Title of Invention

INHIBITORS OF HISTONE DEACETYLASE

Abstract This invention relates to compounds for the inhibition of histone deacetylase. More particularly, the invention provides for a compound for the inhibition of histone deacetylase of the formula and pharmaceutically acceptable salts thereof. The invention further provides methods for inhibiting histone deacetylase enzymatic activity with the compound.
Full Text INHIBITORS OF HISTONE DEACETYLASE
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Application
10/358,556.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] This invention relates to the inhibition of histone
deacetylase. More particularly, the invention relates to compounds
and methods for inhibiting histone deacetylase enzymatic activity.
Summary of the Related Art
[0003] In eukaryotic cells, nuclear DNA associates with histones to
form a compact complex called chromatin. The histones constitute a
family of basic proteins which are generally highly conserved across
eukaryotic species. The core histones, termed H2A, H2B, H3, and H4,
associate to form a protein core. DNA winds around this protein core,
with the basic amino acids of the histones interacting with the
negatively charged phosphate groups of the DNA. Approximately 146
base pairs of DNA wrap around a histone core to make up a nucleosome
particle, the repeating structural motif of chromatin.
[0004] Csordas, Biochem. J., 286: 23-38 (1990) teaches that histones
are subject to posttranslational acetylation of the aes-amino groups
of N-terminal lysine residues, a reaction that is catalyzed by histone
acetyl transferase (HAT1). Acetylation neutralizes the positive
charge of the lysine side chain, and is thought to impact chromatin
structure. Indeed, Taunton et al., Science, 272: 408-411 (1996),
teaches that access of transcription factors to chromatin templates is
enhanced by histone hyperacetylation. Taunton et al. further teaches
that an enrichment in underacetylated histone H4 has been found in
transcriptionally silent regions of the genome.
[0005] Histone acetylation is a reversible modification, with
deacetylation being catalyzed by a family of enzymes termed histone
deacetylases (HDACs). Grozinger et al., Proc. Natl. Acad. Sci. USA,
96: 4868-4873 (1999), teaches that HDACs is divided into two classes,
the first represented by yeast Rpd3-like pzx>teins, and the second

represented by yeast Hdal-like proteins. Grozinger et al. also
teaches that the human HDAC1, HDAC2, and HDAC3 proteins are members 'of
the first class of HDACs, and discloses new proteins, named HDAC4,
HDAC5, and HDAC6, which are members of the second class of HDACs. Kao
et al., Genes & Dev., 14: 55-66 (2000), discloses HDAC7, a new member
of the second class of HDACs. Van den Wyngaert, FEBS, 478: 77-83
(2000) discloses HDAC8, a new member of the first class of HDACs.
[0006] Richon et al., Proc. Natl. Acad. Sci. USA, 95: 3003-3007
(1998), discloses that HDAC activity is inhibited by trichostatin A
(TSA) , a natural product isolated from Streptomyces hygroscopicus, and
by a synthetic compound, suberoylanilide hydroxamic acid (SAHA).
Yoshida and Beppu, Exper. Cell Res., 177: 122-131 (1988), teaches that
TSA causes arrest of rat fibroblasts at the Gx and G2 phases of the
cell cycle, implicating HDAC in cell cycle regulation. Indeed,' Finnin
et al., Nature, 401: 188-193 (1999), teaches that TSA and SAHA inhibit
cell growth, induce terminal differentiation, and prevent the
formation of tumors in mice. Suzuki et al., U.S. Pat. No. 6,174,905,
EP 0847992, JP 258863/96, and Japanese Application No. 10138957,
disclose benzamide derivatives that induce cell differentiation and
inhibit HDAC. Delorme et al., WO 01/38322 and PCT IB01/00683,
disclose additional compounds that serve as HDAC inhibitors.
[0007] The molecular cloning of gene sequences encoding proteins with
HDAC activity has established the existence of a set of discrete HDAC
enzyme isoforms. Grozinger et al., Proc. Natl. Acad. Sci. USA,
96:4868-4873 (1999), teaches that HDACs may be divided into two
classes, the first' represented by yeast Rpd3-like proteins, and the
second represented by yeast Hdal-like proteins. Grozinger et al. also
teaches that the human HDAC-1, HDAC-2, and HDAC-3 proteins are members
of the first class of HDACs, and discloses new proteins, named HDAC-4,
HDAC-5, and HDAC-6, which are members of the second class of HDACs.
Kao et al., Gene & Development 14:55-66 (2000), discloses an
additional member of this second class, called HDAC-7. More recently,
'Hu, E. et al. J. Bio. Chem. 275:15254-13264 (2000) discloses the
newest member of the first class of histone deacetylases, HDAC-8. It
has been unclear what roles these individual HDAC enzymes play.
[0008] These findings suggest that inhibition of HDAC activity
represents a novel approach for intervening in cell cycle regulation
and that HDAC inhibitors have great therapeutic potential in the


treatment of cell proliferative diseases or conditions. To date, few
inhibitors of histone deacetylase are known in the art. There is thus
a need to identify additional HDAC inhibitors and to identify the
structural features required for potent HDAC inhibitory activity.
BRIEF SUMMARY OF THE INVENTION
[0009] The invention provides compounds and methods for treating cell
proliferative diseases. The invention provides new inhibitors of
histone deacetylase enzymatic activity.
[0010] In a first aspect, the invention provides compounds that are
useful as inhibitors of histone deacetylase.
[0011] In a second aspect, the invention provides a composition
comprising an inhibitor of histone deacetylase according to the
invention and a pharmaceutically acceptable carrier, excipient, or
diluent.
[0012] In a third aspect, the invention provides a method of
inhibiting histone deacetylase in a cell, comprising contacting a cell
in which inhibition of histone deacetylase is desired with an
inhibitor of histone deacetylase of the invention.
[0013] The foregoing merely summarizes certain aspects of the
invention and is not intended to be limiting in nature. These aspects
and other aspects and embodiments are described more fully below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figure 1 is a graph showing the antitumor activity of compound
106 in an HCT 116 human colorectal tumor model.
[0015] Figures 2-11 show additional data for other compounds used in
the in vivo experiment described in Assay Example 2.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] The invention provides compounds and methods for inhibiting
histone deacetylase enzymatic activity. The invention also provides
compositions and methods for treating cell proliferative diseases and
conditions. The patent and scientific literature referred to herein
establishes knowledge that is available to those with skill in the
art. The issued patents, applications, and references that are cited
herein are hereby incorporated by reference to the same extent as if
each was specifically and individually indicated to be incorporated by
reference. In the case of inconsistencies, the present disclosure
will prevail.


[0017] For purposes of the present invention, the following
definitions will be used (unless expressly stated otherwise):
[0018] As used herein, the terms "histone deacetylase" and "HDAC" are
intended to refer to any one of a family of enzymes that remove acetyl
groups from the aee-amino groups of lysine residues at the N-terminus
of a histone. Unless otherwise indicated by context, the term
"histone" is meant to refer to any histone protein, including HI, H2A,
H2B, H3, H4, and H5, from any species. Preferred histone deacetylases
include class I and class II enzymes. Preferably the histone
•deacetylase is a human HDAC, including, but not limited to, HDAC-1,
HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, and HDAC-8. In some
other preferred embodiments, the histone deacetylase is derived from a
protozoal or fungal source.
[0019] The terms "histone deacetylase inhibitor" and "inhibitor of
histone deacetylase" are used to identify a compound having a
structure as defined herein, which is capable of interacting with a
histone deacetylase and inhibiting its enzymatic activity.
"Inhibiting histone deacetylase enzymatic activity" means reducing the1
ability of a histone deacetylase to remove an acetyl group from a
histone. In some preferred embodiments, such reduction of histone
deacetylase activity is at least about 50%, more preferably at least
about 75%, and still more preferably at least about 90%. In other
preferred embodiments, histone deacetylase activity is reduced by at
least 95% and more preferably by at least 99%.
[0020] Preferably, such inhibition is specific, i.e., the histone
deacetylase inhibitor reduces the ability of a histone deacetylase to
remove an acetyl group from a histone at a concentration that is lower
than the concentration of the inhibitor that is required to produce
another, unrelated biological effect. Preferably, the concentration
of the inhibitor required for histone deacetylase inhibitory activity
is at least 2-fold lower, more preferably at least 5-fold lower, even
more preferably at least 10-fold lower, and most preferably at least
20-fold lower than the concentration required to produce an unrelated
biological effect.
[0021] For simplicity, chemical moieties are defined and referred to
throughout primarily as univalent chemical moieties (e.g., alkyl,
aryl, etc.). Nevertheless, such terms are also used to convey
corresponding multivalent moieties under the appropriate structural


circumstances clear to those skilled in the art. For example, while
an "alkyl" moiety generally refers to a monovalent radical (e.g. CH3-
CH2-), in certain circumstances a bivalent linking moiety can be
"alkyl," in which case those Bkilled in the art will understand the
alkyl to be a divalent radical (e.g., -CH2-CH2-) , which is equivalent
to the term "alkylene." (Similarly, in circumstances in which a
divalent moiety is required and is stated as being "aryl," those
skilled in the art will understand that the term "aryl" refers to the
corresponding divalent moiety, arylene.) All atoms are understood to
have their normal number of valences for bond formation (i.e., 4 for
carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the
oxidation state of the S). On occasion a moiety may be defined, for
example, as (A)a-B-, wherein a is 0 or 1. In such instances, when a
is 0 the moiety is B- and when a is 1 the moiety is A-B-. Also,' a
number of moieties disclosed herein exist in multiple tautomeric
forms, all of which are intended to be encompassed by any given
tautomeric structure.
[0022] The term "hydrocarbyl" refers to a straight, branched, or
cyclic alkyl, alkenyl, or alkynyl, each as defined herein. A "C0"
hydrocarbyl is used to refer to a covalent bond. Thus, WC0-C3-
hydrocarbyl" includes a covalent bond, methyl, ethyl, propyl, and
cyclopropyl.
[0023] The term "alkyl" as employed herein refers to straight and
branched chain aliphatic groups having from 1 to 12 carbon atoms,
preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms,
which is optionally substituted with one, two or three substituents.
Preferred alkyl groups include, without limitation, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and
hexyl. A "C0" alkyl (as in "C0-C3-alkyl") is a covalent bond (like
"C0" hydrocarbyl).
[0024] The term "alkenyl" as used herein means an unsaturated
straight or branched chain aliphatic group with one or more carbon-
carbon double bonds, having from 2 to 12 carbon atoms, preferably 2-8
carbon atoms, and more preferably 2-6 carbon atoms, which is
optionally substituted with one, two or three substituents. Preferred
alkenyl groups include, without limitation, ethenyl, propenyl,
butenyl, pentenyl, and hexenyl.

[0025] The term "alkynyl" as used herein means an unsaturated
straight or branched chain aliphatic group with one or more carbon-
carbon triple bonds, having from 2 to 12 carbon atoms, preferably 2-8
carbon atoms, and more preferably 2-6 carbon atoms, which is
optionally substituted with one, two or three substituents. Preferred
alkynyl groups include, without limitation, ethynyl, propynyl,
butynyl, pentynyl, and hexynyl.
[0026] An "alkylene," "alkenylene," or "alkynylene" group is an
alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is
positioned between and serves to connect two other chemical groups.
Preferred alkylene groups include, without limitation, methylene,
ethylene, propylene, and butylene. Preferred alkenylene groups
include, without limitation, ethenylene, propenylene, and butenylene.
Preferred alkynylene groups include, without limitation, ethynylene,
propynylene, and butynylene.
[0027] The term "cycloalkyl" as employed herein includes saturated
and partially unsaturated cyclic hydrocarbon groups having 3 to 12
carbons, preferably 3 to 8 carbons, and more preferably 3 to 6
carbons, wherein the cycloalkyl group additionally is optionally
substituted. Preferred cycloalkyl groups include, without limitation,
cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,
cyclohexenyl, cycloheptyl, and cyclooctyl.
[0028] The term "heteroalkyl" refers to an alkyl group, as defined
hereinabove, wherein one or more carbon atoms in the chain are
replaced by a heteratom selected from the group consisting of 0, S,
and N.
[0029] An "aryl" group is a C6-C14 aromatic moiety comprising one to
three aromatic rings, which is optionally substituted. Preferably,
the aryl group is a C6-C10 aryl group. Preferred aryl groups include,
without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An
"aralkyl" or "arylalkyl" group comprises an aryl group covalently
linked to an alkyl group, either of which may independently be
optionally substituted or unsubstituted. Preferably, the aralkyl
group is (C1-C6)alk{C6-C10)aryl, including, without limitation, benzyl,
phenethyl, and naphthylmethyl.
[0030] A "heterocyclyl" or "heterocyclic" group is a ring structure
having from about 3 to about 8 atoms, wherein one or more atoms are
selected from the group consisting of N, 0, and S. The heterocyclic


group is optionally substituted on carbon at one or more positions.
The heterocyclic group is also independently optionally substituted on
nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl,
arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on
sulfur with oxo or lower alkyl. Preferred heterocyclic groups
include, without limitation, epoxy, aziridinyl, tetrahydrofuranyl,
pyrrolidinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl,
oxazolidinonyl, and morpholino. In certain preferred embodiments, the
heterocyclic group is fused to an aryl, heteroaryl, or cycloalkyl
group. Examples of such fused heterocyles include, without
limitation, tetrahydroquinoline and dihydrobenzofuran. Specifically
excluded from the scope of this term are compounds having adjacent
annular 0 and/or S atoms.
[0031] As used herein, the term "heteroaryl" refers to groups having
5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6,
10, or 14 n electrons shared in a cyclic array; and having, in
addition to carbon atoms, from one to three heteroatoms per ring
selected from the group consisting of N, O, and S. A "heteroaralkyl"
or "heteroarylalkyl" group comprises a heteroaryl group covalently
linked to an alkyl group, either of which is independently optionally
substituted or unsubstituted. Preferred heteroalkyl groups comprise a
C1-C6 alkyl group and a heteroaryl group having 5, 6, 9, or 10 ring
atoms. Specifically excluded from the scope of this term are
compounds having adjacent annular O and/or S atoms. Examples of
preferred heteroaralkyl groups include pyridylmethyl, pyridylethyl,
pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl,
thiazolylmethyl, and thiazolylethyl. Specifically excluded from the
scope of this term are compounds having adjacent annular 0 and/or S
atoms.
[0032] An "arylene," "heteroarylene," or "heterocyclylene" group is
an aryl, heteroaryl, or heterocyclyl group, as defined hereinabove,
that is positioned between and serves to connect two other chemical
groups.
[0033] Preferred heterocyclyls and heteroaryls include, but are not
limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,
benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,


chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, iraidazolidinyl,
imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl,
indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,
isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-
oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,
oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl,
piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,
pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,
pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-
quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroguinolinyl, tetrazolyl, 6H-1,2,5-
thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-
thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl,
thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,
triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-
triazolyl, and xanthenyl.
[0034] As employed herein, when a moiety (e.g., cycloalkyl,
hydrocarbyl, aryl, heteroaryl, heterocyclic, urea, etc.) is described
as "optionally substituted" it is meant that the group optionally has
from one to four, preferably from one to three, more preferably one or
two, non-hydrogen substituents. Suitable substituents include,
without limitation, halo, hydroxy, oxo (e.gr., an annular -CH-
substituted with oxo is -C(O)-) nitro, halohydrocarbyl, hydrocarbyl,
aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl,
arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, ,
alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido,
aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.
Preferred substituents, which are themselves not further substituted
(unless expressly stated otherwise) are:
(a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino,
guanidino,

(b) C1-C5 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido,
carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl,
arylalkyl, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkoxy, C1-C8
alkoxycarbonyl, aryloxycarbonyl, C2-C8 acyl, C2-C8
acylamino, C1-C8 alkylthio, arylalkylthio, arylthio, C1-C8
alkylsulfinyl, arylalkylsulfinyl, arylsulfinyl, C1-C8
alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C0-C6 N-
alkyl carbamoyl, C2-C15 N,N-dialkylcarbamoyl, C3-C7
cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl
fused to a cycloalkyl or heterocycle or another aryl ring,
C3-C7 heterocycle, or any of these rings fused or spiro-
fused to a cycloalkyl, heterocyclyl, or aryl, wherein each
of the foregoing is further optionally substituted with one
more moieties listed in (a), above; and
(c) - (CH2)S-NR30R31, wherein s is from 0 (in which case the
nitrogen is directly bonded to the moiety that is
substituted) to 6, and R30 and R31 are each independently
hydrogen, cyano, oxo, carboxamido, amidino, C1-C8
hydroxyalkyl, C1-C3 alkylaryl, aryl-C1-C3 alkyl, C1-C8 alkyl,
C1-C8 alkenyl, C1-C8 alkoxy, C1-C8 alkoxycarbonyl,
aryloxycarbonyl, aryl-C1-C3 alkoxycarbonyl, C2-CB acyl, C1-C8
alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, aroyl,
aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein each
of the foregoing is further optionally substituted with one
more moieties listed in (a), above; or
R30 and R31 taken together with the N to which they are attached
form a heterocyclyl or heteroaryl, each of which is optionally
substituted with from 1 to 3 substituents from (a), above.
[0035] In addition, substituents on cyclic moieties (i.e.,
cycloalkyl, heterocyclyl, aryl, heteroaryl) include 5-6 membered mono-
and 10-12 membered bi-cyclic moieties fused to the parent cyclic
moiety to form a bi- or tri-cyclic fused ring system. For example, an
optionally substituted phenyl includes the following:

[0036] A "halohydrocarbyl" is a hydrocarbyl moiety in which from one
to all hydrogenB have been replaced with one or more halo.
[0037] The term "halogen" or "halo" as employed herein refers to
chlorine, bromine, fluorine, or iodine. As herein employed, the term
"acyl" refers to an alkylcarbonyl or arylcarbonyl substituent. The
term "acylamino" refers to an amide group attached at the nitrogen
atom (i.e., R-CO-NH-). The term "carbamoyl" refers to an amide group
attached at the carbonyl carbon atom (i.e., NH2-CO-). The.nitrogen
atom of an acylamino or carbamoyl substituent is additionally
substituted. The term "sulfonamido" refers to a sulfonamide
substituent attached by either the sulfur or the nitrogen atom. The
term "amino" is meant to include NH2, alkylamino, arylamino, and
cyclic amino groups. The term "ureido" as employed herein refers to a
substituted or unsubstituted urea moiety.
[0038] The term "radical" as used herein means a chemical moiety
comprising one or more unpaired electrons.
[0039] A moiety that is substituted is one in which one or more
hydrogens have been independently replaced with another chemical
substituent. As a non-limiting example, substituted phenyls include
2-flurophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluor-
3-propylphenyl. As another non-limiting example, substituted n-octyls
include 2,4 dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included
within this definition are methylenes (-CH2-) substituted with oxygen
to form carbonyl -CO-),
[0040] An "unsubstituted" moiety as defined above (e.g.,
unsubstituted cycloalkyl, unsubstituted heteroaryl, etc.) means that
moiety as defined above that does not have any of the optional
substituents for which the definition of the moiety (above) otherwise
provides. Thus, for example, while an "aryl" includes phenyl and
phenyl substituted with a halo, "unsubstituted aryl" does not include
phenyl substituted with a halo.
[0041] Preferred embodiments of a particular genus of compounds of
the invention include combinations of preferred embodiments. For
example, paragraph [0043] identifies a preferred Ay1 and paragraph
[0047] identifies preferred Ar1 (both for compound (1) of paragraph
[0042]). Thus, another preferred embodiment includes those compounds
of formula (1) in paragraph [0042] in which Ay1 is as defined in
paragraph [0043] and Ar1 is as defined in paragraph [0047].


Compounds
[0042] In a first aspect, the invention provides novel inhibitors of
histone deacetylase. In a first embodiment, the novel inhibitors of
histone deacetylase are represented by formula (1):
(1)
and pharmaceutically acceptable salts thereof, wherein
R3 and R4 are independently selected from the group consisting of
hydrogen, L1, Cy1, and -I^-Cy1, wherein
L1 is C1-C6 alkyl, C2-C6 heteroalkyl, or C3-C6 alkenyl; and
Cy1 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each
of which optionally is substituted, and each of which optionally
is fused to one or more aryl or heteroaryl rings, or to one or
more saturated or partially unsaturated cycloalkyl or
heterocyclic rings, each of which rings optionally is
substituted; or
R3 and R4 are taken together with the adjacent nitrogen atom to
form a 5-, 6-, or 7-membered ring, wherein the ring atoms are
independently selected from the group consisting of C, O, S, and N,
and wherein the ring optionally is substituted, and optionally forms
part of a bicyclic ring system, or optionally is fused to one or more
aryl or heteroaryl rings, or to one or more saturated or partially
unsaturated cycloalkyl or heterocyclic rings, each of which rings and
ring systems optionally is substituted;
Y1 is selected from the group consisting of -NCR1) (R2) , -CH2-C{0)-
N(R1)(R2), halogen, and hydrogen, wherein
R1 and R2 are independently selected from the group
consisting of hydrogen, L1, Cy1. and -L1-Cy1, wherein
Lx is C1-C6 alkyl, C2-Cs heteroalkyl, or C3-C6 alkenyl; and
Cy1 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each
of which optionally is substituted, and each of which optionally
is fused to one or more aryl or heteroaryl rings, or to one or
more saturated or partially unsaturated cycloalkyl or
heterocyclic rings, each of which rings optionally is
substituted; or

R1 and R2 are taken together with the" adjacent nitrogen atom
to form a 5-, 6-, or 7-membered ring, wherein the ring atoms are
independently selected from the group consisting of C, O, S, and
N, and wherein the ring optionally is substituted, and
optionally may form part of a bicyclic ring system, or
optionally is fused to one or more aryl or heteroaryl rings, or
to one or more saturated or partially unsaturated cycloalkyl or
heterocyclic rings, each of which rings and ring systems
optionally is substituted;
Y2 is a chemical bond or N(R°) , where R° is selected- from the
group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl;
Ak1 is C1-C6 alkylene, C1-C6-heteroalkylene (preferably, in which
one -CH2- is replaced with -NH-, and more preferably -NH-CH2-) , C2-C6
alkenylene or C2-C6 alkynylene;
Ar1 is arylene or heteroarylene, either of which optionally is
substituted; and
Z1 is selected from the group consisting of

wherein Ay1 is aryl or heteroaryl, which optionally is
substituted.
[0043] Preferably in the compounds according to paragraph [0042], Ay1
is phenyl or thienyl, each substituted with -OH or -NH2.
[0044] . More preferably in the compounds according to paragraph
[0042], Ay1 is optionally amino- or hydroxy-substituted phenyl or
thienyl, wherein the amino or hydroxy substituent is preferably ortho
to the nitrogen to which Ay2 is attached.
[0045] More preferably in the compounds according to paragraph
[0042], Ay1 is ortho aniline, ortho phenol, 3-amino-2-thienyl, or 3-
hydroxy-2-thienyl, and tautomers thereof.
[0046] In some preferred embodiments of the compounds according to
paragraph [0042], Z1 is

[0047] In some preferred embodiments of the compounds according to
paragraph [0042], Ar1 is phenylene. In some embodiments, Ak1 is


alkylene, preferably methylene, in some prererrea embodiments, Y2 is
-NH-. In some preferred embodiments, Y1 is -N(R1) (R2) or -CH2-C(O)-
N(R1)(R2).
[0048] In some embodiments of the compounds according to paragraph
[0042] , R1 and R2 are each independently selected from the group
consisting of hydrogen, L1, Cy1, and -L1-Cy1. In some embodiments, R1
and/or R2 is hydrogen. In other embodiments, R1 and/or R2 is alkyl or
alkenyl, preferably allyl. In still other embodiments, R1 and/or R2 is
aryl, heteroaryl, aralkyl, or heteroaralkyl, the rings of each of
which optionally is substituted and optionally is fused to one or more
aryl rings. Some preferred aryl, heteroaryl, aralkyl, and
heteroaralkyl groups comprise a phenyl, pyridyl, or pyrrolyl ring. In
still other embodiments, R1 and/or R2 is cycloalkyl, e.g.,'cyclopropyl,
cyclopentyl, or cyclohexyl, which optionally is substituted and
optionally is fused to one or more aryl rings.
[0049] In some embodiments of the compounds according to paragraph
[0042] , R3 and R4 are each independently selected from the group
consisting of hydrogen, L1, Cy1, and -L1-Cy1. In some embodiments, R3
and/or R4 is hydrogen. In other embodiments, R3 and/or R4 is alkyl or
alkenyl, preferably allyl. In still other embodiments, R3 and/or R4 iB
aryl, heteroaryl, aralkyl, or heteroaralkyl, the rings of each of
which optionally is substituted and optionally is fused to one or more
aryl rings. Some preferred aryl, heteroaryl, aralkyl, and
heteroaralkyl groups comprise a phenyl, pyridyl, or pyrrolyl ring. In
still other embodiments, R3 and/or R4 is cycloalkyl, e.g., cyclopropyl,
cyclopentyl, or cyclohexyl, which optionally is substituted and
optionally is fused to one or more aryl rings.
[0050] As set forth above, L1 is C1-C6 alkyl, C2-C6 heteroalkyl, or C3-
C6 alkenyl. However, one skilled in the art will understand that when
L1 is not a terminal group, then L1 is C1-C6 alkylene, C2-C6
heteroalkylene, or C3-C6 alkenylene. In some embodiments, L1 is
alkylene, preferably methylene or ethylene. In other embodiments, L1
is alkenyl, preferably ailyl. In some embodiments, Cy1 is the radical
of a heterocyclic group including, without limitation, piperidine,
pyrrolidine, piperazine, and morpholine, each of which optionally is
substituted and optionally is fused to one or more aryl rings. In
other embodiments Cy1 is cycloalkyl, e.g., cyclopropyl, cyclopentyl,
or cyclohexyl. In still other embodiments, Cy1 is aryl or heteroaryl,


e.g., phenyl, pyridyl, or pyrrolyl, each of which optionally is
substituted and optionally is fused to one or more aryl rings. In
some embodiments, Cy1 is fused to one or two benzene rings. In some
embodiments, Cy1 has between one and about five substituents selected
from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, and halo.
Examples of preferred substituents include methyl, methoxy, and
fluoro.
[0051] In some embodiments of the compounds according to paragraph
[0042], R1 and R2 and/or R3 and R4 are taken together with the adjacent
nitrogen atom to form a 5- or 6-membered ring, wherein the ring atoms
are independently selected from the group consisting of C, 0, and N,
and wherein the ring optionally is substituted, and optionally is
fused to one or more aryl rings. In some preferred embodiments, R1
and R2 and/or R3 and R4 are taken together with the adjacent nitrogen
atom to form a ring such as, for example, pyrrolidine, piperidine,
piperazine, and morpholine, wherein the ring optionally is
substituted, and optionally is fused to an aryl ring. In some
embodiments, the ring comprising R1 and R2 or R3 and R4 is fused to a
benzene ring. In some embodiments, the ring comprising R1 and R2 or R3
and R* has a substituent comprising an aryl or cycloalkyl ring, either
of which optionally is substituted and optionally is fused to a
cycloalkyl, aryl, heteroaryl, or heterocyclic ring. Preferred
substituents include, without limitation, phenyl, phenylmethyl, and
phenylethyl, the phenyl ring of which optionally is fused to a
cycloalkyl, aryl, or heterocyclic ring.
[0052] In a preferred embodiment, the HDAC inhibitors of the
invention comprise compounds of formula 1(a):
(la
and pharmaceutically acceptable salts thereof, wherein
J is d-Cj-hydrocarbyl, -N(R20)-, -N(R20)-CH2-, -O-, or -O-CH2-;
R20 is -H or -Me;
X and Y are independently selected from -NH2, cycloalkyl,
heterocyclyl, aryl, heteroaryl, and A- (C1-C6-alkyl)n-B-;

A is H, C1-C6-alkyloxy, cycloalkyl, heterocyclyl, aryl, or
heteroaryl;
B is -NH-, -O-, or a direct bond; and
n is 0 (in which case A is directly bonded to B) or 1.
[0053] Preferably in the compounds according to paragraph [0052], A
is phenyl optionally substituted with one or more moieties selected
from halo (preferably chloro) and methoxy, and B is -NH-. In another
preferred embodiment, A is selected from cyclopropyl, pyridinyl, and
indanyl.
[0054] Preferably in the compounds according to paragraph [0052], J
is -NH-CH2-, -O-CH2-, -N(CH3) -CH2-, -CH=CH-, or -CH2-CH2-.
[0055] Preferably in the compounds according to paragraph [0052], R20
is -H.
[0056] In the compounds according to paragraph [0052] X is preferably
selected from
[0058] In a second aspect, the novel histone deacetylase inhibitors
of the invention are represented by formula (2):
(2)
and pharmaceutically acceptable salts thereof, wherein .
Cy2 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of
which is optionally substituted and each of which is optionally fused
to one or more aryl or heteroaryl rings, or to one or more saturated
or partially unsaturated cycloalkyl or heterocyclic rings, each of
which rings is optionally substituted;
X1 is selected from the group consisting of a covalent bond, M1-
L2-M1, and L2-M2-L2 wherein
L2, at each occurrence, is independently selected from the
group consisting of a chemical bond, C0-C4 hydrocarbyl, C0-C4-
hydrocarbyl- (NH) -C0-C4-hydrocarbyl, C0-C4-hydrocarbyl- (S) -C0-C4-
hydrocarbyl, and C0-C4-hydrocarbyl- (O) -C0-C4-hydrocarbyl, provided
that L2 is not a chemical bond when X1 is M1-L2-M1;
M1, at each occurrence, is independently selected from the
group consisting of -O-, -N(R7)-, -S-, -S(O)-, S(O)2-, -
S(O)2N(R7)-, -N(R7)-S(O)2-, -C(O)-, -C(O)-NH-, -NH-C(O)-,
-NH-C(O)-O--and -O-C(O)-NH-, wherein R7 is selected from the
group consisting of hydrogen, alkyl, aryl, aralkyl, acyl,
heterocyclyl, and heteroaryl; and
M2 is selected from the group consisting of M1,
heteroarylene, and heterocyclylene, either of which rings
optionally is substituted;
Ar2 is arylene or heteroarylene, each of which is optionally
substituted;
R5 and R6 are independently selected from the group consisting of
hydrogen,- alkyl, aryl, and aralkyl;
g is 0 or 1; and
Ay2 is a 5-6 membered cycloalkyl, heterocyclyl, or heteroaryl
substituted with an amino or hydroxy moiety (preferably these groups
are ortho to the amide nitrogen to which Ay2 is attached) and further
optionally substituted;

provided that when Cy2 is naphthyl, X1 is -CH2-, Ar2 is phenyl, Rs
and R6 are H, and q is 0 or 1, Ay2 is not phenyl or o-hydroxyphenyl.
[0059] In a preferred embodiment of the compounds according to
paragraph [0058], when Ay2 is o-phenol optionally substituted by halo, .
nitro, or methyl, Ar2 is optionally substituted phenyl, X1 is -O-, -
CH2-, -S-, -S-CH2-, -S(O)-, -S(O)2-, -C(O)-, or -OCH2-, then Cy2 is not
optionally substituted phenyl or naphthyl.
[0060] In another preferred embodiment of the compounds according to
paragraph [0058], when Ay2 is o-anilinyl optionally substituted by
halo, C1-6-alkyl, C1-6-alkoxy or -N02, g is 0, Ar2 is phenyl, and X1
is -CH2-, then Cy2 is not substituted pyridone (which substituents of
the pyridone are not limited to substituents described herein).
[0061] In another preferred embodiment of the compounds according to
paragraph [0058], when X1 is -CH2-, Ar2 is optionally substituted
phenyl, q is 1, and R6 is H, then Cy2 is not optionally substituted
imidazole.
[0062] In another preferred embodiment of the compounds according to
paragraph [0058] , when Ar2 is amino or hydroxy substituted phenyl, X1
is C0-C„-alkyl-Xla- C0-C8-alkyl, wherein Xla is -CH2-, -O-, -S-, -NH-, -
C(O)-, then Cy2 is not optionally substituted naphthyl or di- or -
tetrahydronaphthalene.
[0063] In another preferred embodiment of the compounds according to
paragraph [0058] , when Ay2 is o-phenol, Ar2 is substituted phenyl, X1
is -O-, -S-, -CH2-, -O-CH2-, -S-CH2-, or -C(O)-, and R5 and R6 are H,
then Cy2 is not optionally substituted naphthyl.
[0064] In another preferred embodiment of the compounds according to
paragraph [0058] , when Ay2 is o-anilinyl, q is 0, Ar2 is unsubstituted
phenyl, X1 is -CH2-, then Cy2 is not substituted 6-hydroitnidazolo[5,4-
d]pyridazin-7-one-l-yl or substituted 6-hydroimidazolo[5,4-
d]pyridazine-7-thione-l-yl.
[0065] Preferably in the compounds according to paragraph [0058], Ay2
is phenyl or thienyl, each substituted with -OH or -NH2.
[0066] More preferably in the compounds according to paragraph
[0058], Ay2 is optionally amino- or hydroxy-substituted phenyl or
thienyl, wherein the amino or hydroxy substituent is preferably ortho
to the nitrogen to which Ay2 is attached.

[0067] aMore preferably in the compounds according to paragraph
[0058], Ay2 is ortho aniline, ortho phenol, 3-amino-2-thienyl, or 3-
hydroxy-2-thienyl, and tautomers thereof.
[0068] aIn a another embodiment, the novel histone deacetylase
inhibitors of the invention are those according to paragraph [0058]
wherein
q is 1;
M1, at each occurrence, is' selected from the group consisting of
-N(R7)-, -S-, -C(O)-NH-, .and -O-C(O)-NH-, where R7 is selected from the
group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl; and
Ay2 is anilinyl, which optionally is substituted.
[0069] In some preferred embodiments of the compounds according to
paragraph [0068] , the -HH2 group of Ay2 is in an ortho position with
respect to the nitrogen atom to which Ay2 is attached. In some
embodiments, R5 and R6 are independently selected from the group
consisting of .hydrogen and C1-C4 alkyl. In some preferred embodiments,
R5 and R6 are hydrogen.
[0070] In some embodiments of the compounds according to paragraph
[0068] , Ar2 has the formula

wherein G, at each occurrence, is independently N or C, and C
optionally is substituted. In some preferred embodiments, Ar2 has the
formula
[0071] In some preferred embodiments of the compounds according to
paragraph [0070], Ar2 is selected from the group consisting of
phenylene, pyridylene, pyrimidylene, and quinqlylene.
[0072] In some embodiments of the compounds according to paragraph
[0068], X1 is a chemical bond. In some embodiments, X1 is L2-M2-L2, and
M2 is selected from the group consisting of -NH-, -N(CH3)-, -S-,
-C(O)-N(H)-, and -O-C(O) -N(H) -. In some embodiments, X1 is L2-M2-L2,
where at least one occurrence of L2 is a chemical bond. In other
embodiments, X1 is L2-M2-L2, where at least one occurrence of L2 is
alkylene, preferably methylene. In still other embodiments, X1 is L2-


M2-L2, where at least one occurrence of L2 is alkenylene. In some
embodiments, X1 is M1-L2-M1 and M1 is selected from the group consisting
of -NH-, -N(CH3)-, -S-, and -C(O)-N(H)-.
[0073] In some embodiments of the compounds according to paragraph
[0068], Cy2 is aryl or heteroaryl, e.g., phenyl, pyridyl, imidazolyl,
or quinolyl, each of which optionally is substituted. In some
embodiments, Cy2 is heterocyclyl, e.g.,

each of which optionally is substituted and optionally is fused to one
or more aryl rings. In some embodiments, Cy2 has from one and three
substituents independently selected from the group consisting of
alkyl, alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy.
Examples of preferred substituents include methyl, methoxy, fluoro,
trifluoromethyl, trifluoromethoxy, nitro, amino, aminomethyl, and
hydroxymethyl.
[0074] In a preferred embodiment of the compounds of paragraph
[0058], the invention comprises compounds of structural formula (2a):
(2a)
and pharmaceutically acceptable salts thereof, wherein
Ara is phenyl or thienyl;
R6 is H, or C1-6-alkyl (preferably --CH3) ;
Y and Z are independently -CH= or -N=;
W is halo, (V'-L4)t-V-L3-;
L3 is a direct bond, -C1-C6-hydrocarbyl, - (C1-C3-hydrocarbyl)m1-
X'-(C1-C3- hydrocarbyl)m2, -NH-(C0-C3-hydrocarbyl) , (C1-C3-
hydrocarbyl)-NH-, or -NH-(C1-C3- hydrocarbyl)-NH-;
'ml and m2 are independently 0 or 1;
X' is -N(R21)-, -C(O)N(R21)-, N(R21)C(O)-, -O-, or -S-;
R21 is -H, V"-(C1-C6-hydrocarbyl)c;;

L4 .is (C1-C6-hydrocarbyl)a-M-(C1-C6-hydrocarbyl)b;
a and b are independently 0 or 1;
M is -NH-, -NHC(O)-, -C(O)NH-, -C(O)-, -SO2-, -NHSO2-, or -
SO2NH-
V, V, and V" are independently selected from cycloalkyl,
heterocyclyl, aryl, and heteroaryl; -.
.t is 0 or 1;
or W, the annular C to which it is bound, and Y together form a
monocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
wherein the A and Ara rings are optionally further substituted
with from 1 to 3 substituents independently selected from methyl,
hydroxy, methoxy, halo, and amino.
[0075] In a preferred embodiment of the compound according to
paragraph [0074] :
Y and Z are -CH= and R6 is H;
W is V-L3;
L3 is -NH-CH- or -CH-NH-;
V is phenyl optionally substituted with from 1 to 3 moieties
independently selected from halo, hydroxy, C1-C6-hydrocarbyl,
C1-C6-hydrocarbyl-oxy or -thio (particularly methoxy or
methylthio), wherein each of the hydrocarbyl moieties are
optionally substituted with one or more moieties independently
selected from halo, nitroso, amino, sulfonamido, and cyano;
and
Ara is phenyl and the amino moieties to which it is bound are
ortho to each other.
[0076] In some preferred embodiments of the compound according to
paragraph [0074], V is an optionally substituted ring moiety selected
from:
[0077] In another preferred embodiment of the compounds according to
paragraph [0074] , w is selected from:,
[0078] In another preferred embodiment of the compounds according to
paragraph [0074], the A and Ara rings are not further substituted.
[0079] In a particularly preferred embodiment of the compounds
according to paragraph [0074], the compounds of the invention are
selected from the following, in which, unless expressly displayed
otherwise, Ara is phenyl (and, preferably, the amide nitrogen and the
amino nitrogen bound to Ara are ortho to each other) :
[0080] In a preferred embodiment, the compounds of the invention ¦
comprise compounds of the formula (2b):
and pharmaceutically acceptable salts thereof, wherein
Ay2 is phenyl or thienyl, each substituted at the ortho position
with -NH2 or -OH and each further optionally substituted with one to
three substituents independently selected from -NH2, -OH, and halo;
X1 is selected from -CH2-, -NH-CH2-, and -S-CH2-;
Cy2 is monocyclic or fused bicyclic aryl or heteroaryl optionally
substituted with one to three substituents selected from CH3-, CH3O-,
phenyl optionally substituted with one to three CH30-, morphylinyl,
morphylinyl-C1-C3-alkoxy, cyano, and CH3C(O)NHT;
provided that when Cy2 is naphthyl, X1 is -CH2-, and q is 0 or 1,
Ay2 is not o-hydroxyphenyl.
[0081] Preferably in the compounds according to paragraph [0080] , Ay2
is selected from:

[0082] Preferably in the compounds according to paragraph [0080], Cy2
is phenyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl,
thienyl, tetrahydroquinozolinyl, or l,3-dihydroquinazoline-2,4-dione,
each optionally substituted with one to three CH30-. More preferably,
Cy2 is phenyl substituted with one to three CH30-.
[0083] In a third embodiment, the novel inhibitors of histone
deacetylase are represented by formula (3):
(3)
and pharmaceutical salts thereof, wherein
Ar3 is arylene or heteroarylene, either of which optionally is
substituted;
Cy3 is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of
which optionally is substituted, and each of which optionally is fused
to one or more aryl or heteroaryl rings, or to one or more saturated
or partially unsaturated cycloalkyl or heterocyclic rings, each of
which rings optionally is substituted;
provided that'when Cy3 is a cyclic moiety having -C(O)-, -C(S)-,
-S{0)-, or -S(O)2- in the ring, then Cy3 is not additionally
substituted with a group comprising an aryl or heteroaryl ring; and
X2 is selected from the group consisting of a chemical bond, L3,
W1-L3, L3-W1, W1-L3-W1, and L3-Wl-L3, wherein


W1, at each occurrence, is S, 0, or N(R9) , where R9 is
selected from the group consisting of hydrogen, alkyl, aryl, and
aralkyl; and
L3 is C1-C4 alkylene, C2-C4 alkenylene, or C2-C4 alkynylene;
provided that X2 does not comprise a -C(O)-, -C(S)-, -S(O)-, or
-S(O)2- group;
and further provided that when Cy3 is pyridine, then X2 is L3, W1-L3, or
L3-W1.
[0084] Preferably, Ar3 has the structure:

wherein Q, at each occurrence, is independently N or C, and C
optionally is substituted.
[0085] Preferably in the compounds according to paragraph [0083], X2
is selected from the group consisting of L3,, Wx-L3, L'-W1, W1-L3-W1, and
L3-Wx-L[0086] Preferably in the compounds according to paragraph [0083],
when X2 is a chemical bond, then Ar3 is not

and Cy3 is not the radical of a substituted or unsubstituted diazepine
or benzofuran.
[0087] In some embodiments of the compounds according to paragraph
[0083], Q at each occurrence is C(R8), where RB is selected from the
group consisting of hydrogen, alkyl, aryl, aralkyl, alkoxy, amino,
nitro, halo, haloalkyl, and haloalkoxy. In some other embodiments,
from one to about three variables Q are nitrogen. In some preferred
embodiments, Ar3 is selected from the group consisting of phenylene,
pyridylene, thiazolylene, and quinolylene.
[0088] In some embodiments of the compounds according to paragraph
[0083], X2 is a chemical bond. In other embodiments, X2 is a non-
cyclic hydrocarbyl. In some such embodiments, X2 is alkylene,
preferably methylene or ethylene. In other such embodiments, X2 is
alkenylene or alkynylene. In still other such embodiments, one carbon
in the hydrocaryl chain is replaced with -NH- or -S-. In some
preferred embodiments, X2 is W1-L3-W1 and W1 is -NH- or -N(CH3)-.


[0089] In some embodiments ot the compounds according to paragraph
[0083], Cy3 is cycloalkyl, preferably cyclohexyl.' In other
embodiments, Cy3 is aryl or heteroaryl, e.g., phenyl, pyridyl,
pyrimidyl, imidazolyl, thiazolyl, oxadiazolyl, quinolyl, or fluorenyl,
each of which optionally is substituted and optionally is fused to one
or more aryl rings. In some embodiments, the cyclic moiety of Cy3 is
fused to a benzene ring. In some embodiments, Cy3 has from one to
three substituents independently selected from the group consisting of
alkyl, alkoxy, aryl, aralkyl, amino, halo, haloalkyl, and
hydroxyalkyl. Examples of preferred substituents include methyl,
methoxy, fluoro, trifluoromethyl, amino, nitro, aminomethyl,
hydroxymethyl, and phenyl. Some other preferred substituents have the
formula -k1-NCH) (R10) , wherein
K1 is a chemical bond or C1-C4 alkylene;
R10 is selected from the group consisting of Z' and -Ak2-Z' ,
• wherein
Ak2 is C1-C4 alkylene; and
Z' is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each
of which optionally is substituted, and each of which optionally
is fused to one or more aryl or heteroaryl rings, or to one or
more saturated or partially unsaturated cycloalkyl or
heterocyclic rings.
[0090] Examples of such preferred substituents according to paragraph
[0089] include

[0091] In some embodiments of the compounds according to paragraph
[0083], Cy3 is heterocyclyl, e.g.,
and

each of which optionally is substituted and optionally is fused to one
or more aryl rings. In some embodiments, the heterocycle of Cy3 is
fused to a benzene ring.
[0092] Preferably in the compounds of paragraph [0083], when Ar4 is
quinoxalinylene, then X3 is not -CH(OH)-!'
[0093] In another preferred embodiment, Ar3 is
wherein X is -CH2-, -NH-, 0, or S. Preferably Ar3 is
and X is S or 0.
[0094] In a preferred embodiment, the novel histone deacetylase
inhibitors of the invention are those according to paragraph [0058]
wherein
Ay2 is ortho-anilinyl;
q is 0; and
X1 is M1-L2-M1 or L2-M2-L2.
[0095] In a preferred embodiment of the compounds according to
paragraph [0094] , Ar2 is aryl or heteroaryl; and Cy2-X1- is
collectively selected from the group consisting of
a) A1-L1-B1-, wherein A1 is an optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heterocyclyl; wherein Lx is -(CH2) 0-1NH(CH2)0-1-, -NHC(O)-, or
-NHCH2-; and wherein B1 is phenyl or a covalent bond;
b) A2-L2-B2-, wherein A2 is CH3{C=CH2)-, optionally substituted
cycloalkyl, optionally substituted alkyl, or optionally
substituted aryl; wherein L2 is -C=C-; and wherein B2 is a
covalent bond;
c) A3-L3-B3-, wherein A3 is an optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heterocyclyl; wherein L3 is a covalent bond; and wherein B3 is
-CH2NH- ;
d) A4-L4-B4-, wherein A4 is an optionally substituted aryl;
wherein L4 is -NHCH2-; and wherein B4 is a thienyl group;

e) A5-L5-B5-, wherein A5 is an optionally substituted heteroaryl
or optionally substituted heterocyclyl; wherein L5 is a
covalent bond; and wherein B5 is -SCH2-;
f) morpholinyl-CH2-
g) optionally substituted aryl;
h) A5-L5-B5-, wherein A^ is an optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heterocyclyl; wherein L6 is a covalent bond; and wherein B6 is
-NHCH2-;
i) A7-L7-B7-, wherein A7 is an optionally substituted heteroaryl
or optionally substituted heterocyclyl; wherein L7 is a
covalent bond; and wherein B7 is -CH2-;
j) aptionally substituted heteroaryl or optionally substituted
heterocyclyl;
k) AaL8-B8-, wherein A8 is optionally substituted phenyl; wherein
LB iB a covalent bond; and wherein B8 is -O-;
1) A9-L9-B9-, wherein A9 is an optionally substituted aryl;
wherein L9 is a covalent bond; and wherein B9 is a furan
group;
m) A10-"l10-B10, wherein A10 is an optionally substituted heteroaryl
or optionally substituted heterocyclyl; wherein L10 is -
CH(CH2CH3)-; and wherein B10 is -NHCH2-;
n) Aii-Lh-Bu-, wherein AX1 is an optionally substituted heteroaryl
or optionally substituted heterocyclyl; wherein LX1 is a
covalent bond; and wherein BX1 is -0CH2-;
o) Ai2-Li2-Bi2-, wherein Ai2 is an optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heterocyclyl; wherein L12 is-NHC(O)-; and wherein Bi2 is -
N(optionally substituted aryl)CH2-;
p) A13-L1.3-B13-, wherein A12 is an optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heterocyclyl; wherein L13 is a covalent bond; and wherein B13
is -NHC(O)-;
q) Ai4-L14-Bi4-, wherein Ai4 is an optionally substituted aryl,
optionally .substituted heteroaryl or optionally substituted
heterocyclyl; wherein I>n is-NHC(O)(optionally substituted
heteroaryl); and wherein.B14 is -S-S-;
r) F3CC(O)NH-;


s) Als-Lis-B15-, wnerem A15 is an optionally substituted aryl,
optionally substituted.heteroaryl or optionally substituted
heterocyclyl; wherein L1S is-(CH2)0-iNH (optionally substituted
heteroaryl)-; and wherein B15 is -NHCH2-,-
t) A16-Li6-Bi6-, wherein A16 is an optionally substituted aryl, .
optionally substituted heteroaryl or optionally substituted
heterocyclyl; wherein L16 is a covalent bond; and wherein B16
is -N(optionally substituted alkyl)CH2-; and
u) A16-L16-B16-, wherein A16 is an optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heterocyclyl; wherein L16 is a covalent bond; and wherein B16
is -(optionally substituted aryl-CH2)2-N-.
[0096] In another preferred embodiment of the compounds according to
paragraph [0094] , Cj^-X1- is collectively selected from the group
consisting of
a) Di-Ei-Fi-, wherein na is an optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heterocyclyl; wherein Ex is -CH2- or a covalent bond; and
wherein Bx is a covalent bond;
b) D2-E2-F2-, wherein D2 is an optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heterocyclyl; wherein E2 is -NH(CH2)0-2-; and wherein F2 is a
covalent bond;
c) D3-E3-F3-, wherein D3 is an optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heterocyclyl; wherein E3 is - (CH2)o-2NH-; and wherein F3 is a
covalent bond;
d) D4-E4-F4-, wherein D4 is an' optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heterocyclyl; wherein E4 is -S(CH2)0-2_; and wherein F4 is a
covalent bond;
e) D5-E5-F5-, wherein D5 is an optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted
heterocyclyl; wherein E5 is -(CH2)0-2S-; and wherein Fs is a
covalent bond; and
f) D6-E6-F6-, wherein D6 is an optionally substituted aryl,
optionally substituted heteroaryl or optionally substituted

heterocyclyl; wherein E€ is -NH(CH2)o-2NH-; ana wherein F6 is a
covalent bond.
[0097] In a preferred embodiment, the HDAC inhibitors of the
invention comprise compounds of paragraph [0058] having formula (3b):
(3b)
and pharmaceutical]^ acceptable salts thereof, wherein Y and Z are
independently N or CH and W is selected from the group consisting of:
[0100] In yet another a preferred embodiment, the novel histone
deacetylase inhibitors of the invention are selected from the group
consisting of the following and their pharmaceutically acceptable
salts:

[0101] In another preferred embodiment, the compounds are selected
from those listed in Tables 2a-b, 3a-d, 4a-c, and 5a-5f.
Synthesis
[0102] Compounds of formula (1), wherein Y1 is' -NfR1) (R2) , preferably
may be prepared according to the synthetic route depicted in Scheme 1.
Thus, trichlorotriazine I reacts with amine II in the presence of
diisopropylethylamine to produce dichloroaminotriazine III. The amine
R^NH is added to dichloroaminotriazine III to produce
diaminochlorotriazine V. Treatment of V with ammonia or R3R4NH in
tetrahydrofuran (THF) or 1,4 dioxane affords triaminotriazine VI.
[0103] Alternatively, dichloroaminotriazine III may be reacted with
ammonia gas in 1,4 dioxane to produce diaminochlorotriazine IV.
Treatment of IV with R1r2NH in THF or 1,4 dioxane in a sealed flask
then affords triaminotriazine VI.
[0104] Hydrolysis of the ester moiety in VI is effected by treatment
with a hydroxide base, such as lithium hydroxide, to afford the
corresponding acid VII. Treatment of the acid VII with 1,2-
phenylenediamine in the presence of BOP reagent, triethylamine, and
dimethylformamide (DMF) yields the anilinyl amide VIII.
[0105] Compounds of formula (1), wherein Y1 is -CH2-C(O)-N(Ra) (R2) ,
preferably may be prepared as outlined in Scheme 2. Thus, piperazine


IX is treated with acetyl chloride and triethylamine to produce amide
X. Reaction of X with dichloromorpholyltriazine and lithium
hexamethyldisiloxane affords compound XI. The chloride of XI is
converted to the anilinyl amide of XII as described above with respect
to Scheme 1: treatment with the amine and diisopropylethylamine;
followed by lithium hydroxide; followed by BOP reagent,
.phenylenediamine, triethylamine, and DMF.
Scheme 2
[0106] Compounds of formula (.2), wherein Ar2 is pyridylene and X1
comprises -N(R7)-, compounds of formula (3), wherein Ar3 is pyridylene
and X2 comprises -N(R9)-, and compounds of formula (4), wherein Ar4 1b
pyridylene and X3 comprises -N(RU)-, preferably may be prepared
according to the procedures illustrated in Scheme 3. Dibromopyridine
XIII or XIV is treated with amine RNH2 to produce aminobromopyridine
XV or XVI, respectively. Treatment of XV or XVI with
diacetoxypalladium, diphenylphosphinoferrocene, DMF,
diisopropylethylamine, and phenylenediamine under carbon monoxide
yields anilinyl amide XVII or XVIII, respectively.
[0107] Treatment of XV or XVI with tert-butylacrylate,
diisopropylethylamine, dibenzylacetone palladium, and tri-o-
tolylphosphine (POT) in DMF under nitrogen affords compounds XIX and
XX, respectively. The ester moiety of XIX or XX is hydrolyzed to
produce the corresponding acid moiety in XXI or XXII, respectively, by
reaction with trifluoroacetic acid in dichloromethane. Treatment of


the acid XXI or XXII with, phenylenediamine, HOP,* e&id triethylamine
affords the anilinyl amide XXIII or XXIV, respectively.

[0108] Compounds of formula (2), wherein X1 comprises -O-C(O)-NH-,
preferably may be prepared according to the synthetic route depicted
in Scheme 4. Thus, carbinol XXV is added to bromobenzylamine XXVI
with carbonyldiimidazole (CDI), triethylamine, and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF to produce compound XXVII.
The remaining synthetic steps in the production of anilinyl amide
XXVIII are as described above for Scheme 3.
[0109] • Compounds of formula (2), wherein X1 comprises -N(R7)-,
preferably may be prepared as outlined in Scheme B. Amine XXIX is
reacted with p-bromobenzylbromide in the presence of potassium carbonate
in DMF to produce bromobenzylamine XXX. Treatment of XXX with
nitroacrylanilide, dibenzylacetone palladium, POT,
anddiisopropylethylamine in DMF affords nitroanilide XXXI. Nitroanilide
XXXI is converted to the corresponding anilinyl amide XXXII by treatment
with stannous chloride in methanol and water.
[0110] Treatment of amine XXXI in formic acid with paraformaldehyde
provides methylamine XXXIII. The nitroanilide moiety in XXXIII is then
converted to the corresponding anilinyl amide moiety in XXXIV by
treatment with stannous chloride in methanol and water.
10111] Alternatively, compounds of formula (2), wherein X1 comprises
-N(R7)-, may be prepared according to the synthetic route depicted in
Scheme 6. Carboxylic acid XXXV in methanol is treated with hydrochloric
acid to produce ester XXXVI. Conversion of the primary amine moiety in
XXXVI to the secondary amine moiety in XXXVI is effected by treatment
with a catalyst such as triethylamine, methoxybenzylchloride, sodium
iodide, and potassium carbonate in DMF at 60 °C. Ester XXXVI is
converted to anilinyl amide XXXVII by treatment with sodium hydroxide,
THF, and methanol, followed by BOP, triethylamine, and phenylenediamine
in DMF, as described above for Scheme 3.
Scheme 6
[0112] Compounds of formula (2), wherein X1 comprises or
-C(O)-NH-, preferably may be prepared according to the procedures
illustrated in Scheme 7. Addition of amine 68 to haloaryl compound
XXXVIII or XXXIX and potassium carbonate in DMF provides arylamine XL or
XL1, respectively. Anilinyl amide XLII or XLIII is then prepared using
procedures analogous to those set forth in Schemes 3-6 above.
Scheme 7

[0113] Compounds such as XLVII and XLXX preferably may be prepared as
outlined in Scheme 8. Dibromopyridine is combined with diaminoethane to
produce amine XLIV. Treatment of amine XLIV with isatoic anhydride LV
in methanol and water, followed by refluxing in formic acid affords
compound XLVI. Treatment of amine XLIV with the reaction products of
benzylaminodiacetic acid and acetic anhydride provides compound XLVIII.
Bromopyridylamines XLVi and XLVIII are then converted to the
corresponding diene anilinylamides XLVII and XLIX, respectively, by
procedures analogous to those set forth in Schemes 3-7 above.
[0114] Compounds such as LIV preferably may be prepared according to
the synthetic route depicted in Scheme 9. Trichlorotriazine is treated
with aminoindan and diisopropylethylamine to produce
dichloroaminotriazine L. Treatment with bromobenzylamine and
diisopropylethylamine affords diaminochlorotriazine LI. Addition of
ammonia gas and dioxane provides triaminotriazine LII. Treatment with
protected acrylanilide, triethylamine, POT, and dibenzylacetone
palladium then yields diene anilinylamide LIII, which is deprotected
with trifluoroacetic acid to provide the final product LTV.
[0115] Compounds of formula (2) , wherein Ar2 is guinolylene and X1
comprises -N(R7)-, compounds of formula (3), wherein Ar3 is quinolylene
and X2 comprises -N(R9)-, and compounds of formula (4), wherein Ar* is
quinolylene and X3 comprises -N(RX1)-, preferably may be prepared
according to the procedures illustrated in Scheme 10.
Dihydroxyquinoline LV with dimethylaminopyridine (DMAP) in pyridine is
treated with trifluoromethanesulfonic anhydride to provide
bis(trifluoromethanesulfonyloxy)-quinoline LVI. Treatment of LVI with
p-methoxybenzylamine affords aminoquinoline LVII. Anilinyl amides LVIII
and LIX are then prepared using procedures analogous to those described
for Schemes 1-9 above.
Scheme 10
[0116] Compounds of formula (3), wherein X' comprises a sulfur atom, and
compounds of formula (4), wherein X3 comprises a sulfur atom, preferably
may be prepared as outlined in Scheme 11. Bromide LX is converted to
diaryl ester LXI using procedures analogous to those described for
Scheme 6 above. Synthetic methods similar to those set forth in Scheme
1 above are then used to convert ester LXI to the corresponding acid
LXIV. Alternatively, ester LXI may be treated with
chloroethylmorphonline, sodium iodide, potassium carbonate,
triethylamine, and tetrabutylammonium iodide (TBAI) in DMF to produce
ester LXIII, which is then converted to acid LXIV as in Scheme 1.
Conversion of the acid LXIV to the anilinyl amide LXV is effected by
procedures analogous to those set forth in Scheme 1 above.
LXIII
[0117] Alternatively, compounds of formula (3), wherein X2 comprises a
sulfur atom, and compounds of formula (4) , wherein X3 comprises a sulfur
atom, may be prepared according to the procedures illustrated in Scheme
12. Sulfanyl anilinylamide LXVIII is prepared using procedures
analogous to those set forth in Schemes 3 and 5 above.
[0118] Compounds of formula (3), wherein X2 comprises -N(R9)-, and
compounds of formula (4), wherein X3 comprises -N(RU)-, preferably may be

prepared according to the synthetic route depicted in Scheme 13. Amino
anilinyl amide LXXI is prepared according to synthetic steps similar to
those described for Schemes 1 and 6 above.
Scheme 13

[0119] Compounds of formula (3), wherein X2 comprises a sulfur atom, and
compounds of formula (4), wherein X3 comprises a sulfur atom, preferably
may be prepared as outlined in Scheme 14. Phenylenediamine is reacted
with di-tert-butyldicarbonate, followed by iodobenzoic acid,
dimethylaminopropylethylcarbodiimide, hydroxybenzotriazole, and
triethylamine to provide protected anilinyl amide LXXII. The iodide
moiety of LXXII is converted to the methyl ester moiety of LXXIII using
procedures analogous to those set forth for Scheme 3 above. The methyl
ester moiety of LXXIII is converted to the hydroxyl moiety of LXX1V by
treatment with a reducing agent such as diisobutylaluminum hydride
(DIBAL-H). Addition of the heterocyclylsulfhydryl compound Het-SH with
triphenylphosphine and diethylazodicarboxylate converts the hydroxyl
moiety of LXXIV to the sulfanyl moiety of LXXV. LXXV is deprotected
with trifluoroacetic acid to afford the sulfanyl anilinyl amide LXXVT.
[0120] Compounds of formula (3) , wherein X2 is a chemical bond,
preferably may be prepared according to the synthetic route depicted in
Scheme 15. Thus, chloroarylanilinyland.de LXXVII is treated with aryl
boronic acid, benzene, ethanol, aqueous sodium carbonate, and
triphenylphosphine palladium to afford the diarylanilinylamide LXXVTII.
[0121] Compounds such as LXXXI preferably may be prepared according to
the procedues illustrated in Scheme 16. Thus, benzene-1,2-carbaldehyde
LXXIX in acetic acid is treated with p-aminomethylbenzoic acid to
produce the benzoic acid LXXX. The acid LXXX is converted to the
corresponding anilinylamide LXXXI by treatment with
hydroxybenzotriazole, ethylenedichloride, and phenylenediamine.
[0122] Compounds such as LXXXVI and LXXXIX preferably may be prepared
according to the procedures illustrated in Scheme 18. Phthalic
anhydride LXXXV and p-aminomethylbenzoic acid are combined in acetic
acid to produce an intermediate carboxylic acid, which is converted to
the anilinylamide LXXXVI using procedures analogous to those set forth
in Schemes 15 and 16 above.
[0123] The addition of 4-(2-atninoethyl)phenol to phthalic anhydride
LXXXV in acetic acid affords the hydroxyl compound LXXXVTI. The
hydroxyl group of LXXXVII is converted to the triflate group of LXXXVTII
by treatment with sodium hydride, THF, DMF, and phenylaminoditriflate.
Treatment of LXXXVIII according to procedures analogous to those
described for Scheme 3 above affords the anilinylamide LXXXIX.
Scheme 18
[0124] Compounds such as XCI-XCVI preferably may be prepared according
to the synthetic route depicted in Scheme 19. Treatment of isatoic
anhydride XC with p-aminomethylbenzoic acid in water and triethylamine,
followed by formic acid affords an intermediate carboxylic acid, which
is converted to anilinylamide XCI using procedures analogous to those
described for Scheme 16 above.
[0125] Alternatively, treatment of isatoic acid XC with p-
aminomethylbenzoic acid in water and triethylamine, follwed by
hydrochloric acid and sodium nitrite affords an intermediate carboxylic
acid, which is converted to anilinylamide XCII using procedures
analogous to those described for Scheme 16 above.
[0126] Alternatively, treatment of isatoic acid XC with p-
aminomethylbenzoic acid in water and triethylamine affords benzoic acid
XCIII. Treatment of XCIII with sodium hydroxide, dioxane,
methylchloroformate, and methanol affords an intermediate
quinazolinedione carboxylic acid, the acid moiety of which is then
converted to the anilinylamide moiety of XCIV using procedures analogous
to those described for Scheme 16 above. Alternatively, the intermediate
quanzolinedione carboxylic acid in DMF is treated with potassium
carbonate and methyl iodide to produce an intermediate benzoic acid
methyl ester, which is converted to an intermediate benzoic acid by
treatment with sodium hydroxide, methanol, and water. The benzoic acid
is then converted to the corresponding anilinylamide XCV using
procedures analogous to those described for Scheme 16 above.
[0127] Alternatively, treatment of XCIII with acetic anhydride followed
by acetic acid produces.an intermediate carboxylic acid, which is
converted to anilinylamide XCVI using procedures analogous to those
described for Scheme 16 above.

[0128] Compounds such as C preferably may be prepared as outlined in
Scheme 20. Alkylamine XCVII is treated with thiocarbonyl diimidazole in
dichloromethane, follwed by ammonium hydroxide to afford thiourea
XCVIII. Treatment of thiourea XCVIII with methylmethoxyacrylate in
dioxane and N-bromosuccinimide produces thiazole ester IC. The ester IC
is converted to the corresponding anilinylamine C using procedures
analogous to those set forth in Scheme 1 above.

[0129] Compounds of formula (3) , wherein X2 is a chemical bond and Cy3
has an amino substituent preferably may be prepared according to the
synthetic route depicted in Scheme 21. Thus, protected
iodoarylanilinylamide CI is treated according to procedures analogous to
those described for Scheme 15 above afford the diarylanilinylanri.de C1I.
The aldehyde moiety in CII is converted to the corresponding secondary
amine moiety by treatment with the primary amine and sodium
triacetoxyborohydride followed by glacial acetic acid. The resultant
compound is deprotected to yield CIII using procedures analogous to
those set forth in Scheme 3 above.
Scheme 21
[0130] Compounds of formula (3), wherein X comprises an alkynylene
moiety, and compounds of formula (4), wherein X3 comprises an alkynylene
moiety, preferably may be prepared as outlined in Scheme 22. Treatment
of protected iodoarylanilinylamide CI with triphenylphosphine palladium
chloride, cuprous iodide, and 1-ethynylcyclohexylamine affords the
alkynylarylanilinylamide CIV. The primary amine moiety in CIV is
converted to the corresponding secondary amine and the aniline moiety is
deprotected to afford CV using procedures analogous to those described
for Scheme 21 above.
Scheme 22
CVIII
[0131] Compounds such as CVIII preferably may be prepared according to
the synthetic route depicted in Scheme 24. Dichloroaminotriazine CVI is
treated with methyl-4-aminobenzoate in the presence of
diisopropylethylamine to produce diaminotriazine CVII. Addition of
ammonia gas and dioxane, followed by a saponification and a peptide
coupling using the same procedures analogous to those described for
Scheme 1 above.
Scheme 30
[0132] Compounds Buch as CX preferably may be prepared according to the
synthetic route depicted in Scheme 30. The Grignard reaction of

trichloroaminotriazine with various alkyl magnesium bromide, followed by
a treatment with methyl-4-aminobenzoate in the presence of
diisopropylethylamine yields alkylaminotriazine CIX. Synthetic methods
similar to those set forth in Scheme 1 above are then used to convert
ester CIX to the corresponding anilinyl amide CX.
Scheme 32
[0133] Amination of dichlorotriazine proceeded using the usual
condition described in Scheme 1 to afford CXI. Stille coupling using
vinyl stannane provides CXII. Treatment with protected iodoanilide,
triethylamine, POT and dibenzylacetone palladium then yields
anilinylamide, which is deprotected with trifluoroacetic acid to provide
the alkene CXIII. Hydrogenation of the alkene affords the final compound
CXIV.
[0134] Compounds such as CXVIII preferably may be prepared according to
the synthetic route depicted in Scheme 33. Treatment of
methoxyaminobenzothiazole with tribromide boron affords the
corresponding acid CXV. Mitsunobu reaction using hydroxyethyl morpholine
in the presence of diethylazodicarboxylate and triphenylphosphine yields
the amine CXVI. Reductive amination with methyl-4-formylbenzoate using
phenylsilane and tin catalyst yields to the ester CXVII. Saponification
followed by the usual peptide coupling analogous to those describe for
Scheme 1 above provides the desired anilide CXVIII.
[0135] Treatment 4-methylcyanobenzoic acid with hydrogen sulfide
affords CXIX, which is subjected to cyclization in the presence of 1,3-
dichloroacetone to yield CXX. Treatment with morpholine followed by a
peptide coupling using the standard condition produces CXXI.
[0136] Compounds such as CXXIII and CXXVII preferably may be prepared
according to the synthetic scheme 49. Consecutive treatment of acetyl
acetone with methyl bromomethylbenzoate in the presence of NaOMe and
phenyl hydrazine followed by saponification, afforded the intermediate
acid CXXII. This material was coupled with 1,2-diaminobenzene in a
standard fashion to afford CXXIII.
[0137] Consecutive treatment of acetyl acetone with methyl
bromomethylbenzoate in the presence of NaOMe and a 1:1 mixture AcOH-HCl
(cone.) afforded the intermediate acid CXXIV. This keto-acid reacting
with sulfur and malonodinitrile in the presence of a base, produced the
thiophene CXXV, which was converted into the desired CXXVII using
standard procedures.

cxxx
[0138] Compounds such, as CXXX preferably may be prepared according to
the synthetic scheme 50. Treatment of 4-cyanomethylbenzoic acid with
hydroxylamine produced the amidoxime CXXVIII, which upon treatment with
acetic anhydride was converted into the oxadiazole CXXIX. The latter was
coupled with 1,2-diaminobenzene in a standard fashion to afford CXXX.

[0139] Compounds such as CXXXIII preferably may be prepared according
to the synthetic route depicted in Scheme 57. Treatment of 4-
formylbenzoic acid with thionyl chloride afford the acyl chloride which
is coupled with protected anilide to produce CXXXI. Reductive amination
with dimethoxyaniline using phenylsilane and tin catalyst yields to the
protected anilide CXXXII. Treatment with isocyanate followed by
deprotection with trifluoroacetic acid provides the ureidoanilide
CXXXIII.
Pharmaceutical Compositions
[0140] In a second aspect, the invention provides pharmaceutical
compositions comprising an inhibitor of histone deacetylase according to
the invention and a pharmaceutically acceptable carrier, excipient, or
diluent. Compounds of the invention may be formulated by any method
well known in the art and may be prepared for administration by any
route, including, without limitation, parenteral, oral, sublingual,
transdermal, topical, intranasal, intratracheal, or intrarectal. In
certain preferred embodiments, compounds of the invention are
administered intravenously in a hospital setting. In certain other
preferred embodiments, administration may preferably be by the oral
route.
[0141] The characteristics of the carrier will depend on the route of
administration. As used herein, the term "pharmaceutically acceptable"
means a non-toxic material that is compatible with a biological system
such as a cell, cell culture, tissue, or organism, and that does not
interfere with the effectiveness of the biological activity of the.
active ingredient(s). Thus, compositions according to the invention may
contain, in addition to the inhibitor, diluents, fillers, salts,
buffers, stabilizers, solubilizers, and other materials well known in
the art. The preparation of pharmaceutically acceptable formulations is
described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition,
ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990.
[0142] As used herein, the term pharmaceutically acceptable salts
I
refers to salts that retain the desired biological activity of the
above-identified compounds and exhibit minimal or no undesired
toxicological effects. Examples of such salts include, but are not
limited to acid addition salts formed with inorganic acids (for example,
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
nitric acid, and the like), and salts formed with organic acids such as
acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,
ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid,
polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid,
67
and polygalacturonic acid. The compounds can also be administered as
pharmaceutically acceptable quaternary salts known by those skilled in
the art, which specifically include the quaternary ammonium salt of the
formula -NR + Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a
counterion, including chloride, bromide, iodide, -O-alkyl,
toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate
(such as benzoate, succinate, acetate, glycolate, maleate, malate,
citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,
benzyloate, and diphenylacetate).
[0143] The active compound is included in the pharmaceutically
acceptable carrier or diluent in an amount sufficient to deliver to a
patient a therapeutically effective amount without causing serious toxic
effects in the patient treated. A preferred dose of the active compound
for all of the above-mentioned conditions is in the range from about
0.01 to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally
0.5 to about 25 mg per kilogram body weight of the recipient per day. A
typical topical dosage will range from 0.01-3% wt/wt in a suitable
carrier. The effective dosage range of the pharmaceutically acceptable
derivatives can be calculated based on the weight of the parent compound
to be delivered. If the derivative exhibits activity in itself, the
effective dosage can be estimated as above using the weight of the
derivative, or by other means known to those skilled in the art.
Inhibition of Histone Deacetylase
[0144] In a third aspect, the invention provides a method of inhibiting
histone deacetylase in a cell, comprising contacting a cell in which
inhibition of histone deacetylase is desired with an inhibitor of
histone deacetylase according to the invention. /Because compounds of
the invention inhibit histone deacetylase, they are useful research
tools for in vitro study of the role of histone deacetylase in
biological processes. In addition, the compounds of the invention
selectively inhibit certain isoforms of HDAC.
[0145] Measurement of the enzymatic activity of a histone deacetylase
can be achieved using known methodologies. For example, Yoshida et al.,
J. Biol. Chem., 265: 17174-17179 (1990), describes the assessment of
histone deacetylase enzymatic activity by the detection of acetylated

histories in trichostatin A treated cells. Taunton et al., Science, 272:
408-411 (1996), similarly describes methods to measure histone
deacetylase enzymatic activity using endogenous and recombinant HDAC-1.
[01463 In some preferred embodiments, the histone deacetylase inhibitor
interacts with and reduces the activity of all histone deacetylases in
the cell. In some other preferred embodiments according to this aspect
of the invention, the histone deacetylase inhibitor interacts with and
reduces the activity of fewer than all histone deacetylases in the cell.
In certain preferred embodiments, the inhibitor interacts with and
reduces the activity of one histone deacetylase (e.g., HDAC-1), but does
not interact with or reduce the activities of other histone deacetylases
(e.g., HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, and HDAC-8). As
discussed below, certain particularly preferred histone deacetylase
inhibitors are those that interact with, and reduce the enzymatic
activity of, a histone deacetylase that is involved in tumorigenesis.
Certain other preferred histone deacetylase inhibitors interact with and
reduce the enzymatic activity of a fungal histone deacetylase.
[0147] Preferably, the method according to the third aspect of the
invention cauBes an inhibition of cell proliferation of the contacted
cells. The phrase "inhibiting cell proliferation" is used to denote an
ability of an inhibitor of histone deacetylase to retard the. growth of
cells contacted with the inhibitor as compared to cells not contacted.
An assessment of cell proliferation can be made by counting contacted
and non-contacted cells using a Coulter Cell Counter (Coulter, Miami,
FL) or a hemacytometer. Where the cells are in a solid growth (e.g., a
solid tumor or organ), such an assessment of cell proliferation can be
made by measuring the growth with calipers and comparing the size of the
growth of contacted cells with non-contacted cells.
[0148] Preferably, growth of cells contacted with the inhibitor is
retarded by at least 50% as compared to growth of non-contacted cells.
More preferably, cell proliferation is inhibited by 100% (i.e., the
contacted cells do not increase in number). Most preferably, the phrase
"inhibiting cell proliferation" includes a reduction in the number or
size of contacted cells, as compared to non-contacted cells. Thus, an
inhibitor of histone deacetylase according to the invention that

inhibits cell proliferation in a contacted cell may induce the contacted
cell to undergo growth retardation, to undergo growth arrest, to undergo
programmed cell death (i.e., to apoptoBe), or to undergo necrotic cell
death.
[0149] The cell proliferation inhibiting ability of the histone
deacetylase inhibitors according to the invention allows the
synchronization of a population of asynchronously growing cells. For
example, the histone deacetylase inhibitors of the invention may be used
to arrest a population of non-neoplastic cells grown in vitro in the. Gl
lor G2 phase of the cell cycle. Such synchronization~aiiows, for
example, the identification of gene and/or gene products expressed
during the Gl or G2 phase of the cell cycle. Such synchronization of
cultured cells may also be useful for testing the efficacy of a new
transfection protocol, where transfection efficiency varies and is
dependent upon the particular cell cycle phase of the cell to be
transfected. Use of the histone deacetylase inhibitors of the invention
allows the synchronization of a population of cells, thereby aiding
J detection of enhanced transfection efficiency.
[0150] In some preferred embodiments, the contacted cell is a
neoplastic cell. The term "neoplastic cell" is used to denote a cell
that shows aberrant cell growth. Preferably, the aberrant cell growth of
a neoplastic cell is increased cell growth. A neoplastic cell may be a
hyperplastic cell, a cell that shows a lack of contact inhibition of
growth in vitro, a benign tumor cell that is incapable of metastasis in,
vivo, or a cancer cell that is capable of metastasis in vivo and that
may recur after attempted removal. The term "tumorigenesis" is used to
denote the induction of cell proliferation that leads to the development
of a neoplastic growth. In some embodiments, the histone deacetylase
inhibitor induces cell differentiation in the contacted cell. Thus, a
neoplastic cell, when contacted with an inhibitor of histone deacetylase
may be induced to differentiate, resulting in the production of a non-
neoplastic daughter cell that is phylogenetically more advanced than the
contacted cell.
[0151] In some preferred embodiments, the contacted cell is in an
animal. Thus, the invention provides a method for treating a cell

proliferative disease or condition in an animal, comprising
administering to an animal in need of such treatment a therapeutically
effective amount of a histone deacetylase inhibitor of the invention.
Preferably, the animal is a mammal, more preferably a domesticated
mammal. Most preferably, the animal is a human.
[0152] The term "cell proliferative disease or condition" is meant to
refer to any condition characterized by aberrant.cell growth, preferably
abnormally increased cellular proliferation. Examples of such cell
proliferative diseases or conditions include, but are not limited to,
cancer, restenosis, and psoriasis. In particularly preferred
embodiments, the invention provides a method for inhibiting neoplastic
cell proliferation in an animal comprising administering to an animal
having at least one neoplastic cell present in its body a
therapeutically effective amount of a histone deacetylase inhibitor of
the invention.
[0153] It is contemplated that some compounds of the invention have
inhibitory activity against a histone deacetylase from a protozoal
source. Thus, the invention also provides a method for treating or
preventing a protozoal disease or infection, comprising administering to
an animal in need of such treatment a therapeutically effective amount
of a histone deacetylase inhibitor of the invention. Preferably the
animal is a mammal, more preferably a human. Preferably, the histone
deacetylase inhibitor used according to this embodiment of the invention
inhibits a protozoal histone deacetylase to a greater extent than it
inhibits mammalian histone deacetylases, particularly human histone
deacetylases.
[0154] The present invention further provides a method for treating a
fungal disease or infection comprising administering to an animal in
need of such treatment a therapeutically effective amount of a histone
deacetylase inhibitor of the invention. Preferably the animal is a
mammal, more preferably a human. Preferably, the histone deacetylase
inhibitor used according to this embodiment of the invention inhibits a
fungal histone deacetylase to a greater extent than it inhibits
mammalian histone deacetylases, particularly human histone deacetylases.
[0155] The term "therapeutically effective amount" is meant to denote a
dosage sufficient to cause inhibition of histone deacetylase activity in
the cells of the subject, or a dosage sufficient to inhibit cell
proliferation or to induce cell differentiation in the subject.
Administration may be by any route, including, without limitation,
parenteral, oral, sublingual, transdermal, topical, intranasal,
intratracheal, or intrarectal. In certain particularly preferred
embodiments, compounds of the invention are administered intravenously
in a hospital setting. In certain other preferred embodiments,
administration may preferably be by the oral route.
[0156] When administered systemically, the histone deacetylase
inhibitor is preferably administered at a sufficient dosage to attain a
blood level of the inhibitor from about 0.01 \m to about 100 uM, more
preferably from about 0.05 uM to about 50 uM, still more preferably from
about 0.1 |iM to about 25 \M, and still yet more preferably from about 0.5
uM to about 25 |iM. For localized administration, much lower
concentrations than this may be effective, and much higher
concentrations may be tolerated. One of skill in the art will
appreciate that the dosage of histone deacetylase inhibitor necessary to
produce a therapeutic effect may vary considerably depending on the
tissue, organ, or the particular animal or patient to be treated.
[0157] In certain preferred embodiments of the third aspect of the
invention, the method further comprises contacting the cell with an
antisense oligonucleotide that inhibits the expression of a histone
deacetylase. The combined use of a nucleic acid level inhibitor (e.g.,
antisense oligonucleotide) and a protein level inhibitor (i.e.,
inhibitor of histone deacetylase enzyme activity) results in an improved
inhibitory effect, thereby reducing the amounts of the inhibitors
required to obtain a given inhibitory effect as compared to the amounts
necessary when either is used individually. The antisense
oligonucleotides according to this aspect of the invention are
complementary to regions of RNA or double-stranded DNA that encode HDAC-
1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC7, and/or HDAC-8 (see
e.g., GenBank Accession Number U50079 for HDAC-1, GenBank Accession
Number U31814 for HDAC-2, and GenBank Accession Number U75697 for HDAC-
3) .
[0158] For purposes of the invention, the term "oligonucleotide"
includes polymers of two or more deoxyribonucleosides, ribonucleosides,
or 2'-substituted ribonucleoside residues, or any combination thereof.
Preferably, such oligonucleotides have from about 6 to about 100
nucleoside residues, more preferably from about 8 to about 50 nucleoside
residues, and most preferably from about 12 to about 30 nucleoside
residues. The nucleoside residues may be coupled to each other by any
of the numerous known internucleoside linkages. Such internucleoside
linkages include without limitation phosphorothioate,
phosphorodithioate, alkylphosphonate, alkylphosphonothioate,
phosphotriester, phosphoramidate, siloxane, carbonate,
carboxymethylester, acetamidate, carbamate, thioether, bridged
phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate
and sulfone internucleoside linkages. In certain preferred embodiments',
these internucleoside linkages may be phosphodiester, phosphotriester,
phosphorothioate, or phosphoramidate linkages, or combinations thereof.
The term oligonucleotide also encompasses such polymers having
chemically modified bases or sugars and/ or having additional
substituents, including without limitation lipophilic groups,
intercalating agents, diamines and adamantane.
[0159] For purposes of the invention the term "2'-substituted
ribonucleoside" includes ribonucleosides in which the hydroxyl group at
the 2' position of the pentose moiety is substituted to produce a 2'-O-
substituted ribonucleoside. Preferably, such substitution is with a
lower alkyl group containing 1-6 saturated or unsaturated carbon atoms,
or with an aryl or allyl group having 2-6 carbon atoms, wherein such
alkyl, aryl or allyl group may be unsubstituted or may be substituted,
e.g., with halo, hydroxy, trifluoromethyl, cyano, nitro, acyl, acyloxy,
alkoxy, carboxyl, carbalkoxyl, or amino groups. The term "2'-
substituted ribonucleoside" also includes ribonucleosides in which the
2'-hydroxyl group is replaced with an amino group or with a halo group,
preferably fluoro.
[0160] Particularly preferred antisense oligonucleotides utilized in
this aspect of the invention include chimeric oligonucleotides and
hybrid oligonucleotides.
[0161] For purposes of the invention, a "chimeric oligonucleotide"
refers to an oligonucleotide having more than one type of
internucleoside linkage. One preferred example of such a chimeric
oligonucleotide is a chimeric oligonucleotide comprising a
phosphorothioate, phosphodiester or phosphorodithioate region,
preferably comprising from about 2 to about 12 nucleotides, and an
alkylphosphonate or alkylphosphonothioate region (see e..g., Pederson et
al. U.S. Patent Nos. 5,635,377 and 5,366,878). Preferably, such
chimeric oligonucleotides contain at least three consecutive
internucleoside linkages selected from phosphodiester and
phosphorothioate linkages, or combinations thereof.
[0162] For purposes of the invention, a "hybrid oligonucleotide" refers
to an oligonucleotide having more than one type of nucleoside. One
preferred example of such a hybrid oligonucleotide comprises a
ribonucleotide or 2'-substituted ribonucleotide region, preferably
comprising from about 2 to about 12 2'-substituted nucleotides, and a
deoxyribonucleotide region. Preferably, such a hybrid oligonucleotide
contains at least three consecutive deoxyribonucleosides and also
contains ribonucleosides, 2'-substituted ribonucleosides, preferably 2'-
O-substituted ribonucleosides, or combinations thereof (see e.g.,
Metelev and Agrawal, U.S. Patent No. 5,652,355).
[0163] The exact nucleotide sequence and chemical structure of an
antisense oligonucleotide utilized in the invention can be varied, so
long as the oligonucleotide retains its ability to inhibit expression of
the gene of interest. This is readily determined by testing whether the
particular antisense oligonucleotide is active. Useful assays for this
purpose include quantitating the mRNA encoding a product of the gene, a
Western blotting analysis assay for the product of the gene, an activity
assay for an enzymatically active gene product, or a soft agar growth
assay, or a reporter gene construct assay, or an in vivo tumor growth
assay, all of which are described in detail in this specification or in
Ramchandani et al. (1997) Proc. Natl. Acad. Sci. USA 94: 684-689.

[0164] Antisense oligonucleotides utilized in the invention may
conveniently be synthesized on a suitable solid support using well known
chemical approaches, including H-phosphonate chemistry, phosphoramidite
chemistry, or a combination of H-phosphonate chemistry and
phosphoramidite chemistry (i.e., H-phosphonate chemistry for some cycles
and phosphoramidite chemistry for other cycles). Suitable solid
supports include any of the standard.solid supports used for solid phase
oligonucleotide synthesis, such as controlled-pore glass (CPG) (see,
e.g., Pon, R.T. (1993) Methods in Molec. Biol. 20: 465-496).
[0165] Particularly preferred oligonucleotides have nucleotide
sequences of from about 13 to about 35 nucleotides which include the
nucleotide sequences shown in Table 1. Yet additional particularly
preferred oligonucleotides have nucleotide sequences of from about 15 to
about 26 nucleotides of the nucleotide sequences shown in Table 1.
[0166] The following examples are intended to further illustrate
certain preferred embodiments of the invention, and are not intended to
limit the scope of the invention.
EXAMPLES
Example 1
4-{ [4-Amino-6-(2-indanyl-amino)-[l,3,5]-triazin-2-yl-aniino] -methyl}-N-(2-
amino-phenyl) -benzamide (confound 8)
Step 1: Methyl-4-[(4,6-dichloro-[1,3,5]triazin-2-yl-amino)-methyl]-
benzoate (compound 3)
[0167] To a stirred solution at -78°C of cyanuric chloride 1 (8.23 g,
44.63 mmol) in anhydrous THF (100, mL) under nitrogen was added a
suspension of methyl 4--(aminomethyl)benzoate.HCl 2 (10.00 g, 49.59
mmol), in anhydrous THF (50 mL), followed by i-Pr2NEt (19.00 mL, 109.10
mmol) . After 30 min, the reaction mixture was poured into a saturated
aqueous solution of NH4C1, and diluted with AcOEt. After separation, the
organic layer was successively washed with sat. NH4C1, H2O and brine,
dried over anhydrous MgSO4, filtered and concentrated. The crude residue
was then purified by flash chromatography on silica gel (AcOEt/CH2Cl2:
5/95) to afford the title compound 3 (12.12 g, 38.70 mmol, 87% yield) as
a pale yellow solid. 1H NMR (300 MHz, CDCl3) d (ppm) : AB system (8A =
8.04, 8B = 7.38, J = 8.5 Hz; 4H), 6.54 (bt, 1H), 4.76 (d, J = 6.3 Hz,
2H), 3.93 (s, 3H).
Pathway A
Step 2: Methyl-4-[(4-amino-6-chloro-[1,3,5] triazin-2-yl-amino)-methyl]-
benzoate (compound 4)
[0168] In a 150 mL sealed flask, a solution of 3 (6.00 g, 19.16 mmol)
in anhydrous 1,4-dioxane (60 mL) was stirred at room temperature,
saturated with NH3 gas for 5 min, and warmed to 70°C. for 6 h. The
reaction mixture was allowed to cool to room temperature, the saturation
step with NH3 gas was repeated at room temperature for 5 min, and the
reaction mixture was warmed to 70°C again for 18 h. Then, the reaction
mixture was allowed to cool to room temperature, poured into a saturated
aqueous solution of NH4C1, and diluted with AcOEt. After separation, the
organic layer was successively washed with sat. NH4C1, H2O and brine,
dried over anhydrous MgSO4, filtered and concentrated. The crude residue
was then purified by flash chromatography on silica gel (AcOEt/CH2Cl2:
30/70) to afford the title compound 4 (5.16 g, 17.57 mmol, 91% yield) as

a white solid. 1H NMR (300 MHz, CDCl3) d (ppm): AB system (5A =8.01, 5B -
= 7.35, J = 8.1 Hz, 4H), 5.79 (bs, 1H), 5.40-5.20 (m, 2H) , 4.72-4.63 (m,
2H), 3.91 (s, 3H).
Pathway B
Step 2: Methyl 4- [ (4-chloro-6-(2-indanyl-amino)-[l,3,5]triazin-2-yl-
amino)-methyl]-benzoate (compound 5)
[0169] To a stirred solution at room temperature of 3 (3.00 g, 9.58
mmol) in anhydrous THF (50 ml>) under nitrogen were added i-Pr2NEt (8.34
mL, 47.90 mmol) and 2-aminoindan.HCl (1.95 g, 11.50 mmol) or R^NH (1.2
equiv), respectively. After IB h, the reaction mixture was poured into
a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After
separation, the organic layer was successively washed with sat. NH4Cl,
H2O and brine, dried over anhydrous MgSO4, filtered and concentrated to
afford the title compound 5 (4.06 g, 9.91 mmol, quantitative yield) as a
white powder. 1H NMR (300 MHz, CDC13) 5 (ppm) : mixture of rotamers,
8.06-7.94 (m, 2H), 7.43-7.28 (m, 2H), 7.24-7.12 (m, 4H), 6.41 and 6.05
(2 bt, 1H), 5.68-5.44 (m, 1H), 4.92-4.54 (m, 3H), 3.92 (bs, 3H), 3.41-
3.12 (m, 2H), 2.90-2.70 (m, 2H).
Step 3: Methyl-4- [(4-amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-
amino)-methyl] -benzoate (compound 6)
General procedure for the amination with NH3 gas:
[0170] In a 150 mL sealed flask, a solution of 5 (3.90 g, 9.51 mmol) in
anhydrous 1,4-dioxane (80 mL) was stirred at room temperature, saturated
with NH3 gas for 5 min, and warmed to 140°C for 6 h. The reaction
mixture was allowed to cool to room temperature, the saturation step
with NH3 gas was repeated for 5 min, and the reaction mixture was warmed
to 140°C again for 18 h. Then, the reaction mixture was allowed to cool
to room temperature, poured into a saturated aqueous solution of NH4Cl,
and diluted with AcOEt. After separation, the organic layer was
successively washed with sat. NH4C1, H2O and brine, dried over anhydrous
MgSO4, filtered and concentrated. The crude residue was then purified by
flash chromatography on silica gel (MeOH/CH2Cl2: 3/97) to afford the
title compound 6 (3.50 g, 8.96 mmol, 94% yield) as a pale yellow sticky
solid. 1H NMR (300 MHz, CDCl3) d (ppm): 7.99 (bd, J = 8.2 Hz, 2H) ,

7.41-7.33 (m, 2H) , 7.24-7.13 (m, 4H), 5.50-5.00 (m, 2H) , 4.90-4.55 (m,
5H) , 3.92 (s, 3H), 3.40-3.10 (m, 2H) , 2.90-2.70 (m, 2H) . X3C NMR: (75
MHz, CDC13) 5 (ppm): 166.88, 167.35, 166.07, 144.77, 141.07, 129.82,
128.93, 127.01, 126.61, 124.70, 52.06, 51.80, 44.25, 40.16. HRMS
(calc): 390.1804, (found): 390.1800.
Pathways A and B, step 3, general procedure with primary and/or
secondary amines:
[0171] In a 50-75 mL sealed flask, a stirred solution of 4 (500 mg,
1.70 mmol, 1 eguiv) , i-Pr2NEt (1.48 mL, 8.51 mmol, 5 eguiv) and R^NH or
R3R*NH (1.5-3 equiv) in anhydrous THF or 1,4-dioxane (20-30 mL) was
warmed to 120-140°C for 15-24 h. Then, the reaction mixture was allowed
to cool to room temperature, poured into a saturated aqueous solution of
NH«Cl, and diluted with AcOEt. After separation, the organic layer was
successively washed with sat. NH4C1, H2O and brine, dried over anhydrous
MgSO4, filtered and concentrated. The crude residue was then purified by
flash chromatography on silica gel to afford the title compound.
Step 4: 4-[(4-Amino-6-(2-indanyl-amino) -[1,3,5]triazin-2-yl-amino)-
methyl]-benzoic acid (compound 7)
[0172] To a stirred solution at room temperature of 6 (2.07 g,'
5.30mmol) in THF (50 mL) was added a solution of LiOH.H2O (334 mg, 7.96
mmol) in water (25 mL). After 18 h, the reaction mixture was diluted in
water and acidified with 1 N HC1 until pH 5-6 in order to get a white
precipitate. After 1 h, the suspension was filtered off and the cake
was abundantly washed with water, and dried to afford the title compound
7 (1.73 g, 4.60 mmol, 87% yield) as a white solid. 1H NMR (300 MHz,
acetone-d6) 5 (ppm): 8.05 (bd, J= 8.1 Hz, 2H) , 7.56-7.42 (m, 2H) , 7.30-
7.10 (m, 4H), 5;90-5.65 (m, 2H), 4.85-4.60 (m, 4H), 3.40-2.80 (m, 4H).
HRMS (calc): 376.1648, (found): 376.1651.
Step 5: 4-{ [4-Amino-6- (2-indanyl-amino) -[l,3,5]-triazin-2-yl-amino] -
methyl}-Iff-(2-amino-phenyl)-benzamide (compound 8)
[0173] To a stirred solution at room temperature of 7 (200 mg, 0.53
mmol) in anhydrous DMF (5 mL) under nitrogen were added Et3N (74 \il, 0.53
mmol) and BOP reagent (282 mg, 0.64 mmol), respectively. After 40 min,
a solution of 1,2-phenylenediamine (64 mg, 0.58 mmol), Et3N (222 jil, 1.59

mmol) in anhydrous DMF (2 mL) was added dropwise. After 1.5 h, the
reaction mixture was poured into a saturated aqueous solution of NH4C1,
and diluted with AcOEt. After separation, the organic layer was
successively washed with sat. NH4C1, H2O and brine, dried over anhydrous
MgSO4, filtered and concentrated. The crude residue was then purified by
flash chromatography on silica gel (MeOH/CH2Cl2: 2/98-»5/95) to afford the
title compound 8 (155 mg, 0.33 mmol, 63% yield) as a pale yellow foam.
XH NMR (300 MHz, acetone-d6) 5 (ppm) : 9.04 (bs, 1H) , 7.96 (bd, J = 8.0
Hz, 2H), 7.50-7.40 (m, 2H), 7.30 (dd, J = 8.0 Hz, 1.4 Hz, 1H), 7.22-7.08
(m, 4H), 6.99 (ddd, J = 8.0 Hz, 7.5 Hz, 1.5 Hz, 1H), 6.86 (dd, J = 8.0
Hz, 1.4 Hz, 1H), 6.67 (dt, J = 7.5 Hz, 1.4 Hz, 1H), 6.60-5.49 (m, 4H) ,
4.80-4.50 (m, 4H) , 3.30-3.08 (m, 2H) , 2.96-2.74 (m, 2H) .
EXAMPLES 2-28
[0174] Examples 2 to 28 describe the preparation of compounds 9 to 35
using the same procedure as described for compound 8 of Example 1.
Characterization data are presented in Tables 2a and 2b.
Example 29
W-(2-Amino-phenyl)-4-({4-[2-(4-benzo[l,3]dioxol-5-ylmethyl-piparazin-
1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-[1,3,5] triazin-2-ylamino}-methyl)-
benzamide (compound 39)
Step 1: JJ-Acetyl-1-piperonylpiperazine (compound 37)
[0175] To a stirred solution at 0°C of 1-piperonylpiperazine 36 (5.00
g, 22.7 mmol) in anhydrous CH2C12 (60 mL) was added Et3N (6.33 mL, 45.4
mmol) followed by acetyl chloride (1.94 mL, 27.2 mmol). The reaction
mixture was stirred 30 min. at 0°C and then 2 h at room temperature.
The reaction mixture was poured into a saturated aqueous solution of
NH4C1, and diluted with AcOEt. After separation, the organic layer
was successively washed with sat. NH4C1, H2O and brine, dried over
anhydrous MgSO4, filtered and concentrated. The crude residue was
then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 4/96)
to afford the title compound 37 (5.52 g, 21.11 mmol, 93% yield) as a
yellow solid. XH NMR: (300 MHz, CDC13) 5 (ppm) : 6.83 (s, 1H) , 6.72 (m,
2H), 5.92 (s, 2H), 3.59 (t, J = 5.1 Hz, 2H), 3.44-3.40 (m, 4H), 2.42
(dt, J = 5.1 Hz, 5.1 Hz, 4H), 2.06 (s, 3H).
Step 2: 2-Chloro-4-morpholin-4-yl-6-[2-(4-benzo[1,3]dioxol-5-ylmethyl-
piperazin-1-yl)-2-oxo-ethyl]-[1,3,5]triazine (compound 38)
[0176] To a stirred solution of 37 (3.00 g, 11.4 mmol) in anhydrous
THF (25 mL) at -78°C was slowly added a solution of LiHMDS (11.4 mL,

11.4 mraol, 1 M in THF). The reaction mixture was stirred 1 h at -78°c
and a solution of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (2.69
g, 11.4 nimol) in anhydrous THF (25 mL) was added. The reaction
mixture was slowly warmed up at room temperature and the reaction was
quenched after 16 h with a saturated aqueous solution of NH4C1. The
THF was evaporated and the residue was diluted with AcOEt. The organic
layer was successively washed with sat. NH4Cl and brine, dried over
anhydrous MgSQ,, filtered and concentrated. The crude residue was
then purified by flash chromatography on silica gel (MeOH/CH2Cl2:
l/99-»3/97) to afford the title compound 38 (4.84 g, 10.49 mmol, 92%
yield) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) d (ppm) : 6.84
(S, 1H), 6.77-6.69 (m, 2H), 5.95 (s, 2H) , 3.75-3.43 (m, 16H), 2.42 (m,
4H) .
Step 3; N- (2-Amino-phenyl)-4-({4-[2-(4-benzo[l,3]dioxol-5-ylmethyl-
piperazin-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-[1,3,5]triazin-2-
ylamino)-methyl)-benzamide (compound 39)
[0177] The title compound 39 was obtained following the same
procedure as Example 1, step 5. aH NMR (CDC13) 5 (ppm): 7.96 (bs, 1H) ,
7.87 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.5
Hz, 1H), 7.10 (dt, J = 7.6 Hz, 1.2 Hz, 1H) , 6.87-6.81 (m, 3H), 6.75-
6.68 (m, 2H), 5.93 (s, 2H), 5.67 (bs, 1H), 4.64 (s, 2H), 3.90 (bs,
2H), 3.75-3.35 (m, 16H), 2.45-2.30 (m, 4H).
Example 40
N- (2-aminophenyl) -6- (2-phenylaraino-ethylaiciino) -nicotinamide (compound
44)
Step 1: N- (5-Bromo-pyridin-2-yI) -N' -phenyl-ethane-'l, 2-diamine
(compound 42)
[0178] A mixture of 2,5-dibromopyridine 40 (2.08 g, 8.6 mrnol) and
phenyl-l,2-ethyldiamine (1.98 g; 14.6 mrnol, 1.7 equiv.) was stirred
under nitrogen at 120°C for 6h. After cooling down to room
temperature, the solid mixture was ground in a mortar, dissolved in
ethyl acetate (200 mL), washed with saturated NaHC03 (2 x 50 mL) ,
dried (MgSO4) , filtered and concentrated. After a quick purification
through a short chromatographic column' (silica gel, elution 50% ether

in hexanes), a pale yellow solid 42 (1.75 g, 6.01 mmol, 70% yield) was
obtained. 13C NMR (300MHz, acetone-d6) 5 (ppm): 158.6, 149.6, 148.8,
139.9, 129.8, 117.1, li3.1, 110.8, 106.6, 43.9, 41.5. LMRS = 294.0
(M+V .
Step. 2: N- (2-aminophenyl) -6- (2-phenylamino-ethylaming) -nicotinamide
(compound 44)
[0179] A mixture of 5-bromo-2-N-alkanyl-2-aminopyridine 42 (352 mg,
1.2 mmol), 1,2-phenylenediamine (3.95 mmol, 3.3 equiv.), Pd(0Ac)2
(0.31 mmol, 26% mol) and 1,1'-bis (diphenylphosphino) ferrocene (124
mg, 0.22 mmol) was suspended in degassed DMF (3mL), treated with
diisopropylethyl amine (0.9 mL, 5.2 mmol) and the system flushed with
CO. The reaction mixture was warmed up to 60°C and stirred under CO
(balloon) for 18 h at this temperature. After evaporation of the DMF
under vacuo, the residue was purified through a chromatographic column
(silica gel, elution 3% to 6% methanol in dichloromethane) to give 258
mg (0.74 mmol, 62 % yield) of the aminoanilide 44. XH-NMR (CD3OD-d4) , 8
(ppm): 8.67 (d, J = 2.2 Hz, 1H), 7.97 (dd, J= 8.9 Hz, 2.5 Hz, 1H) ,
7.58 (m, 1H), 7.51 (m, 1H) , 7.15 (dd, J = 7.7 Hz, 1.1 Hz, 1H) , 7.08
(m, 2H), 6.89 (dd, J = 8.0 Hz, 1.4 Hz, 1H), 6.76 (dt, J= 7.7 Hz, 4.4
Hz, 1H) , 6.67 (t, J = 7.7 Hz, 2H), 6.60 (m, 2H), 4.87 (bs, 4H) , 3.60
(t, J = 6.3 Hz, 2H), 3.35 (t, J = 6.3 Hz, 2H).
Example 41
N- (2-amino-phenyl)-6-(4-mathoxy-benzylamino)-nicotinamide (compound
45)
Step 1: N- (5-Bromo-pyridin-2-yl) -4-methoxybenzylamine (compound 43)
[0180] A mixture of 2,6-dibromopyridine 41 (6.03 mmol, 2 equiv.) and
para-methoxybenzyl amine (413 mg, 3.01 mmol) was stirred under
nitrogen at 120°C for 6h. After identical work-up procedure described
before and purification through a pad of silica gel (elution 50% ether
in hexanes), a pale yellow solid 43 (773 mg, 2.60 mmol, 87% yield) was
obtained. "C NMR (300 MHz, CDC13) d (ppm): 159.1, 139.7, 132.1, 130.5,
128.9, 127.2, 116.2, 114.3, 104.8, 55.4, 46.0. LMRS = 295.0 (M+l).

Step 2:. N- (2-amino-phenyl)-6-(4-methoxy-benzylamino)-nicotinamide
(compound 45)
[0181] Following the procedure described in Example 40, step 2, but
substituting 43 for 42, the title compound 45 was obtained in 61%
yield.
Example 42
N- (2-aminophenyl)-3-[6-(2-phenylamino-ethylamino)-pyridin-3-yl]-
acrylamide (compound 50)
Step 2: 3-[6-(2-Phenylamino-ethylamino)- pyridin-3-yl)-acrylic acid
tert-butyl ester (compound 46)
[0182] In a 50 mL flask, a mixture of 42 (308 mg, 1.05 mmol), tert-
butylacrylate (0.8 mL, 5.5 mmol), diisopropylethylamine (0.8 mL, 4.6
mmol), tri-o-tolylphosphine (POT, 192 mg, 0.63 mmol), Pd2(dba)3 (73 mg,
0.08 mmol) in anhydrous DMF (4 mL) was stirred at 120°C (preheated oil
bath) for 2h under nitrogen. After DMF removal, the crude residue was
submitted to a chromatographic purification (column silica gel, 50%
ether in hexanes) to afford 316 mg of 4.6 (88% yield) . 13C NMR (300 MHz,
CDC13) d (ppm): 166.6, 159.3, 149.6, 147.8, 140.7, 134.9, 129.1,
119.8, 117.3, 115.9, 112.6, 107.8, 80.0, 43.5, 40.9, 28.1. LRMS =
340.3 (M+l).
Step 3: 3-[6-(2-Phenylamino-ethylamino)- pyridin-3-yl)-acrylic acid
(compound 48)
[0183] Ester 46 (0.93 mmol) was dissolved 40 % TFA in dichloromethane
(10 mL) and the solution stirred at room temperature overnight. The
solvent was removed under vacuo distilling with acetonitrile (3x10 mL)
and stored under high vacuum for 6h. The solid residue 48 was employed
for the next reaction without further purification. LRMS = 284.1
(M+l).
Step 4: N- (2-aminophenyl)-3-[6-(2-phenylamino-ethylamino)-pyridin-3-
yl]-acrylamide (compound 50)
[0184] A mixture of acid 48 (0.93 mmol), BOP (495 mg, 1.12 mmol) and
1,2-phenylenediamine (124 mg, 1.15 mmol) were dissolved in dry
acetonitrile (4 mL) and treated with triethylamine (0.8 mL, 5.7 mmol).
The solution was stirred under nitrogen at room temperature for 16h.
After concentration under vacuo, the crude was purified through
chromatographic column (5% methanol in. dichloromethane), then was


crystallized from chloroform to give 50 (247 mg, 71% yield) . 1H-NMR
(DMS0-d6), d (ppm): 9.25 (bs, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.67 (d,
J = 8.5 Hz, 1H), 7.43 (d, J = 15.7 Hz, 1H), 7.32 (d, J =7.4 Hz, 1H),
. 7.24 (t, J = 1.0 Hz, 1H), 7.08 (t, J = 7.4 Hz, 2H), 6.91 (t, J = 8.0
Hst 1H), 6.75 (dt, J= 8.0 Hz, 0.4 Hz, 1H), 6.57 (m, 6H), 5.20 (ba,
1H), 3.48 (t, J = 6.3 Hz, 2H) , 3.33 (bs, 2H) , 3.21 (t, J = 6.'3 Hz,
2H) .
Example 43
N- (2-aminophenyl) -3- [6- (4-methoxy-benzylamino) -pyridin-2-yl] -
acrylamide (compound 51)
Step 2: N- (2-aminophenyl) -3- [6- (4-methoxy-benzylamino) -pyridin-2-yl] -
acrylamide (compound 51)
[0185] Following the procedure described in Example 42, steps 2, 3,
4, but substituting 43 for 42, the title compound 51 was obtained in
50% yield (on 2 steps). 1H-NMR (CDCla) , d (ppm): 7.60 (bs, 1H), 7.55
(bs, 1H), 7.43 (t, J, = 7.7 Hz, 1H), 7.29 (d, J = 8.3 Hz, 2H), 7.17 (d,
J = 15.1 Hz, 1H) , 7.06 (t, J = 7.7 Hz, 1H) , 6.88 (d, J = 8.3 Hz, 2H),
6.80 (m, 2H), 6.70 (m, 3H), 6.41 (d, J = 8.5 Hz, 1H), 4.50 (d, J = 5.5
Hz, 2H), 3.80 (s, 3H), 3.45 (bs, 2H).

Example 44
4- [2- (2-axnino-phenylcarbamoyl) -vinyl] -benzyl}-carbamic acid pyridin-3-
yl methyl ester (compound 55)
Step 1: (4-bromo-benzyl)-carbamic acid pyridin-3-yl-methyl ester
(compound 54)
[0186] 4-bromobenzylamine HC1 (3.0g, 13.4 mmol) was dissolved in DMF
(60 mL) at rt and then Et3N (4.13 niL, 29.7 mmol) was added dropwise
over 10 min to give cloudy solution. To this, DBU (2.42 mL, 16.2 mmol)

and 1,1'-carbonyl diimidazole (2.41g, 14.8 mmol) were added. After
being stirred for 1 h at rt, 3-pyridylcarbinol (1.44 mL, 14.8 mmol)
was added dropwise over 10 min. The resulting reaction mixture was
stirred overnight and then concentrated under reduced pressure. The
residue obtained was diluted with ether/EtOAc (9:1) and then washed
with H2O. The organic layer was dried over Na2SO4, filtered and then
concentrated to give the crude product which was recrystallized from
EtOAc to give 2.55g of product 54 (59% yield, LRMS = 323 (M+l).
Step 2; 4-[2-(2-amino-phenylcarbamoyl)-vinyl]-benzyl}-carbamic acid
pyridin-3-yl methyl ester (compound 55)
[0187] Following the procedure described in Example 42, steps 2, 3,
but substituting 54 for 42, and acrylic acid for tert-butyl acrylate
the title compound 55 was obtained in an overall yield of 20%. XH NMR-.
(DMSO-d6) d (ppm): 10.03 (s, 1H) , 9.32 (s, 1H), 8.65 (s, 1H) , 8.55 (d,
J = 3.3 Hz, 1H), 7.85 (d, J = 7.69 Hz, 1H), 7.40-7.60 (m, 6H), 7.31
.(d, J = 7.69 Hz, 1H), 6.89 (dd, J = 7.14 Hz, J = 7 Hz, 1H), 6.71-6.79
(m, 2H), 6.55 (dd, J = 7.1 Hz, J = 7 Hz, 1H), 5.20 (s, 2H), 4.93 (bs,
2H) .
Example 45
N-(2-aminophenyl) -3-{4-[(3,4,5-trimethoxy-benzylamino) -methyl] -
phenyl}-acrylamide (compound 59)
Step 1: (4-Bromo-benzyl)-(3,4,5-trimethoxy-benzyl)-amine (compound 57)
[0188] To a stirred suspension of K2C03 (522 mg, 3.77 mmol) in dry
DMF was added 3,4,5-trimethoxybenzylamine (1.10 mL, 6.44 mmol, 2.2
equiv.) followed by a solution of p-bromo benzylbromide (0.73 g, 2.91
mmol) in dry DMF (8 mL). The mixture was stirred at room temperature
under nitrogen for two days in the dark, diluted with dichloromethane
(200 mL), washed with brine, dried (MgSO4), filtered and concentrated.
The crude residue was purified by chromatographic column on silica gel
(elution 5% methanol in dichloromethane) to give 2.59 mmol (89% yield)
of dibenzylamine 57. 13C NMR (300 MHz, CDC13) d (ppm) : 152.5, 138.8,
136.1, 135.4, 130.6, 129.2, 119.8, 104.2, 59.9, 55.3, 52.6, 51.7. LRMS
= 368.4 (M+l).
Step 2: N- (2-Nitro-phenyl)-3-(4-[(3,4,5-trimethoxy-benzylamino)-
methyl]-phenyl)-acrylamide (compound 58)
Preparation of the nitroacrylanilide
[0189] To a mixture of 2-nitroaniline (1.73 g, 12.5 mmol), DMAP (321
mg, 2.6 mmol) and 2, 6-di-fcert-butyl-4-methylphenol (308 mg) in dry
dichloromethane (50 mL) at 0°C was added triethylamine (10.6 mL, 7£

nvmol) followed by acryloylchloride (3.2 mL, 38 mrnol, 3.0 equiv.), and
the mixture was stirred at room temperature for 16h. The solution was
diluted with dichloromethane (250 mL), cooled to 0°C and the excess of
reagent quenched with saturated NaHC03 (stirring for 1 h) . The organic
layer was then washed (5% KHSO4/ then brine), dried (MgSO4) , filtered
and concentrated under reduced pressure. After purification through
chromatographic column on silica gel (elution 50% ether in hexanes),
642 mg (3.34 mmol, 27% yield) of the amide was obtained. 13C NMR (300
MHz, CDC13) d (ppm): 163.6, 136.0, 135.6, 134.5, 131.3, 128.6, 125.4,
123.1, 121.8. LRMS = 193.2 (M+l).
Step 3; N- (2-aminophenyl)-3-{4-[(3,4,5-trimethoxy-benzylamino)-
methyl]-phenyl)-acrylamide (59)
[0190] A mixture of nitro-compound 58 (127 mg, 0.27 nimbi), SnCl2 (429
mg, 2.26 mmol, 8.4 equiv.) and NH40Ac (445 mg) was suspended in
methanol (9.5 mL) and water (1.5 mL), and the mixture was heated at
70°C for 45 min. The mixture,was diluted with ethylacetate (100 mL)
and washed with brine and then saturated NaHC03, dried (MgSO4) ,
filtered, and concentrated. Purification by chromatographic column on
silica gel (elution 5 to 10% methanol in dichloromethane) gave 52 mg
(43% yield) of 59. XH-NMR (CDC13) , d (ppm): 8.25 (bs, 1H) , 7.59 (d, J =
15.6 Hz, 1H), 7.38 (d, J = 7.5 Hz, 2H), 7.29 (d, J = 7.5 Hz, 2H), 7.25
(m 1H), 7.02 (t, J = 6.8 Hz, 1H), 6.75 (m, 2H), 6.62 (d, J = 15.6 Hz,
1H), 6.58 (s, 2H), 3.97 (bs, 3H), 3.80 (s, 9H), 3.78 (s, 2H), 3.72 (s,
2H) .
Example 46
N- (2-aminophenyl)-3-(4-{[(3,4,5-trimethoxy-benzyl)-amino]-xnethyl}-
phenyl)-acrylamide (compound 61)
Step 1: 3-{4-{[Methyl-(3,4,5-trimethoxy-benzyl)-amino]-methyl)-
phenyl)-N- (2-nitro-phenyl)-acrylamide (compound 60)
[0191] Amine 58 (180.2 mg, 0.38 mmol) was dissolved in 88% of HC02H
(6 mL), treated with excess of paraformaldehyde (7.67 mmol) and the
mixture stirred at 70°C for 2.5h. A saturated NaHC03 solution, was
added slowly, extracted with dichloromethane (2 x 75 mL), dried
(MgSO4) , filtered and concentrated. After chromatographic: column on
silica gel (elution 3 to 5% methanol in dichloromethane), pure N-
methyl amine 60 (118 mg, 63% yield) was obtained. 13C NMR" (300 MHz,


CDCl3) d (ppm): 164.5, 153.1, 143.5, 142.3, 136.8, 136.1, 136.0,
135.3, 134.9, 132.9, 129.3, 128.2, 125.8, 123.1, 122.2, 120.3, 105.4,
62.2, 61.2, 60.8, 56.0, 42.5. LRMS = 492.5 (M+l).
St pp 2: N- (2 - aminophenyl )-3-(4-([(3,4,5- trimethoxy-benzyl) - amino] -
methyl)- phenyl)-acrylamide (compound 61)
[0192] Following the procedure described in Example 45, step 3, but
substituting the nitro-compound 60 for 58, the title compound 61 was
obtained in 72% yield. ^-NMR (DMSO-d6), d (ppm): 9.15 (bs, 1H) , 8.13
(bs, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.30 (m 4H), 7,12 (d, J = 7.7 Hz,
1H), 6.91 (m 3H), 6.75 (d, J = 7.8 Hz, 1H), 6.57 (m 2H), 4.83 (bs,
2H), 4.43 (d, J = 5.5 Hz, 2H), 3.72 (s, 3H), 3.33 (s, 3H). .
Example 47
N- (2-aminophenyl) -3-{4- (4-methoxy-benzylamino) -phenyl}-acrylamide
(compound 65)
Step 1: Methyl-3-(4-amino-phenyl)-acrylate hydrochloride (compound 63)
[0193] 4-amino-cinnamic acid (10.41 g, 0.052 mol) was dissolved in
methanol (100 mL) at rt. A solution of HC1 in dioxane (15.6 mL, 4 N)
was then added. The reaction mixture was heated at reflux overnight.
The clear solution was evaporated to a half volume and then settled
down at rt. The white suspension obtained was collected by vacuum
filtration. The mother liquid was evaporated again to a quart volume
and cooled down to rt. The suspension was filtered again. The
combined the solid collected from two filtration was dried in vacuo
to give 7.16 g of 63 (64.3% yield). LRMS: 178 (M+l).

Step 2: Methyl-3-{4-(4-methoxy-benzylamino)-phenyl}- acrylate
hydrochloride (compound 64)
[0194] To a suspension of compound 63 (3.57 g, 16.7 mmol) in DMF (30
Mil was added Et3N. after 10 min 4-methoxybenzyl chloride (2.0 g, 12.8
tranpl) , Nal (0.38 g, 2.6 mmol) and K2C03 (3.53 g, 25.5 mmol) were added
successively. The mixture was heated at 60°C overnight and evaporated
to dryness. The residue was partitioned between NaHC03 sat. solution
(50 mL) and EtOAc (50mLx3). The combined organic layers were washed
with brine, and then evaporated to dryness. The residue was purified
by flash chromatography and then recrystallized from isopropylalcohol
to give 1.16 g 64 (yield 30.6%, LRMS = 298) and 1.46g of 63 (49%
recovered yield).
Step 3: N- (2-aminophenyl)-3-(4-(4-methoxy-benzylamino)-phenyl)-
acrylamide (compound 65)
[0195] Following the procedure described in Example 42, step 4, but
substituting 64 for 48, the title compound 65 was obtained in 32%
yield. XH NMR: (DMSO-d6) d (ppm) : 9.15 (s, 1H) , 7.24 -7.38 (m, 6H) ,
6.84-6.90 (m, 3H), 6.72 (ra, 2H), 6.49-6.60 (m, 4H), 4.84 (s, 2H ),
4.22 (d, J = 5.77 Hz,' 2H) .
Example 48
N- (2-Amino-phenyl) -3- (4-styrylamino-phenyl) -acrylamide (compound 71)
Step 1: N- (4-Iodo-phenyl)-(3-phenyl-allyl)-amine (compound 69)
[0196] Following the procedure described in Example 47, step 2, but
substituting 68 for 63, the title compound 69 was obtained in 70%
yield. LRMS = 288 (M+l)
Step 2: N- (2-Amino-phenyl)-3-(4-styrylamino-phenyi)-acrylamide (71)
[0197] Following the procedure described in Example 42, steps 2, 4,
but substituting 69 for 42, and acrylic acid for tert-butyl acrylate
the title compound 71 was obtained in an overall yield of 60%. 1H NMR:


{DMSO-d6) d (ppm): 9.22 (bs, 1H) , 7.45 (d, J = 6.9 Hz, 2H) , 7.39 (d,
J = 9.0 Hz, 2H), 7.34 (d, J = 7.4 Hz, 2H), 7.26 (dt, J = 7.4 Hz, 6.8
Hz, 2H), 6.93 (dt, J = 7.9 Hz, 7.1 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H),
~6>£9 (d, J = 8.5 Hz, 2H), 6.63-6.55 (m, 4H), 6.44-6.37 (m, 1H), 4.95
(bs, 2H), 3.95 (bs, 2H).
Example 49
N- (2-Amino-phenyl)-3-[4-(4-methoxy-benzamide)]-aorylamide (compound
72)
Step 1; N- (4-Iodo-phenyl)-4-methoxy-benzamide (compound 70)
[0198] Following the procedure described in Example 47, step 2, but
substituting 68 for 63, the title compound 70 was obtained in 90%
yield. LRMS = 354.0 (M+l)
Step 2: N- (2-Amino-phenyl) -3- [4- (4-methoxy-benzamide)] -acrylamide
(compound 72)
[0199] Following the procedure described in Example 42, steps 2, 4,
but substituting 70 for 42, and acrylic acid for tert-butyl acrylate
the title compound 72 was obtained in an overall yield of 90%. XH NMR:
(DMSO-de) d (ppm): 9.4 (bs, 1H), 7.60(d, J = 8.5 Hz, 1H), 7.54-7.45
(m, 3H), 7.87(d, J = 7.7 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.95-6.77
(m, 3H), 6.62 (d, J = 7.7 Hz, 2H), 6.08-6.04 (m, 2H), 4.98 (bs, 2H) ,
3.72 (s, 3H).
Example 50
N- (2-amine-phenyl)-3-{6-[2-(4-oxo-4ff-quinazolin-3-yl)-ethylamino]-
pyridin-3-yl}-acrylamide (compound 76)
Step 1: N- (5-Bromo-pyridin-2-yl)-ethane-1,2-diamine (compound 73)
[0200] Following the procedure described in Example 40, step 1, but
using 1,2-diaminoethane as alkyl amine, the title compound 73 was1
obtained in 84% yield. "C NMR (300 MHz, CD3OD) : 159.1, 148.7, 140.7,
111.7, 107.2, 44.3, 41.7. LRMS = 218.1 (M+l)
Step 2: 3-[2-(5-Bromo-pyridin-2-ylamino) -ethyl]-3H-quinazolin-4-one
(compound 75)
[0201] A suspension of primary amine 73 (1.17 g, 5.40 mmol) and
isatoic anhydride 74 (880 mg, 5.40 mmol) in methanol (25 mL) was
stirred for 3 h at 50°C and then concentrated. The resulting oily
residue was dissolved in 88% formic acid (20 mL) and refluxed
overnight. After removal of formic acid, the solid residue was
purified through column chromatography on silica gel (5% methanol in
dichloromethane) to give 1.24 g (3.6 mmol, 67% yield) of 75. 13C NMR
(300 MHz, CDCla) : 161.6, 156.8, 147.7, 147.6, 147.2, 139.8, 134.5,
127.4, 126.8, 126.3, 121.6, 110.1, 107.0, 46.3, 40.1. LRMS = 347.1
(M+l).


Step 3; W-(2-aminophenyl)-3-(6-[2-(4-oxo-4H-quinazolin-3-yl)-
ethylaminoj -pyridin-3-yl)-acrylamide (compound 76)
[0202] Following the procedure described in Example 42, steps 2 to 4,
---but substituting 75 for 42, the title compound 76 was obtained in an
overall yield of 68 %. aH-NMR (DMSO-d£), d (ppm): 9.24 (bs, 1H), 8.17
(dd, J = 8.0 Hz, 1.6 Hz, 1H), 8.11 (bs, 1H), 8.08 (d, J = 1.9 Hz, 1H) ,
7.82 (dt, J = 8.5 Hz, 1.4 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.25 (t,
J = 5.8 Hz, 1H), 6.90 (dt, J = 15.7 Hz, 1H), 6.74 (dd, J = 8.0 Hz, 1.4
Hz, 1H), 6.58 (m, 3H), 4.95 (bs, 2H), 4.17 (t, J = 5.2 Hz, 2H), 3.68
(m, J = 5.2 Hz, 2H).
Example 51
N- (2-aminophenyl) -3-{6- [2- (4-benzyl-2,6-dioxo-piperazin-l-yl) -
ethylamino]-pyridin-3-yl}-acrylam±de (compound 78)
Step 2 : 4-Benzyl-l- [2- (5-bromo-pyridin-2-ylamino) -ethyl] -piperazine-
2,6-dione (compound 77)
[0203] A suspension of benzyliminodiacetic acid (702 mg, 3.15 mmol)
and acetic anhydride (15 mL) was stirred at 120°C for 45 min. The
reaction mixture was diluted with dry toluene and concentrated in
vacuo to remove the volatiles. The residue was dissolved in dry
toluene (15 mL) and transferred via cannula to a reaction flask
containing the amine 73 (475 mg, 3.2 mmol). The mixture was heated at
90°C for 16 h, concentrated and chromatographed by column on silica
gel (elution 5% methanol in dichloromethane) to give 684mg (1.70 mmol,
54% yield) of 77.
Step 3: N- (2-aminophenyl)-3-{6-[2-(4-benzyl-2, 6-dioxo-piperazin-l-yl)-
ethylamino]-pyridin-3-yl}-acrylamide (compound 78)
[0204] Following the procedure described in Example 42, steps 2 to 4,
but substituting 77 for 42, the title compound 78 was obtained in an
overall yield of 60%. ^-NMR (CD30D-d4), 5 (ppm): 8.09 (d, J = 1.8
Hz, 1H), 7.68 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 7.53 (d, J = 15.6 Hz, 1H),
7.29' (m, 6H), 7.20 (dd, J = 7.8 Hz, 1.2 Hz, 1H) , 7.02 (dt, J = 9.0 Hz,
1.2 Hz, 1H), 6.86 (dd, J = 8.1 Hz, 1.2 Hz, 1H) , 6.73 (dt, J = 7.5 Hz,
1.5 Hz, 1H), 6.61 (d, J = 15.6 Hz, 1H), 6.50 (d, J = 8.7 Hz, 1H), 4.85
(bs, 3H), 3.97 (t, J = 7.5 Hz, 2H), 3.60 (s, 2H) , 3.57 (t, J = 7.5 Hz,
2H), 3.38 (s, 4H).
Example 52
(E) -4-{t4-Amino-6-(2-indanyl-amino)-[1,3,5] triazin-2-yl-amino]-
methyl}-^-(2-amino-phenyl)-cinnamide (compound 83)
Step 1: 4,6-Dichloro-2-(2-indanyl-amino)-[1,3,5]triazine (compound 79)
[0205] To a.stirred solution at -78°C of cyanuric chloride (13.15 g,
71.33 mmol) in anhydrous THF (100 mL) under nitrogen was slowly
canulated a solution of 2-aminoindan (10.00 g, 75.08 mmol), i-Pr2NEt
(14.39 mL, 82.59 mmol) in anhydrous THF (60 mL). After 50 min, the
reaction mixture was poured into a saturated aqueous solution of
NH4C1, and diluted with AcOEt. After separation, the organic layer
was successively washed with sat. NH«C1, HzO and brine, dried over
anhydrous MgSO4, filtered and concentrated. The crude residue was
then purified by flash chromatography on silica gel (AcOEt/CH2Cl2:
2/98-»5/95) and by co^precipitation (AcOEt/hexanes) to afford the •
title compound 79 (18.51 g, 65.78 mmol, 92% yield) as a beige powder.
XH NMR (300 MHz, CDC13) 5 (ppm): 7.29-7.18 (m, 4H), 6.02 (bd, J = 6.3
Hz, 1H), 4.94-4.84 (m, 1H), 3.41 (dd, J = 16.2, 6.9 Hz, 2H), 2.89 (dd,
J = 16.1, 4.5 Hz, 2H).
Step 2; 2-(4-Bromo-benzyl-amino)-4-chloro-6-(2-indanyl-amino)-
[1,3,5]triazine (compound 80)
[0206] To a stirred solution at room temperature of 79 (2.68 g, 9.52
mmol) in anhydrous THF (50 mL) under nitrogen were added i-Pr2NEt
(4.79 mL, 27.53 mmol) and 4-bromobenzylamine.HC1 (2.45 g, 11.01 mmol),
respectively. After 17 h, the reaction mixture was poured into a
saturated aqueous solution of NH4C1, and diluted with AcOEt. After

separation, the organic layer was successively washed with sat. NH4C1,
H2O and brine, dried over anhydrous MgSO4, filtered and concentrated.
The crude residue was then purified by flash chromatography on silica
"gsl (AcOEt/CH2Cl2: 3/97-»5/95) to afford the title compound 80 (4.00 g,
£.29 mmol, 97% yield) as a white powder. 1H NMR (300 MHz, CDC13) 5
(ppm): mixture of rotamers, 7.52-7.42 (m, 2H), 7.26-7.11 (m, 6H), 6.51
and 6.12 (2 m, 1H), 5.72-5.46 (m, 1H), 4.94-4.64 (m, 1H) , 4.62-4.46
(m, 2H), 3.43-3.16 (m, 2H) , 2.92-2.74 (m, 2H).
Step 3: 4-Amino-2-(4-bromo-benzyl-amino)-6-(2-indanyl-amino)-
[l,3,5]triazine (compound 81)
[0207] In a 75 mL sealed flask, a solution of 80 (2.05 g, 4.76 mmol)
in anhydrous 1,4-dioxane (60 mL) was stirred at room temperature,
saturated with NH3 gas for 5 min, and warmed to 140°C for 18 h. The
reaction mixture was allowed to cool to room temperature, the
saturation step with NH3 gas was repeated for 5 min, and the reaction
mixture was warmed to 140°C again for 24 h. Then, the reaction
mixture was allowed to cool to room temperature, poured into IN HC1,
and diluted with AcOEt. After separation, the organic layer was
successively washed with sat. NH4C1, H2O and brine, dried over
anhydrous MgSO4, filtered and concentrated. The crude residue was
then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 5/95)
to afford the title compound 81 (1.96 g, 4.76 mmol, quantitative
yield) as a colorless foam. 1H NMR (300 MHz, CDC13) 5 (ppm): 7.43 (d,
J= 8.2 Hz, 2H), 7.25-7.12 (m, 6H), 5.70-5.10 (m, 2H) , 5.00-4.65 (m,
3H) , 4.52 (bs, 2H), 3.40-3.10 (m, 2H), 2.90-2.65 (m, 2H) .
Step 4: (E)-4-([4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-
amino] -methyl }-N- [2- (JW-t-butoxycarbonyl) -amino-phenyl] -cinamide
(compound 82)
Preparation of N- [2-(JV-t-Butoxycarbonyl)-amino-phenyl]-acrylamide
[0208] Following the procedure described in Example 45, step 2, but
substituting the nitro-compound 2- (itf-t-butoxycarbonyl)-amino-aniline
for 2-nitroaniline, the title compound was obtained in 77% yield. 1H NMR (300 MHz, CDC13) 5 (ppm): 8.51 (bs, 1H) , 7.60-7.45 (m, 1H) , 7.38-
7.28 (m, 1H), 7.20-7.05 (m, 2H), 6.98 (bs, 1H), 6.41 (dd, J = 17.0 Hz,
1.1 Hz, 1H), 6.25 (dd, J = 16.9 Hz, 10.0 Hz, 1H), 5.76 (dd, J = 10.2
Hz, 1.4 Hz, 1H) , 1.52 (s, 9H) .


[0209] In a 50 mL sealed flask, a solution of 81 (300 mg, 0.73 mmol),
the acrylamide (230 mg, 0.88 mmol), Et3N (407 ul, 2.92 mmol), tri-o-
tolylphosphine (POT, 13 mg, 0.04 mmol), Pd2(dba)3 (20 mg, 0.02 mmol) in
anhydrous DMF (10 mL) was stirred at room temperature, saturated with
N2' gas for 15 min, and warmed to 100°C for 15 h. Then, the reaction
mixture was allowed to cool to room temperature, poured into a
saturated aqueous solution of NH4C1, and diluted with AcOEt. After
separation, the organic layer was successively washed with sat. NH4C1,
H2O and brine, dried over anhydrous MgSO4, filtered and concentrated.
The crude residue was then purified by flash chromatography on silica
gel (MeOH/CH2Cl2: 2/98-»5/95) to afford the title compound 82 (240 mg,
0.41 mmol, 56% yield) as a beige solid. XH NMR (300 MHz, CDC13) d
(ppm): 8.46 (bs, 1H), 7.71 (bd, J = 15.7 Hz, 1H) , 7.62-7.05 (m, 13H),
6.54 (bd, J = 15.9 Hz, 1H), 5.95-4.90 (m, 4H), 4.85-4.48 (m, 3H) ,
3.40-3.14 (m, 2H), 2.90-2.70 (m, 2H), 1.52 (s, 9H).
Step 5: (B)-4-([4-Amino-6-(2-indanyl-amino)-[1,3,5] triazin-2-yl-
amino]-methyl}-N-(2-amino-phenyl)-cinnamide (compound 83)
[0210] To a stirred solution at room temperature of 82 (230 mg, 0.39
mmol) in CH2C12 (5 mL) was added TFA (1 mL, 95% in water) . After 18 h,
the reaction mixture was poured into a saturated aqueous solution of
NaHCOj, and diluted with AcOEt. After separation, the organic layer
was successively washed with sat. NaHC03, H2O and brine, dried over
anhydrous MgSO4/ filtered and concentrated. The crude residue was
then purified by flash chromatography on silica gel (MeOH/CH2Cl2: 5/95)
to afford the title compound 83 (170 mg, 0.35 mmol, 89% yield) as a
yellow solid. 1H NMR (300 MHz, acetone-ds) d (ppm): 8.87 (bs, 1H),
7.69 (d, J = 15.7 Hz, 1H), 7.59 (bd, J = 7.7 Hz, 2H) , 7.49-7.34 (m,
3H), 7.28-7.11 (m, 4H), 7.05-6.91 (m, 2H), 6.88 (dd, J = 8.0, 1.4 Hz,
1H) , 6.69 (td, J= 7.6, 1.4 Hz, 1H), 6.65-5.50 (m, 4H), 4.83-4.53 (m,
5H) , 3.34-3.11 (m, 2H), 2.98-2.80 (m, 2H).
N- (2-aminophenyl)-2-(4-methoxy-benzylamino)-quinolin-6-yl-amide
(compound 87)
Step 1: 2,6-ditrifluoromethanesulfonyloxy-quinoline (compound 85);
[0211] A solution of 2,6-dihydroxyquinoline 84 (1.254 g, 7.78 mmol)
and DMAP (a few crystals) in dry pyridine (15 mL) was treated with
neat trifluoromethanesulfonic anhydride (5.2 g, 18,4 mmol, 1.2 equiv.)
and stirred at 0°C for 5 h. This solution was then poured on a mixture
brine/sat NaHC03 and extracted with dichlorqmethane (2 x 150 mL),
dried (MgSOj , filtered and concentrated. Purification by column
chromatography on silica gel (30% to 50% ether in hexanes) gave 2.58 g
(6.1 mmol, 78% yield) of 85. 13C NMR (300 MHz, CDC13) : 154.5, 147.8,
144.5, 142.0, 131.6, 127.8, 124.9, 119.3, 118.7, 114.9. LRMS = 426.0
(M+l).
Step 2: N- (2-aminophenyl) -2- (4-methoxy-benzylamino) -quinolin-6-yl-
amide (compound 87)
[0212] Following the procedure described in Example 40, steps 1, 2,
but substituting 85 for 40, the title compound 87 was obtained in 92%
yield. ^-NMR (DMSO-dff) , d (ppm) : 9.66 (bs, 1H) , 8.32 (s, 1H) , 8.05
(d, J = 8.8 Hz, 1H), 7.96 (dd, J = 9.1 Hz, 2.2 Hz, 1H), 7.72 (d, J =
2.2 Hz, 1H), 7.55 (dd, J = 8.5 Hz, 2.2 Hz, 1H), 7.34 (dd, J = 8.5 Hz,
2.2 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.97 (t, J = 7.7 Hz, 1H), 6.90
(m 2H), 6.80 (d, J = 7.9 Hz, 1H), 6.61 (t, J = 6.3 Hz, 1H), 4.90 (bs
2H), 4.58 (d, J = 3.3 Hz, 2H), 3.73 (s, 3H), 3.33 (bs, 1H).

Example 54
N- (2-aminophenyl) -3- [2- (4-methoxy-benzylaioino) -quinolin-6-yl] -
acrylamide (compound 88)
-step 3: N- (2-aminophenyl) -3- [2- (4-methoxy-benzylamino) -quinolin-6-yl] -
acfrylamide (compound 88)
[0213] Following the procedure described in Example 42, steps 1 to 4,
but substituting 85 for 40, the title compound 88 was obtained in an
overall yield of 71%. XH-NMR (DMSO-dff), d (ppm) : 9.70 (bs, 1H), 9.40
(bs, 1H), 8.20 (d, J = 8.9 Hz, 1H), 8.03 (bs, 2H), 7.94 (d, J = 7.2
Hz, 1H), 7.64 (dd, J = 15.7 Hz, 2.5 Hz, 1H), 7.41 (d, J = 8.5 Hz,
2H) , 7.39 (m, 1H) , 7.14 (d, J = 8.9 Hz, 1H) , 7.05 (d, J = 15.7 Hz,
1H), 6.97 (m, 1H) , 6.95 (d, J = 8.5 Hz, 2H) , 6.81 (d, J = 8.0 Hz, 1H),
6.65 (t, J = 7.2 HZ, 1H), 4.76 (s, 2H), 3.75 (a, 3H) ..
Examples 55-84
[0214] Examples 55 to 84 describe the preparation of compounds 89 to
118 using the same procedures as described for compounds 44 to 88 in
Examples 40 to 54. Characterization data are presented in Tables 3a-
d.
«.
o
o
Example 85
N- (2-Amino-phenyl) -4- (lIT-benzimidazol-2-ylsulfanylniethyl) -benzamide
(compound 126)
Step 1: 4- (lff-Benzimidazol-2-ylsulfanylmethyl)-benzoic acid methyl
ester (compound 122)
[0215] Following the procedure described in Example 47, step 2, but
using 119 and substituting 121 for 63, the title compound 122 was
obtained in 95% yield. LRMS = 299.1 (M+l).
Step 2 : N- (2-Amino-phenyl) -4- (lff-benzimidazol-2-ylsulfanylmethyl) -
benzamide (126)
[0216] Following the procedure described in Example 1, steps 4 and 5,
but substituting 122 for 6, the title compound 126 was obtained in 62%
yield. XH NMR: (DMSO-d6) 5 (ppm) : 9.57 (s, 1H), 7.89 (d, J= 8.2 Hz,
2H) , 7.55 (d, J = 8.2 Hz, 2H), 7.53 (bs, 2H), 7.36 (bs, 2H), 7.14-7.08
(m, 3H), 6.94 (t, J = 8.2 Hz, 1H), 6.74 (d, J = 6.9 Hz, 1H), 6.56 (t,
J = 8.0 Hz, 1H), 4.87 (bs, 2H), 4.62 (s, 2H).
Example 87 a a a a a a'
W- (2-Amino-phenyl) -4- [6- (2-morpholin-4-yl-ethylamino) -benzothiazol-2-
ylsulfanylmethyl]-benzamide (compound 128)
Step 1: 4-(6-Amino-benzothiazol-2-ylsulfanylmethyl)-benzoic acid
methyl ester (122)
[0217] Following the procedure described in Example 47, step 2, but
using 120 and substituting 121 for 63, the title compound 122 was
obtained in 45% yield. LRMS = 331.0 (M+l).

Step 2: 4-[6-(2-Morpholin-4-yl-ethylamino)-benzothiazol-2-
ylaulfanylmethyl]-benzoic acid methyl ester (compound 124)
[0218] To a solution of 4-(6-Amino-benzothiazol-2-ylsulfanylmethyl)-
benzoic acid methyl ester 122 (800 mg, 2.42 mrnol), in DMF (24 itiL),
were added successively solid 4-(2-chloroethyl)morpholine
hydrochloride (296 mg, 2.66 mmol), K2C03 (611 mg, 5.08 mmol), Nal (363
mg, 2.42 mrnol), Et3N (370 jiL, 2.66 mmol) and tetrabutylammonium iodide
(894 mg, 2.42 mrnol), The mixture was stirred at 120°C for 24h and more
4-(2-chloroethyl)morpholine hydrochloride (296 mg, 2.66 mrnol) was
added. The mixture was stirred for 8h at 120"C and the solvent was
removed in vacuo. The resulting black syrup was partitioned between
HjO and EtOAc. The organic layer was successively washed with HC1 IN
and saturated aqueous NaHC03. The precipitate was extracted twice
with EtOAc, dried over MgSO4 and concentrated. Purification by flash
chromatography (MeOH/CHCl3l 5:95 to 10:90) afforded 48 mg (4% yield) of
124 as a light yellow oil. LRMS = 444.1 (M+l).
Step 3: N- (2-Amino-phenyl)-4-[6-(2-morpholin-4-yl-ethylamino)-
benzothiazol-2-ylsulfanylmethyl]-benzamide (compound 128) .
[0219] Following the procedure described in Example 1, steps 4 and 5,
but substituting 124 for 6, the title compound 128 was obtained in 76%
yield. XH NMR: (Acetone-d6) 5 (ppm) : 9.06 (bs, 1H) , 7.98 (d, J = 8.2
Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.29 (d,
J = 8.0 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 7.02-6.97 (m, 1H), 6.87-
6.82 (m, 2H), 6.66 (dt, J= 7.4 Hz, 1.4 Hz, 1H), 4.63 (s, 2H), 3.64-
3.60 (m, 4H), 3.25 (t, J = 6.3 Hz, 2H), 2.63 (t, J = 6.3 Hz, 2H),
2.54-2.42 (m, 4H).

Example 88
N- (2-Amino-phenyl) -4- (quinolin-2-ylsulfanylmethyl) -benzamide (compound
131)
Step 1; 2-(4-Bromo-benzylsulfanyl) -quinolme (compound 130)
[0220] Following the procedure described in Example 47, step 2, but
substituting 129 for 63, the title compound 130 was obtained in 89%
yield. LRMS = 332.0 (M+l).
Step 2: N- (2-Amino-phenyl) -4- (quinolin-2-ylsulfanylmethyl) -benzamide
(131)
[0221] Following the procedure described in Example 40, step 2, but
substituting 129 for 42, the title compound 131 was obtained in 70%
yield. 1H NMR: (DMSO-ds) d (ppm) : .9.62 (bs, 1H) , 8.21 (d, J = 8.8 Hz,
1H), 8.00-7.69 (m, 4H), 7.79 (dd, J = 6.8 Hz, 1.3 Hz, 1H), 7.68 (d, J
= 6.3 Hz, 2H), 7.56 (t, J = 6.8 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H),
7.17 (d, J = 8.2 Hz, 1H) , 6.99 (dt, J = 7.9 Hz, 7.4 Hz, 1H)., 6.79 (d,
J = 6.9 Hz, 1H), 6.61 (dt, J = 7.7 Hz, 7.4 Hz, 1H) , 4.69 (s, 2H) '.

Example 89
N- (2-Amino-phenyl) -4- (pyrimidin.-2-ylaminomethyl) -benzamide (compound
134)
Step 1: 4-(Pyrimidin-2-ylaminomethyl)-benzoic acid methyl ester
(compound 133)
[0222] Following the procedure described in Example 47, step 2, but
substituting 132 for 63, the title compound 133 was obtained in 76%
yield. LRMS = 244.2 (M+l).
Step 2: N- (2-Amino-phenyl)-4-(pyrimidin-2-ylaminomethyl)-benzamide
(134)
[0223] Following the procedure described in Example 1, steps 4 and 5,
but substituting 129 for 6, the title compound 134 was obtained in 91%
yield'. XH NMR: (DMSO-d6) d (ppm): 9.6 (bs, 1H) , 8.32 (d, J = 4.9 Hz,
2H), 7.97 (dt, J = 9.9 Hz, 7.9 Hz, 2H), 7.85-7.83 (m, 1H) , 7.47, (d, J
= 8.2 Hz, 2H), 7.20 (d, J = 7.9 Hz, 1H), 7.01 (dt, J = 7.7 Hz, 7.4 Hz,
1H), 6.82 (d, J= 7.9Hz, 1H), 6.66-6.62 (m, 1H), 4.98 (bs,' 2H), 4.61
(d, 2H).
Example 90
N-(2-Amino-phenyl)-4-(l-methyl-lH-imidazol-2-ylsulfanylmethyl]-
benzamide (compound 139)
Step 1: [2-(4-Iodo-benzoylamino)-phenyl]-carbamic acid tert-butyl
ester (compound 135)
[0224] To a solution of di-tert-butyldicarbonate (39 g, 181 mmol) in
THF (139 mL) placed in a water bath, was added 1,2-phenylenediamine
(15 g, 139 mmol) and DMAP (1.7 g, 14 mmol). The mixture was stirred
at r.t. for 16 h and the solvent was removed in vacuo. The crude
material was partitioned between EtOAc and water. The organic layer
was washed with HC1 1 N and then with aqueous saturated NaHC03. The
combined organic layers were washed with brine, dried over MgSO* and
concentrated affording the compound (18.9 g, 65% yield) as-a light
beige powder. LRMS = 209.1 (M+l).
[0225] To a solution of 4-iodobenzoic acid (8.0 g, 32.3 mmol) in DMF
(65 mL) at r.t., were successively added 1-[3-(dimethylamino)propyl]-
3-ethylcabodiimide hydrochloride (8.0 g, 41.9 mmol) and 1-
hydroxybenzotriazole (5.2 g, 38.7 mmol). The mixture was stirred for
1 h and a solution of (2-amino-phenyl)-carbamic acid tert-butyl ester
(6.3 g,- 30.2 mmol) in DMP (20 mL) was added to the mixture via
cannula, followed by triethylamine (5.9 mL, 4.9 mmol). The mixture

was stirred for IS h and the solvent was removed in vacuo. The crude
material was partitioned between chloroform and water. The organic
layer was washed with aqueous saturated NaHC03, dried over MgSO4 and
Concentrated to a light brown syrup which was crystallized in hot
EtOAc or Et20, yielding 135 (9.3 g, 70% yield) as a white solid.
LRMS = 461.0 (M+Na+) .
Step 2: N- [2-tert-butoxycarbonylamino-phenyl)-terephtalamic acid
methyl ester (compound 136)
[0226] Following the procedure described in Example 40, step 2, but
substituting 135 for 42, the title compound 136 was obtained in 95%
yield. LRMS = 393.1 (M+Na*) .
Step 3: [2 (4-Hydroxymethyl-benzoylamino) -phenyl] -carbamic acid tert-
butyl ester (137)
[0227] To a solution of 136 (7.5g, 20.6 mmol) in THF (40 mL), cooled
down to -20°C under Na, was added a 1M solution of DIBAL-H (122 mL,
122 mmol) in toluene. After stirring for 18 h. at r.t., the mixture
was cooled down to 0°C and carefully quenched by a dropwise addition
of H2O (10 mL) and of 2N NaOH (5 mL) . The aluminum salts were allowed
to decant and the supernatant was removed. The organic layer was
washed with H2O, 1 N HC1 (6 times), satd. aqueous NaHC03/ brine, dried
over MgSO4 and concentrated (2.04 g, 43%) . Purification of the crude
material by flash chromatography (EtOAc/hexanes 50:50 to 70:30)
afforded 137 (1.14 g, 16% yield) as a solid foam. LRMS = 3 65.2
(M+Ka+) .
Step 4: {2-[4-(l-Methyl-imidazol-2-ylsulfanylmethyl)-benzoylamino]7
phenyl)-carbamic acid tert-butyl ester (compound 138)
[0228]. To a solution of N-methyl-2-mercaptoimidazole (28 mg, 0.25
mmol) in THF (1 mL) , at r.t. under N2 atmosphere were successively
added 137 (70 mg, 0.20 mmol), triphenylphosphine (70 mg, 0.27 mmol)
followed by dropwise addition of diethyl azodicarboxylate (48 /iL, 0.31
mmol) . The mixture was stirred for 2 h and the solvent was removed in
vacuo. Purification by flash chromatography using MeOH/CHCl3 (5:95)
as the eluent afforded the title compound 138 (81 mg), in 91% yield,
which was found to contain some diethyl hydrazodicarboxylate residus.
The compound was used as is without further purification.

Step 5: N-(2-Amino-phenyl) -4-(i-methyl-lH-imidazo-1-2-
ylsulfanylmethyl]-benzamide (compound 139)
[0229] Following the procedure described in Example.42, step 3, but
substituting 138 for 46, the title compound 139 was obtained in 62%
yield. XH NMR: (Acetone-dg) d (ppm) : 9.07 (bs, 1H), 7.93 (d, J = 8.2
Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.10 (d,
J = 1.1 Hz, 1H), 7.03-6.96 (m, 2H), 6.86 (dd, J = 8.0 Hz, 1.4 Hz, 1H),
6.67 (dt, J = 7.4 Hz, 1.1 Hz, 1H), 4.63 (bs, 2H), 4.29 (s, 2H) , 3.42
(S, 3H).
Example 91
N-(2-Amino-phenyl)-6-(3-methoxyphenyl)-nicotinamide (compound 141)
[0230] To a mixture of 3-methoxyphenyl boronic acid (152 mg, 1.0
rnmol) and 140 (248 g, 1.0 mmol) were added benzene (8 mL) and ethanol
(4 mL) followed by 2 M Na2C03 aqueous solution (3.2 mL, 6.4 mmol) . The
reaction mixture was stirred under nitrogen for 30 min and then
Pd(PPh3) the mixture was cooled to room temperature, filtered through a pad of
celite and rinsed with ethyl acetate (30 mL). The organic solution was
washed with brine (5 mL), dried (MgSO4), and concentrated.
Purification by flash silica gel chromatography (Hexane/Ethyl acetate:
1/1) afforded 141 (3~02 mg, 95% yield). XH NMR (CDC13) d (ppm): 9.11 (d, J
= 1.8 Hz, 1H), 8.30 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.57 (d, J = 8.4 Hz,
1H) , 7.52-7.47 (m, 1H), 7.36 (m, 1H), 7.22 (m, 1H), 7.09-6.78 (m, .4H),
3.84 (s, 3H), 3.39 (br s, 2H).
Example 92
N-(2-Amino-phenyl)-4-(1-oxo-l,3-dihydro-isoindol-2-yImethyl)-benzamide
(compound 144)
Step 1: 4-(l-Oxo-l,3-dihydro-isoindol-2-ylmethyl)-benzoic acid
(compound 143)
[0231] To a solution of benzene-1,2-carbaldehyde 142 (1.0 g, 7.46
mmol) in 10 mL of acetic acid was added 4-aminomethylbenzoic acid
(1.13 g, 7.46 mmol). The reaction mixture was refluxed 5 min and
cooled to the room temperature. A crystalline precipitate was formed
and triturated with CH2C12 to produce the title compound 143 (1.29 g,
49%) .
Step 2: N- (2-Amino-phenyl)-4-(1-oxo-l,3-dihydro-isoindol-2-ylmethyl)-
benzamide (compound 144)
[0232] To a solution of the carboxylic acid (0.32 g, 0.89 mmol) in
DMF (8 mL) at rt, was added HOBt (0.16 g, 1.15 mmol) and EDC (0.25 g,
1.33 mmol) and the solution was stirred for 1.5 h. Lastly,
phenylenediamine (0.12 g, 1.07 mmol) was added and the mixture was
allowed to stir for 18-20 h. DMF was removed in vacuo and the crude
was partitioned between ethyl acetate and H2O. The organic layer was
dried over Na2SO4 and concentrated. Purification by column
chromatography (CH2Cl2-MeOH (19:1)) afforded 144 in 46% yield. XH NMR:
(DMSO-d6) D 9.71 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0
Hz, 2H) , 7.55-7.70 (m, 3H), 7.46 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 7.7
Hz, 1H) , 7.02 (t, J = 7.7 Hz, 1H) , 6.83 (d, J = 8.0 Hz, 1H), 6.65 (t,
J = 7.4 Hz, 1H), 4.93 . (bs, 2 H), 4.87 (s, 2 H), 4.47 (s, 2H).
Example 94
N- (2-Amino-phenyl)- 4-(1,3-dioxo-l,3-dihydro-isoindol-2-ylmethyl)-
benzamide (compound 149)
[0233] Phthalic anhydride 148 (1.3 g, 8.9 mmol) and 4-
aminomethylbenzoic acid in 20 mL acetic acid were refluxing for 3 h,
cooled to the room temperature and evaporated to yield a solid residue
which was triturated with water, filtered off and dried to produce the
intermediate carboxylic acid (1.7 g, 68%). LMRS = 282.0 (M+l).
[0234] Following a procedure analogous to that described in Example
92, step 2, but substituting the acid for 143, the title compound 149
was obtained in 17% yield. XE NMR: (DMSO d6) D 9.59 (s, 1H), 7.82-7.91
(m, 6H) , 7.40 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 1H), 6.93 (t,
J = 7.7 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.55 (t, J = 7.4 Hz, 1H),
4.83 (bs, 4H).
Example 95
N- (2-Amino-phenyl) -4-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethyl]-
benzamide (compound 152)
Step 1: 2-[2-(4-Hydroxy-phenyl)-ethyl]-isoindole-l,3-dione (compound
150)
[0235] Following a procedure analogous to that described in Example
94, step 1, but substituting 4-aminomethylbenzoic acid for tyramine
the title compound 150 was obtained in 48% yield. LMRS = 268.0 (M+l).
Step 2: 4-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl) ethyl)-phenyl
trifluoromethane-sulfonate (151)
[0236] To a solution of sodium hydride (90 mg, 25 mmol) in dry THP
(20 mL) at 0°C, 150 (500 mg, 8.9 mmol) was added followed by the
addition of dry DMF (2 mL) . The reaction mixture was stirred for 20
min at 0°C, treated portionwise with PhN(Tf)a, stirred for additional 2
h and evaporated to produce a solid material which was purified by
chromatography on a silica gel column, (CHjClj - MeOH (19:1)) to
provide 151 (639 mg, 86% yield). LMRS = 400.0 (M+l).
Step 3: N-(2-Amino-phenyl)-4-[2-(1,3-dioxo-l,3-dihydro-isoindol-2-yl)-
ethyl]-benzamide (compound 152)
[0237] Following a procedure analogous to that described in Example
40, Step 2, but substituting 151 for 42, the title compound 152 was
obtained in 15% yield. 1H NMR: (DMSO d6) D 9.57 (s, 1H), 7.78-7.87 (m,
6H), 7.31 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.7 Hz, 1H), 6.93 (t, J =
6.9 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.56 (t, J = 7.4.Hz, 1H), 4.83
(bs, 2 H), 3.85 (t, J = 7.1 Hz, 2 H), 3.00 (t, J = 7.1 Hz, 2 H).

N- (2-Amino-phenyl) -4- (4-oxo-4ff-quinazolin-3-ylxaethyl) -benzamide
(compound 154)
[0238] A suspension of 4-aminomethyl benzoic acid (1.00 g, 6.60 mmol)
in water (20 mL) was treated with Et3N (0.86 mL, 6.60 mmol) followed
by the addition of isatoic anhydride 153 (980 mg, 6.00 mmol). The
reaction mixture was heated 3 h at 40°C and evaporated to form an oily

residue, which was refluxing in formic acid (2.0 mL) for 7 h. Formic
acid was removed in vacuum to produce a solid, which was triturated
with water and filtered off to provide the carboxylic acid (1.61 g,
11%). LMRS = 281.0 (M+l).
[0239] Following a procedure analogous to that described in Example
92, step 2, but substituting the carboxylic acid for 143, the title
compound 154 was obtained was obtained in 43% yield. XH NMR: (DMSO dg)
D 9.71 (s, 1H), 8.68 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.01 (d, J = 8.0
Hz, 1H), 7.92 (t, J = 8.0, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.63 (t, J =
7.4, 1H), 7.55 (d, J = 7.7 Hz, 2H), 7.22 (d, J = 7.4 Hz, 1H), 7.04 (t,
J = 7.1 Hz, 1H) , 6.85 (d, J = 8.0 Hz, 1H) , 6.67 (t, J = 7.4 Hz, 1H) ,•
5.35 (s, 2 H).
Example 97
N- (2-Amino-phenyl)-4-(4-oxo-4ff-benzo[d] [1,2,3]triazin-3-ylmethyl)-
benzamide (compound 155)
[0240] A suspension of 4-aminomethyl benzoic acid (1.00 g, 6.60 mmol)
in water (20 mL) was treated with Et3N (0.86 mL, 6.60 mmol) followed
by the addition of isatoic anhydride (980 mg, 6.00 mmol). The reaction
mixture was heated 3 h at 40°C and cooled to' 0°C. The cold reaction
mixture was acidified with cone. HC1 (5 mL) and treated drop wise with
NaN02 solution (520 mg, 7.5 mmol in 5 mL water) over 5 min period of
time, then left overnight at room temperature. A precipitate formed
which was collected, washed with water and dried to provide the
carboxylic acid (1.62 g, 96%). LMRS = 282.0 (M+l).
[0241] Following a procedure analogous to that described in Example
92, step 2, but substituting the carboxylic acid for 143, the title
compound 155 was obtained in 27% yield. 1H NMR: (DMSO d6) 0 9.62 (s,
1H) , 8.25 (t, J = 6.7 Hz, 2H), 8.11 (ddd, J = 7.1 Hz, 1.4 Hz, 1H),
7.93-7.98 (m, 3H), 7.49 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 7.7 Hz, 1H) ,
6.94 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.57 (t, J = 7.7
Hz, 1H), 5.66 (s, 2 H), 4.87 (bs, 2 H).
Example 98
N- (2-Amino-phenyl) -4- (2,4-dioxo-l,4-dihydro-2H-quinazolin-3-ylmethyl) -
benzamide (compound 157)
Step 1:' 4- [ (2-Amino-benzoylamino) -methyl] -benzoic acid (compound 156)
[0242] To a suspension of 4-aminomethylbenzoic acid (5.09 g, 33.7
mmol) in H2O (50 mL) , was added Et3N (4.7 mL., 33.7 mmol) followed by
isatoic anhydride 153 (5.0 g, 30.6 mmol). The brown mixture was heated


at 40°C for 2 h until the mixture became homogeneous and then Et3N was
removed in vacuo. The resulting aqueous solution was acidified (10%
HC1/H2O) and the mixture was partitioned between HaO and ethyl acetate,
The combined organic extracts were dried over Na2SO4, filtered and
evaporated to give 156 as a white solid (6.0 g, 72 %). LMRS = 271.0
(M+l).
Step 2: N-(2-Amino-phenyl) -4- (2,4-dioxo-l,4-dihydro-2H-quinazolin-3-
ylmethyl)-benzamide (compound 157)
[0243] The carboxylic acid 156 (1.72 g, 6.36 mmol) was suspended in a
solution of NaOH (2.55 g, 63.6 mmol) in H2O (12 mL) . To this solution
was added dioxane (10 mL) until mixture became homogeneous. The
solution was cooled to 0°C in an ice-bath and methyl chloroformate
(1.25 mL, 16.1 mmol) was added portionwise over 2 h. After completion
of the reaction, the excess methyl chloroformate and dioxane were
removed in vacuo and the mixture was diluted with methanol (80 mL) and
H2O (20 mL) . The solution was heated to 50°C for 1 h: until the
cyclization was complete. Methanol was removed in vacuo and then the
aqueous layer was extracted with ethyl acetate. Subsequently, the
aqueous phase was acidified (10% HC1/H2O) and extracted with ethyl
acetate (2 X 300 mL) . These organic extracts were combined, dried over
Na2SO4, filtered and evaporated to dryness. The resulting crude was
triturated with warm methanol to afford the carboxylic.acid as a white
solid (1.7 g, 90%). LMRS = 319.0 (M+Na).
[0244] Following.a procedure analogous to that described in Example
92, step 2, but substituting the quinazolinedione carboxylic acid for
143, the title compound 157 was obtained. XH NMR: (DMSO-ds) Q 11.56
(brs, 1H), 9.59 (brs, 1H), 7.96-7.88 (m, 3H), 7.67 (dt, J = 8.4, 1.4
Hz, 1H), 7.30 (d, J = 7.8 Hz, 2H), 7.21 (t, J = 7.5 Hz, 2H), 7.13 (d,
J = 6.9 Hz, 1H), 6.92 (dt, J = 6.9, 1.2 Hz, 1H) , 6.75 (d, J = 6.9 Hz,
1H), 6.57 (t, J = 6.9 Hz, 1H), 5.15 (brs, 2H), 4.86 (brs, 2H).
Example 99
N- (2-Amino-phenyl)-4-(l-methyl-2,4-dioxo-l,4-dihydro-2H-quinazolin-3-
ylraethyl)-benzamide (compound 158)
Step 2: •4-(l-Methyl-2,4-dioxo-l,4-dihydro-2H-quinazolin-3-ylmethyl)-
benzoic acid methyl ester
[0245] To a solution of the quinazolinedione carboxylic acid (1.0 g,
3.38 mmol) in DMF (7 mL) , was added K2C03 (1.4 g, 10.1 mmol) and the
mixture was then cooled to 0CC. Subsequently, Mel (1.05 mL, 16.9
161

mmol) was added and the mixture was allowed to warm to rt in the ice
bath overnight. Excess methyl iodide and DMP were removed in vacuo and
the crude was partitioned between ethyl acetate and H2O. The aqueous
phase was washed again with ethyl acetate, the combined organic
extracts were dried over Na2SO4 and then concentrated in vacuo to yield
the desired product as an off-white solid (0.93 g, 85%). LMRS = 325.0
(M+l).
Step 3 ; 4- (l-Methyl-2>4-dioxo-l>4-dihydro-2H-quinazolin-3-ylmethyl) -
benzoic acid •
[0246] To a suspension of the methyl ester (1.25 g, 3.85 mmol) in
methanol (35 mL) , was added IN NaOH (30 mL, 38.5 mmol) and the mixture
was heated to 45-50°C for 3 h. until it became homogeneous. Methanol
was removed in vacuo and the crude was partitioned between ethyl
acetate and H2O. The aqueous phase was acidified (10% HC1/H2O) and
extracted with ethyl acetate (2 X 300 mL). These organic extracts were
dried over Na2SO« and concentrated in vacuo to afford product 5 as a
white solid (1.15 g, 96%). LMRS = 311.0 (M+l).
Step 4: N- (2-Amino-phenyl)-4-(l-methyl-2,4-dioxo-l/4-dihydro-2g-
quinazolin-3-ylmethyl)-benzamide (compound 158)
[0247] Following a procedure analogous to that described in Example
92, step 2, but substituting the carboxylic acid for 143, the title
compound 158 was obtained in 10% yield. lH NMR: (DMS0-d6) 8 9.59 (brs,
1H), 8.03 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.8 Hz, 2H) 7.80 (dt, J =
6.9, 1.5 Hz, 1H), 7.49 (d, J - 8.7 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H),
7.32 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 6.95 (t, J = 7.6
Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.57 (t, J = 7.5 Hz, 1H), 5.21
(brs, 2H), 4.86 (brs, 2H), 3.54 (s, 3H).
Example 100
N- (2-Amino-phenyl) -4- (2-methyl-4-oxo-4H-quinazolin-3-ylmethyl) -
benzamide (compound 159)
[0248] A suspension of 156 (903 mg, 3.34 mmol) in acetic anhydride
(15 mL) was heated at 50°C for 1 h. Acetic anhydride was evaporated
under vacuum and the solid material formed was dissolved in acetic
acid (30 mL). This solution was refluxed 48h and evaporated to form
another solid material, which was recrystallized from a mixture
. AcOEt/CHCl3 to produce the intermediate carboxylic acid (420 mg, 43%
yield). LMRS = 385.0 (M+l):

[0249] Following a procedure analogous to that described in Example
92, step 2, but substituting the carboxylic acid for 143, the title
compound 159 was obtained in 49 % yield. 1H NMR: (DMSO) d (ppm) : 9.64
(bs, 1H), 8.17 (dd, J = 8.0, 1.6 Hz, 1H) , 7.95 (d, J = 8.2 Hz, 2H),
7.95 (dd, J» 8.8, 2.5 Hz, 1H), 7.84 (ddd, J = 7.6, 7.0, 1.5 Hz, 1H),
7.64 (d, J = 7.7 Hz, 1H), 7.53 (ddd, J = 7.6, 7.6, 1.1 Hz, 1H), 7.33
(d, J - 8.2 Hz, 2H), 7.14 (dd, J = 7.7, 1.1 Hz, 1H), 6.96 (ddd, J =
7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, J = 8.0, 1.4 Hz, 1H), 6.58 (ddd, J =
7.6, 7.6, 1.3 Hz, 1H), 5.46 (s, 2H) , 4.89 (bs, 2H) 2.5 (s, 3H,
overlaps with the DMSO signals).
Example .101
N- (2-aminophenyl) -2- (4-Methoxy-benzylamino) -thiazol-5-yl-amide
(compound 163)
Step 1: 4-Methoxybenzyl-thiourea (compound 161)
[0250] To a solution of thiocarbonyl diimidazole (1.23g, 6.22 mmol,
1.5 eguiv.) in dry dichloromethane (10 mL), neat alkylamine 160 (4.15
mmol, 1.0 eguiv.) was added dropwise at 0°C, and the solution stirred
from 0°C to 15°C during 16 h. A solution of concentrated ammonium
hydroxide (3 mL, 45 mmol, 3.6 eguiv.) in 1,4-dioxane (6 mL) waB added
at 0°C and stirred at room temperature for 7 h. The solution was
diluted with ethyl acetate (250 mL) , washed with brine (2 x 50 mL) ,
dried (MgSO4), filtered and concentrated. After purification by column
chromatography (silica gel, elution 5% methanol in dichloromethane),
161 was obtained as yellow solid (700.2 mg, 3.6 mmol, 86% yield). XH
NMR: {Acetone-d6) 5 (ppm): 7.53 (bs, 1H) , 7.28 (d, J = 8.8 Hz, 2H) ,
6.87 (d, J= 8.8 Hz, 2H), €.67 (bs, 2H) , 4.67 (s, 2H), 3.77 (s, 3H).
LMRS = 197.1 (M+l).

Step 2; 2- (4-Methoxybenzylamino)thiazole-5-carboxylic acid methyl
ester (compound 162)-
[0251] A solution of trans methyl-2-methoxyacrylate (461 mg, 3.97
mol, 1 equiv.) in 50% 1,4-dioxane in water (4 mL) stirred at -10°C,
was treated with N-bromosuccinimide (792 mg, 4.46 mmol, 1.12 equiv.),
stirred at the same temperature for lh, transferred to a flask
containing the thiourea 161 (700.2 mg, 3.6 mmol) and the mixture was
stirred at 80°C for 2h. After cooling down to room temperature,
concentrated NH4OH (0.8 mL) was added, stirred for 10 min and the
' resulting precipitated filtered and washed with water, giving 363 mg
(1.3 mmol, 36% yield) of 162, plus 454 mg additional (91 % pure by
HPLC) as residue from evaporation of the filtrated (ca. 77% overall
yield). XH NMR: (Acetone-d*) d (ppm): 7.97 (bs, 1H), 7.72 (bs, 1H),
7.33 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H), 4.52 (b, 2H), 3.78
(s, 3H), 3.75 (s, 3H). LMRS = 279.1 (M+l).
Step- 3: N- (2-aminophenyl)-2-(4-Methoxy-benzylamino)-thiazol-5-yl-amide
(compound 163)
[0252] Following the procedure described in Example 1, steps 4 and 5,
but substituting 162 for 6, the title compound 163 was obtained in 50%
yield. XH-NMR (methanol-d4), d (ppm): 7.86 (s, 1H), 7.29 (d, J= 8.8
Hz, 2H), 7.11 (dd, J = 8.0 Hz, 1.4 Hz/ 1H), 7.04 (dt, J = 8.0 Hz, 1.4
. Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.86 (m, 1H), 6.74 (dt, J = 7.4 Hz,
1.4Hz, 1H), 4.85 (bs, 4H), 4.45 (s, 2H), 3.78 (s, 3H).
Examples 102-121
[0253] Examples 102 to 121 describe the preparation of compounds 164
to 183 using the same procedures as described for compounds 62 to 163
in Examples 47 to 101. Characterization data are presented in Tables
4a and 4b.
Example 122 a a a a.
Step 1: (2-[(3'-Formyl-biphenyl-4-carbonyl)-amino]-phenyl)-carbamic
acid tert-butyl ester (185)
[0254] Following the procedure described in Example 15, step 1, but,
substituting 184 for 140, the title compound 185 was obtained in 74%
yield. 1H NMR (CDC13) : 8 10.10 (s, 1H) , 9.41(s, 1H) , 8.13 (m, 1H) ,
8.07 (d, J = 8.4 Hz, 2H) , 7.89 (m, 2H), 7.77 (m, 1H), 7.70 (d, J =
8.4 Hz, 2H), 7.S4 (m, 1H), 7.27-7.09 '(m, 3H), 7.03 (s, 1H) , 1.52 (s,
9H) .
Step 2: N- (2-Aminophenyl) -4- [3- (indan-2-ylaminomethyl)phenyl) ] -
benzamide (186)
[0255] To a stirred solution of biphenyl aldehyde (.104 mg, 0.25
mmol) and 2-aminoindane (33.3 mg, 0.25 mmol) in dichloroethane (lmL)
was added sodium triacetoxyborohydride (80 mg, 0.375 mmol) followed
by a glacial acetic acid (15ul, 0.25 mmol), and then the mixture was
stirred at room temperature for 3h. After a removal of the
volatiles, the residue was partitioned between ethyl acetate and 10%
aqueous sodium bicarbonate solution. The combined organic layers
were washed with water, dried and concentrated. Purification by
flash chromatography (10% methanol in chloroform) gave the desired
Boc-monoprotected product (112mg, 84% yield) as a white solid. 1H NMR
(CDCI3): DD9.21 (s, 1H), 8.03 (d, J = 8.7 Hz, 2H), 7.83 (m, 1H), 7.69
(d, J = 8.7 Hz, 2H), 7.65 (s, 1H), 7.54-7.38 (m, 3H), 7.28 (m, 7H),
6.82 (s, 1H), 3.95 (s, 2H), 3.74 (m, 1H) , 3.22 (dd, J = 15.6, 6.9
Hz, 2H),-2.89 (dd, J= 15.6, 6.6 Hz, 2H), 1.53 (s, 9H).
[0256] Following the procedure described in Example 42, step 3, but
substituting the previous compound for 46, the title compound 186
was obtained in 98 % yield. XH NMR (20% CD30D in CDC13) : 8 7.95 (d, J =
8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.57 (m, 1H), 7.54-6.79 (m,

11H), 3.95 (s, 2H), 3.66 (m, 1H), 3.16 (dd, J - 15.6, 6.9 Hz, 2H),
2.81 (ddi J = 15.6, 6.6 Hz, 2H).
Examples 123-126
10257] Examples 123 to 126 (compounds 187 - 190) were prepared
using the same procedure as described for compound 186 in Example
122 (scheme 21).
Scheme 22
Example 127
Step 1: {2-[4-(1-Amino-cyclohexylethynyl)-benzoylaminoj-phenyl)-
carbamic acid tert-butyl ester (191)
[0258] A mixture of iodide 184 (438 mg, 1.0 mmol), Pd(PPh3)2Cl2 (35
mg, 0.05 mmol), triphenylphosphine (7.6 mg, 0.025 mmol), and 1-
ethynyl'cyclohexylamine (185 mg, 1.5 mmol) was stirred at room
temperature in THF (4 mL) containing triethylamine (0.56 mL, 4.0
mmol) for 20 min. To this Cul (3.8 mg, 0.02 mmol) was added and
stirring continued for 2 h. The reaction mixture was then diluted
with ethyl acetate (30 mL) , washed with water, and the organic layei
was dried and concentrated. Purification by flash chromatography
(10% methanol in chloroform) gave the desired product 191 (420 mg,
97% yield). XH NMR (CDC13) : 89.36 (s, 1H) , 7.94 (d, J = 8.4 Hz, 2H) ,
7.77 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.25-6.85 (m,
3H) , 2.10-1.30 (m. 10H), 1.51 (s, 9H).
Step 2: if-(2-Aminophenyl)-4-[l-(4-methoxy-benzylamino)-
cyclohexylethynyl]-benzamide (192)
[0259] Following the procedure described in Example 122, step 2,
but substituting p-anisaldehyde for 2-aminoindane, the title
compound 192 was obtained in 74 % yield. XH NMR (CDC13) : 5 8.44 (s,
1H), 7.82 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.31 "(d, J

= 8.4 Hz, 2H), 7.23 (m, 1H), 7.05 (m,lH), 6.84 (d, J =8.7 Hz, 2H),
6.78 (m, 2H), 3.97 (s, 2H), 3.76 (s, 3H), 2.10-1.30 (m. 10H) .
Scheme 23
TMS~=
Example 134
Example 133 .
Step 1: N- [2-(t-Butyloxycarbonyl)-amino-phenyl]-4-
(trimethyl3ilylethynyl)benzamide (197)
[0260] To a stirred solution of 184 (5.00 g, 11.41 mmol) in
anhydrous THF (100 ml) under nitrogen at 0°C were added Pd(PPh3)2Cl2
(240 mg, 0.34 mmol), Cul (130 mg, 0.69 mmol), and
trimethylsilylacetylene (2.10 ml, 14.84 mmol), respectively. Then,
anhydrous Bt3N (6.36 ml, 45.66 mmol) was added dropwise. The
temperature was slowly warmed up to room temperature over 4 h. The
reaction mixture was poured into a saturated aqueous solution of
NH4C1, and diluted with ethyl acetate. After separation, the organic
layer was successively washed with sat. NH4CI, H2O and brine, dried
over anhydrous MgSO4, filtered and concentrated. The crude residue
was then purified by flash chromatography on silica gel
(AcOEt/hexane: 20/80->50/50) to afford the title compound 197 (4.42
g, 10.83 mmol, 94% yield) as a yellow powder. lH NMR (300 MHz, CDC13)
6 (ppm) : 9.26 (bs, 1H) , AB system (SA = 7.91, 5s = 7.55, J = 8.3 Hz,

4H) , 7.85 (d, J = 7.9 Hz, 1H) , 7.32-7.13 (m, 3H) , 6.70 (bs, 1H) ,
1.53 (s, 9H), 0.28 (s, 9H).
Step 2; lM2-Amino-phenyl)-4-(trimethylsilylethynyl)benzamide (198)
[0261] Following the procedure described in Example 42, step 3, but
substituting the previous compound for 46, the title compound 198
(70 mg, 0.23 mmol) was obtained as a white solid with a major
fraction composed of a mixture of 198 and 199. 1H NMR (300 MHz,
acetone-d6) d (ppm) : 9.20 (bs, 1H) , AB system (5A = 8.07, 5b = 7.62, J
= 8.2 Hz, 4H), 7.32 (d, J = 7.6 Hz, 1H), 7.05 (td, J « 7.6, 1.2 Hz,
1H), 6.90 (d, J = 7.6 Hz, 1H), 6.72 (t, J = 7.3 Hz, 1H), 4.66 (bs,
2H), 0.30 (s, 9H).
Step 3: JW-(2-Amino-phenyl)-4-ethynylbenzamide (199)
[0262] To a stirred solution at -20°C of a mixture of 198 and 199
in anhydrous THF (15 ml) under nitrogen-was added a solution of TBAF
(1 ml, 1.0 M in THF) . The reaction mixture was allowed to warm up
to room temperature over 2 h and stirred at room temperature for 18
h. Then, the reaction mixture was poured into a saturated aqueous
solution of NH4C1 and diluted with ethyl acetate. After separation,
the organic layer was successively washed with sat. NH4C1, H2O and
brine, dried over anhydrous MgSO4, filtered and concentrated. The
crude residue was then purified by flash chromatography on silica
gel (AcOEt/hexane: 30/70) to afford the title compound 199 (215 mg,
0.91 mmol, 46% yield over 2 steps) as a pale yellow powder. 1H NMR
(300 MHz, acetone-d«) d (ppm): 9.19 (bs, 1H) , AB system (8X = 8.08, 8B
= 7.66, J = 8.5 Hz, 4H), 7.33 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.3
Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 4.67
(bs, 2H), 3.88 (s, 1H).
Example 134
Step 1: N- [2- (t-Butyloxycarbonyl) -amino-phenyl] -4-ethynylbenzamide
(200)
[0263] To a stirred solution at -20°C of a mixture of 199 (3.48 g,
8.53 mmol) in anhydrous THF (50 ml) under nitrogen was slowly added
a solution of TBAF (9.4 ml, 9.38 mmol, 1.0 M in THF). The reaction
mixture was allowed to warm up.to room temperature over 2 h and
stirred at room temperature for 4 h. Then, the reaction mixture was
concentrated, diluted with ethyl acetate, and successively washed
with a saturated aqueous solution of NH4C1, H2O and brine, dried over
anhydrous MgSO4, filtered and concentrated. The crude residue was


then purified by riasn cnromatograpny on siixca gei lAcOEt/hexane:
25/75-^30/70) to afford the title compound 200 (2.53 g, 7.53 mmol,
88% yield) as a pale yellow foam. 1H NMR (300 MHz, CDC13) d (ppm) :
2.31 (bs, 1H), AB system (8A = 7.94, 8b = 7.59, J = 8.5Hz, 4H) , 7.83
(d, J= 7.6 Hz, 1H), 7.30-7.10 (m, 3H), 6.75 (bs, 1H), 3.23 (a, 1H),
1.53 (s, 9H).
Step 2: N- (2-amino-phenyl) -4- [3- (4-chlorophenyl) -3-morpholin-4-yl-l-
propyn-1-yl]-benzamide (201)
To a stirred solution at room temperature of 200 (200 mg, 0.60 mmol)
in anhydrous 1,4-dioxane (5 ml) under nitrogen were added 4-
chlorobenzaldehyde (100 mg, 0.71 mmol), morpholine (60 ul, 0.68
mmol), and Cul (6 mg, .0.03 mmol), respectively. The reaction
mixture was bubbled with nitrogen for 5 min and warmed up to 105°C.
After 18 h, the reaction mixture was allowed to cool to room
temperature, diluted with ethyl acetate, and successively washed
with a saturated aqueous solution of NH4C1, H2O and brine, dried over
anhydrous MgSO4, filtered and concentrated. The crude residue was
then purified by flash chromatography on silica gel (AcOEt/hexane:
40/60) to afford the desired compound (193 mg, 0.35 mmol, 59% yield)
as a pale yellow foam. XH NMR (300 MHz, CDC13) 5 (ppm): 9.40 (bs,
1H) , AB system (8A = 7.96, 6B = 7.36, J = 8.5 Hz, 4H) , 7.79 (d, J =
7.9 Hz, 1H), 7.59 (d, J = 8.4.Hz, 4H), 7.25-7.10 (m, 3H), 6.91 (s,
1H) , 4.80 (s, 1H), 3.82-3.68 (m, 4H), 2.69-2.58 (m, 4H), 1.53 (s,
9H) .
[0264] Following the procedure described in Example 42, step 3, but
substituting the previous compound for 46, the title compound 201
was obtained in 67 % yield. XH NMR (300 MHz, DMSO-d6) d (ppm) : 9.80
(bs, 1H) , AB system (8A = 8.06, 8b = 7.71, J = 8.1 Hz, 4H) , AB system
(8A = 7.65, 8B = 7.52, J = 8.3 Hz, 4H) , 7.20 (d, J = 7.9 Hz, 1H) ,
7.02 (t, J = 7.3 Hz, 1H), 6.82 (d, J = 7.0 Hz, 1H), 6.64 (t, J = 7.5
Hz, 1H), 5.10.(s, 1H), 4.97 (bs, 2H), 3.72-3.58 (m, 4H) , 2.67-2.46
(m, 4HK
Example 135 204
Example 135
Step 1: Methyl 4- (4-chloro-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-
amino)-benzoic ester (203)
[0265] To a stirred solution at room temperature of 202 (2.00 g,
7.11 mmol) in anhydrous THF (50 ml) under nitrogen were added i-
Pr3NEt (1.86 ml, 10.66 mmol) and methyl 4-aminobenzoate (1.29 g, 8.53
mmol) or ArNH2 (1.2 equiv), respectively. The reaction mixture was
then refluxed for 24 h. After cooling, the reaction mixture was
poured into a saturated aqueous solution of NH4Cl, and diluted with
AcOEt. After separation, the organic layer was successively washed
with sat. NH4Cl, H2O and brine, dried over anhydrous MgSO4, filtered
and concentrated. The crude residue was then purified by flash
chromatography on silica gel (AcOEt/CH2Cl2: 2/98-»5/95) to afford the
title compound 203 (1.70 g, 4.30 mmol, 60% yield) as a beige powder.
1H NMR (300 MHz, CDC13) 5 (ppm): mixture of rotamers, 2 AB system (8A
= 8.03, 8A. = 8.00, 5b = 7.70, 5b- = 7.61, JM = JA,B. = 8.8 Hz, 4H) ,
7.43 and 7.31 (2 bs, 1H), 7.29-7.19 (m, 4H), 5.84 and 5.78 (2 d, J =
7.2 and 7.7 Hz, 1H), 4.98-4.77 (2 m, 1H), 3.91 and 3.90 (2 s, 3H) ,
3.41 (dd, J = 16.1, 7.0 Hz, 2H), 2.94 and 2.89 (2 dd, J = 15.9, 4.9
Hz, 2H).
Step 2: 4- [4-amino-6- (2-indanyl-amino) -fl, 3, 5l-triazin-2-ylamino] -N-
(2-amino-phenyl)-benzamide (204)
[0266] The title compound 204 was obtained from 203 in 3 steps
following the same procedure as Example 1, Pathway B steps 3-5. *H

NMR (300 MHz, acetone-ds) 5 (ppm): mixture of rotamers, 8.98 (m, 1H),
8.49 and 8.28 (2m, 1H), 8.10-7.92 (m, 4H) , 7.35-7.14 (m, 5H), 7.03
(td, J = 7.6, 1.5 Hz, 1H), 6.90 (dd, J = 6.6, 1.3 Hz, 1H), 6.71 (td,
J=7.6, 1.3 Hz, 1H), 6.57 and 6.42 (2m, 1H), 6.04 and 5.86 (2m,
2H), 4.92-4.76 (m, 1H), 4.70-4.58 (m, 1H) , 3.44-3.26 (m, 2H), 3.08-
2.92 (m, 2H) . HRMS (calc): 452.2073, (found): 452.2062.
Example 136
Step 1: Methyl 4-[(4-chloro-6-(2-indanyl-amino)-[1,3,5]triazin-2-
yloxy)-methyl]-benzoic ester (206)
[0267] To a stirred solution at 0°C of 205 (2.00 g, 7.11 mmol) in
anhydrous THF (50 ml) under nitrogen were added i-Pr2NEt (1.86 ml,
10.66 mmol) and methyl 4-(hydroxymethyl)benzoate (1.30 g, 7.82
mmol) . After few minutes, NaH (95%, 186 mg, 7.11 mmol) was added
portionwise. Then, the reaction mixture was allowed to warm to room
temperature. After 24 h, the reaction mixture was poured into a
saturated aqueous solution of NH4C1, and diluted with AcOEt. After
separation, the organic layer was successively washed with sat.
NHUCl, H2O and brine, dried over anhydrous MgSO4, filtered and
concentrated. The crude residue was then purified by flash
chromatography on silica gel (AcOEt/CH2Cl2: 2/98) to afford the title
compound 206 (2.00 g, 4.88 mmol, 69% yield) as a colorless sticky
foam. XH NMR (300 MHz, CDC13) d (ppm): mixture of rotamers, 2 AB
system (SA = 8.06, 8A. = 8.03, 5b = 7.52, 8B. = 7.46, JM = >W = 8.5

Hz, 4H), 7.26-7.17 (m, 4H), 5.94 and 5.85 (2 bd, J = 7.8 Hz, 1H) ,
5.48 and 5.39 (2 s, 2H), 4.92-4.76 {2 in, 1H), 3.94 and 3.92 (2 s,
3H), 3.39 and 3.33 (2 dd, J = 16.0, 7.0 Hz, 2H), 2.89 and 2.84 (2
1l37 J = 16.0, 4.9 Hz, 2H).
Step 2; 4-( [4-amino-6-(2-indanyl-amino)-fl,3,5]-triazin-2-yloxy] -
methyl)-N- (2-amino-phenyl) -benzamide (207)
[0268] The title compound 207 was obtained from 206 in 3 steps
following the same procedure as Example 1, Pathway B steps 3-5. 1H
NMR (300 MHz, acetone-d6 + e DMSO-ds) d (ppm) : 9.49 (m, 1H) , 8.12-
8.03 (m, 2H), 7.60 (t, J = 7.7 Hz, 2H), 7.35 (d, J =7,1 Hz, 1H) ,
7.28-7.13 (m, 4H), 7.07-6.94 (m, 2H), 6.90 (dd, J = 7.3, 1.4 Hz,
1H), 6.70 (td, J = 7.3, 1.1 Hz, 1H), 6.44 (bs, 1H), 6.25 (bs, 1H),
5.47 and 5.41 (2s, 2H), 4.87-4.68 (m, 3H), 3.35-3.20 (m, 2H), 3.02-
2.88 (m, 2H) . HRMS (calc): 467.2070, (found): 467.2063.
Scheme 26
Example 210
Methyl 4-[(4-chloro-6-phenethyl-amino-[1,3,5] triazin-2-yl-amino)
methyl]-benzoic ester (208)
[0269] The title compound 208 was obtained from 2 following the
same procedure as in Example 1, pathway B steps 2 (R1R2NH =
phenethylamine).

Step It Methyl 4-[(4-phenethylamino-[1,3,5]triazin-2-yl-amino)-
methyl]-benzoic ester (209)
[0270] To a degazed solution of 208 (300 mg, 0.75 mmol) in MeOH (35
m£)_ was added 10% Pd/C (24 mg, 0.023 mmol). The reaction mixture
was stirred under a 1 atm pressure of Ha at room temperature for 20 h
then it was purged with N2. The palladium was removed by filtration
through celite and the reaction mixture was concentrated. The crude
residue was purified by flash chromatography on silica gel
(MeOH/CH2Cl2: 4/96) to afford the title compound 209 (135 mg, 0.37
mmol, 50% yield). 1H NMR (300 MHz, CDC13) d (ppm) : 8.08 (d, J = 8.1
Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.50-7.15 (m, 6H) , 4.85-4.65 (m,
2H)., 3.98 (s,.3H), 3.82-3.62 (m, 2H) , 3.05-2.85 (m, 2H) .
Step 2: N- (2-Mino-phenyl) -4- [ (4-phenethylamino- [1,3,5] triazin-2-yl-
amino)-methyl]-benzamide (210)
[0271] The title compound 210 was obtained from 209 in 2 steps
following the same procedure as in Example 1, steps 4 and 5. 1H NMR:
(300 MHz, acetone-d6) d (ppm): 9.03 (s, 1H), 8.17-7.87 (m, 3H) , 7.49
(dd, J = 19.2, 8.2 Hz, 2H), 7.32-7.03 (m, 6H), 6.99 (t, J = 7.6 Hz,
1H), 6.86 (d, J = 8.0 Hz, 1H), 6.67 (t, J = 7.4 Hz, 1H), 6.60-6.30
(m, 2H), 4.72 (t, J = 6.3 Hz, 1H), 4.65-4.56 (m, 1H), 3.67-3.51 (m,
2H), 2.95-2.80 (m, 2H).

Scheme 27

Example 138
Step 1: Methyl 4-[(4,6-dimethoxy-[1,3,5]triazin-2-yl-amino)-methyl]-
benzoic ester (211)
[0272] In a 75ml sealed flask, a stirred suspension of 2-chloro-
4,6-dimethoxy-l,3,5-triazine (540 mg, 3.08 mmol), methyl 4-
(aminomethyl)benzoate.HCl 2 (689 mg, 3.42 mmol), i-Pr2NEt (1.49 ml,
8.54 mmol) in anhydrous THF (30 ml) was warmed at 80°C for 5 h.
Then, the reaction mixture was allowed to cool to room temperature,
poured into a saturated aqueous solution of NH^Cl, and diluted with
AcOEt. After separation, the organic layer was successively washed
with sat. NH4CI, H2O and brine, dried over anhydrous MgSO4, filtered
and concentrated. The crude residue was then purified by flash
chromatography on silica gel (AcOEt/CH2Cl2: 10/90-»30/70) to afford
the title compound 211 (870 mg, 2.86 mmol, 93% yield) as a white .
solid. 1H NMR (300 MHz, CDC13) d (ppm) : AB system (8A = 8.01, 8B =
7.39, Jab = 8.5 Hz, 4H), 6.08-6.00 (m, 1H), 4.73 (d, J = 6.3 Hz, 2H),
3.95 (s, 6H), 3.92 (s, 3H).
[0273] The title compound 212 was obtained from 211 in 2 steps
following the same procedure as Example 1, steps 4 and 5. JH NMR
(300 MHz, acetone-d6 + £ DMSO-d6) d (ppm): 9.58 (bs, 1H) , 8.27 (t, J
= 6.3 Hz, 1H), AB system (8A = 8.04, 83 = 7.53, Ja = 8.4 Hz, 4H) ,
. 7.31 (d, J = 6.9 Hz, 1H), ), 7.02 (td, J =7.6, 1.6 Hz, 1H), 6.88
(dd, J = 7.9, 1.4 Hz, 1H), 6.68 (td, J = 7.6, 1.4 Hz, 1H), 4.86-4.78

(m, 2H), 4.69 (d, J = 6.3 Hz, 2H), ), 3.90 and 3.89 (2s, 6H) . aHRMS
(calc): 380.1597, (found): 380.1601.
Step 2: N- (2-Amino-phenyl) -4- [ (4>6-dimethoxy-[l/3,5l-triazin-2-yl-
araino)-methyl]-benzamide (212)
Example 139
Step 1: 4-[(6-(2-Indanyl-amino)-4-methoxy-[1,3,5]triazin-2-yl-
amino)-methyl]-benzoic acid (213)
[0274] To a stirred solution at room temperature of 5 (300 mg, 0.73
mmol) in a mixture of MeOH/THF (10 ml/5 ml) was added an aqueous
solution of KOH (10%, 5 ml). After 3 days, the reaction mixture was
concentrated on the rotavap, diluted in water and acidified with IN
HC1 until pH 5-6 in order to get a white precipitate. After 15 min,
the suspension was filtered off and the cake was abundantly washed
with water, and dried to afford the title compound 213 (282 mg, 0.72
mmol, 98% yield) as a white solid. MS: m/z = 392.1 [MH]-+.
Step 2: N- (2-amino-phenyl)-4-{[6-(2-indanyl-amino)-4-methoxy-[l,3,5]-
triazin-2-yl-amino]-methyl)-benzamide (214)
[0275] The title compound 214 was- obtained from 213 in one step
following the same procedure as Example 1, step 5. XH NMR (300 MHz,
acetone-ds + e DMSO-d6) d (ppm): mixture of rotamers, 9.69-9.53 (m,
1H), AB system (8A = 8.04, 5b = 7.52, JM = 7.8 Hz, 4H) , 7.80-7.60 (m,
1H), 7.45-7.10 (m, 6H), 7.01 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.2
Hz, 1H), 6.68 (t, J = 7.6 Hz, 1H), 4.92-4.60 (m, 5H), 3.90-3.78 (m.
3H), 3.35-3.22. (m, 2H) , 3.02-2.83 (m, 2H) . HRMS (calc): 481.2226,
(found): 481.2231.

Example 29
Step !:• Methyl 4-[(4,6-dichloro-[1,3,5]triazin-2-yl-M-methyl-amino)-
methyl]-benzoic ester (216)
[0276] To a stirred suspension at room temperature of NaH (95%,' 81
mg, 3.19 mmol) in anhydrous THF (10 ml) under nitrogen were
successively added a solution of 3 (500 mg, 1.60 mmol) in anhydrous
THF (10 ml) and Mel (298 yl, 4.79 mmol). After 16 h, the reaction
mixture was poured into a saturated aqueous solution of NH4C1, and
diluted with AcOEt. After separation, the organic layer was
successively washed with sat. NH4Cl, H2O and brine, dried oyer
anhydrous MgSO4, filtered and concentrated. The crude residue was
then purified by flash chromatography on silica gel (AcOEt/hexane:
10/90->20/80) to afford the title compound 215 (200 mg, 0.61 mmol,
38% yield) as a white crystalline solid. 1H NMR (300 MHz, CDC13) 5
(ppm) : AB system (5A = 8.04, 8b = 7.31, JM = 8.2 Hz, 4H) , 4.93 (s,
2H), 3.93 (s, 3H), 3.18 (s, 3H).

Step 2: 4-( [4-amino-6- (2-indanyl-amino) -[l,3,5l-triazin-2-yl-N-
methyl-amino] -methyl)-N- (2-amino-phenyl) -benzamide (216)
[02771 aThe title compound 216 from 215 in 4 steps was obtained
following the same procedure as Example 1, Pathway B steps 2-5. aXH
NMR (300 MHz, acetone-dg) 8 (ppm) : 9.11 (bs, 1H), 8.03 (d, J - 8.0
Hz, 2H), 7.43 (bs, 2H), 7.33 (d, J = 7.7 Hz, 1H) , ), 7.28-7.09 (m,
4H), 7.04 (td, J =7.6, 1.5 Hz, 1H), 6.90 (dd, J - 8.0, 1.4 Hz, 1H),
6.71 (td, J = 7.5, 1.3 Hz, 1H), 6.25-6.05 (m, 1H), 5.82 and 5.64
(2bs, 2H), 5.00-4.56 (m, 5H) , 3.42-2.76 (m, 7H) . aHRMS (calc):
480.2386, (found): 480.2377.
Scheme 30
Example 141 218 :R1 = Me, R2R3N = 2-indany)-am!no
Example 141:
Step 1: Methyl 4-[(4-chloro-6-methyl-[1,3,5] triazin-2-yl-amino)-
methyl]-benzoic ester (217)
[0278] To a stirred solution at -30°C of cyanuric chloride 1 (2.0(
g, 10.85 mmol) in anhydrous THF (100 ml) under nitrogen was slowly
added a solution of MeMgBr (17 ml, 23.86 mmol, 1.4 M in anhydrous
THF/toluene) . After 1 h, the reaction mixture was allowed to warm
to room temperature over 3 h. Then, methyl 4-
(aminomethyl)benzoate.HCl 2 (2.08 g, 10.30 mmol) and i-Pr2NEt (3.78
ml, 21.69 mmol) were added, respectively. After 18 h, the reaction
mixture was poured into a saturated aqueous solution of NH4C1, and
diluted with AcOEt. After separation, the organic layer was
successively washed with sat. NH4CI, H2O and brine, dried over
anhydrous MgSO4, filtered and concentrated. The crude residue was
then purified by flash chromatography on silica gel {AcOEt/CH2Cl2:
10/90?15/85) to afford the title compound 217 (780 mg, 2.67 mmol,
25% yield) as a yellow powder. 1H NMR (300 MHz, CDC13) 5 (ppra) :
mixture of rotamers, 2 AB system (8A = .8.03, dA. = 8.02, 8b = 7.39, db-
- 7.38, J = 8.5 Hz, 4H), 6.28-6.08 (2 m, 1H), 4.76 and 4.74 (2d, J =
6.3 Hz, 2H), 3.92 (s, 3H), 2.46 and 2.42 (2s, 3H).
Step 2 ; N- (2-amino-phenyl) -4-( [6- (2-indanyl-amino) -4-methyl-fl, 3,51-
triazin-2-yl-amino]-methyl)-benzamide (218)
[0279] The title compound 218 was obtained from 217 in 3 steps
following the same procedure as Example 1, steps 3-5. 1H NMR (300
MHz, acetone-d6 + S DMSO-d6) d (ppm) : mixture of rotamers, 9.62-9.50
(m, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.68-7.37 (m, 3H), 7.33 (d, J =
7.7 Hz, 1H), 7.28-7.07 (m, 5H), 7.02 (t, J = 7.4 Hz, 1H), 6.89 (d, J
= 7.9 Hz, 1H), 6.69 (t, J = 7.4 Hz, 1H), 4.92-4.60 (m, 5H), 3.35-
3.10 (m, 2H), 3.02-2.82 (m, 2H), 2.25-2.12 (m, 3H).
Scheme 31
Example 142
Step 1: (2-(4-[2-(4,6-Diamino-[1,3,5]triazin-2-yl)-vinyl]-
benzoylamino)-phenyl)-carbamic tert-butyl ester (219)
[0280] To a degazed solution of 184 (40 mg, 0.091 mmol) and 2-
vinyl-4,6-diamino-l,3,5-triazine (11 mg, 0.083 mmol.) in dry DMF (1
mL) was added tri-o-tolylphosphine (POT) (1.5 mg, 0.005 mmol)
followed by Et3N (46 nh, 0.33 mmol) and
tris(dibenzylideneacetone)dipalladium(O) (2 mg, 0.0025 mmol). The
solution was heated at 100 °C for 16h. Then, DMF was removed under
reduced pressure. The reaction mixture was partitioned between
AcOEt and a solution of sat. NH4C1. After separation, the organic

layer was washed with brine, dried over anhydrous Na2SO4, filtered
and concentrated. The crude residue was then purified by flash
chromatography on silica gel (MeOH/CH2Cl2: 5/95) to afford the title
compound '219 (25 mg, 0.056 tnmol, 67% yield) . 1H NMR (300 MHz,
Acetone-d«) 5 (ppm) : 8.27 (s, 1H), 8.06 (d, J = 8.1 Hz, 2H), 7.96 (d,
J = 15.9 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H) , 7.76-7.69 (m, 1H) , 7.62-
7.55 (m, 1H), 7.26-7.15 (m, 2H), 6.90 (d, J = 15.9 Hz), 6.21 (s,
4H), 1.50 (s, 9H).
Step 2: N- (2-Amino-phenyl)-4- [2-(4,6-diamino-[1,3,5]triazin-2-yl)-
vinyl]-benzamide (220)
[0281] To a stirred solution at room temperature of 219 (25 mg,
0.056 tnmol) in CH2C12 (1.5 mL) was added TFA (0.3 mL, 4.3 mmol) .
After 30 min, a solution of sat. NaHC03 was slowly added until pH 8
is reached, CH2C12 was removed under reduced pressure, AcOEt was
added, and the phases were separated. The organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered arid concentrated.
The crude residue was purified by flash chromatography on silica gel
(MeOH/CH2Cl2: 10/90) to afford the title compound 220 (19 mg, 0.054
mrnol, 98% yield). 1H NMR: (300 MHz, acetone-dg) d (ppm): 8.33, 8.13
(2d, J = 7.5 Hz, 1H), 8.22 (d, J = 15.9 Hz, 1H) , 8.01 (d, J = 8.1
Hz, 2H), 7.84 (d, J = 8.1 Hz, 2H), 7.38-6.96 (m, 2H), 7.03 (d, J =
15.9Hz, 1H), 6.94-6.62 (m, 2H).

Example 143a
Step 1: 2-Amino-4-chloro-6-piperidin-l-yl-[1,3,5] triazin (221)
[0282] Ammonia was bubbled for 5 min in a solution of 2,4-dichloro-
^-piperidin-l-yl-[l,3,5]triazine (500 mg, 2.15 mmol) in dry 1,4-
dioxane (20 mL). The solution was heated at 70°C for 16h in a sealed
tube. The reaction mixture was allowed to cool to room temperature,
and partitioned between AcOEt and a solution of sat. NH4CI. After
separation, the organic layer was washed with water and brine, dried
over anhydrous Na2SO4, filtered and concentrated to afford the title
compound 221 (453 mg, 2.12 mmol, 98% yield). LRMS: [MH]-+ = 214.1.
Step 2: 2-Amino 4-piperidin-l-yl-6-vinyl-[1,3,5]triazin (222)
[0283] To a solution of- 221 (358 mg, 1.68 mmol) in dry toluene (7
mL) was added tributyl (vinyl) tin (514 nh, 1.76 mmol) followed by
Pd(PPh3)4 (97 mg, 0.084 mmol) and the reaction mixture was heated at
100°C for 16h in a sealed tube. Then, the reaction mixture was
allowed to cool to room temperature, concentrated, and purified
directly by flash chromatography on silica gel (AcOEt/hexane:
10/90->30/70) to afford the title compound 222 (containing
tributyltin chloride).
Steps 3: N- (2-Amino-phenyl)-4t [2-(4-amino-6-piperidin-l-yl-
[l,3,5]triazin-2-yl)-vinyl]-benzamide (223)
[0284] The title compound 223 was obtained from 222 in 2 steps
following the same procedure as in scheme 31, steps 1 and 2. 1H NMR:
(300 MHz, DMSO-de) d (ppm) : 9.69 (s, 1H) , 8.01 (d, J = 7.5 Hz, 2H) ,
7.87 (d, J = 16.0 Hz, 1H), 7.80 (d, J = 7.5 Hz, 2H) , 7.18 (d, J «
7.5 Hz, 1H), 7.04-6.92 (m, 1H), 6.91 (d, J = 16 Hz, 1H), 6.85-6.68
(m, 3H) , 6.60 (t, J = 7.2 Hz, 1H), 4.93 (s, 2H), 3.77 (s, 4H), 1.63
(s, 2H), 1.52 (s, 4H).
Example 143b
Step 4: Jff- (2-Amino-phenyl)-4- [2-(4-amino-6-piperidin-l-yl-
[l,3,5]triazin-2-yl)-ethyl]-benzamide (224)
[0285] To a solution of 223 (18 mg, 0.043 mmol) in MeOH (5 mL) was
added 10% Pd/C (10 mg, 0.021 mmol) . The reaction mixture was shaked
under a pressure of H2 (40 psi).at room temperature for 16 h using an
hydrogenation apparatus. Then, the reaction mixture was purged with
N2, filtered through celite, and concentrated. The crude residue was
then purified by flash chromatography on silica gel (MeOH/CH2Cl2:

2/98-»4/96) to afford the title compound 224 (10 mg, 0.024 mmol, 56%
yield). XH NMR (300 MHz, CDCl3-CD3OD) d (ppm) : 7.82 (d, J = 8.1 Hz,
2H), 7.35 (d, J = 8.1 Hz, 2H) , 7.08 (t, J = 7.0 Hz, 1H), 6.89-6.79
J-y 2H), 7.80-6.90 (m, 1H), 3.76 (s, 4H), 3.13 (t, J = 8.1 Hz, 2H) ,
2.88 (t, J = 8.1 Hz, 2H),1.90-1.40 (m, 10H).

Example 144
Step 1: 2-Amino-benzothiazol-6-ol (225):
[0286] A suspension of 2-am±no-6-methoxybenzothiazole (5.00 g, 27.8
mmol) in dichloromethane (70 mL) was cooled to 0°C under nitrogen
and boron tribromide (3.93 mL, 41.6 mmol) was added dropwise. The
light yellow mixture was stirred for 3 h, allowing to warm-up slowly
from 0°C to 10°C. The reaction was slowly quenched by dropwise
addition of methanol and tafter stirring overnight at room
temperature, the white solid was collected by filtration (6.04 g,
88% yield). This hydrobromic salt was dissolved in water, washed
with ethyl acetate, and neutralized with a saturated aqueous
solution of NaHC03. The resulting crystals were collected by '
filtration and dried in the oven at 135°C for lh to afford the title
compound 225 as colorless crystals (3.63 g, 79% yield). XH NMR:
(CD30D) 5 (ppm): 7.27 (d, J=8.8 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H) ,
6.80 (dd, J=8.4, 2.2 Hz, 1H).
Step 2: 6-(2-Morpholin-4-yl-ethoxy)-benzothiazol-2-ylamine (226)
[0287] To a solution of benzothiazole 225 (3.62 g, 21.8 mmol) in
THF at room temperature under nitrogen, were successively added 4-
(2-hydroxyethyl)morpholine -(3.17 mL, 26.1 mmol), triphenylphosphine
(7.43 g, 28.3 mmol) followed by a dropwise addition of diethyl

azpdicarboxylate (4.46 mL, 28.3 mmol) . The solution was stirred for
3.5 h and THF was partially removed in vacuo. The mixture was
partitioned between ethyl acetate and H2O. The combined organic
layers were extracted with IN HC1. The combined acidic extracts were
neutralized using a saturated aqueous solution of NaHC03 and the
precipitate was dissolved with ethyl acetate. These combined
organic layers were washed with brine, dried over MgSO4, and
concentrated. The filtrate was concentrated, to afford the title
compound 226 (5.83 g, 96% yield) as a light yellow oil. 1H NMR:
(Acetone-d6). d (ppm) : 7.37 (d, J=8.8 Hz, 1H) , 7.34 (d, J=2.6 Hz,
1H) , 6.94 (dd, J=8.8, 2.6 Hz, 1H), 6.60 (bs, 2H), 4.19 (t, J=6.2 Hz,
2H) , 3.70-3.67 (m, 4H), 2.90 (s, 2H), 2.81 (t, J=6.2 Hz, 2H), 2.62-
2.58 (m, 4H).
Step 3: 4-{[6-(2-Morpholin-4-yl-ethoxy)-benzothiazol-r2-ylamino3-
methyl)-benzoic acid methyl ester (227);
[0288] To a round-bottom flask containing benzothiazole 226 (5.80
g, 20.8 mmol) was added methyl 4-formylbenzoate (5.11 g, 31.1 mmol),
followed by THF (8 mL), dibutyltin dichloride (315 mg, 1.04 mmol)
and dropwise addition of phenylsilane (3.24 mL, 31.1 mmol). The
resulting mixture was stirred overnight at room temperature under
nitrogen. The mixture was diluted in ethyl acetate and filtered.
The filtrate was partitioned between ethyl acetate and water and the
combined organic layers were washed with IN HC1. The combined
acidic layers were neutralized using a saturated aqueous solution .of
NaHC03 and the precipitate was extracted with ethyl aceate. The
combined organic layers were washed with brine, dried over MgSO4, and
concentrated. The resulting crude was purified by flash
chromatography using MeOH/CHCl3 (10:90) to afford 227 (3.69 g, 42%
yield). 1H NMR: (Acetone-ds) d (ppm): 8.04 (d, J=8.5 Hz, 2H) , 7.65
(d, J=8.8 Hz, 2H), 7.41 (d, J= 8.8 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H),
6.94 (dd, J= 8.5, 2.7 Hz, 1H), 4.50 (t, J=5.5 Hz, 2H), 3.86 (s, 3H).
Step 4: N- (2-Amino-phenyl) -4- ([6- (2-morpholin-4-yl-ethoxy) -
benzothiazol-2-ylamino3-methyl)-benzamide (228):
[0289] Following the procedure described in Example 1, step 4, 5
but substituting the previous compound for 6, the title compound 228
was obtained (958 mg, 46%) as a colorless solid. 1H NMR: (CD3OD) d (ppm): 8.04 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.40 (d,
J=8.8 Hz, 1H), 7.31 (d, J=2.5 Hz, 1H), 7.25 (d, J=7.4 Hz, 1H), 7.15

(t, J=7.4 Hz, 1H), 6.97 (dd, J=8.8, 2.5 Hz, 2H) , 6.84 (t, J=7.4 Hz,
1H), 4.78 (s, 2H), 4.21 (t, J=5.2 Hz, 2H), 3.81-3.77 (m, 4H) ,
2.87 (t, J=5.5, 2H), 2.69-3.66 (m, 4H).
Example 145
Step 1: 4-[(5-Bromo-benzothiazol-2-ylamino)-methyl]-benzoic acid
methyl ester (229):
[0290] Following the procedure described in Example 144, step 3,
but substituting the 2-amino-6-bromobenzothiazole for 226, the title
compound 229 was obtained in 56% yield. 1H NMR: (DMSO-d«) d (ppm) :
8.78 (t, J- 5.9 Hz, 1H), 8.01 (d, J= 8.2 Hz, 2H) , 7.99 (s, 1H), 7.56
(d, J= 8.2 Hz, 2H), 7.43-7.34 (m, 2H), 4.74 (d, J= 5.9 Hz, 2H) , 3.90
(s, 3H).
Step 2: 4-{[5-(3,4,5-Trimethoxy-phenyl)-benzothiazol-2-ylamino]-
methyl)-benzoic acid methyl ester (230):
[0291] Following the procedure described in Example 15, step 1, but
substituting 229 for 140, the title compound 230 was obtained in
44%yield as colorless crystals. 1H NMR: (DMSO-d6) d (ppm): 8.73 (t,
J=5.7 Hz, 1H), 8.11 (d, J=1.8 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.63-
7.57 (m, 3H), 7.48 (d, J=8.4 Hz, 1H), 6.97 (s, 2H), 4.77 (d, J=5.7
Hz, 2H), 3.92 (m, 6H), 3.90 (s, 3H), 3.74 (s, 3H).
Step 3: N- (2-Amino-phenyl)-4-([5-(3,4,5-trimethoxy-phenyl)-
benzothiazol-2-ylamino]-methyl)-benzamide (231):
[0292] Following the procedure described in Example 1, step 4, 5
but substituting the previous compound for 6, the title compound 231

was obtained in 69% yield. XH NMR: (Acetone-d6) d (ppm): 8.31 (d,
J=7.9 Hz, 2H) , 8.20 (d, J=7.5 Hz, 1H), 8.13 (s, 1H), 7.73-7.58 (m,
3H), 7.63 (d, J=7.5 Hz, 2H), 7.48-7.43 (m, 2H), 7.05 (s, 2H), 4.98
(a, 2H), 4.00 (s, 6H), 3.84 (s, 3H) . •
Scheme 35
Example 146
Step 1: 4-[(6-Methoxy-benzothiazol-2-ylamino)-methyl]-benzoic acid
methyl ester (232):
[0293] To a solution of 2-amino-6-methoxybenzothiazole (2.00 g,
11.1 mmol) in a mixture of dichloroethane (20 mL) and THF (20 mL),
were successively added methyl 4-formylbenzoate (1.82 g, 11.1 mmol),
sodium triacetoxyborohydride (3.53 g, 16.7 mmol) and acetic acid
(1.27 mL, 22.2 mmol) . The mixture was stirred over 2 days and was
quenched by adding aqueous saturated solution of NaHC03. The mixture
was poured in a separating funnel containing water and was extracted
with dichloromethane. The combined organic extracts were washed with
brine, dried over MgS0 material was purified by flash chromatography using EtOAc/ hexane
(20:80 to 30:70) to afford the title compound 232 (1.85g, 51%
yield) . XH NMR: (Acetone-d6) d (ppm): 8.04 (d, J=8.5 Hz, 2H) , 7.65
(d, J=8.8 Hz, 2H), 7.41 (d, J= 8.8 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H) ,
6.94 (dd, J= 8.5, 2.7 Hz, 1H), 4.50 (t, J=5.5 Hz, 2H), 3.86 (s, 3H) .
Step 2: N- (2-Amino-phenyl) -4- [ (6-methoxy-benzothiazol-2-ylamino) -
methyl]-benzamide(233):
[0294] Following the procedure described in Example 1, step 4, 5
but substituting the previous compound for 6, the title compound 233
was obtained in 19% yield as a light beige solid. XH NMR: (DMSO-d6) 8

(ppm): a9.68 (s, 1H), 8.44 (t, J=5.8 Hz, 1H) , 8.00 (d, J=8.2 Hz,
2H), 7.55 (d, J=8.2 Hz, 2H), 7.39 (d, J=2.7 Hz, 1H), 7.34 (d, J=8.8
Hz, 1H), 7.21 (d, J=6.6 Hz, 1H), 7.05 (t, J=6.3 Hz, 1H), 7.00 (d,
J-1.4 Hz, 1H), 6.88 (dd, J=8.8, 2.7 Hz, 1H), 6.86 (dd, J=8.0, 1.4
Hz, 1H), 6.65 (td, J=«7.4, 1.4 Hz, 1H), 4.95 (s, 2H) , 4.70 (d, J=5.8
Hz, 2H), 3.79 (s, 3H).

Example 147
Step 1: 4-(6-Methoxy-lH-benzoimidazol-2-ylsulfanylmethyl)-benzoic
acid methyl ester hydrobromide (234):
[0295] To a solution of methyl 4-(bromomethyl)benzoate (2.51g, 11.0
mmol) in DMP (50 mL) was added 5-methoxy-2-benzimidazolethiol
(1.98g, 11.0 mmol). The mixture was stirred at room temperature for
24 h and the solvent was evaporated in vacuo. The residue was
suspended in ethyl acetate and the hydrobromide salt was collected
by filtration to afford the title compound 234 (4.10g, 91% yield) as
a colorless solid. XH NMR: (DMS0-ds) d (ppm): 7.90 (d, J= 8.2 Hz,
2H), 7.55 (d, J= 8.2 Hz, 2H), 7.45 (d, J= 8.2 Hz, 1H), 7.03 (s,lH),
6.94 (d, J= 8.2 Hz,lH)', 4.65 (s,2H), 3.82 (s,3H), 3.79 (s, 3H) .
Step 2;: 4-[6-(2-Morpholin-4-yl-ethoxy)-lH-benzoimidazol-2-
ylsulfanylmethyl]-benzoic acid methyl ester (235):
[0296] Following the procedure described in Example 144, step 1, 2
but substituting the previous compound for 2-atnino-6-
methoxybenzdthiazole, the title compound 235 was obtained in 37%
yield. XH NMR: (CDC13) 6 (ppm): 8.04-8.00 (m, 2H) ,, 7.77-7.72 (m,
1H), 7.69-7.59 (m, 1H), 7.56-7.49 (m, 2H), 6.96-6.90 (m, 1H), 4.68

'(S, 2H), 4.31-4.16 (m, 4H), 3.97 (s, 3H), 3.98-3.91 (m, 2H), 3.82-
3.72 (m, 2H), 2.75-2.47 (ra, 4H):
Step 3: N-(2-Amino-phenyl)-4-[6-(2-morpholin-4-yl-ethoxy)-1H-
benzoimidazol-2-ylsulfanylmethyl] -benzamide (236):
[0297] Following the procedure described in Example 1, step 4, 5
but substituting the previous compound for 6, the title compound 236
was obtained in 11% yield. 1H NMR: ,{CDsOD) d (ppm) : 7.89 (d, J= 8.2
Hz, 2H), 7.45 (d, J= 8.2 Hz, 2H), 7.28 (d, J= 8.5 Hz, 1H), 7.19-7.06
(m, 3H), 6.93-6.79 (m, 3H), 4.55 (s, 2H), 4.18 (t, J= 6.3 Hz, 2H),
3.65-3.62 (m, 4H), 2.51 (t, J- 6.6 Hz, 2H), 2.46-2.42 (m, 4H) .

Example 148
Step 1; 4-Morpholin-4-yl-benzoic acid methyl ester (237):
[0298] A' flame-dried pressure vessel was charged with cesium
carbonate (912 mg, 2.80 mmol) and toluene (8 mL) and the flasked was
purged with nitrogen. Palladium acetate (9.0 mg, 0.004 mmol) and
rac-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (37 mg, 0.06 mmol).
The mixture was degassed and heated at 100°C for 18 h. It was
allowed to cool to room temperature and was filtered through celite,
rinsed with ethyl acetate and partitioned between ethyl acetate and
water. The organic layer was washed with a saturated solution of
NaHC03., brine, dried over MgSO4 and concentrated in vacuo to afford
the title compound 237 (443 mg, 100% yield). 1H NMR: (CDC13) 8
(ppm):8.02 (d, J=9.2 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 3.95 (s, 4H),
3.92 (s, 3H), 3.38-3.35 (m, 4H).
Step 2: jW-(2-Amino-phenyl)-4-morpholin-4-yl-benzamide. (238) :
[0299] Following the procedure described in Example 1, step 4, 5
but substituting the previous compound for 6, the title compound 238
was obtained in 33 % yield. 1H NMR: (DMSO-dg) d (ppm): 7.20 (d, J=
7.9 Hz, 1H), 7.07 (d, J= 8.8 Hz, 2H), 7.01 (t, J= 7.0 Hz, 1H), 6.83
(d, J= 7.9 Hz, 1H), 6.65 (t, J= 7.5 Hz, 1H), 4.90 (s, 2H), 3.81-3.79
(m, 4H), 3.32-3.28 (m, 4H).
Example 149
Step 1; 3-Methylsulfanyl-3-(pyridin-4-ylamino)-acrylonit,rile (239)
[0300] To a solution of pyridin-4-ylamine (1.0 g, 11.0'imnol) and
3,3-Bis-methylsulfanyl-acrylonitrile (2.05 g, 12.6 mmol) in DMF at
room temperature, was added powdered 4A molecular sieves. The
mixture was stirred for 1 hr. Subsequently the mixture was cooled to
0 °C, 60% NaH dispersion in oil (0.92 g, .23.0 mmol) was added
' portionwise over 1 hr. and it was stirred at 0 °C for an additional 2
hrs. The cold bath was removed and the mixture was stirred at room
temperature for 20 hrs. DMF was removed in vacuo and the crude was
purified by column chromatography (gradient of EtOAc to 25%
MeOH/EtOAc) to afford the desired product as an off-white solid (1.9
g, 89%).
Step 2: N- (2-Amino-phenyl)-4-{[2-cyano-l-(pyridin-4-ylamino)-
vinylamino]-methyl)-benzamide (240)
[0301] To a mixture of 3-methylsulfanyl-3-(pyridin-4-ylamino)-
acrylonitrile (0.2 g, 1.0 mmol), 4-aminomethyl-benzoic acid (0.173
g, 1.14 mmol), DMAP (1 mg) and Et3N (0.14 ml, 1.0 mmol) was added dry
pyridine (0.5 ml). The resulting stirring mixture was-heated to 55 °C
for 4.5 hrs., additional Et3N (0.14 ml) was added and mixture was
heated from 75 °C to 90 °C over a period of -30 hrs. When the
reaction was complete, pyridine was partially removed in vacuo and
the crude was purified by column chromatography (gradient of EtOAc
to 20% MeOH/EtOAc) to afford the desired product as an off-white
solid (130 mg, 44%).
[0302] Following the procedure described in Example 1, step 4, 5
but substituting the previous compound for 6, the title compound 240
was obtained in 33 % yield. 1H NMR: 1H NMR: (300 MHz, DMSO-d6) d
(ppm): 9.69 (br, 2H), 8.48 (br, 3H), 8.03 (d, J = 7.9 Hz, 2H), 7.51

(d, J - 8.4 Hz, 2H), 7.29 (br, 2H), 7.23 (d, J = 7.9 Hz, 1H), 7.03
(t, J= 7.0 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H) , 6.65 (t, J . 7.3 Hz,
1H), 4.96 (br, 2H), 4.62 (d, J = 5.7 Hz, 2H).
Example 150
Example 150
Step 1: 4-[(2-Chloro-9H-purin-6-ylanu.no)-methyl]-benzoic acid
methyl ester (241)
[0303] A suspension of 2,6-dichloro-9H-purine (1 g, 5.29 mmol), 4-
aminomethyl-benzoic acid methyl ester hydrochloride (1.2 equiv.,
1.28 g) and NaHC03 (2.1 equiv., 935 mg) in water was heated at 100°C.
The homogeneous solution thus formed was refluxed 30 min. The
resulting white precipitate was filtered, washed with cold water and
dried under vacuum giving the title compound 241 (1 g, 3.14 mmol,
60%). LRMS calc:317.7, found: 318.3 (MH)+.
Step 2: 4-{[2-Chloro-9-(2-methoxy-ethyl)-9ff-purin-6-ylamino]-
methyl)-benzoic acid methyl ester (242)
[0304] Following the procedure described in Example 144, step 2 but
substituting the previous compound for 2-amino-6-
methoxybenzothiazole, the title compound 242 was obtained in 41%
yield.
Step 3: N-(2-Amino-phenyl)-4-([2-chloro-9-(2-methoxy-ethyl)-3H-
purin-6-ylamino]-methyl}-benzamide (243):
[0305] Following the procedure described in Example 1, step 4, 5
but substituting the previous compound for 6, the title compound 243

was obtained in 85% yield.. aH NMR (CDC13) d (ppm) : 9-64 (s, 1H) , 8.94
(bs, 1H), 8.18 (s, 1H), 7.96 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.8
Hz, 2H), 7.21 (d, J = 7.7 Hz, 1H), 7,01 (dd, J = 7.3, 8.0 Hz, 1H),
6.81 (d, J = 8.0 Hz, 1H),.6.62 (dd, J = 1.2, 7.7 Hz, 1H) , 4.91 (bs,
2H), 4.78 (bs, 2H), 4.18 (m, 2H), 3.70 (m, 2H), 3.26 (s, 3H)
Scheme 40
Example 151
Example 151
Step 1: Methyl-4-( [3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-
4-carbonyl]-amino-methyl)-benzoic acid ester (244)
[0306] To a stirred suspension at 0°C of methyl 4-
(aminomethyl)benzoate.HCl 2 (809 mg, 4.01 mmol) in anhydrous CH2C12
(25 ml) under nitrogen were successively added i-Pr2NEt (1.91 ml,
10.95 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-
carbonyl chloride (1.00 g, 3.65 mmol). After 45 min, the reaction
mixture was allowed to warm up to room temperature for 3 h. Then, .
the reaction mixture was concentrated, diluted with AcOEt, and
successively washed with sat. NH„C1, H2O, sat. NaHC03, H2O and brine,
dried over anhydrous MgSO,, filtered and concentrated to afford the
title compound 244 (1.50 g, quantitative yield) as a colorless
sticky foam. XH NMR (300 MHz, CDC13) d (ppm): 7.93 (d, J = 7.9 Hz,
2H), 7.46-7.35 (m, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.15-7.05 (m, 3H) ,
5.49 (bs, 1H), 4.46 (d, J= 5.7 Hz, 2H), 3.92 (s, 3H), 2.80 (s, 3H) .

Step 2; 4-([3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-
carbonyl] -amino-methyl)-benzoic acid (245)
[0307] To a stirred solution at room temperature of 244 (1.45 g,
3^0 mmol) in THF (20 ml) was added a solution of LiOH.HaO (453 mg,
10.80 mmol) in water (20 ml) . After 20 h, the reaction mixture was
concentrated, diluted with water and acidified with IN HCl until pH
6 in order to get a white precipitate. After 10 min, the suspension
was filtered off and the cake was abundantly washed with water, and
dried to afford the title compound 245 (1.23 g, 3.15 mmol, 88%
yield) as a white solid. 1H NMR (300 MHz, DMSO-ds) d (ppm) : 8.69 (t,
J = 5.9 Hz, 1H), 7.91 (d, J = 7.9 Hz, 2H) , 7.70-7.58 (m, 1H), 7.51
(d, J = 7.9 Hz, 1H), 7.45-7.30 (m, 3H), 4.44 (d, J = 5.7 Hz, 2H),
2.72 (s, 3H).
Step 3: 4-(9-Chloro-3-methyl-4-oxo-4H-isoxazolo[4,3-c]quinolin-5-
ylmethyl)-benzoic acid (246)
[0308] To a stirred suspension at room temperature of 245 (795 mg,
2.05 mmol) in anhydrous DMF (10 ml) was added a solution of NaOH
(409 mg, 10.22 mmol) in anhydrous MeOH (5.1 ml) . Then, the reaction
mixture was warmed up to 40°C. After 3 days, the reaction mixture
was concentrated, diluted with water and acidified with IN HCl until
pH 5 in order to get a pale pinky precipitate. After 30 min, the
suspension was filtered off and the cake was abundantly washed with
water, and dried to afford the title compound 246 (679 mg, 1.84
mmol, 90% yield) as a pale pinky solid. 1H NMR (300 MHz, DMS0-ds)
d (ppm): AB system (8A = 7.92, 8B = 7.40, J = 8.4 Hz, 4H) , 7.56 (t, J =
8.1 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H),
5.59 (bs, 2H), 2.95 (s,3H).
Step 4: N- (2-Amino-phenyl) -4-(9-chloro-3-methyl-4-oxo-4H-
isoxazblo[4> 3-c] quinolin-5-ylmethyl) -benzamide (247)
[0309] The title compound 247 was obtained from 246 in one step
following the same procedure as Example 1, steps 5. ^-H NMR (300 MHz,
DMSO-ds) 5 (ppm): 9.65 (s, 1H), AB system (8A = 7.95, 8b = 7.42, J =
8.1 Hz, 4H), 7.58 (t, J = 8.1 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H),
7.35 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.00 (t, J =7.3
Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.62 (t, J = 7.3 Hz, 1H) , 5.61
(bs, 2H), 4.91 (s, 2H), 2.97 (s, 3H) .
Example 152
Step 1; 4-(LET-Imidazol-2-yl)-benzoic acid (248)
[0310] To a stirred solution of 4-formylbenzoic acid (2.00 g, 12.3
mmol) in ammonium hydroxide (9 ml) was added glyoxal (2.86 ml, 20.0
mmol). The reaction mixture was stirred 16 h at room temperature. IN
HC1 was added to the reaction mixture to acidify to pH 5. The
solvent was evaporated and the residue was triturated 30 min. ill
water (20 ml) and filtered to obtain the title compound 248 (2.08 g,
83%) as a white solid. LRMS: 188.1 (Calc); 189.1 (found).
Step 2: N-(2-Andno-phenyl)-4-(lH-imidazol-2-yl)-benzamide (249)
[0311] The title compound 249 was obtained following the same
procedure as Example 1, step 5. XH NMR (CDC13) d (ppm) : 1H NMR:
(DMSO) d (ppm): 9.72 (bs, 1H) , 8.07 (s, 4H), 7.26 (s, 2H), 7.18 (d,
J = 7.9 Hz, 1H), 6.98 (dd, J = 7.5, 7.5 Hz, 1H), 6.79 (d, J = 7.9
Hz, 1H), 6.60 (dd, J = 7.5, 7.5 Hz, 1H). MS: (calc.) 278.1; (obt.)
279.1 (MH)+.
Example 153
Step 1: 4-Thiocarbamoylmethyl-benzoic acid (250)
[0312] To a stirred suspension of 4-cyanomethyl-benzoic acid (1.65
g, 10.24 mmol) and Et3N (5 ml) in pyridine, H2S was bubbled during 3
h. The reaction mixture was stirred 16. h at room temperature. Water

was then added to the reaction mixture which was agitated for 1 h
before acidifying to pH 6 with 1M HC1. The solvent was evaporated
and the residue was triturated 30 min. in water (20 ml) and filtered
to obtain the title compound 250 (2:08 g, 83%) as a white solid. *H
NMR (DMSO) d (ppm) : 12.85 (bs, 1H), 9.53 (bs, 1H) , 9.43 (bs, 1H),
7.88 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 3.88 (s, 2H) .
Step 2; 4-(4-Chloromethyl-thiazol-2-ylmethyl)-benzoic acid (251)
[0313] A solution of 250 (729 mg, 3.73 mmol) and 1,3-
i
dichloroacetone (474 mg, 3.73 mmol) in THF (30 ml) was stirred at
40°C during 48h. The solvent was evaporated then the residue was
dissolved in ethyl acetate, washed with brine, dried over anhydrous
MgSO4, filtered and concentrated. The crude residue was purified by
flash chromatography on silica gel (2-4% MeOH/CH2ci2) to afford the
title compound (827 mg, 83% yield) as a white solid. XH NMR (DMSO) d
(ppm): 12.93 (bs, 1H), 7.91 (d, J - 8.1 Hz, 2H), 7.63 (s, 1H), 7.46
(d, J = 8.1 Hz, 2H), 4.78 (s, 2H), 4.42 (s, 2H).
Step 3: N- (2-Amino-phenyl) -4- (4-morpholin-4-ylmethyl-thiazol-2-
ylmethyl)-benzamide (252)
[0314] KaC03 (599 mg, 4.33 mmol) was added to a solution of 251 (527
mg, 1.97 mmol) and morpholine (189 Dl, 2.17 mmol) in THF (15 ml)
was refluxed during 48h. The solvent was evaporated. The crude
residue was purified by flash chromatography on silica gel (3-50%
MeOH/CH2Cl2) to afford the title compound 252 (238 mg, 38% yield) as
a pale yellow solid. LRMS: 318.2 (calc) 319.2 (found).
[0315] The title compound 252 was obtained following the same
procedure as Example 1, step 5. 1H NMR (DMSO) d (ppm): 9.63 (bs,
1H), 7.94 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.33 (s,
1H), 7.15 (d, J = 8.1Hz, 1H), 6.97 (dd, J = 7.7, 7.7 Hz, 1H), 6.77
(d, J = 7.3 Hz, 1H), 6.59 (dd, J = 8.1, 8.1 Hz, 1H), 4.90 (bs, 2H),
4.40 (s, 2H), 3.59-3.56 (m, 6H), 2.44-2.38 (m, 4H) . LRMS: 408.2
(calc) 409.2 (found).
Example 154
Step 1; Methyl 3-[3-(4-methoxycarbonyl-benzyl)-ureido]-thiophene-2-
carboxylate (253)
[0316] The procedure described by Nakao (K. Nakao, R. Shimizu, H.
Kubota, M. Yasuhara, Y. Hashimura, T. Suzuki, T. Fujita and H.
Ohraizu; Bioorg. Med. Chem. 1998, 6, 849-868.) was followed to afford
the title compound 253 (1.01 g, 91%) as a yellow solid. XH NMR
(CDClj) d (ppm): 9.55 (bs, 1H), 8.00-7.97 (m, 3H), 7.42-7.37 (m, 3H),
5.45 (t, J = 5.8 Hz, 1H), 4.52 (d, J = 6.0 Hz, 2H), 3.91 (s, 3H),
3.82 (s, 3H).
Step 2; 4-(2,4-Dioxo-l,4-dihydro-2H-thieno[3,2-d3pyrimidin-3-
ylmethyl)-benzoic acid (254)
[0317] To a suspension of 253 (422 rag, 1.21 mmol) in MeOH (15 ml)
was added NaOH (145 mg, 3.63 mmol). The reaction mixture was heated
at 60°C during 16 h. Water. (1 ml) was then added and the reaction
mixture was stirred for 1 more hour. The solvent was evaporated and
the residue was dissolved in water and acidified to pH 5 with HC1
1M. The precipitate was filtered to afford the desired compound 254
(348 mg, 95%) as a white solid. LRMS: 302.0 (Calc); 303.0 (found).
Steps 3: ff-(2-Amino-phenyl) -4- (l-ethyl-2,4-dioxo-l,4-dihydro-2H'-
thieno[3,2-d]pyrimidin-3-ylmethyl)-benzamide (255)
[0318] The title compound 255 was obtained as a yellow solid (73%)
following the same procedure as Example 99, step 2-, 3, then followed
by Example 1, step 5. XH NMR: (DMSO) 5 (ppm): 9.61 (bs, 1H, NH) > 8.22
(d, J = 5.5 Hz, 1H, CH), 7.91 (d, J = 8.2 Hz, 2H, Cff) , 7.43-7.40 (m,
3H, CH), 7.15 (d, J = 7.4 Hz, 1H, CH), 6.96 (dd, J - 7.6, 7.6 Hz,
1H, CH), 6.77 (d, J - 7.1 Hz, 1H, CH), 6.59 {dd, J = 7.4, 7.4 Hz,
1H, CH) , 5.17 (s, 2H, NCHa), 4.88 (bs, 2H, NH2) 4.09 (q, J = 7.0, 2H,
CH^, 1.22 (t, J= 7.0, 3H, CH3) . LRMS: 420.1 (calc); 421.0 (found). "
Example 155
Step 1; 3H-Thieno[3,2-dlpyrimidin-4-oiie (256)
[0319] Methyl-3-amino-2-thiophene carboxylate (510 mg, 3.24 mmol)
was dissolved in formamide (20 ml) and heated at 170°C 16h. The
solvent was evaporated. The crude residue was then purified by flash
chromatography on silica gel (2-4% MeOH/CH2Cl2 ) to afford the title
compound 256 (157 mg, 32% yield). LRMS: 152.0 (Calc); 152.9
(found).
Step 2: N- (2-Aminophenyl) -4- (4-oxo-4H-thieno[3 ^-dlpyrimidin-S-
ylmethyl) -benzamide (257)
[0320] Following the procedure described in Example 85, step 1 but
substituting the previous compound for 119, followed by Example 1,
step 4, 5, the title compound 257 was obtained in 41% yield. XH NMR:
(DMSO) 5 (ppm): 9.61 (bs, 1H), 8.70 (s, 1H), 8.22 (dd, J = 5.2, 0.5
Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H),7.44
(dd, J = 5.2, 0.6 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 6.96 (dd, J =
6.9, 6.9 Hz, 1H) , 6.77 (d, J = 7.1Hz, 1H) , 6.58 (dd", J = 7.0, 7.0
Hz, 1H) , 5.31 (s, 2H), 4.87 (bs, 2H) . MS: 376.1 (calc); 377.1
(found).

Example 156
Step 1; Methyl 2-amino-4,5-dimethyl-thiophene-3-carboxylate (258)
[0321] The procedure described by Hozien (Z. A. Hozien, P. M. Atta,
. Hassan, A. A. Abdel-Wahab and S. A. Ahmed; Synht. Commun..
1996, 26(20), 3733-3755.) was followed to afford the title compound
258 (1.44 g, 17%) as a yellow solid. LRMS: 197.1 (Calc); 200.1
(found).
Steps 2 : N- (2-Amino-phenyl) -4- (5,6-dimethyl-4-oxo-4H-thieno [2,3-
d]pyrimidin-3-ylmethyl) -benzamide (259)
[0322] Following the procedure described in Example 155, step 1, 2
but substituting 258 for 256, the title compound 259 was obtained as
a white solid (55%). XH NMR: (DMSO) 5 (ppm) : 9.61 (bs, 1H), 8.57' (s, '
1H), 7.94 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.7 Hz, 2H), 7.16 (d, J
= 7.7 Hz, 1H), 6.96 (dd, J = 7.6, 7.6 Hz, 1H) , 6.77 (d, J = 8.0 Hz,
1H), 6.59 (dd, J = 7.4, 7.4 Hz, 1H), 5.25 (s,.2H), 4.87 (bs, 2H),
2.39 (b, 3H), 2.37 (s, 3H). LRMS: 404.1 (calc); 405.0 (found).

Example 157
Step .1: Methyl 4-(4-oxo-chroman-3-ylidenemethyl)-benzoate (260)
[0323] Concentrated H2SO4 (2 ml) was slowly added to a solution of
4^j?roraanone (2.00 g, 13.50 mmol) and methy.l-4-formylbenzoate (2.11
g, 12.86 ramolj in glacial acetic acid. The reaction mixture was
stirred 16 h at room temperature. The solvent was concentrated to
half volume the resulting precipitate was filtered and rinsed with
ethyl acetate to afford the title compound 260 (3.11 g, 82%) as a
purple solid. lH HMR: (DMSO) d (ppm) : 8.05 (d, J = 8.2 Hz, 2H) , 7.90
(d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.64-7.59(m, 3H), 7.15 (dd, J -
7.6, 7.6 Hz, 1H) , 7.07 (d, J =. 8.2 Hz, 1H) , 5.43 (s, 2H) , 3.89 (s,
3H) .
Step 2*. Methyl-4-(4-Qxo-4H-chromen-3-vlmethyl)-benzoate (261)
[0324] Water (0.2 ml) and RhCl3.H30 (7 mg, 0.034 mmol) was added to
a suspension of compound 260 (200 mg, 0.680 mmol) in EtOH (2 ml) and
CHCL3 (2 ml) . The reaction mixture was stirred 16 h at 70°C. The
reaction mixture was cooled down and diluted in ethyl acetate,
washed with brine, dried over anhydrous MgSO4, filtered and
concentrated. The crude residue was then purified by flash
chromatography on silica gel (0.5-1% MeOH/CH2Cl2)to afford the title
compound 261 (118 mg, 59%) as a white solid. 1H NMR: (DMSO) 5 (ppm) :
8.45 (s, 1H), 8.03 (dd, J = 7.9, 1.8 Hz, 1H) , 7.87 (d, J = 8.4 Hz,
2H), 7.83-7.77(m, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.50-7.43 (m3, 1H) ,
3.82 (s, 3H), 3.80 (s, 2H).
Step 3 : N- (2-Amino-phenyl) -4- (4-oxo-4H-chromen-3-ylmethyl) -benzamide
(262)
[0325] The title compound 262 was obtained following the same
procedure as Example 1, step 4, 5. 1H NMR: (DMSO) d (ppm): 9.56 (bs,
1H), 8.45 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 8.4 Hz,
2H), 7.80 (dd, J = 7.5, 7.5 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.51-
7.42 (m, 3H), 7.14 (d, J = 7.9 Hz, 1H), 6.96 (dd, J = 7.3, 7.3 Hz,
1H), 6.76 (d, J = 7.9 Hz, 1H), 6.58 (dd, J = 7.3, 7.3 Hz, 1H), 4.86
(bB, 2H), 3.80 (s, 2H) . LRMS: 370..1 (calc); 371.1 (found).
Example 158
Step 2: Methyl 4-chroman-3-ylmethyl-benzoate (263)
[0326] Pd/C 10% was added to a suspension of 260 (200 mg, 0.68
mmol) in MeOH (40 ml) and DMA (10 ml) which was previously purged

under vacuum. The reaction mixture was stirred during 4 h at room
temperature. After evaporation of the MeOH, water was added to the
oily residue and the precipitate obtained was filtered. The crude
residue was then purified by flash chromatography on silica gel (5-
8% AcOEt/Hex )to afford the title compound 263 (114 mg, 59%) as a
white solid. LRMS: 282.1 (Calc); 283.0 (found).
Step 3: N-(2-Amino-phenyl) -4-chroman-3-ylmethyl-benzamide (265)
[0327] The title compound 265 was obtained following the same
procedure as Example 1, steps 4 and 5. XH NMR: (acetone) 5 (ppm) :
9.06 (bs, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H),
7.31 (d, J =¦ 7.9 Hz, 1H), 7.08-6.98 (m, 3H) , 6.87 (d, J =» 7.5 Hz,
1H),6.82-6.66 (m, 3H), 4.62 (s, 2H), 4.22-4.17 (m, 1H), 4.88-3.81
(m, 1H), 2.88-2.71 (m, 3H), 2.61-2.53 (m, 1H), 2.41-2.33 (m, 1H) .
LRMS: 358.2 (calc); 359.1 (found).
Example 159
Step 2: Methyl 4-(4-oxo-chroman-3-ylmethyl)-benzoate (264)
[0328] A suspension of 260 (400 mg, 1.36 mmol) and benzenesulfonyl
hydrazine (702 mg, 4.08 mmol) in DMF (7 ml) was stirred at 100°C
during 48h. The solvent was evaporated and the residue was diluted
in AcOEt, washed with NH4C1 sat., brine, dried over anhydrous MgSO4,
filtered and concentrated. The crude residue was then purified by
flash chromatography on silica gel (5% AcOEt/HEx )to afford the
title compound 264 (170 mg, 42%) as a white solid. LRMS: 296.1
(CalcJ; 297.0 (found).
Step 3; N- (2-Amino-phenyl) -4- (4-oxo-chroman-3-ylmethyl) -benzamide
(266) a a a a a a a a a a a a a aI
[0329] The title compound 266 was obtained following the same
procedure as Example 1, steps 4 and 5. 1H NMR: (acetone) d (ppm) :
9.62 (bs, 1H), 7.93 (d, J = 7.9 Hz, 2H), 7.79 (d, J = 7.9 Hz, 1H) ,
7.58 (dd, J = 7.0, 7.0 Hz, 1H), 7.39 (d, J = 7.9 Hz, 2H), 7.17-7.04
(m, 3H), 6.97 (dd, J = 7.0, 7.0 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H) ,
6.60 (dd, J = 7.5, 7.5 Hz, 1H), 4.88 (s, 2H), 4.44-4.39 (m, 1H) ,
4.28-4.21 (m, 1H), 2.26-3.21 (m, 2H), 2.83-2.74 (m, 1H). LRMS: 372.1
(calc); 372.1 (found) .
Example 160
Step 1: Methyl 4- (3-oxo-3,4-dihydro-2H-benzo[l,4] oxazin-2-ylmethyl) -
benzoate (266)
[0330] Et3N (3.18 ml, 22.8 mmol) was added to a stirring solution
of 2-H-l,4-benzoxazin-3-(4H)one (2.50 g, 16.8 mmol) and methyl 4-
formylbenzoate (4.59 g, 27.5 mmol) in Ac20 (20 ml). The reaction
mixture was refluxed 16h. After this mixture was cooled for 3 days,
the solid was filtered and rinsed with ethyl acetate to afford the
title compound 266 (657 mg, 13%) as a yellow solid. LRMS: 295.1
(Calc); 296.0 (found) .
Step 2: Methyl 4-(3-oxo-3,4-dihydro-benzo[l,43oxazin-2-
ylidenemethyl)-benzoate (267)
[0331] The title compound 267 was obtained following the same
procedure as Example 158, step 2. LRMS: 297.1 (Calc); 298.1
(found).
Step 3: N- (2-Amino-phenyl)-4-(4-ethyl-3-oxo-3,4-dihydro-2H-
benzo[l,4]oxazin-2-ylmethyl)-benzamide (269)
[0332] The title compound 269 was obtained from 267 following the
same procedure as Example 99, step 2, 3., then followed, by Example 1,

Step 4, 5. 1H NMR: (DMSO) 5 (ppm) : 9.61 (bs, 1H) , 7.91 (d, J = 7.9
Hz, 2H), 7.39 (d, J = 7.9 Hz, 2H), 7.22 (d, J =7.9 Hz, 1H), 7.17 (d, ,
J =7.5 Hz, 1H), 7.11-6.91 (m, 4H), 6.77 (d, J = 7.0 Hz, 1H), 6.60
(dd J=7.0, 7.0 Hz, 1H), 4.95-4.91 (m, 1H), 4.89 (bs, 2H) ,. 3.95
(q, J = 7.0 Hz, 2H), 3.28-3.22 (m, 1H) , 3.17-2.89 (m, 1H), 1.16 (t,
J = 7.0 Hz, 3H) . LRMS: 401.2 (calc); 402.1 (obt.).
Example 161
Step 1; N- (2-Amino-phenyl)-4-(3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-
2-ylmethyl)-benzamide (270)
[0333] The title compound 270 was obtained from 267 following the
same procedure as Example 1, step 4, 5. XH NMR: (DMSO) d (ppm): 10.74
(bs, 1H), 9.61 (bs, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 7.9.
Hz, 2H) , 7.17 (d, J =7.5 Hz, 1H) , 6.99-6.85 (m, 5H) ,. 6.78 (d, J =
7.5 Hz, 1H), 6.60 (dd, J =• 7.0, 7.0 Hz, 1H), 4.92-4.89 (m, 3H) ,
3.29-3.23 (m, 1H), 3.15-3.07 (m, 1H). MS: (calc.) 373.1; (obt.)
374.1 (MH)+.
Example 162
Step l: Methyl 4-(l-oxo-indan-2-ylmethyl)-benzoate (271)
[0334] A 2M LDA solution in THP (4.16 ml, 8.32 mmol) was added to a
solution of indanone (1.00 g, 7.57 mmol) in THF (10 ml) at -60°C. The
solution was slowly warmed to 0°C during a period of 15 min. and was

agitated for 15 more min. The reaction was then cooled to -78°C and a
solution of methyl-4-bromobenzoate (1.73 g, 7.57 mmol) was slowly
added. The solution was slowly warmed to -20°C and stirred during 4
hours. The reaction mixture was quenched with HCL 1M and the solvent
was evaporated. The residue was diluted in ethyl acetate, washed
with brine, dried over anhydrous MgSO«, filtered and concentrated.
The crude residue was then purified by flash chromatography on
silica gel (5-20% AcOEt/HEx )to afford the title compound 271 (245
mg, 17%) as a white solid. LRMS: 280.1 (Calc); 281.1 (found).
Step 2: N- (2-Amino-phenyl) -4-(l-oxo-indan-2-ylmethyl)-benzamide
(272)
[0335] aThe title compound 272 was obtained following the same
procedure as Example 1, step 4, 5. 1H NMR (DMSO) 5 (ppm): .9.59 (bs,
1H), 7.91 (d, J = 7.6 Hz, 2H), 7.69-7,64 (m, 2H), 7.54 (d, J =7.6
Hz, 1H), 7.45-7.40 (m, 3H), 7.16 (d, J = 8.2 Hz, 1H), 6.96 (dd, J =»
7.3, 7.3 Hz, 1H) , 6.77 (d, J - 8.2 Hz, 1H), 6.59 (dd, J = 7.3, 7.3
Hz, 1H),.4.87 (bs, 2H), 3.23-3.14 (m, 3H), 2.85-2.81 (m, 2H). LRMS:
356.1 (calc); 357.2 (found).
Example 163
Step 1: 4-(l-Oxo-indan-2-ylidenemethyl)-benzoic acid (273)
[0336] To a suspension of indanone (2.00 g, 15.1 mrnol) and 4-
carboxybenzaldehyde (1.89g, 12.6 mrnol) in EtOH (10 ml) was added KOH
(1.77 g , 31.5 mmol) at 0°C. The reaction mixture was stirred 30 min
at 0°C then at room temperature for 16 h. The solvent was evaporated
and the residue was dissolved in water, acidified to pH 5 with HC1 1
M. The precipitate was filtered and rinsed with water to afford the
title compound 273 (2.27 g, 57%) as a yellow solid. LRMS: 264.1
(Calc); 265.0 (found) .
Step 2: N- (2-Amino-phenyl) -4- (l-oxo-indan-2-ylidenemethyl) -benzamide
(274)
[0337] The title compound 274 was obtained following the same
procedure as Example 1, step 5. LRMS: 354.1 (Calc); 355.0 (found).
Step 3: N- (2-Amino-phenyl)-4-(l-hydroxy-indan-2-ylmethyl)-benzamide
(275)
[0338] To a suspension of 274 (300 mg, 0.85 mmol) in MeOH (8 ml)
and water (1 ml) was added NaBH4 (75 mg, 1.95 mmol) . The reaction
mixture was stirred at 50°C 16h and cooled down. Water was added to

the solution and the precipitated was filtered and rinsed with cold
water to afford the title compound 275 (224 mg, 74%) as a white
solid. 1H NMR: (acetone) 5 (ppm) : 9.05 (bs, 1H), 8.00 (dd, J = 8.2,
2.7Hz, 2H), 7.47 (d, J = 8.5 Hz, 1H) , 7.43 (d, J =8.2 Hz, 1H) ,
7.38-7.30 (m, 2H), 7.22-7.12 (m, 3H), 7.01 (ddd, J= 7.6, 7.6, 1.5
Hz, 1H), 6.87 (dd, J = 8.0, 1.1 Hz, 1H), 6.68 (dd, J » 7.6, 7.6 Hz,
1H), 4.98 (t, J = 5.8 Hz, 0.4H), 4.89 (t, J = 6.7 Hz, 0.6H), 4.63
(bs, 2H), 4.45 (d, J = 6.9 Hz, 0.6H), 4.06 (d, J = 6.0 Hz, 0.4H),
3.30-3.19 (m, 1H) , 2.88-2.48 (m, 3H, CH2) . LRMS: 358.2 (calc); 359.1
(found).
Scheme 49

Example 164
Step l: 4-(3,5-Dimethyl-l-phenyl-lH-pyrazol-4-ylmethyl)-benzoic acid
(276)
10339] To a solution of NaH (60% in mineral oil, 250 rag, 6.3 mmol)
at 0°C. acetyl acetone (0.646 ml, .6.3 mmol) was added.followed by 4-
bromomethyl-benzoic acid methyl ester 2 (1.2 g, 5.2 mmol). The
reaction mixture stirred 1 hour at room temperature and refluxed for
2 hours. Phenyl hydrazine (0.51 ml, 5.2 mmol) was added and the
reaction mixture refluxed for an additional hour. THF was removed in
vacuum and the oily residue was partitioned between water and ethyl
acetate. Organic layer was separated, dried, evaporated and purify
by chromatography on a silica gel column, eluent EtOAc - hexane
(1:1) to produce an oily material (800mg) which was treated with a
solution of NaOH (0.8 g, 20 mmol) in 20 ml water for 1 hour at room
temperature. The following steps, - acidification with HC1 (pH 6),
extraction of the resultant emulsion with ethyl acetate, drying the
extract with sodium sulfate, evaporation and column chromatography
(eluent EtOAc - hexane, 1:1) afforded 390 mg of a mixture of 276
(the title compound) and 278 (molar ratio 1:2). [M-l] + 3.07.0 and
191.1. This mixture was taken for the next step as is.
Step 2 . N- (2-Amino-phenyl) -4- (3,5-dimethyl-l-phenyl-lff-pyrazol-4-
ylmethyl)-benzami de (277)
[0340] Following a procedure analogous to that described in Example
92, step 2, but substituting 276 for 143, the title compound 277 was
obtained in 25% yield (purified by chromatography using as eluent
EtOAc - hexane, 1:1). lH NMR: (300 MHz, DMSO-d6, 5 (ppm) : 9.64 (s,
1H); 7.97 (d, J = 7.6 Hz, 2H), 7.42-7.56 (m, 5H) , 7.37 (d, J = 8.2
Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.84
(d, J = 8.2 Hz, 1H), 6.66 (t, J = 7.6 Hz, 1H), 4.93 (s, 2H) , 3.92
(s, 2H), 2.34 (s, 3H), 2.18 (s, 3H).
Example 165
Step 1: 4-(3-Oxo-butyl)-benzoic acid (278)
[0341] To a solution of acetyl acetone (5.0 ml, 49 mmol) at room
temperature NaOMe (25% wt, 10.8 ml, 47.3 mmol) was added followed by
4-bromomethyl-benzoic acid methyl ester 2 (9.0 g, 39.3 mmol). The
reaction mixture refluxed 3 hours, cooled to the room temperature
and acidified with HC1 (pH 1-2). Evaporation of the resultant

solution yielded a residue, which was refluxed in a mixture of
glacial AcOH (50 ml) and cone. HC1 (25 ml) for 4 hours. Acids were
removed in vacuum and the residue was triturated with water to form
a crystalline material, which was collected by filtration and dried
to afford 278 (6.72 g, 80% yield). [M-l] 191.1.
Step 2. 4- (5-Amino-4-cyano-3-methyl-thiophen-2-ylmethyl) -benzoic
acid 279
[0342] To a refluxing suspension of 4-(3-oxo-butyl)-benzoic acid
278 (700 mg, 3.65 mmol), malonodinitrile (241 mg, 3.65 mmol) and
sulfur (130 mg, 3.65 mmol) in 20 ml EtOH, diethylamine (0.5 ml, 4.8
mmol) was added. The reaction mixture refluxed 1 hour, cooled to the
room temperature, acidified with cone. HC1 (pH 4-5) and evaporated
to yield a solid residue. This material was partitioned between
water and ethyl acetate, organic layer was separated, dried,
evaporated and chromatographed on a silica gel column, eluent EtOAc-
hexane, 1:1, to afford the title compound 279 (300 mg, 30% yield). 1H
NMR: (300 MHz, DMSO-ds, 8 ppm) : 7.87 (d, J = 8.4 Hz, 2H) , 7.29 (d, J
= 7.9 Hz, 2H), 6.98 (s, 2H), 3.92 (s, 2H), 2.03 (s, 3H).
Step 3. 4-(5-Acet/lamino-4-cyano-3-methyl-thiophen-2-ylmethyl)-
benzoic acid 280
[0343] To a solution of 4- (5-amino-4-cyano-3-methyl-thiophen-2-
ylmethyl)-benzoic acid 279 (230 mg, 0.86 mmol) iii a solvent mixture
acetone (5 ml) - dichloromethane (5 ml) at room temperature acetyl
chloride (0.305 ml, 4.3 mmol) was added. After 2 hours of stirring
at the same conditions a precipitate of the title compound 280
formed which was collected and dried (200 mg, 75% yield). [M-l]
313.1.
Step 4; N- (2-Amino-phenyl)-4-(5-acetylamino-4-cyano-3-methyl-
thiophen-2-ylmethyl) - benzamide (281)
[0344] . Following a procedure analogous to that described in Example
92, step 2, but substituting 280 for 143, the title compound 281 was
obtained in 25% yield. 1H NMR (DMSO) d (ppm): 9.61 (s, 1H); 7.91 (d,
J = 7.9 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 7.5 Hz, 1H),
6.96 (t, J = 6.6 Hz, 1H), 6.77 (d, J = 7.0 Hz, 1H) , 6.59 (t, J = 7.9
Hz, 1H), 4.89 (s, 2H), 4.10 (s, 2H), 2.19 (s, 3H), 2.16 (s, 3H).
[M+l] 405.0.
Example 166
Step 1. 4-(N-Hydroxycarbamimidoylmethyl)-benzoic acid (282)
[0345] A suspension of 4-cyanomethyl benzoic acid (2.07 g, 12.86
mmol), NHjOH.HCl (1.79 g, 25.71 mmol) and potassium hydroxide (2.16
g, 38.57 mmol) in 70 ml ethanol refluxed for 36 hours, poured into
100 ml water and acidified with cone. HCl (pH 5-6). EtOH was removed
in vacuum and the remaining suspension was treated with another 100
ml water. A precipitate formed which was collected and dried to
afford the title compound 282. [M+l]195.1.
Step 2. 4-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-benzoic acid (283)
[0346] A solution of 4- (W-hydroxycarbamimidoylmethyl) -benzoic acid
282 (388 mg, 2.0 mmol) in pyridine (8 ml) was treated with acetic
anhydride (0.283 ml, 3.0 mmol). The resultant solution refluxed 6
hours, evaporated in vacuum and the remaining solid was triturated
with water, collected by filtration, dried and purified by
chromatography on a silica gel column, eluent EtOAc, EtOAc-MeOH
(10:1) and finally EtOAc-MeOH (1:1), to produce 283 (164 mg, 38%
yield).[M-l]' 217.1
Step 3. N- (2-Amino-phenyl) -4- (5-methyl- [1,2,4] oxadiazol-3-ylmethyl) -
benzamide (284)
[0347] For the preparation of the title compound 284, a procedure
analogous to that described in Example 92, step 2, but substituting
283 for 143, the title compound 284 was obtained. 1H NMR: (DMSO) d
(ppm) : 9.62 (s, 1H), 7.93 (d, J = 7.9 Hz, 2H) , 7.42 (d, J = 8.4 Hz,
1H), 7.16 (d, J = 7.5 Hz, 1H), 6.97 (t, J = 7.9 Hz^ 1H), 6.78 (d, J

= 7.5 Hz, 1H), 6.60 (t, J = 7.9 Hz, 1H), 4.92 (s, 2H), 4.14 (s, 2H),
2.55 (s, 3H). [M+l]*'309.2
Scheme 51
Example 167
i: Acetyl acetone/EtOH;
ii: HOBt/EDCxHCI then 1,2-diamlnobenzene;
Example 167
Step 1: 4-(3,5-Dimethyl-pyrazol-l-yl)-benzoic acid (285)
[0348] A solution of 4-hydrazino-benzoic acid (0.60 g, 3.95 mmol)
and acetyl acetone (0.405 ml, 3.95 mmol) in ethanol (20 ml) refluxed
for 1 hour. Ethanol was removed in vacuum and the remaining solid
was triturated with water and collected by filtration to produce 285
(0.71 mg, 83% yield). [M-l]" 215.1.
Step 2. N- (2-Amino-phenyl) -4- (3,5-dimethyl-pyrazol-l-yl) -benzamide
(286)
[0349] For the preparation of the title compound 286, a procedure
analogous to that described in Example 92, step 2, but substituting
285 for 143, the title compound 286 was obtained in 34% yield
(purified by chromatography using as eluent CH2Cl2-methanol, 19:1) .
lH NMR: (DMSO) 5 (ppm): 9.73 (s, 1H); 8.09 (d, J = 8.4 Hz, 2H), 7.64
(d, J = 8.4 Hz, 2H), 7.17 (d, J = 7.5 Hz, 1H), 6.98 (t, J = 7.0 Hz,
1H), 6.78 (d, J = 7.9 Hz, 1H), 6.60 (t, J = 7.5 Hz, 1H), 6.13 (s,
1H), 4.92 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H). [M+l]* 303.3
Step 1: 2-(3,4,'5-Trimethoxy-phenyl)-2,3-dihydro-furan (287)
[0350] To a solution of 5-iodo-l,2,3-trimethoxybenzene (900 mg,
3.06 mmol) and 2,3-dihydrofuran (1.16 mL, 15.3 mmol) in dry DMF (8
mL) were added PPh3 (20 rag, 0.077 mmol), KOAc (901 mg, 9.18 mmol), n-
BU4NCI (850 mg, 3.06 mmol) and Pd(OAc)2 (17 mg, 0.077 mmol). The
reaction mixture was stirred 18 h at 80°C. The reaction mixture was
diluted with AcOEt and water. After separation, the organic layer
was washed with brine, dried over anhydrous NajSO4/ filtered and
concentrated. The crude residue was then purified by flash
chromatography on silica gel (AcOEt/Hexane: 20/80) to afford the
title compound 287 (311 mg, 1.32 mmol, 43% yield). JH NMR: (300 MHz,
CDCI3) 8 (ppm): 6.59 (s, 2H), 6.45 (m, 1H), 5.45 (dd, J = 10.5, 8.4

Hz, 1H), a4.97 (m, 1H), 3.B7 (a, 6H), 3.84 (s, 3H), 3.06 (m, 1H),
2.62 (m, 1H).
Step 2: 4- [5-(3,4,5-Trimethoxy-phenyl)-2,5-dihydro-furan-2-yl]-
benzoic acid ethyl ester (288)
[0351] To a solution of 287 (200 mg, 0.846 mmol) and 4-Iodo-benzoic
acid ethyl ester (468 mg, 1.69 mmol) in dry acetonitrile (4 mL) were
added PPh3 (20 mg, 0.076 mmol), AgaC03 (467 mg, 1.69 mmol) and
Pd(OAc)2 (7 mg, 0.03 mmol). The reaction mixture was stirred 18 h at
80°C. The reaction mixture was filtered through celite and washed
with AcOEt. Water was added and the phases were separated. The
organic layer was washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated. The crude residue was then purified by
flash. chromatography on silica gel (AcOEt/Hexane: 30/70) to afford
the title compound 288 (280 mg, 0.728 mmol, 86% yield). 1H NMR (300
MHz, CDC13) d (ppm) : 8.05 (d, J = 7.5 Hz, 2H) , 7.45 (d, J = 7.5 Hz,
2H), 6.61 (s, 2H), 6.18-5.95 (m, 4H), 4.38 (q, J = 7.0 Hz, 2H), 3.88
(s, 6H), 3.84 (s, 3H), 1.39 (t, J = 7.0 Hz).
Step 3; N- (2-Amino-phenyl)-4-[5-(3,A;5-trimethoxy-phenyl)-2,5-
dihydro-furan-2-yl]-benzamide (289)
[0352] Following a procedure analogous to that described in Example
1, step 4, 5, but substituting 288 for 6, the title compound 289 was
obtained in 48% yield. XH NMR (DMSO) d (ppm): 8.00 (s, 1H) , 7.91 (d,
J = 7.9 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 7.33 (d, J = 7.5'Hz, 1H),
7.09 (t, J = 7.5 Hz, 1H), 6.92-6.82 (m, 2H), 6.61 (s, 2H), 6.14-5.99
(m, 4H), 3.89 (s, 6H), 3.84 (s, 3H).
Example 169
Step 1: N- (2-Amino-phenyl)-4-[5-(3,4,5-trimethoxy-phenyl)-
tetrahydro-furan-2-yl]-benzamide. (290)
[0353] To a degazed solution of 289 (43 mg, 0.096 mmol) in AcOEt (4
mL) was added Pt02 (3 mg, 0.01 mmol) and the reaction mixture was
stirred at room temperature under a 1 atm pressure.of H2 for 16 h.
The reaction flask was purged with N2 then the reaction mixture was
filtered through celite, rinsed with MeOH and concentrated. The
crude residue was purified three times by flash chromatography on
silica gel (MeOH/DCM: 2/98, AcOEt/DCM: 30/70 and AcOEt/CHC13: 30/70)
to afford the title compound 290 (10 mg, 0.22 mmol, 23% yield). lH
NMR (CDCI3) d (ppm): 8.10 (s,' 1H) , 7.91 .(d, J = 8.0 Hz, 2H) , 7.50 (d,
J = 8.0 Hz, 2H), 7.34 (d, J = 7.5 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H),


6.96-6.85 (m, 2H), 6.64 (s, 2H), 5.33 (t, J = 7.0 Hz, 1H), 5.21 (t,
J = 7.0 Hz, 1H), 3.89 (s, 6H), 3.85 (s, 3H), 2.59-2.40 (m, 2H),
2.09-1.88 (m, 2H).
Example 169
Step 1: [2-(4-Vinyl-benzoylamino)-phenyl]-carbamic acid tert-butyl
ester (291)
[0354] Following a procedure analogous to that described in Example
143, step 2, but substituting 184 for 221, the title compound 291

was obtained in 90% yield as a dark yellow oil. 1H NMR: (300 MHz,
CDC13) 5 (ppm): 9.18 (s, 1H) , 7.94 (d, J = 8.5 Hz, 2H), 7.77 (d, J =
7.5 Hz,' 1H) , 7.49 (d, J = 8.5 Hz, 2H) , 7.30-7.10 (m, 3H) , 6.89 (s,
1H, (dd, J = 17.4, 11.0 Hz, 1H) , 5.87 (d, J = 17.4 Hz, 1H),
5.39 (d, J = 11.0 Hz, 1H), 1.52 (s, 9H).
Step 2; [2- (4-Oxiranyl-benzoylamino) -phenyl] -carbamic acid tert-
butyl ester (292)
[0355] To a solution of 291 (4.1 g, 12.1 ittmol) in dry CHClj (60 tnL)
was added m-CPBA 70% (3.6 g, 14.5 mmol) . The reaction mixture was
stirred at room temperature for 5 h then additional m-CPBA (0.6 g,
2.4 mmol) was added and the stirring continued for 1 h. A further
amount of m-CPBA (0.6 g, 2.4 mmol) was added and the reaction
mixture was stirred for 16 h. Chloroform arid a 10% solution of NaHCOa
were added and the phases were separated. The organic layer was
washed with water and brine, dried over anhydrous Na2SO4, filtered
and concentrated. The crude residue was then purified by flash
chromatography on Bilica gel (AcOEt/Hexane: 1/3) to afford the title
compound 292 (2.86 g, 8.07 mmol, 66% yield). 1H NMR (300 MHz, GDC13)
d (ppm): 9.20 (s, 1H) , 7.95 (d, J = 8.1 Hz, 2H) , 7.86-7.75 (m, 1H),
7.38 (d, J= 8.1Hz, 2H), 7.26-7.10 (m, 3H), 6.84-6.70 (m, 1H) , 3.93
(t, J = 3.0 Hz, 1H), 3.20 (t, J = 5.0 Hz, 1H), 2.80 (dd, J = 5.0,
3.0 Hz, 1H), 1.52 (s, 9H) .
Step 3: (2-{4-[l-Hydroxy-2-(3,4,5-trimethoxy-phenylamino)-ethyl]-
benzoylamino)-phenyl)-carbamic acid tert-butyl ester (295) and (2-
(4- [2-Hydroxy-l-(3,4,5-trimethoxy-phenylamino) -ethyl] -benzoylamino)-
phenyl)-carbamic acid tert-butyl ester (293)
[0356] To a stirred solution of CoCl2 (8 mg, 0.06 mmol) in dry
acetonitrile (10 mL) was added 292 (1 g, 2.8 mmol) followed by
3,4,5-trimethoxyaniline (516 mg, 2.8 mmol) and the reaction mixture
was allowed to react for 16 h at room temperature then it was heated
at 60"C for 5 h. The reaction mixture was partitioned between AcOEt
and water- and the phases were separated. The organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated. The crude residue was purified by flash chromatography
on silica gel (AcOEt/Hexane: 1/1) to afford compounds 293 and 295
(combined: 1.07 g, 1.99 mmol, 71% yield, ratio 292/295 = 5/1) which '
can be separated by flash chromatography on silica gel
(AcOEt/Hexane: 1/1). XH NMR (300 MHz, CDC13) 6 (ppm): Compound 292:

9.21 (s, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 6.6 Hz, 1H) ,
7.46 (d, J = 8.1 Hz,. 2H), 7.28-7.10 (m, 3H), 6.90 {s, 1H), 5.83 (s,
2H), 4.54-4.44 (m, 1H), 3.93 (dd, J = 8.1, 3.9 Hz, 1H), 3.84-3.72
Jm^lH), 3.71 (s, 3H), 3.66 (s, 6H), 1.47 (s, 9H) . Compound 295;
9.22 (s, 1H), 7.91 (d, J - 8.1 Hz, 2H), 7.77 (d, J = 7.2 Hz, 1H),
7.46 (d, J = 8.1 Hz, 2H), 7.30-7.21 (in, 3H) , 6.88 (a, 1H) , 6.15 (s,
2H), 5.16-5.06 (m, 1H), 3.81 (s, 6H), 3.78 (s, 3H), 3.50-3.25 (m,
2H), 1.51 (s, 9H).
Step 4; If-(2-Amino-phenyl) -4- [2-hydroxy-l- (3,4,5-trimethoxy-
phenylamino)-ethyl]-benzamide (294)
[0357] Following a procedure analogous to that described in Example
42, step 3, but substituting 293 for 46, the title compound 294 was
obtained in 50% yield. 'H NMR (DMSO) 5 (ppm): 8.36 (a, 1H) , 7.74 (d,
J = 6.9 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 6.9 Hz, 1H),
7.00 (t, J = 7.2 Hz, 1H), 6.72 (m, 2H), 5.69 (s, 2H), 4.34 (m, 1H) ,
4.02-3.52 (m, 2H), 3.66 (s,•3H), 3.57 (s, 6H) . .
Example 170
Step 1: N- (2-Amino-phenyl) -4- [2-oxo-3- (3,4,5-trimethoxy-phenyl) -
oxazolidin-4-yl]-benzamide (296)
[0358] To a solution of 293 (200 mg, 0.372 mmol) in toluene (5 mL)
and THF (1 mL)' was added 1,1'-carbonyldiimidazole (72 mg, 0.45 mmol)
followed by Et3N (156 nh, 1.12 mmol) and the mixture was stirred at
room temperature for 5 h then at 90"C for 48 h. The reaction
mixture was diluted with AcOEt, a solution of sat. NH4Cl was added
and the phases were separated. The organic layer was washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated. The
crude residue was purified by flash chromatography on silica gel
(DCM/AcOEt: 80/20) to afford the desired compound (120 mg, 0.21
mmol, 57% yield) . XH NMR (DMSO) 5 (ppm): 9.37 (s, 1H) , 7.98 (d, J =
8.1 Hz, 2H),'7.76 (d, J = 7.5 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H) ,
7.25-15 (m, 3H), 6.88 (s, 1H), 6.61 (s, 2H), 5.40 (dd, J = 8.7, 6.0
Hz, 1H), 4.79 (t, J = 8.7 Hz, 1H), 4.19 (dd, J = 8.7, 6.0 1H), 3.75
(s, 3H), 3.72 (s, 6H), 1.47 (s, 9H).
[0359] Following a procedure analogous to that described in Example
42, step 3, but substituting the previous compound for 46, the title
compound 296 was obtained in 81% yield. ) . 1H NMR (DMSO) .5 (ppm) :
8.03 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H) ,

7.30 (d, J = 7.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 7.5
Hz, 2H), 6.61 (s, 2H), 5.40 (dd, J = 8.7, 6.0 Hz, 1H) , 4.78 (t, J =
8.7 Hz, 1H), 4.18 (dd, J = 8.7, 6.0 Hz, 1H), 3.75 (s, 3H), 3.71 (s,
Example 171
Step 1: N- (2-Amino-phenyl) -4- [2-oxo-3 - (3,4,5-trimethoxy-phenyl) -
oxazol idin- 5 -yl ] -benzamide (297)
[0360] To a solution of 295 (130 mg, 0.242 mmol) in DCM (2 mL) was
added 1,1'-carbonyldiimidazole (47 mg, 0.29 mmol) and the mixture
was stirred at room temperature for 16 h. DCM was removed under
reduced pressure, AcOEt and a solution of sat. NH,C1 were added and
the phases were separated. The organic layer was washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated. The crude
residue was purified by flash chromatography on silica gel
(Hexane/AcOBt: 30/70) to afford the desired compound (80 mg, 0.14
mmol, 58% yield). XH NMR (DMSO) d (ppm) : 9.39 (s, 1H) , 8.04 (d, J =
8.1 Hz, 2H) , 7.84 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H),
7.26-7.12 (m, 3H), 6.86-6.74 (m, 3H), 5.70 (t, J = 8.4 Hz, 1H), 4.24
(t, J = 8.7 Hz, 1H), 3.97-3.87 (m, 1H), 3.87 (s, 6H), 3.82 (s, 3H),
1.52 (s, 9H).
[0361] Following a procedure analogous to that described in Example
42, step 3, but substituting the previous compound for 46, the title
compound 297 was obtained in 94% yield. ) . XH NMR (DMSO) d (ppm) :
8.38 (s, 1H), 7.97 (d, J =7.5 Hz, 2H),'7.47 (d, J . 8.1 Hz, 2H) ,
7.35 (d, J = 7.0 Hz, 1H), 7.08 (t, J = 7.0 Hz, 1H), 6.97-6.87 (m,
2H), 6.79 (s, 2H), 5.66 (t, J = 8.1 Hz, 1H), 4.41 (t, J = 9.0 Hz,
1H), 3.91 (t, J = 7.8 Hz, 1H), 3.86 (s, 6H) , 3.82 (s, 3H) '.
MG5833X
Example 172
Step 1: (2- [4-(l-Azido-2-hydroxy-ethyl)-benzoylamino] -phenyl)-
carbamic acid tert-butyl ester (298) and {2-[4-(2-Azido-1-hydroxy-
ethyl)-benzoylamino]-phenyl)-carbamic acid tert-butyl ester (302)
[0362] To a solution of 292 (210 mgr 0.59 mmol) in acetonitrile (9
mL) and water (1 mL) was added CeCl3 heptahydrate (110 mg, 0.296
mmol) followed by NaN3 (42 mg, 0.65 mmol) . The reaction mixture was
refluxed for 3 h then acetonitrile was removed under reduced
pressure. The residue was diluted with DCM, washed with brine, dried
over anhydrous Na2SO4/ filtered and concentrated. Purification by
flash chromatography on silica gel (AcOEt/Hexane: 1/1) afforded a
1:1 mixture of title compounds 298 and 302 (combined: 187 mg, 0.47
mmol, 80% yield) which were separated by flash chromatography on
silica gel (AcOEt/Hexane: 2/5) . Compound 298: 1H NMR: (300 MHz,
CDCI3/CD3OD) 5 (ppm): 7.95 (d, J = 8.1 Hz, 2H), 7.70-7.63 (m, 1H) ,
7.43 (d, J = 8.1 Hz, 2H), 7.36-7.29 (m, 1H), 7.24-7.14 (m, 2H) , 4.69
(dd, J = 7.5, 4.8 Hz, 1H), 3.80-3.65 (m, 2H) , 1.49 (s, 9H). Compound
302: 1H NMR: (300 MHz, CDC13) d (ppm): 9.28 (s, 1H) , 7.86 (d, J = 8.4
Hz, 2H), 7.71 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.25-
7.08 (m, 3H), 7.01 (s, 1H), 4.87 (dd, J= 6.9, 5.1Hz, 1H) , 3.47-
3.38 (m, 2H), 3.32-3.21 (bs, 1H), 1.50 (s, 9H).

Step 2; (2- [4- (l-Amino-2-hydroxy-ethyl) -benzoylamino] -phenyl)-
carbamic acid tert-butyl ester (299)
[0363] To a solution of 298 (156 mg, 0.39 mmol) in MeOH (2 mL) was
added Pd/C 10% (20 mg, 0.02 mmol) . The reaction mixture was stirred
under a 1 atm pressure of H2 at room temperature for 16 h then it was
purged with N2. The palladium was removed by filtration through
celite and the MeOH was evaporated under reduced pressure to afford
the title compound 299 (88 mg, 0.24 mmol, 60% yield), which was used
without purification. lH NMR (300 MHz, CDC13) d (ppm) : 9.24 (s, 1H) ,
7.90 7.8 Hz, 2H), 7.31-7.10 (m, 3H), 7.06-6.94 (m, 1H), 4.12 (dd, J =
7.5, 4.5 Hz, 1H), 3.74 (dd, J = 7.8, 5.4 Hz, 1H), 3.64-3.51 (m,
1H), 2.64 (s, 3H), 1.49 (s, 9H).
Step 3: (2-(4-[1-(3,4-Dimethoxy-benzoylamino)-2-hydroxy-ethyl]-
benzoylamino)-phenyl)-carbamic acid tert-butyl ester (300)
[0364] To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM
(2 mL) at -20°C was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25
mmol) followed by Et3N (37 nh, 0.26 mmol). The reaction mixture was
allowed to warm up to room temperature then was stirred for 48 h. A
solution of sat. NH4C1 was added, followed by DCM and the phases were
separated. The organic layer was washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated. The crude residue was
purified by flash chromatography on silica gel (MeOH/DCM: 4/96) to
afford title compound 300 (91 mg, 0.17 mmol, 71% yield). 1H NMR (300
MHz, CDC13) d (ppm): 9.29 (s, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.65-
7.58 (m, 1H), 7.46 (m, 7H), 6.80 (d, J = 8.1 Hz, 1H), 5.20-5.10 (m,
1H), 3.95-3.78 (m, 2H), 3.88 (s, 3H) 3.84 (s, 3H), 1.47 (s, 9H).
Step 4: N- (2-Amino-phenyl) -4- [2- (3,4-dimethoxy-phenyl) -4,5-dihydro-
oxazol-4-yl]-benzamide (301)
[0365] To a solution of 300 (91 mg, 0.17 mmol) in dry THP (2 mL)
was added the Burgess reagent (44 mg, 0.19 mmol) and the mixture was
stirred at 70°C for 2 h. The reaction mixture was partitioned
between AcOEt and water and the phases were separated. The organic
layer was washed with brine, dried over anhydrous Na2SO4, filtered
and concentrated. The crude residue was purified by flash
'chromatography on silica gel (MeOH/DCM: 3/97) to afford the Boc-
protected intermediate (75 mg, 0.14 mmol, 85% yield). XH NMR (CDC13)
d (ppm): 9.31 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 7.5

Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.39 (d, J = 8.1
Hz, 2H), 7.27 (d, J = 6.0 Hz, 1H), 7.23-7.08 (m, 3H), 6.93 (d, J =
8.7 Hz, 1H), 5.43 (t, J = 9.0 Hz, 1H), 4.84 (t, J = 9.3 Hz, 1H) ,
4.26 (t, J = 8.4 Hz, 1H), 3.95 (s, 3H) , 3.94 (s, 3H) ,' 1.50 (s, 9H) .
[0366] Following a procedure analogous to that described in Example
42, step 3, but substituting the previous compound for 46, the title
compound 301 was obtained in 82%. 1H NMR (CDCl3) § (ppm) : 8.01 (s,
1H), 7.89 (d, J = 7.9 Hz, 2H), 7.65 (dd, J = 8.4, 1.5 Hz, IE), 7.60
(d, J - 1.5 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 7.9 Hz,
1H), 7.08 (t, J = 6.6 Hz, 1H), 6.92 (d, J - 8.4 Hz, 1H), 6.84 (d, J
= 7.9 Hz, 2H), 5.43 (dd, J = 9.7, 8.4 Hz, 1H), 4.83 (dd, J = 9.7,
8.4 Hz, 1H), 4.25 (t, J = 8.1 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H).
Example 173
Step 1: {2-[4-(2-Amino-l-hydroxy-ethyl)-benzoylamino]-phenyl)-
carbamic acid tert-butyl ester (303)
[0367] The title compound 303 was obtained in 94% yield from 302
following the same procedure as in Example 172, step 2. The compound
303 was used directly for next step without purification.
Step 2: 2-(4-[2-(3,4-Dimethoxy-benzoylamino)-1-hydroxy-ethyl]-
benzoylamino)-phenyl)'-carbamic acid tert-butyl ester (304)
[0368] The title compound 304 was obtained in 40% yield from 303
and 3,4-dimethoxybenzoyl chloride following the same procedure as in
Example 172, Step 3. XH NMR (CDC13) d (ppm): 9.31 (s, 1H) , 7.78 (d, J
= 8.1 Hz, 2H), 7.68 (d, J = 6.9 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H),
7.33 (d, J = 8.1 Hz), 7.30-7.06 (m, 4H), 7.00-6.93 (m, 1H), 6.79 (d,
J = 8.4 Hz, 1H), 4.89-4.82 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H),
3.85-3.73 (m, 1H), 3.44-3.32 (m, 1H), 1.46 (s, 9H).
Step 3: N- (2-Amino-phenyl)-4-[2-(3,4-dimethoxy-phenyl)-4,5-dihydro-
oxazol-5-yl]-benzamide (305)
[0'369] Following a procedure analogous to that described in Example
172, step 4, 5, but substituting 304 for 300, the title compound 305
was obtained in 63%. XH NMR (CDC13) d (ppm): 8.02 (s, 1H) , 7.93 (d, J
= 8.1 Hz, 2H), 7.63 (dd, J = 8.4, 1.8 Hz, 1H), 7.60 (s, 1H), 7.44
(d, J = 8.1 Hz, 2H), 7.33 (d, J = 7.5 Hz, 1H), 7.09 (t, J = 7.5 Hz,
1H), 6.91 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.1 Hz, 2H) , 5.74 (dd, J
= 10.0, 7.8 Hz, 1H), 4.51 (dd, J = 14.5, 10.0 Hz, 1H), 4.00-3.90 (m,
7H) .
STEP 1: [2- (4-FORMYL-BENZOYLAMINO) -PHENYL] -CARBAMIC ACID TART-BUTYL
ESTER (315)
[0370] To-a suspension of 4-carboxybenzaldehyde {6 g, 40 mmol) in
dichloromethane (10 mL) was added thionyl chloride (4.1 mL, 56 mmol,
1.4 eq), followed by DMF (1 mL) dropwiBe. The mixture was refluxed
for 4 hours and excess of thionyl chloride and DMF were removed
under reduced pressure. To a solution of (2-aminophenyl)-carbamic
acid tert-butyl ester (8.32 g, 40 mmol, 1 eq) in dichloromethane (80
mL), stirred at 0°C, was added a suspension of 4-formyl benzoyl
chloride in dichloromethane (20 mL), followed by diisopropyl
ethylamine (3.61 mL, 20 mmol, 1 eq). The mixture was stirred for 30
minutes at 0°C then at room temperature for 30 minutes. The crude
residue was diluted with dichloromethane (300 mL) and washed with
water. The combined organic layers were dried (MgSOj , filtered and
concentrated under vacuo. The crude residue was purified by column
chromatography on silica gel (elution 20% ethyl acetate in hexane)
to give 6.1 g (45% yield) of anilide 315. XH NMR (CDC13) : 5 10.18
(s, 1H), 9.64 (brs, 1H), 8.20 (d, J = 7.9 Hz, 2H), 8.06 (d, J = 7.9
Hz, 2H), 7.96 (d, J = 7.9 Hz, 1H), 7.28-7.38 (m, 1H), 7.24 (d, J =
4.4Hz, 1H), 6.84 (s, 1H), 6.81 (d, J =8.8 Hz, 1H), 1.58 (s, 9H).

Step 2: (2-{4-[(3,4-Dimethoxyphenylamino)-Methyl]-Benzoylamino)-
Phenyl)-Carbamic Acid Tert-Butyl Ester (316)
[0371] Following a procedure analogous to that described in Example
144, step 3, but substituting the previous compound for 226, the
title compound 316 was.obtained in quantitative yield. 1H NMR
(CDC13) : S 9.21 (brs, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 7.0
Hz, 1H), 7.55 (d, J = 8:3 Hz, 2H), 7.20-7.34 (m, 3H), 6.89 (brs,
1H), 6.81 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H>, 6.23 (dd, J
= 2.6, 8.3 Hz, 1H), 4.45 (s, 2H), 3.89 (s, 3H) , 3.88 (s, 3H), 1.58
(s, 9H).
Step 3 : N- (2 -Amine-phenyl )-4-[l-(3,4- dimethoxyphenyl) - 3 - (4 -
methylsulf anylphenyl) -ureidomethyl] -benzamide 317
[0372] To a solution of anilide 316 (£00 tng, 1.047 mmol) in
chloroform/THF (1:1, 10 mL) was added isocyanate (169 }iL, 1.205
mmol, 1.15 eq) . The mixture was stirred overnight at room
temperature under nitrogen and the crude residue was concentrated
and purified by column chromatography on silica gel (elution 40%
ethyl acetate in hexane) to give 606 mg (90% yield) of the desired
compound. XH NMR (CDC13) : 8 9.25 (s, 1H) , 7.96 (d, J = 8.3 Hz, 2H) ,
7.85 (d, J = 7.0 Hz, 1H) , 7.44 (d,' J = 8.3 Hz, 2H) , 7.20-7.36 (m,
6H), 6.93 (d, J = 3.5 Hz, 1H), 6.90 (s, 1H), 6.75 (dd, J = 2.2, 8.3
Hz, 1H), 6.68 (dd, J = 2.6 Hz, 1H), 6.33 (s, 1H), 5.0 (s, 2H), 3.97
(s, 3H), 3.85 (s, 3H), 2.51 (s, 3H), 1.57 (s,. 9H).
[0373] Following a procedure analogous to that described in Example
42, step 3, but substituting the previous compound for 46, the title
compound 317 was obtained in 85% yield. XH NMR (DMSO-d6) : 810.14
(brs, 1H), 7.99 (d, J = 7.9 Hz, 2H), 7.93 (s, 1H), 7.49 (d, J = 8.35
Hz, 4H), 7.39 (d, J = 7.5 Hz, 1H), 7.10-7.30 (2m, 5H), 6.97 (dd, J
= 2.2, 8.35 Hz, 1H), 6.77 (dd, J = 2.2, 8.35 Hz, 1H), 5.02 (s, 2H),
3.80 (s, 3H), 3.77 (s, 3H), 2.48 (s, 3H) .
319
Example 179
Example 179
Step 1: N- (2-Amino-phenyl)-6-chloro-nicotinamide (318)
[0374] Following the procedure described in Example 42, step 2, the
title compound 318 was obtained in 80% yield. LRMS = calc:246.69,
found:247.7.
Step 2: N- (2-Amino-phenyl) -6- (quinolin-2-ylsulfanyl) -nicotinamide
(319)
[0375] Following the procedure described in Example 45, step 1 but
substituting 318 for 3,4,5-trimethoxybenzylamine, the tite compound
319 was obtained in 20% yield. XH NMR: (CD3OD-d6) d (ppm) : 9.08 (d,
J= 1.9 Hz, 1H), 8.35-8.25 (m, 2H), 7.99-7.56 (m, 7H), 7.23 (dd, J =
1.2, 7.9Hz, 1H), 7.12 (dd J=1.4, 7.9, 14.0 Hz, 1H), 6.93 (dd,
.J=1.2, 8.0Hz, 1H), 6.79 (ddd, J=1.4, 7.7, 13.7 Hz, 1H).
Step 1: 4- [ (4-Morpholin-4-yl-phenylamino) -methyl] -benzoic acid
(402a).
[0376] A suspension of 4-formylbenzoic acid (2.53g; 16.8 mmol; 1
eq), 4-morpholinoaniline (3g; 16.8 nunol; 1 eq) and Bu2SnCl2 (510 mg;
1.68 nunol; 0.1 eq) in dry THF (20 ml) was treated with PhSiH3
(3.3lml; 16.8 mmol; 1 eq) at room temperature for 12 h. The reaction
was filtered and the solid product was washed with MeOH. The yield
of the reaction was 5.25g (99%). LRMS: calc 312.37; found: 313.2.
Step 2; N-(2-Amino-phenyl)-4-[(4-morpholin-4-yl-phenylamino)-
methyl]-benzamide (402)
[0377] To a solution of acid 402a (2.61g; 8,36 mmol; 1 eq), 1,2-
phenylenediamine (903 mg; 8.36 mmol; 1 eq) and BOP (3.70g; 8.36
mmol; 1 eq) in dry DMF (20 ml) was added Et3N (4.64ml; 33.4 mmol; 4
eq). After stirring overnight most of the DMF was removed under
reduced pressure and chromatographed (Hex:EtAcO: 1:2/ EtAcO). The
crystal 402 was obtained in 70% (2.35g). 1H-NMR (300.07 MHz; DMS0-d6)
d (ppm): 9.65 (s, 1H), 7.97 (d, J=7.9, 2H), 7.53 (d, J=7.9, 2H),
7.22 (d, J=7.5, 1H), 7.03 (dd, J=7.0, 7.5, 1H), 6.83 (d, J=7.9, 1H),
6.77 (d, J=8.8, 2H), 6.65 (dd, J=7.5, 7.0,1H), 6.57 (d, J=8.8, 2H),
4.93 (bs, 2H), 4.36 (d, J=5.7, 2H), 3.75 (m, 4H), 2.93 (m, 4H).
LRMS: calc 402.49; found: 403.4.
Step 1. 4- [(3,4-Dimethoxyphenylamino) -methyl] -benzoic acid (424a)
[0378] In a 50 ml flask, a mixture of 4-aminoveratrole (1.53 g, 10
rnrnol), 4-formyl-benzoic acid (1.50 g, 10 mmol), dibutyltin
dichloride (304 mg, 1 mmol), phenylsilane (2.47 ml, 20 mmol) in
anhydrous THF (10 mL) and DMA (10 ml) was stirred overnight, at room
temperature. After solvents removal, the crude residue was dissolved
in ethyl acetate (100 ml) and then washed with saturated aqueous
solution of NaHC03 (50 ml x 3) . The combined aqueous layers were
acidified with 6% of NaHSO4 to pH = 4. The resulting white
suspension was filtrated and then the filter cake was washed with
water (5 ml x 3) . The cake was dried over freeze dryer to afford
acid (1.92 g, 67 %) white solid product. LRMS = 288 (MH)+.
Step 2. N-(2-Aminophenyl)-4-[ (3,4-dimethoxyphenylamino)-methyl] -
benzamide (424b)
[0379] In a 150 ml flask, a mixture of acid (1.92 g, 6.59 mmol),
benzotriazol-l-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (BOP, 3.26 g, 7.37 mmol), triethylamine ( 1.87
ml, 13.4 mmol), o-phenylenediamine (1.30g, 12.02 mmol) in
methylenechloride ( 67 ml) was stirred at rt for 2 h. After
solvents removal,- the crude residue was dissolved in EtOAc (100 ml)
and then washed with NaHC03 saturated solution and brine 50 ml. The
combined organic layers were dried over Na2SO4 and the filtrate, was
concentrated to dryness. The crude material was submitted to a
chromatographic purification (column silica, 55%-70 % EtOAc in 1%
Et3N of hexanes) and then the all interested fractions were
concentrated to dryness. The residue was suspended in minimum
quantities of ethyl acetate and then filtered to afford final
product (1.49 g, 59 %) . XH NMR (300 MHz, DMSO-ds) d (ppm) : 9.65 (s,
1H), 7.98 (d, J a 7.9 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H), 7.22 (d, J
• 7.'9 Hz, 1H), 7.02 (dd, J = 7.9, 7.9 Hz, 1H), 6.83 (d, J = 7.9 Hz,
1H), 6.72 (d, J = 8.79 Hz, 1H) , 6.45 (dd, J =-7.5, 7.5 Hz, 1H), 6.39
(d, J = 2.2 Hz, 1H), 6.01-6.08 (m, 2H), 4.94 (s, 2H, NH2) , 4.36 (d, J
= 6.16. Hz, 2H) , 3.72 (s, 3H) , 3.65 (s, 3H) .
Example 283b
Step 1: N- (4-Aminothiophen-3-yl) -4- [ (3,4-dimethoxyphenylamino) -
methyl]-benzamide:
[0380] Acid 424a (1040 mg; 3.62 mmol); 3,4-diaminothiophene
dihydrochloride (1017 mg; 5.44 mmol; 1.50 eq.) and BOP (1770 mg; 4.0
mmol; 1.1 eq.) were suspended in MeCN, treated with triethylamine (4
mL; 29 mmol) and stirred for 18h at room temperature; concentrated
and purified by chromatographic column on silica gel (elution 50%
EtOAc in DCM) to render 527 mg (1.37 mmol; 38 % yield) of compound
424c which was 90% pure. 1H-NMR (300.07 MHz; DMSO-dff) d (ppm): 8.56
(s, 1H), 7.78 (d, J=7.9 Hz, 2H), 7.43 (d, J = 3.5 Hz, 1H), 7.38 (d,
J = 7.9 Hz, 2H), 6.73 (d, J = 8.8 Hz, 1H), 6.33 (d, J = 3.5 Hz, 1H),
6.58 (d> J = 2.6 Hz, 1H), 6.13 (dd, J = 2.6, 8.3 Hz, 1H), 4.33 (s,
2H), 3.80 (s, 3H), 3.78 (s, 3H). LRMS: calc: 383.4642; found: 384.2
(M+H); 406.2 (M+Na) and 192.6 (M+2H)/2.
Step 1: Methyl-(5-nitrobenzothiazol-2-yl)-amine (456a)
[0381] A mixture of 2-fluoro-5-nitroaniline (861 mg; 5.52 mmol;
1.02 eq) ; Im2CS (960.3 mg; 5.39 mmol) and dry K2CO3 (1.45g) was

suspended in dry DME (10 mL) and stirred under nitrogen for 90 min
at room temperature. The yellow suspension was made fluid by
diluting with DME (10 mL) followed by addition of 40% MeNH2 in water
mL; 46.5 mmol; 8.6 eq) . The system was heated up to 65C and
stirred at this temperature for 3.5 h, cooled down, diluted with
ethyl acetate and washed with saturated NaCl (X2) . After
conventional work-up procedures, the dark crude mixture was purified
through chromatographic column on silica gel (elution 50% EtOAc in
hexane, then 5% MeOH in DCM) , to afford 836.8 mg (4.0 mmol; 72%
yield) of compound 456a.
Step 2; ff-Methyl-benzothiazole-2,5-diamine (456b)
[0382] A mixture of nitro compound 456a (593 mg; 2.83 mmol); SnCl2
( 4.02 g; 20.8 mmol; 7.35 eq) and NH4OAc (4.5g) was suspended in
THF:MeOH:H2O .= 1:1:1 (60 mL) and stirred at 70°C for 2 h, cooled
down, diluted with ethyl acetate and successively washed with
saturated NaHC03 and brine; dried (MgSO4) filtered and concentrated.
The residue (443 mg; 2.43 mmol; 87%) showed consistent spectrum and
suitable purity degree for synthetic purposes, therefore was
submitted to the next step without further purification.
Step 3: 4-[ (2-Methylaminobenzothiazol-5-Ylamino)-Methyl]-Benzoic
Acid (456c)
[0383] A.solution of aniline 456b (509 mg; 2.8 mmol); 4-
formylbenzoic acid (426 mg; 2.8 mmol) and Bu2SnCl2 (198 mg; 0.65
mmol; 23% mol) in DME (14 mL) was stirred at room temperature for 3
min and treated with neat PhSiH3 (0.6 mL; 4.7 mmol; 1.7 mmol) and
allowed to react for 18h. After quenching the excess of silane with
MeOH, the mixture was concentrated and purified by chromatographic
column on silica gel (elution 5% MeOH in DCM) to give 729 mg (2."54
mmol; 91% yield) of acid 456c.
Step 4: N- (2-Aminophenyl) -4- [ (2-methylaminobenzothiazol-5-ylamino) -
methyl]-benzamide (456)
[0384] A mixture of acid 456c (729 mg; 2.54 mmol), 1,2-
phenylenediamiiie (376 mg; 3.47 mmol; 1.36 eq) and BOP (1.43 g; 3.23
mmol; 1.27 eq) was dissolved in acetonitrile (15 mL) , treated with
triethylamine (3mL) and stirred overnight. The reaction mixture was
quenched with methanol, concentrated and purified by chromatographic
column on silica gel (40% EtOAc in DCM) and the obtained material
crystallized from DCM to give 358 mg (0.88 mmol; 35 % yield) of pure

compound. 456. XH-NMR (300 MHz; DMSO-d6) 5 (ppm) : 9.57 (s, 1H), 7.92
(d, J = 7.9 Hz, 2H), 7.66 (d, J = 4.8 Hz, 1H), 7.48. (d, J = 8.3 Hz,
2H), 7.26 (d, J = 8.3 Hz, 1H) , 7.15 (d, J = 7.9 Hz, 1H), 6.95 (t, J
£ 7.5 Hz, 1H), 6.76 4.87 (bs, 2H), 6.58 (t, J =7.5 Hz, 1H), 6.54
(d, J = 1.8 Hz, 1H), 6.13 (dd, J . 1.8, 8.3 Hz, 1H), 6.27 (t, J =
5.7 Hz, 1H), 4.87 (bs, 2H), 4.36 (d, J - 5.7 Hz, 2H) , 2.85 (d, J =
4.8 Hz, 3H) . LRMS: calc: 403.5008, found: 404.2 (M+NH) and 202.6
(M+2H)/2.
Example 235
Step 1: Methyl - 4 - (5 -methoxy- lH-benzimidazol - 2 -yl - sulf anylmethyl) -
benzoate (376a)
[0385] To a solution 5-methoxy-2-thiobenzimidazole (2.00 g, 11.1
mmol of in anhydrous DMF (40 ml) was added methy-4-(bromomethyl)-
benzoate (2.54 g, 11.1 mmol). The reaction mixture was stirred 16 h
at room temperature. The DMF was evaporated and the residue was
triturated in ethyl acetate during 30 min and then filtered and
dried. The desired compound was isolated as the HBr salt: 98% yield,
(4.44 g) . aH NMR: (DMSO) d (ppm): 7.90 (d, J. = 8.8 Hz, 2H) , 7.56-
7.52 (m, 3H), 7;09 (d, J = 2.2 Hz, 1H), 7.01 (dd, J = 8.8 , 2.2
Hz, 1H), 4.73 (s, 2H), 3.82 (s, 6H). MS: (calc.) 328.1, (obt.),
329.2 (MH)+.
Step 2: 4-(5-Methoxy-lH-benzimidazol-2-yl-sulfanylmethyl)-benzoic
acid (376b)
[0386] A solution of LiOH.H2O (1.02 g, 24.4 mmol) in water (15 ml)
was added to a suspension of 376a (3.99 g, 9.75 mmol of in THF (10

ml). The reaction mixture was stirred 16 h at room temperature. The
reaction mixture was acidified with a solution of HC1 .1 M to pH 4.
The desired product was triturated 20 min. at 0°C and then filtered
gand dried. Compound 376b was obtained as a white powder (100% yield,
3.05 g). XH NMR: (DMSO) d (ppm) : 12.85 (bs, 1H), 7.86 (d, J = 8.1 Hz,
2H), 7.53 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 1H), 6.97 (d,
J = 2.2 Hz, 1H) , 6.76 (dd, J = 8.8 , 2.2 Hz, 1H), 4.60 (s, 2H),
3.82 (s, 3 H). MS: (calc.) 314.1, (obt.), 315.1 (MH)+.
Step 3; N- (2-Amino-phenyl) -4-(5-methoxy-lH-benzimidazol-2-yl-
sul f anylmethyl) -benzamide (376)
[0387] Following the procedure described in Example 1 step 5 but
substituting 4-(5-methoxy-lH-benzimidazol-2-yl-sulfanylmethyl)-
benzoic acid 2 for 7 the title compound 376 was obtained as a white
powder.: 36% yield (933 mg) . XH NMR: (DMSO) d (ppm): 12.42 (bs, 1H) ,
9.57 (bs, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.55 (d, J » -8.1 Hz, 2H),
7.34 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 7.3 Hz, 1H), 6.98-6.93 (m,
2H) , 6.77-6.55 (m, 2H), 6.58 (dd, J = 7.3, 7.3 Hz, 1H), 4.87 (s,
2H), 4.59 (s, 2H), 3.77 (s, 3 H). MS: (calc.) 404.1, (obt.), 405.4
(MH) + .'
Examples 180-328
[0388] Examples 180 to 327 (compounds 320 - 468) were-prepared
using the same procedure aB described for compound 126 to 319 in
Example 85 to 179 (scheme 11 to 58).
Examples 329-344
[0389] Examples 329 to 344 (compounds 470 - 485) were prepared
using the same procedure as described for compound 8 to 224 in
Example 1 to 143 (scheme 1 to 32).
Example 345
Step 1: Methyl 3-(4-bromo-phenyl)-acrylic ester (486)
[0390] To a solution of anhydrous i-Pr2NH (758 pi, 5.40 mmol) in
anhydrous THF (25 ml) stirred at 0°C under nitrogen , was slowly
added a solution of n-BuLi (2.22 ml, 5.54 mmol, 2.5 M in hexane) .
After 30 min, LDA was cooled to -78°C and anhydrous methyl acetate
(430 01, 5.40 mmol) was added dropewise. After 30 min, a solution
of 4-bromobenzaldehyde (500 mg, 2.70 mmol) in anhydrous THF (10 ml)
was slowly added. After 30 min, a solution of 2-chloro-4,6-
dimethoxy-l,3,5-triazine (569 mg, 3.24 mmol) in anhydrous THF (15
ml) was added. Then, the temperature was allowed to warm up to room
temperature overnight. A suspension appeared. The reaction mixture
was poured into a saturated aqueous solution of NH4Cl, and diluted
with AcOEt. After separation, the organic layer was successively
washed with H2O and brine, dried over MgSO4, filtered and
concentrated. The crude product was purified by flash
chromatography on silica gel (AcOEt/hexane: 10/90) to give the title
product 486 (394 mg, 1.9 mmol, 61% yield) as a colorless crystalline
solid. 1H NMR (300 MHz, CDC13) d (ppm) : 7.63 (d, J = 16.2 Hz, 1H) ,
AB system (8A = 7.53, 8B = 7.39, J = 8.4 Hz, 4H) , 6.43 (d, J = 15.8 .
Hz, 1H), 3.82 (s, 3H).

Step 2; Methyl 3-[4-(3,4,5-trimethoxy-phenylamino)-phenyl]-acrylic
ester (487)
[0391] A mixture of CsaC03 (378-mg, 1.16 mtnol) , Pd(OAc)2 (6 mg,
IL.025 mmol) , (rac) -BINAP (23 mg, 0.037 mtnol) , was purged with
nitrogen for 10 min. 486 (200 mg, 0.83 mmol), 3,4,5-
trimethoxyaniline (182 mg, 0.99 mmol), and anhydrous toluene (5 ml)
were added, respectively. The reaction mixture was heated to 100°C
under nitrogen for 24 h. Then, it was allowed to cool to room
temperature, diluted with AcOEt, and successively washed with a
saturated aqueous solution NaHC03, H2O, sat. NH,C1, H2O and brine,
dried over anhydrous MgSO4, filtered and concentrated. ' The crude
residue was then purified by flash chromatography on silica gel
(AcOEt/hexane: 40/60) to afford the title compound 487 (280 mg, 0.82
mmol, 98% yield) as a yellow oil. 1H NMR (300 MHz, CDC13) d (ppm) :
7.64 (d, J = 16.2 Hz, 1H), 7.43 (bd, J = 7.9 Hz, 2H) , 7.12-6.86 (m,
2H), 6.60-6.20 (m, 3H, included at 6.29, d, J = 15.8 Hz), 3.84 (s,
9H) ,3.80 (s, 3H)..
Step 3: N- (2-Amino-phenyl) -3-[4- (3,4,5-trimethoxy-phenylamino) -
phenyl]-acrylamide (488)
[0392] The title compound 488 was obtained from 487 in 2 steps
following the same procedure as Example 1, steps 4 and 5. XH NMR
(300 MHz, DMSO-ds) d (ppm): 9.29 (s, 1H), 8.48 (s, 1H) , 7.60-7.42 (m,
3H), 7.38 (d, J = 7.5 Hz, 1H), 7.12 (d, J « 8.4 Hz, 2H), 6.94 (t, J
» 7.5 Hz, 1H) , 6.78 (d, J = 7.9 Hz, 1H) , 6.71 (d, J = 15.8 Hz, 1H)-,
. 6.61 (t, J = 7.1 Hz, 1H), 6.47 (s, 2H), 4.97 (s, 2H) , 3.79 (s, 6H),
3.66 (s, 3H).

Example 346
Step 1; 3-(4-Formyl-3-methoxy-phenyl)-acrylic acid tert-butyl ester
489
[0393] Following the procedure described in Example 53, step 1, but
substituting 4-hydroxy-2-methoxy-benzaldehyde for 84, followed by
Example 42, step 2, but substituting the previous compound for 42,
the title compound 489 was obtained in 29% yield. LRMS = calc: 262,
found: 263.2 (M+H+) .
Step 2; 3-(3-Methoxy-4-[(3,4,5-trimethoxy-phenylamino)-methyl] -
phenyl)-acrylic acid tert-butyl ester 490
[0394] Following the procedure described in Example 144, step 3,
but substituting 489 for 4-formylbenzaldehyde, the title compound
490 was obtained in 69% yield. LRMS = calc: 429, found: 430.5 (m+h*) .
Step 3 : N- (2-Amino-phenyl) -3- (3-methoxy-4- [(3,4,5-trimethoxy-
phenylamino) -methyl]-phenyl)-acrylamide 491
[0395] Following the procedure described in Example 42, step 3, 4,
but substituting 490 for 46, the title compound 491 was obtained in
67% yield. 1H NMR (CDCl3;, d (ppm) : 8.08 (s, 1H) , 7.74 (d, J = 15.4
Hz, 1H), 7.30 (m, 1H), 7.06 (m, 3H); 6.80 (m, 3H) , 6.70.Cd, J = 15.4
Hz, 1H), 5.98 (S, 2H), 4.40 (s, 2H) ; 4.12 (bs, 3H) , 3 ..94 (s, 3H^,
3.84 (S, 3H), 3.77 (s, 6H).
Example 436
Step 1: Methyl-5-methyl-benzofuran-2-carboxyIate (583)
[0396] A stirring suspension of 5-methylsalicylaldehyde (1.0 mg,
7.5 mmol), K2C03 (1.55 g, 11.0 mmol) , and BvuNBr (322 mg, 1 mmol) in
toluene (30ml) was treated with dimethylbromomalo-nate (1.06 ml, 8.0
mmol) . The suspension was heated to reflux with a Dean-Stark trap
for 20 h. The brown suspension was cooled to 25°C and concentrated in
vacuo. The residue was taken in DCM and filtered. The filtrate was
washed with H2O, IN NaOH and brine. The organic layer was dried over
magnesium sulfate, filtered and concentrated. The crude residue was

purified by column chromatography (10% ethyl acetate/hexane) to
afford the title compound 583 (600mg, 42% yield). LRMS : 190.2 •
(Calc); 191.1 (found) .
step 2; Methyl-5-bromomethyl-benzofuran-2-carboxylate (585)
t'0397], A mixture of 583 (500 mg, 2.63 mmol), N-bromosuccinimide
(561 mg, 3.15 mmol) and l,l'-azobis(cyclohexanecarbonitrile) (Vazo)
(63 mg, 0.26 mmol) in 15 ml of CC14 was heated overnight under
reflux. The mixture was cooled to room temperature, quenched by
adding water and extracted with DCM. The organic layer was washed
with brine and dried over MgSO,,, filtered and concentrated. The crude
residue was purified by column chromatography (30% ethyl
acetate/hexane) to afford the title compound 585 (680mg, 96% yield).
aH NMR: (CDC13) d (ppm) : 7.79 (s, 1H), 7.70-7^52 (m, 3H), 4.69 (s,
2H), 4.06 (s, 3H), 3.72 (s, 2H) . LRMS : 268.2 (Calc); 269.1
(found).
Step 3 ; Methyl-5- [ (3,4-dimethoxy-phenylamino) -methyl] -benzofuran-2-
carboxylate (586)
[0398] Following the procedure described in Example 47, step 2, but
substituting 585 for 63, the title compound 586 was obtained in 40%
yield. LRMS : 341 (Calc); 342.3 (found).
Step 4: 5-[(3,4-Dimethoxy-phenylamino)-methyl]-benzofuran-2-
carboxylic acid (2-amino-phenyl)-amide (587)
[0399] Following the procedure described in Example 1, steps 4,5,
but substituting 585 for 6, the title compound 587 was obtained in
29% yield. lH NMR: (DMSO) d (ppm): 9.83 (s, 1H) , 7.75 (s, 1H) , 7.64
(s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.18
(d, J = 8.0 Hz, 1H) , 6.97 (t, J = 7.5 Hz, 1H) , 6.,78 (d, J = 8.0 Hz,
1H), 6.65 (d, J,= 8.5 Hz, 1H), 6.59 (t, J = 7.5 Hz, 1H), 6.33 (s,
1H), 6.04 (d, J = 8.0 Hz, 1H), 5.92 (d, J = 5.5 Hz, 1H), 4.93 (s,
2H), 4.31 (d, J = 5.5 Hz, 1H) , 2.82 (s, 3H) , 2.76 (s, 3H) . LRMS :
417.46 (Calc); 418.4 (found).
Example 437
Step 1; Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584)
[0400] A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0
g, 21.6 mmol) in DMF (40 ml) at 5°C was treated with K2C03 (3.52 g,
25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The
resulting solution was warmed to 25°C and stirred for 20h. The

solution was then poured into 250ml of ice H2O and the white
precipitate that formed was collected by filtration. Crystallization
from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69%).
Cms : 237.0 (Calc); 238.1 (found) . ^H NMR: (DMSO) d (ppm) : 9.00
(d, J = 2.2 Hz, 1H),8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).
Step 2; Methyl-5-amino-benzo[b]thiophene-2-carboxylate (588)
[0401] A suspension of 584 (3.52 g, 14.8 mmol) in methanol (100 ml)
was treated with Fe powder (6.63 g, 118.7 mmol). The resulting
suspension was heated to reflux, and 12M HC1 (8.5 ml) was slowly
added over 15 min. The resulting green dark suspension was refluxed
for an additional 3 h, then cooled and concentrated. The residue was
taken up in EtOAc and washed with saturated aqueous NaHC03, then
brine, dried aver MgSO4, filtered and concentrated to afford (2.57 g,
84%). 1H NMR: (DMSO) d (ppm): 7.92 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H) ,
7.05 (d, J =1.5 Hz, 1H), 6.88 (dd, J = 1.8, 8.4 Hz, 1H), 5.27 (s,
2H), 3.85 (s, 3H) . LRMS : 207.0 (Calc); 208.1 (found).
Step 3; Methyl-5-(3,4,5-trimethoxy-benzylamino) -behzo[b]thiophene-2-
carboxylate (589)
[0402] Following the procedure described in Example 144, step 3,
but substituting 588 for 226, the title compound 589 was obtained in
68% yield. (DMSO) d (ppm): 7.94 (s, 1H) , 7.69 (d, J = 8.8 Hz, 1H),
7.02-6.99 (m, 2H), 6.73 (s, 2H), 6.41 (t, J = 5.7 Hz, 1H), 4.21 (d,
J= 5.9 Hz, 2H), 3.84 (s, 3H), 3.75 (s, 6H) , 3.62 (s, 3H) . LRMS :
387.1 (Calc); 388.3 (found).
Step 4: 5-(3,4,5-Trimethoxy-benzylamino)-benzo[b]thiophene-2-
carboxylic acid (2-amino-phenyl)-amide (590)
[0403] Following the procedure described in Example 1, steps 4,5,
but substituting 589 for 6, the title compound 590 was obtained in
% yields NMR: (DMSO) d (ppm): 7.79 (s, 1H) , 7.60 (d, J = 8.8 Hz,
1H) , 7.00-6.95 (m, 2H), 6.74 (s, 2H), 4.32 (s, 2H), 3.80 (s, 6H),
3.73 (s, 3H).
Examples 347-425
[04G4] Examples 347 to 425 (compounds 492-570) were prepared using
the same procedure as described for compound 44 to 491 in Example 40
to 346 (scheme 3 to 64).
Example 426
4
Synthesis of N- (2-Amino-phenyl) -4- [(4-pyridin-3-yl-pyrimidin-2-
ylamino) -methyl] -benzamide
Step 1: Synthesis of 4-Guanidinomethyl-benzoic acid methyl ester
Intermediate 1
[0405] The mixture of 4-Aminomethyl-benzoic acid methyl ester HC1
(15.7 g, 77.8 mmol) in DMF (85.6 mL) and DIPEA (29.5 mL, 171.2 mmol)
was stirred at rt for 10 min. Pyrazole-1-carboxamidine HCl (12.55 g,
85.6 mmol) was added to the reaction mixture and then stirred at rt
for 4 h to give- clear solution. The reaction mixture was evaporated
to dryness under vacuum. Saturated NaHC03 solution (35 mL) was added
to give nice suspension. The suspension was filtered and the filter

cake was washed with cold water. The mother liquid was evaporated to
dryness and then filtered. The two solids were combined and re-
suspended over distilled H2O (50 ml) . The filter cake was then washed
fith minimum quantities of cold H2O and ether to give 12.32 g white
crystalline solid intermediate 1 (77% yield, M+l: 208 on MS).
Step 2; Synthesis of 3-Dimethylamino-l-pyridin-3-yl-propenone
Intermediate 2
[0406] 3-Acetyl-pyridine (30.0 g, 247.6 mmol) and DMF dimethyl acetal
(65.8 mL, 495.2 mmol) were mixed together and then heated to reflux
for 4h. The reaction mixture was evaporated to dryness and then 50 mL
diethyl ether was added to give brown suspension. The suspension was
filtered to give 36.97 g orange color crystalline product (85%
yield, M+l: 177 on MS).
Step 3: Synthesis of 4-[ (4-Pyridin-3-yl-pyrimidin-2-ylamino)-methyl]-
benzoic acid methyl ester Intermediate 3
[0407] Intermediate 1 (0.394 g,1.9 mmol) and intermediate 2 (0.402 g,
2.3 mmol) and molecular sieves (0.2 g, 4A, powder, >5 micron) were
mixed with isopropyl alcohol (3.8 mL). The reaction mixture was
heated to reflux for 5h. MeOH (50 mL) was added and then heated to
reflux. The cloudy solution was filtrated over a pad of celite. The
mother liquid was evaporated to dryness and the residue was triturated
with 3 mL EtOAc. The suspension was filtrated to give 0.317g white
crystalline solid Intermediate 3 ( 52%, M+l: 321 on MS).
Step 4: Synthesis of N-(2-Amino-phenyl) -4-[(4-pyridin-3-yl-pyrimidin-
2-ylamino)-methyl]-benzamide
[0408] Intermediate 3 (3.68 g, 11.5 mmol) was mixed with THP (23 mL)
,MeOH (23 mL) and H2O (11.5 mL) at rt.LiOH (1.06 g, 25.3 mmol) was
added to reaction mixture. The resulting reaction mixture was warmed
up to 40°C overnight. HC1 solution (12.8 mL, 2JV) was added to adjust
pH=3 when the mixture was cooled down to rt. The mixture was
evaporated to dryness and then the solid was washed with minimum
quantity of H2O upon filtration. The filter cake was dried over
freeze dryer to give 3.44 g acid of the title compound (95%, M+l: 307
on MS).
[0409] Acid (3.39g, 11.1 mmol) of the title compound, BOP (5.679g,
12.84 mmol) and o-Ph(NH2)2 (2.314 g, 21.4 mmol) were dissolved in the
mixture of DMF (107 mL) and Et3N (2.98 mL, 21.4 mmol). The reaction


mixture was stirred at rt for 5h and then evaporated to dryness. The
residue was purified by flash column (pure EtOAc to 5% MeOH/EtOAc) and
then interested fractions were concentrated. The final product was
triturated with EtOAc to give 2.80 g of title product (66%, MS+1: 397
on MS) . 1H NMR (400 MHz, DMSO-D6) 6 (ppm) : 9.57 (s, 1H), 9.22 (s,lH),
8.6.6 (d, J= 3.5 Hz, 1H), 8.39 (d, J= 5.1 Hz, 2H), 8.00 (t, J = 6.5 Hz,
1H), 7.90 (d, J= 8.2Hz, 2H), 7.50 (m, 3H) , 7.25 (d, J = 5.1 Hz, 1H),
7.12 (d, J = 7.4 Hz, 1H), 6.94 (dd, J = 7.0, 7.8 Hz, 1H), 6.75 (d, J =
8.2 Hz, 1H), 6.57 (dd, J = 7.0, 7.8 Hz, 1H), 4.86 (s, 2H), 4.64 (d, J .
=5.9 Hz, 2H).
Assay Example 1
Inhibition of Histone Deacetylase Enzymatic Activity
1. Human HDAC-1
[0410] HDAC inhibitors were screened against a cloned recombinant
human HDAC-1 enzyme expressed and purified from a Baculovirus insect
cell expression system. For deacetylase assays, 20,000 cpm of the
[3H]-metabolically labeled acetylated histone substrate (M. Yoshida et
al., J. Biol. Chem. 265(28): 17174-17179 (1990)) was incubated with 30
Hg of the cloned recombinant hHDAC-1 for 10 minutes at 37 °C. The
reaction was stopped by adding acetic acid (0.04 M, final
concentration) and HC1 (250 mM, final concentration). The mixture was
extracted with ethyl acetate and the released [3H]-acetic acid was
quantified by scintillation counting. For inhibition studies, the
enzyme was preincubated with compounds at 4 °C for 30 minutes prior to
initiation of the enzymatic assay. IC50 values for HDAC enzyme
inhibitors were determined by performing dose response curves with
individual compounds and determining the concentration of inhibitor
producing fifty percent of the maximal inhibition. IC50 values for
representative compounds are presented in the third column of Table 5.
2. MTT Assay
[0411] HCT116 cells (2000/well) were plated into 96-well tissue
culture plates one day before compound treatment. Compounds at
various concentrations were added to the cells. The cells were
incubated for 72 hours at 37°C in 5% C02 incubator. MTT (3-[4,5-
dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide, Sigma) was
added at a final concentration of 0.5 mg/ml and incubated with the
cells for 4 hours before one volume of solubilization buffer (50% N,N-

dimethylformamide, 20% SDS, pH 4.7) was added onto the cultured cells.
After overnight incubation, solubilized dye was quantified by
colorimetric reading at 570 nM using a reference at 630 nM using an
MR700 plate reader (Dynatech Laboratories Inc.). OD values were
converted to cell numbers according to a standard growth curve of the
relevant cell line. The concentration which reduces cell numbers to
50% of that of solvent treated cells is determined as MTT ICS0. ICS0
values for representative compounds are presented in the fourth column
of Table 5.
3. Histone H4 acetylation in whole cells by immunoblots
[0412] T24 human bladder cancer cells growing in culture were
incubated with HDAC inhibitors for 16 h. Histones were extracted from
the cells after the culture period as described by M. Yoshida efc al.
(J. Biol. Chem. 265(28): 17174-17179 (1990)). 20 g of total histone
protein was loaded onto SDS/PAGE and transferred to nitrocellulose
membranes. Membranes were probed with polyclonal antibodies specific
for acetylated histone H-4 (Upstate Biotech Inc.), followed by horse
radish peroxidase conjugated secondary antibodies (Sigma). Enhanced
Chemiluminescence (ECL) (Amersham) detection was performed using Kodak
films (Eastman Kodak). Acetylated H-4 signal was quantified by
densitometry. Representative data are presented in the fifth column
of Table 5. Data are presented as the concentration effective for
reducing the acetylated H-4 signal by 50% (EC50) .
Cpd a a a Structure lumanMDAC-1 R ICM(nM) *TT(HCT116) r ICso(uM) 14Ac(T24) EC5«(uM)
Me(A^ a* a a a° 22 4 na
0 0 af^V^^NH 3 8 3
59 Dcrsxu^" OMe a a a 0 12 22 na
0 9,b Maonrr»J *6r" 7 12 na
'65 . a a_ a [ | a aH a1. • 4 37 na
" ormJOr^ 10 44 na
0 O af^V^^NH 16 21 na
0 na >39 na
0 10 5 5
0 4 7 5
Assay Example 2
Antineoplastic Effects of Histone Deacetylase
Inhibitors on Human Tumor Xenografts In Vivo
[0413] Eight to ten week old female BALB/c nude mice (Taconic Labs,
Great Barrington, NY) were injected subcutaneously in the flank area
with 2 x 106 preconditioned HCT116 human colorectal carcinoma cells.
Preconditioning of these cells was done by a minimum of three
consecutive tumor transplantations in the same strain of nude mice.
Subsequently, tumor fragments of approximately 30 mgs were excised and
implanted subcutaneously in mice, in the left flank area, under Forene
anesthesia (Abbott Labs, Geneve, Switzerland). When the tumors
reached a mean volume of 100 mm3, the mice were treated intravenously,
subcutaneously, or intraperitoneally by daily injection, with a
solution of the histone deacetylase inhibitor in an appropriate
vehicle, such as PBS, DMSO/water, or Tween 80/water, at a starting
dose of 10 mg/kg. The optimal dose of the HDAC inhibitor was
established by dose response experiments according to standard
protocols. Tumor volume was calculated every second day post infusion
according to standard methods (e.g., Meyer et al., Int. J. Cancer 43:
851-856 (1989)). Treatment with the HDAC inhibitors according to the
invention caused a significant reduction in tumor weight and volume
•31 Q

relative to controls treated with vehicle only (i.e., no HDAC
1
ibitor)'. In addition, the level of histone acetylation when
measured was significantly elevated relative to controls. Data for
selected compounds are presented in Table 6. FIG. 1 shows the full
experimental results for compound 106, which inhibits tumor growth by
80%. Figs. 2-10 show the results of additional compounds tested.
Table 6
Assay Example 3
Combined Antineoplastic Effect of Histone Deacetylase Inhibitors and
Histone Deacetylase Antisense Oligonucleotides on Tumor Cells In Vivo
[0414] The purpose of this example is to illustrate the ability of
the combined use of a histone deacetylase inhibitor of the invention
and a histone deacetylase antisense oligonucleotide to enhance
inhibition of tumor growth in a mammal. Preferably, the antisense
oligonucleotide and the HDAC inhibitor inhibit the expression and
activity of the same histone deacetylase.

[0415] As described in Example 126, mice bearing implanted HCT116
ors (mean volume 100 mm3) are treated daily with saline
preparations containing from about 0.1 mg to about 30 mg per kg body
weight of histone deacetylase antisense oligonucleotide. A second
group of mice is treated daily with pharmaceutically acceptable
preparations containing from about 0.01 mg to about 5 mg per kg body
weight of HDAC inhibitor.
[0416] Some mice receive both the antisense oligonucleotide and the
HDAC inhibitor. Of these mice, one group may receive the antisense
oligonucleotide and the HDAC inhibitor simultaneously intravenously
via the tail vein. Another group may receive the antisense
oligonucleotide via the tail vein, and the HDAC inhibitor
subcutaneously. Yet another group may receive both the antisense
oligonucleotide and the HDAC inhibitor subcutaneously. Control groups
of mice are similarly established which receive no treatment (e.g.,
saline only), a mismatch antisense oligonucleotide only, a control
compound that does not inhibit histone deacetylase activity, and a
mismatch antisense oligonucleotide with a control compound.
[0417] Tumor volume is measured with calipers. Treatment with the
antisense oligonucleotide plus the histone deacetylase protein
inhibitor according to the invention causes a significant reduction in
tumor weight and volume relative to controls.
WE CLAIM:
1. a A histone deacetylase inhibitor of formula (1):

or pharmaceutically acceptable salt.
2. a A composition comprising a compound as claimed in claim 1. and a
pharmaceutically acceptable carrier.
3. a An in vitro method of inhibiting histone deacetylase in a cell, the method
comprising contacting a cell with a compound as claimed in claim 1.
4. a An in vitro method of inhibiting histone deacetylase in a cell, the method
comprising contacting a cell with a composition as claimed in claim 2.


This invention relates to compounds for the inhibition of histone deacetylase. More
particularly, the invention provides for a compound for the inhibition of histone
deacetylase of the formula

and pharmaceutically acceptable salts thereof. The invention further provides
methods for inhibiting histone deacetylase enzymatic activity with the compound.

Documents:

01604-kolnp-2005-abstract.pdf

01604-kolnp-2005-claims.pdf

01604-kolnp-2005-description complete.pdf

01604-kolnp-2005-drawings.pdf

01604-kolnp-2005-form 1.pdf

01604-kolnp-2005-form 3.pdf

01604-kolnp-2005-form 5.pdf

01604-kolnp-2005-international publication.pdf

1604-kolnp-2005-abstract.pdf

1604-KOLNP-2005-ASSIGNMENT 1.1.pdf

1604-kolnp-2005-assignment.pdf

1604-KOLNP-2005-CERTIFIED COPIES(OTHER COUNTRIES).pdf

1604-kolnp-2005-claims.pdf

1604-KOLNP-2005-CORRESPONDENCE 1.1.pdf

1604-kolnp-2005-correspondence.pdf

1604-kolnp-2005-description (complete).pdf

1604-kolnp-2005-drawings.pdf

1604-kolnp-2005-examination report.pdf

1604-kolnp-2005-form 1.pdf

1604-KOLNP-2005-FORM 16-1.1.pdf

1604-KOLNP-2005-FORM 16.pdf

1604-kolnp-2005-form 18.pdf

1604-KOLNP-2005-FORM 27.pdf

1604-kolnp-2005-form 3.pdf

1604-kolnp-2005-form 5.pdf

1604-KOLNP-2005-FORM-27.pdf

1604-kolnp-2005-gpa.pdf

1604-KOLNP-2005-OTHERS 1.1.pdf

1604-KOLNP-2005-PA.pdf

1604-kolnp-2005-reply to examination report.pdf

1604-kolnp-2005-specification.pdf


Patent Number 244607
Indian Patent Application Number 1604/KOLNP/2005
PG Journal Number 51/2010
Publication Date 17-Dec-2010
Grant Date 13-Dec-2010
Date of Filing 10-Aug-2005
Name of Patentee METHYLGENE, INC.
Applicant Address 7220 FREDERICK-BANTING, ST. LAURENT, QUEBEC H4S 2A1
Inventors:
# Inventor's Name Inventor's Address
1 DELORME, DANIEL 793 CHARBONNEAU, ST-LAZARE, QUEBEC J7T 2B2
2 ZHOU, ZHIHONG 104 KIRKLAND BOULEVARD, KIRKLAND, QUEBEC J7T 2B2
PCT International Classification Number C07D 401/04
PCT International Application Number PCT/CA2004/000139
PCT International Filing date 2004-02-04
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10/358,556 2003-02-04 U.S.A.