of claim 54, further comprising reacting the benzimidazolyl quinolinone
compound with lactic acid to provide the lactic acid salt of the benzimidazolyl quinolinone
compound.
56. The method of claim 55, wherein the lactic acid and the benzimidazolyl quinolinone
compound are reacted in a mixture of water and ethanol.
57. The method of claim 1, wherein the first and second compounds are reacted in the presence
of the potassium salt of the base.
58. The method of claim 57, wherein the potassium salt of the base is a potassium alkoxide or a
potassium bis(trialkylsilyl)amide.
59. The method of claim 58, wherein the potassium salt of the base is potassium t-butoxide or
potassium bis(trirnethylsilyl)amide.
60. The method of claim 58, wherein the water content of the reaction mixture is less than or
equal to 0.2%.


The invention discloses a method of synthesizing a substituted or unsubstituted
benzimidazolyl quinolinone compound by reacting a first compound of formula I with a
second compound of formula II in a suitable solvent in the presence of a sodium or
potassium salt of a base

wherein
R1, R2, R3, R4, R5, R6, R7, and R8 are as described in the specification.

Documents:

01201-kolnp-2006-abstract.pdf

01201-kolnp-2006-asignment.pdf

01201-kolnp-2006-claims.pdf

01201-kolnp-2006-correspondence other.pdf

01201-kolnp-2006-correspondence others-1.1.pdf

01201-kolnp-2006-description (complete).pdf

01201-kolnp-2006-form-1.pdf

01201-kolnp-2006-form-3-1.1.pdf

01201-kolnp-2006-form-3.pdf

01201-kolnp-2006-form-5.pdf

01201-kolnp-2006-international publication.pdf

01201-kolnp-2006-pct form.pdf

01201-kolnp-2006-priority document.pdf

1201-KOLNP-2006-ABSTRACT.pdf

1201-KOLNP-2006-ASSIGNMENT.pdf

1201-KOLNP-2006-CANCELLED DOCOMENT.pdf

1201-KOLNP-2006-CLAIMS.pdf

1201-KOLNP-2006-CORRESPONDENCE-1.1.pdf

1201-KOLNP-2006-CORRESPONDENCE.pdf

1201-KOLNP-2006-DESCRIPTION COMPLATE.pdf

1201-KOLNP-2006-EXAMINATION REPORT.pdf

1201-KOLNP-2006-FORM 1-1.1.pdf

1201-KOLNP-2006-FORM 1.pdf

1201-KOLNP-2006-FORM 13-1.1.pdf

1201-KOLNP-2006-FORM 13-1.2.pdf

1201-KOLNP-2006-FORM 13.pdf

1201-KOLNP-2006-FORM 18.pdf

1201-KOLNP-2006-FORM 3-1.1.pdf

1201-KOLNP-2006-FORM 3-1.2.pdf

1201-KOLNP-2006-FORM 5-1.1.pdf

1201-KOLNP-2006-FORM 5-1.2.pdf

1201-KOLNP-2006-FORM 5.pdf

1201-KOLNP-2006-GPA-1.1.pdf

1201-KOLNP-2006-GPA.pdf

1201-KOLNP-2006-GRANTED-ABSTRACT.pdf

1201-KOLNP-2006-GRANTED-CLAIMS.pdf

1201-KOLNP-2006-GRANTED-DESCRIPTION (COMPLETE).pdf

1201-KOLNP-2006-GRANTED-FORM 1.pdf

1201-KOLNP-2006-GRANTED-SPECIFICATION.pdf

1201-KOLNP-2006-INTERNATIONAL EXM REPORT.pdf

1201-KOLNP-2006-OTHERS.pdf

1201-KOLNP-2006-REPLY TO EXAMINATION REPORT-1.1.pdf

1201-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf

abstract-01201-kolnp-2006.jpg


Patent Number 251678
Indian Patent Application Number 1201/KOLNP/2006
PG Journal Number 13/2012
Publication Date 30-Mar-2012
Grant Date 28-Mar-2012
Date of Filing 08-May-2006
Name of Patentee NOVARTIS VACCINES AND DIAGNOSTICS, INC.
Applicant Address 4560, HORTON STREET, EMERYVILLE, CA 94608 UNITED STATES OF AMERICA
Inventors:
# Inventor's Name Inventor's Address
1 CAI, SHAOPEI 4560, HORTON STREET, EMERYVILLE, CA 94608-2917
2 RYCKMAN, DAVID 4560, HORTON STREET, EMERYVILLE, CA 94608-2917
3 SHANG, XIAO 4560, HORTON STREET, EMERYVILLE, CA 94608-2917
4 ZHU, SHUGUANG 4560, HORTON STREET, EMERYVILLE, CA 94608-2917
5 MACHAJEWSKI, TIMOTHY D. 4560, HORTON STREET, EMERYVILLE, CA 94608-2917
6 OKHAMAFE, AUGUSTUS O. 4560, HORTON STREET, EMERYVILLE, CA 94608-2917
7 TESCONI, MARC S. 15 LAKE REGION BLVD., MONROE, NY 10950
8 HARWOOD, ERIC 4560, HORTON STREET, EMERYVILLE, CA 94608-2917
9 CHOU, JOYCE 4560, HORTON STREET, EMERYVILLE, CA 94608-2917
PCT International Classification Number A61K
PCT International Application Number PCT/US2004/037051
PCT International Filing date 2004-11-05
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/546,017 2004-02-19 U.S.A.
2 60/517,915 2003-11-07 U.S.A.
3 60/526,425 2003-12-02 U.S.A.
4 60/526,426 2003-12-02 U.S.A.