TITLE
PREPARATION OF 7-ALKENYL-3 QUINOLINECARBONITRILES VIA A
PALLADIUM MEDIATED COUPLING REACTION
[0001] This application claims the benefit of U.S. Provisional Patent Application
No. 60/771,903, filed February 8,2006, the disclosure of which is incorporated
by reference herein.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] This invention relates to a new synthetic approach for the preparation of
7-alkenyl-3-quinolinecarbonitriles and 2-alkenyl-5-thienopyridinecarbonitriles
using a palladium mediated coupling reaction.
Related Background Art
[0003] The compounds synthesized by the method of the present invention are
known to be inhibitors of protein kinases required for cell growth and
differentiation. These compounds are useful for the treatment of certain diseases
in mammals, for example cancers, osteoporosis and polycystic kidney disease.
U.S. Patent Nos. 6,521,618 and 6,689,772 disclose 3-cyanoquinoline compounds
which exhibit such activity.

[0004] International Publication No. WO 2004/048286 discloses
thieno[3,2-b]pyridine carbonitrile compounds which also possess protein kinase
inhibitory activity useful in the treatment of cancers in mammals.
[00051 The prior references only disclose non-stereoselective methods of
synthesizing these types of compounds. The present invention, however,
involves synthesizing these compounds using a stereoselective palladium
mediated coupling, which provides the desired E-isomer in excellent yields, and
is therefore superior to prior disclosed methodology.
BRIEF DESCRIPTION OF THE INVENTION
[0006] A process for preparing compounds of formula (I):

wherein R1 is independently selected from H, alkyl of 1 to 6 carbon atoms, C1-C12
alkoxy, F, Cl and CF3, R2 is selected from the group H, alkyl of 1 to 6 carbon
atoms, OH, Cl, F, acetyl, -OSO2-C6-C12 aryl, -OSO2-C1-C12 alkyl and -NRI9R20,
where R19 and R20 can independently be H and alkyl of 1 to 6 carbon atoms, or R19
and R20 taken together form a 3 to 8 membered heterocycle containing 1-3
heteroatoms selected from O, S, and N, and where R19 and R20 can be substituted
with groups selected from C1-C6 alkylamino, C2-C12 dialkylamino, and a 3-8
membered heterocycle containing 1-3 heteroatoms selected from O, S, and N, A is
aryl of 6 to 12 carbon atoms optionally substituted with: 1 to 4 substttuents which
are independently selected from H, J, NO2, NH2, OH, SH, CN, COOH, CONH2,
NHC(O)NH2, C(O)H, CF3, OCF3, Rs, OR5, NHR5, Q, S(O)mR5, NHSO2R5, ReOH,
R6OR5, R6NH2, R6NHRS, R6Q, R6SH, R6S(O)mR5, NHR7OH, NHR7OR5,
N(R5)R7OH, N(R5)R7OR5,NHR7NH2, NHR7NHRS, NHR7Q, N(R5)R7NH2,
N(RS)R7NHR5, N(RS)R7Q, OR7OH, OR7ORS, OR7NH2, OR7NHRS, OR7Q,
OC(O)R5, NHC(O)R5, NHC(O)NHRS, OR6C(O)R5, NHR6C(O)R5, C(O)R5,

C(O)OR5, C(O)NHR5, C(O)Q, R6C(O)H, R6C(O)RS, R6C(O)OH, R6C(O)OR5,
RSC(O)NH2, R5C(O)NHR5, R6C(O)Q, R6OC(O)R5, R6OC(O)NH2, R6OC(O)NHR5,
R6OC(O)Q and YR8, wherein Y is independently selected from C(O), C(O)O,
OC(O), C(O)NH, NHC(O), NHSO2, SO2NH, C(OH)H, O(C(R9)2)q,
S(O)m(C(R9)2)q, NH(C(R9)2)q, NR10(C(R9)2)q, (C(R9)2)q, (C(R9)2)qO,
(C(R9)2)qS(O)m, (C(R9)2)qNH, (C(R9)2)qNR10, C=C, cis and trans CH=CH and
cycloalkyl of 3 to 10 carbon atoms, or A is a heteroaryl ring having 5 or 6 atoms
containing 1 to 4 heteroatoms, which may be the same or different, selected from
N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4
substituents which may be the same or different selected from H, J, NO2, NH2, OH,
SH, CN, COOH, CONH2, NHC(O)NH2, C(O)H, CF3, OCF3, Rs, OR5, NHR5, Q,
S(O)mR5, NHSO2R5, R5OH, R5OR5, RfiNH2, R6NHR5, R6Q, R6SH, R6S(O)mR5,
NHR7OH, NHR7OR5, N(R5)R7OH, N(R5)R7OR5, NHR7NH2, NHR7NHR5,
NHR7Q, N(R5)R7NH2, N(R5)R7NHRS, N(R5)R7Q, OR7OH, R7OR5, OR7NH2i
OR7NHR5, OR7Q, OC(O)R5, NHC(O)R5, NHC(O)NHR5, R6C(O)R5,
NHR6C(O)R5, C(O)R5, C(O)OR5, C(O)NHR5, C(O)Q, R6C(O)H, R6C(O)R5,
R6C(O)OH, R6C(O)OR5, R6C(O)NH2, R6C(O)NHR5, R6C(O)Q, R6OC(O)R5,
R6OC(O)NH2, R6OC(O)NHR5, RSOC(O)Q and YR8, wherein Y is independently
selected from C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHSO2, SO2NH,
C(OH)H, O(C(R9)2)q, S(O)m(C(R9)2q, NH(C(R9)2)q, NRI0(C(R9)2)q, (C(R9)2)qO,
(C(R9)2)qS(O)m, (C(R9)2)qNH, (C(R9)2)qNR10, C=C, cis and trans CH=CH and
cycloalkyl of 3 to 10 carbon atoms, or A is a bicyclic heteroaryl ring system having
8 to 20 atoms containing 1 to 4 heteroatoms which may be the same or different
selected from N, O and S wherein the bicyclic heteroaryl ring system may be
optionally substituted with 1 to 4 substituents which may be the same or different
selected from H, J, NO2, NH2) OH, SH, CN, COOH, CONH2, NHC(O)NH2,
C(O)H, CF3, OCF3, R5, OR5, NHR5, Q, S(O)mR5, NHSO2R5, R6OH, R6OR5,
R6NH2, R6NHR5, R6Q, R6SH, R6S(O)mR5, NHR7OH, NHR7OR5, N(RS)R7OH,
N(R5)R7OR5, NHR7NH2, NHR7NHR5, NHR7Q, N(R5)R7NH2, N(RS)R7NHRS,
N(R5)R7Q, OR7OH, OR7OR53 OR7NH2> OR7NHR5, OR7Q, OC(O)RS, NHC(O)R5,
NHC(O)NHRS, OR6C(O)R5, NHR6C(O)R5, C(O)RS, C(O)OR5, C(O)NHRS,
C(O)Q, R6C(O)H, R6C(O)RS, R6C(O)OH, R6C(O)ORS, R6C(O)NH2,

R6C(O)NHR5, R6C(O)Q, R6OC(O)R5, R6OC(O)NH2, R6OC(O)NHRS, R6OC(O)Q
and YR8, wherein Y is independently selected from C(O), C(O)O, OC(O),
C(O)NH, NHC(O), NHSO2, SO2NH, C(OH)H, O(C(R9)2)q, S(O)m(C(R9)2)q,
NH(C(R9)2)q, NR10C(R9)2), (C(R9)2)q, (C(R9)2)qO, (C(R9)2S(O)m, (C(R9)2)qNH,
(C(R9)2)qNR10, C=C, cis and trans CH=CH and cydoalkyl of 3 to 10 carbon
atoms, or A and -YR8 may be taken together to form a tricyclic ring system, J is
selected from F and Cl, m is 0, 1 or 2, q is 0, 1,2,3,4 or 5, s is 0, 1, 2 or 3, t is 1,
2,3,4, 5, 6, 7, 8,9, 10, 11, or 12, Rs is a monovalent group wherein each R5 is
independently selected from alkyl of 1-6 carbons, alkenyl of 2-6 carbon atoms, or
alkynyl of 2-6 carbon atoms, or when two Rs are present on a nitrogen atom they
may together form a hetrocyclic ring, R6 is a divalent group selected from alkyl of
1-6 carbons, alkenyl of 2-6 carbon atoms, or alkynyl of 2-6 carbon atoms, R7 is a
divalent alkyl group of 2-6 carbon atoms, R8 is a cycloalkyl ring of 3-7 carbons
that may be optionally substituted with one or more alkyl groups of 1 to 6 carbons,
or R8 is a phenyl or heteroaryl ring, that can be fused to an additional phenyl or
heteroaryl ring, wherein heteroaryl is as previously defined, and may be optionally
substituted with 1 to 4 substituents selected from the group consisting of-Ph, -
CH2Ph, -NHPh, OPh, -S(O)mPh, J, -NO2, -NH2, -OH, -SH, -CN, -COOH, -CONH2,
-NHC(O)N H2, -C(O)H, -CF3, - OCF3, -R5, -OR5, -NHR5, -NR5R5, -S(O)mR5, -
NHSO2R5, -R11, -OR1!, -NHR11, -R6OH, -R6ORS, -R^Hz, -R6NHR5, -R6NR5R5, -
R6SH, -R6S(O)mR5, -NHR7OH, -NHR7OR5, -N(R5)R7OH, -N(R5)R7OR5, -
NHR7NH2, -NHR7NHR5, -NHR7NRSRS, -N(R5)R7NH2, -N(R5)R7NHRS, -
N(R5)R7NHRSRS1 -OR7OH, -OR7OR5, -OR7NH2, -OR7NHRS, -OR7NRSR5, -
OC(O)R5, -NHC(O)R5, -NHC(O)NHRS, -OR6C(O)RS, -NHR6C(O)RS, -C(O)R5, -
C(O)OR5, -C(O)NHRS, C(O)NR5RS, -R6C(O)H, -RSC(O)R5, -R6C(O)OH, -
R6C(O)OR5, -R6C(O)NH2, -R6C(O)NHR5, -R6C(O)NR5R5, -R6OC(O)R5, -
R6OC(O)NH2, -R6OC(O)NHR5 and -R6OC(O)NR5R5, R9 is independently H, F or
R5, R10 is an alkyl of 1-6 carbon atoms, R15 is independently selected from a group
consisting of H, -R5, -Rn, -(CR92)qPh, -(CR92)q.C2-C9 heteroaryl, -(CR92)q-C2-C9
heterocycle, -(CR92)qOH, -(CR92)qOR10, (CR92)qNH2, -(CR92)qNHR10, -(CR92)qR10,
-(CR92)qS(O)mR10, -(CR92)qCO2R10, -(CR92)qCONHR10, -(CR92)qCONR10R10, -
(CR92)qCOR10, -(CR92)qCO2H, and -(CR92)qCONH2, and Q is NR5RS and further


in the presence of Pd(O) metal with a compound of formula QH):

provided that when each R5 is independently selected from C1-C12 alkyl and C2-C6
alkenyl, each R5 may optionally be taken together with the nitrogen atom to which
they are attached to form a heterocyclic ring of 3 to 8 atoms, optionally containing
1 or 2 additional heteroatoms which may be the same or different selected from N,
O and S, comprising the step of reacting a reagent of formula (II):
wherein X is selected from O-triflate, Br, I and Cl, M is Sn or B, Z is a bond, or an
oxygen atom, with the proviso that Z can only be a bond when M is Sn and Z can
only be an oxygen atom when M is B, u is 1,2 or 3, and R3 is independently
selected from H and alkyl of 1 to 12 carbon atoms, or two R3 groups taken together
with Z and M can form a 3 to 8 membered ring, wherein the atoms of the ring can
be selected from carbon, nitrogen, oxygen and sulfur, any of the substituents
recited herein may be further substituted by groups selected from C1-C12 alkyl, F,
Cl, C1-C'12 fluoroalkyl, C1-C12chloroalkyl, nitro, amino, hydroxyl, cyano, C1-C8
alkylamino, C2-C16dialkylamino, C1-C12alkoxy, C1-C12fluoroalkoxy, C1-C12
chloroalkoxy, -S-C1-C12alkyl, -SH, -S- C1-C12fluoroalkyl, -S- C1-C12-alkyl, chloro
C6-C12 aryl, C6-C12 aryloxy, -S- C6-C12 aryl, C2-C9 heteroaryl, C2-C9 heteroaryloxy,
-S-C2-C9 heteroaryl and C1-C8 acyl, or salts thereof.
[0007] The present invention is also directed to a method of preparing
compounds of formula (IV):



in the presence of a source of Pd(0) metal with a compound of formula (V):

wherein A is selected from phenyl and C2-C9 heteroaryl, any of which may be
substituted by substituents selected from H, F, Cl, alkoxy of 1 to 4 carbon atoms,
alkyl of 1 to 4 carbon atoms, hydroxyl, fluoroalkyl of 1 to 4 carbon atoms,
chloroalkyl of 1 to 4 carbon atoms, C6-C12aryloxy, C2-C9 heteroaryloxy, -S-
alkenyl of 1 to 4 carbon atoms, -S-C6-C12aryl, and -S- C2-C9 heteroaryl, RA, RB and
Rc are independently selected from H, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to
4 carbon atoms, F, Cl and CF3, t is 1,2, 3,4, 5, 6, 7, 8, 9 or 10, and R2 is selected
from OH, C1-C4 alkyl -C(O)O-, alkylamino of 1 to 4 carbon atoms, dialkylamino
of 2 to 8 carbons, C6-C12aryl, cycloalkyl of 3 to 8 carbon atoms, C2-C9
heterocycloalkyl and (alkyl)3 Si-O- containing 3 to 12 carbon atoms, comprising
the step of reacting a reagent of formula (H):
wherein, X is selected from O-triflate, Br, I and Cl, M is Sn or B, Z is a bond or an
oxygen atom, with the proviso that Z is a bond when M is Sn and Z is oxygen
when M is B, u is 1,2 or 3, and R3 is independently selected from H and alkyl of 1
to 12 carbon atoms, or two R3 groups taken together with Z and M can form a 3 to

8 membered ring, wherein the atoms of the ring are selected from carbon, nitrogen,
oxygen and sulfur, or salts thereof.
[0008] Another aspect of this invention is a method of preparing compounds of
formula (VI):


in the presence of a source of Pd(0) metal with a compound of formula (VII):

wherein A is selected from phenyl and C2-C9 heteroaryl, any of which may be
substituted by substituents selected from H, F, Cl, alkoxy of 1 to 4 carbon atoms,
alkyl of 1 to 4 carbon atoms, hydroxyl, fluoroalkyl of 1 to 4 carbon atoms,
chloroalkyl of 1 to 4 carbon atoms, C6-C12 aryloxy, C2-C9 heteroaryloxy, -S-alkenyl
of 1 to 4 carbon atoms, -S- C6-C12 aryl, and -S-C2-C9 heteroaryl, RB is selected
from H, F, Cl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms,
fluoroalkyl of 1 to 4 carbon atoms, chloroalkyl of 1 to 4 carbon atoms, OH, SH and
-S-alkyl of 1 to 4 carbon atoms, t is 1 or 2, R2 is selected from OH, C1-C4
alkyl-C(O)O-, alkylamino of 1 to 4 carbon atoms, dialkylamino of 2 to 8 carbons,
C6-C12aryl, cycloalkyl of 3 to 8 carbon atoms, C1-C9heterocycloalkyl and (alkyl)3
Si-O- containing 3 to 12 carbon atoms, comprising the step of reacting a reagent of
formula (II):

wherein X is selected from O-triflate, Br, I or Cl, M is Sn or B, Z is a bond or an
oxygen atom, with the proviso that Z is a bond when M is Sn and Z is oxygen
when M is B, u is 1, 2 or 3, and R3 is independently selected from H and alkyl of 1
to 12 carbon atoms, or two R3 groups taken together with Z and M can form a 3 to
8 membered heterocyclic ring, or salts thereof.
DETAILED DESCRIPTION
[00091 The present invention is directed to methods of synthesizing compounds
of formulas (I), (TV) and (VI) by reacting a compound of (III), (V) and (VII),
respectively, with a vinyl boronic ester, or acid, or a vinyl stannane, of formula
(II), in the presence of a catalytic amount of palladium metal.
(0010] One of the important features of this invention is that the coupling of a
vinyl boronic ester or a vinyl stannane with a compound of formula (III), (V) or
(VII) occurs stereoselectively, wherein the E-isomer is the predominate product.
[0011] For purposes of this invention the term "alkyl" includes either straight or
branched alkyl moieties. The length of a straight alkyl moiety can be from 1 to
12 carbon atoms, but is preferably 1 to 8 carbon atoms, and more preferably 1 to
4 carbon atoms. Branched alky] moieties can contain 3 to 12 carbon atoms.
These alkyl moieties may be unsubstituted or substituted. The term "alkenyl"
refers to a substituted or unsubstituted radical aliphatic hydrocarbon containing
one double bond and includes alkenyl moieties of both straight, preferably of 2 to
6 carbon atoms and branched, preferably of 2 to 6 carbon atoms. Such alkenyl
moieties may exist in the E or Z configurations; the compounds of this invention
include both configurations. The term "alkynyl" includes substituted and
unsubstituted alkynyl moieties of both straight chain containing 2 to 6 carbon
atoms and branched containing 2 to 6 carbon atoms having at least one triple
bond. The term "cycloalkyl" refers to substituted or unsubstituted alicyclic
hydrocarbon groups having 3 to 12 carbon atoms and includes but is not limited
to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, or
adamantyl. Most preferably the cycloalkyl group contains 3 to 6 carbon atoms.
[0012] For purposes of this invention the term "aryl" is defined as an aromatic
hydrocarbon moiety and may be substituted or unsubstituted. An aryl may be

selected from but not limited to, the group consisting of: phenyl, a-naphthyl, p-
naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, fluorenyl, indanyl,
biphenylenyl, acenaphthenyl, acenaphthylenyl, or phenanthrenyl groups.
Preferably an aryl group contains 6 to 12 carbon atoms.
[0013] For purposes of this invention the term "heteroaryl" is defined as an
aromatic heterocyclic ring system (monocyclic or bicyclic) and may be
substituted or unsubstituted where the heteroaryl moieties are five or six
membered rings containing 1 to 4 heteroatoms selected from the group consisting
of S, N, and O, and include but are not limited to: (1) furan, thiophene, indole,
azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-
methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole,
pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, l-methyl-1,2,4-
triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole,
benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole,
azabenzimidazole, indazole, quinazoline, quinoline, pyrrolidinyl; (2) a bicyclic
aromatic heterocycle where a phenyl, pyridine, pyrimidine or pyridizine ring is:
(i) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one
nitrogen atom; (ii) fused to a 5 or 6-membered aromatic (unsaturated)
heterocyclic ring having two nitrogen atoms; (iii) fused to a 5-membered
aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with
either one oxygen or one sulfur atom; or (iv) fused to a 5-membered aromatic
(unsaturated) heterocyclic ring having one heteroatom selected from O, N or S.
Preferably a heteroaryl moiety contains 2 to 9 carbon atoms, and more preferably
contains a total of 5 or 6 atoms.
[0014] For purposes of this invention the term "heterocycloalkyl" refers to a
substituted or unsubstituted alicyclic ring system (moncyclic or bicyclic) wherein
the heterocycloalkyl moieties are 3 to 12 membered rings containing 1 to 6
heteroatoms selected from the group consisting of S, N, and O- Examples
include, but are not limited to, 1,3-dioxolane, pyrroline,, pyrrolidine, imidazoline,
imidazolidine, pyrazoline, pyrazolidine, piperidine, l,4-dioxane, morpholine,
thiomorpholine, and piperazine. Typically, such moieties contain 1 to 9 carbon
atoms.

[0015] For the purposes of this invention the term "heterocycle" is defined as
being either a heteroaryl or heterocycloalkyl, as defined herein.
[0016] For the purposes of this invention the term "alkoxy" is defined as
alkyl-O-; the term "aryloxy" is defined as aryl-O-; the term "heteroaryloxy" is
defined as heteroaryl-O-; wherein alkyl, aryl, and heteroaryl are as defined above.
[0017] The terms "alkylamino" and "dialkylamino" refer to moieties with one or
two alkyl groups, respectively, wherein the alkyl chain is 1 to 8 carbons, more
preferably 1 to 4 carbon atoms, and the groups may be the same or different. The
terms alkylaminoalkyl and dialkylaminoalkyl refer, respectively, to alkylamino
and dialkylamino moieties with one or two alkyl groups (the same or different)
bonded to the nitrogen atom, which is attached to an alkyl group of 1 to 8 carbon
atoms.
[00181 "Acyl" is a radical of the formula -(C=O)-alkyl, -(C=O)-aryl, or-(C=O)-
perfluoroalkyl wherein the alkyl radical or perfluoroalkyl radical is 1 to 8 carbon
atoms and the aryl radical is as defined herein; preferred examples include but are
not limited to, acetyl, propionyl, butyryl, trifluoroacetyl.
[0019] The terms "fluoroalkyl" and "chloroalkyl" refer to an alkyl radical that is
further substituted by at least one fluorine or chlorine atom, respectively, and
may be fully substituted, for example, -CF3. The terms "fluoroalkoxy" and
"chloroalkoxy" refer to an alkoxy radical that is further substituted by at least one
fluorine or chlorine atom, respectively, and may be fully substituted, for example,
-OCF3.
[0020) The term "substituent" is used herein to refer to an atom radical, a
functional group radical or a moiety radical that replaces a hydrogen radical on a
molecule. Unless expressly stated otherwise, it should be assumed that any of the
substiruents may be optionally substituted with one or more groups selected from:
alkyl, F, Cl, fluoroalkyl, chloroalkyl, nitro, amino, hydroxyl, cyano, alkylamino,
dialkylamino, alkoxy, fluoroalkoxy, chloroalkoxy, -S-alkyl, -SH, -S-fluoroalkyl, -
S-chloroalkyl, aryl, aryloxy, -S-aryl, heteroaryl, heteroaryloxy, -S-heteroaryl or
acyl.
[0021] For the purposes of this invention the term "substituted" refers to where a
hydrogen radical on a molecule has been replaced by another atom radical, a

functional group radical or a moiety radical; these radicals being generally
referred to as "substituents."
[0022] Compounds made by the method of the present invention may contain an
asymmetric carbon atom and some of the compounds of this invention may
contain one or more asymmetric centers and may thus give rise to stereoisomers,
such as enantiomers and diastereomers. While shown without respect to
stereochemistry in Formulas (I), (IV) and (VI), the present invention includes the
synthesis of all the individual possible stereoisomers; as well as the racemic
mixtures and other mixtures of R and S stereoisomers (scalernic mixtures which
are mixtures of unequal amounts of enantiomers) and salts thereof. It should be
noted that stereoisomers of the invention having the same relative configuration
at a chital center may nevertheless have different R and S designations depending
on the substitution at the indicated chiral center.
[0023] For compounds made by the method of the present invention containing
two chiral centers, four possible stereoisomers are possible; these four
stereoisomers are classified as two racemic pairs of diastereomers. These
compounds may be present as racemic diastereomers which would be designated
following the convention described in the 1997 Chemical Abstracts Index Guide,
Appendix IV (Columbus, OH) whereas the first cited chital atom is designated
R* and the next cited chiral atom is designated R* if it possesses the same
chirality as the first cited stereocenter or S* if it possesses opposite chirality to
the first cited stereocenter. Alternatively, these compounds of the invention may
be present as non-racemic mixtures of two diastereomers owing to the existence
of a predefined stereocenter. In these instances, the predefined stereocenter is
assigned based on the Cahn-Ingold-Prelog System and the undefined stereocenter
is designated R* to denote a mixture of both R and S stereoisomers at this center.
[0024] Compounds made by the method of the present invention are alkenes and
therefore can be designated using the (E) - (Z) system. One skilled in the art will
be familiar with this system of nomenclature. Where alkene compounds are
disclosed without stereospecifity it is intended that both of the diasteredmers are
encompassed by the disclosure.

[0025] Compounds made by the method of the present invention may be formed
as salts from addition of oTganic and inorganic acids. For example salts can be
formed from the addition of acids, including but not limited to, acetic, propionic,
lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic,
phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,
methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,
camphorsulfonic, and similarly known acceptable acids.
GENERAL SYNTHETIC PATHWAYS:



[0026] Scheme I illustrates the general synthetic pathway to compounds of
formula (I) from starting 3-quinolinecarbonitriles of formula (III). The starting 3-
quinolinecarbonitrile is coupled with a vinyl boronic ester or stannane of formula
(II) in the presences of palladium metal in catalytic amounts, for example,
Pd(PPh3)4. Where A, R1-R3, X, s, t, u, m and Z are defined herein.
[0027] Palladium-mediated couplings of aryl halides with alk-1-enyl boranes are
known by those skilled in the art. Such couplings were disclosed in Suzuki et al.,
J.C.S. Chem. Comm., 1979, No. 19, pp. 866-867, which is hereby incorporated
by reference.
[0028] These coupling reactions are usually heated above room temperature,
typically in the range of about 60°C to about 120°C, but preferably about 80°C to
about 120°C. Preferably the temperature is raised to at least about 90°C, and
more preferably to at least about 105°C. However the reaction can also be
performed at temperatures as high as about 120°C.
[0029] Vinyl boronic esters or acids can be formed by hydroboration of the
corresponding alkyne using 4,4,5,5-tetramethyl-[l,3,2]dioxaborolane and a
catalytic amount of bis(cyclopentadienyl)zirconium chloride hydrate. This

method of preparation was disclosed in Pereira and Siebnik, Organicmetallics
1995, 14, pp. 3127-3128, which is hereby incorporated by reference.
(0030) Vinyl stannanes can be prepared from the corresponding alkyne by
reacting the alkyne with (alkyl)3 Sn, for example, tributylstannane, and a catalytic
amount of AIBN. This method of preparing vinyl stannanes was disclosed in
Jung et al., Tetrahedron Letters, Vol. 23 (38), pp. 3851-3854,1982, which is
hereby incorporated by reference.
[0031] This reaction can be carried out in a variety of solvents. One skilled in
the art would be familiar with suitable solvents or mixtures of solvents
appropriate for this reaction. Preferred solvents include N-methyl-2-pyrrolidone
(NMP), toluene, benzene, toluene/ethanol/water (10:1:1), DMF, THF and
DMF/THF (50:50).
[0032] In one embodiment of the present invention A is phenyl or substituted
phenyl in the compounds of formulas (I) and (III).
[0033J In another embodiment of the present invention R1 is selected from H, F,
Cl and CH3O in the compounds of formulas (I) and (HI).
[0034] In yet another embodiment of the present invention R2 is selected from
morpholinyl, OH, CH3C(O)O-, pyrrolidinyl, piperidinyl, n-methyl piperazinyl, n-
ethylpiperazinyl, 4-(N-pyrrolidinyl)piperidinyl, 2-tetrahydropyranoxy,
(CH3)3CSi(CH3)2O- and -NR19R20. A more preferred embodiment is where R2 is
-NR19R20.
[0035] Another embodiment of the present invention is where M is Sn and Z is a
bond, or alternatively, where M is B and Z is O.
[0036] Scheme H shows the more specific synthetic method of synthesizing
compounds of formula (IV) by reacting the starting 3-quinoIinecarbomtrile of
formula (V) with a vinyl boronic ester in the presence of a catalytic amount of
palladium metal. The preferred solvent for this reaction is the mixture of toluene,
ethanol and water (10:1:1). More specific reaction conditions are described under
Method I in the General Methods section of this application.
[0037] Scheme HI shows the more specific synthetic method to compounds of
formula (TV) by reacting the starting 3-quinolinecarbonitrile of formula (V) with
a vinyl stannane in the presence of a catalytic amount of palladium metal. The

most preferred solvent for this reaction is NMP. More specific reaction
conditions are described under Method II in the General Methods section herein.
[0038] In one embodiment of the present invention A is phenyl, which may be
substituted, in compounds of formulas (TV) and (V). It is also preferable that A
be substituted by H, Cl, OCH3 or -S-heteroaryl.
10039] In another embodiment of the present invention RA and Rc are H in
compounds of formulas (IV) and (V).
[0040] Another embodiment of the present invention is where R2 is
dialkylamino in compounds of formula (IV).
[0041] In yet another embodiment of the present invention M is Sn and Z is a
bond, or alternatively, M is B and Z is oxygen.
[0042] Scheme IV shows the general method of the present invention for
synthesizing 2-alkenyl-5-thienopyridinecarbonirriles of formula (VI) by coupling
the starting 5-thienopyridinecarbonitrile of formula (VII) with a vinyl boronic
ester, or acid, in the presence of a catalytic amount of palladium metal. The most
preferred solvent fox this reaction is the mixture of toluene, ethanol and water
(10:1:1). This method is analogous to the one disclosed under Scheme II and
therefore more specific conditions can be found under Method I of the General
Methods section herein.
[0043] Scheme V shows the general method for synthesizing compounds of
formula (VI) by reacting the starting 5-thienopyrioline carbonitrile of formula
(VII) with a vinyl stannane in the presence of a catalytic amount of palladium
metal. A preferred solvent for this reaction is NMP. The method is analogous to
the method shown in Scheme HI and therefore the same; conditions described
under Method II in the General Method section herein are applicable.
[0044] In one embodiment of the present invention A is phenyl, which may be
substituted, in compounds of formulas (VI) and (VII). It is also preferable that A
be substituted by H, Cl, OCH3 or -S-heteroaryl.
[0045] In another embodiment of the present invention RB is H in compounds of
formulas (VI) and (VII).
[0046] Another embodiment of the present invention is where R2 is
dialkylamino in compounds of formula (VI).

[0047] In yet another embodiment of the present invention M is Sn and Z is a
bond, or alternatively, M is B and Z is oxygen.
[0048] Similarly, the couplings illustrated in Schemes II-V are usually
performed at a temperature above room temperature, typically in the range of
about 60°C to about 120°C, but preferably about 80°C to about 120°C. Preferably
the temperature is raised to at least about 90°C and more preferably to at least
about 105°C. However the reactions can also be performed at temperatures as
high as about 120°C.
GENERAL METHODS:
Method I
4-[C2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1E)-4-(4-
methylpiperazin-1 -yl)but-l -enyl]quinoline-3 -carbonitrile
[0049] To a mixture of l-but-3-ynyl-4-methyl-piperazine (1.85 g, 14.4 mmol)
(the preparation of which was described in International Publication No.
WO 2002/002558) and 4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (1.46 g, 9.6
mmol) was added bis(cyclopentadienyl)ziTconium chloride hydride (124 mg, 0.48
mmol). The resulting mixture was stirred at room temperature for 24 hours and
was diluted with toluene/ethanol/water (80 mL/8 mL/8 mL). 3-Cyano-4-(2,4-
dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl trifiuoromethanesulfonate
(2.50 g, 4.70 mmol) and Pd(PPh3)4 (285 mg, 0.238 mmol) were added. The
reaction mixture was heated at 90°C for 4 hours and partitioned between saturated
aqueous NaHCO3 and CH2C12. The combined organics were dried over Na2SO4,
concentrated and purified by silica gel flash column chromatography (10:1
CH2Cl2-MeOH) to give 1.92 g of off-white solid, mp 142-143°C, MS (ESI) m/z
526.1.
Method II
4-({3-Chloro-4-[(l-methyl-lH-imidazol-2-yl)thio]pheinyl}amino)-7-[(lE)-5-
(diethylamino)pent-l -enyl]quinoIine-3-carbonitrile
[0050] A mixture of 7-bromo-4-{3-chloro-4-[(l-methyl-lH-imidazol-2-
yl)sulfanyl]anilino}-3-quinolinecarbonitrile (377 mg, 0.80 mmol), (0.50 g, 1.12

mmol), diethyl[E-5-(tributylstannyl)-4-pen.ten-l-yl]amine (0.48 g, 1.12 mmol)
(the preparation of was which disclosed in International Publication No.
WO 2004/033419) and NMP (4.0 mL) was treated under nitrogen with Pd(PPh3)4
(92 mg, 0.08 mmol) and stirred at 105°C for 3 h. The cooled mixture was
partitioned with CH2Cl2 and aqueous NaHCO3. The organic layer was washed
with H2O, dried and concentrated. The residue was triturated with 1:1 hexane-
Et2O to remove NMP and then chromatographed on silica gel with 10:1 CH2Cl2-
MeOH to give an off-white solid, mp 220-225°C (dec). MS (ES+) m/z 533.1
(M+H)+1.
Method III
(2E)-3-[4-({3-chloro-4-[(1-mettiyl-1H-imidazol-2-yl)thio]phenyl}aniino)-3-
cyanoquinolin-7-yl]prop-2-enyl acetate
[0051] A solution of 4-({3-chloro-4-[(1 -methyl-1H-imidazol-2-
yl)thio]phenyl}amino)-7-[(1E)-3-hydroxyprop-1-enyl]quinoline-3-carbonitrile
(1.87 g, 3.2.mmol) (Example 4), 24 ml of Ac2O, and 24 ml of HOAc was stirred
at 50°C for 19 h, concentrated in the presence of toluene, and stirred in aqueous
NaHCO3. The resulting solid was dissolved in 60:30:1 -EtOAc-HOAc and
filtered through a pad of silica gel. The residue obtained on evaporation was
stirred in McOH-H2O containing NaHCO3, filtered, washed with H2O, and dried
to give a light yellow solid, mp 181-193°C (dec); m/z 492.1"(M+H)+1.
Method TV
4-({3-chloro-4-[(1-raethyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-3-
(diethylamino)prop-1-enyl]quinoline-3-carbonitrile
[0052] A mixture of (2E)-3-[4-({3-chloro-4-[(1-methyl-1H-imidazol-2-
yl)thio]phenyl}amino)-3-cyanoquinolin-7-yl]prop-2-enyl acetate (196 mg, 0.40
mmol), diethylamine (165 µl, 1.6 mmol), and 0.80 ml of NMP under nitrogen
was treated with Pd(PPh3)4 (46 mg, 0.04 mmol) and stirred at 25oC for 1 h. The
mixture was stirred with aqueous NaHCO3 and 4:1 hexane-EtOAc and filtered.
The solid product was dissolved in 10:1 CH2Cl2-MeOH and passed through a
short column of silica gel. The washings which contained product were

evaporated to give 93 mg of off-white solid, mp 223-228°C; MS (ES+) m/z 505.0
(M+H)+1.
Method V
4-[(2,4-dichloro-5-methoxyphenyl)ainino]-7-[(lE)-4-(4-ethylpiperazin-1-yl)but-
l-enyl]-6-methoxyquinoline-3-carbonitrile
[0053] To a mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[(lE)-4-
hydroxybut-l-enyl]-6-methoxyquinoline-3-carbonitrile (150 mg, 0.351 minol)
and Et3N (178 mg, 1.76 mmol) in DMF/THF (2 mL/2 mL) was added
methanesulfonyl chloride (121 mg, 1.05 mmol) in THF (1 mL). The resulting
mixture was stirred at room temperature overnight and was then treated with N-
ethylpiperazine (200 mg, 1.76 mmol) at 75°C for 48 h. The cooled reaction
mixture was partitioned between water and CH2Cl2. The combined organics
were dried, concentrated and purified by silica gel flash column chromatograph
to give 95 mg of off-white solid, mp 129-131°C; MS (ESI) m/z 540.1.
Method VI
N-[E-4-(tributylstannyl)-3-buten-1 -yl]pyrrolidine
[0054] To a stirred solution of E-4-(tributylstannyl)-3-buten-l-yl tosylate (1.55
g, 3.0 mmol) (the preparation of which was disclosed in Heterocycles (1997), 46,
523 and is hereby incorporated by reference) in 3.0 ml of THF at 25°C was added
pyrrolidine (1.0 ml, 12 mmol). After 18 h the volatile materials were evaporated
under vacuum, and the residue was partitioned with aqueous NaHCO3 and 1:1
hexane-Et2O. The organic layer was washed with H2O, dried and evaporated to
give an oil; 1HNMR (CDCl3) δ 5.95 (m, 2H, vinyl), 2.53 (m, 8H), 2.37 (m, 4H),
1.78 (m, 6H), 1.49 (m, 6H), 1.30 (m, 6H), 0.89 (t, J=7.3 Hz, 9H).

EXAMPLES:
Example 1
4-[(2,4-dichlorophenyl)amino]-7-[(l E)-5-rnoipholin-4 -ylpent-1 -enyl]quinoline-3-
carbonitrile
[0055] The title compound is prepared using a procedure analogous to Method II
from 7-bromo-4-(2,4-dichloro-phenylamino)-quinoline-3-carbonitrile and 4-[(E)-
5-(tributyJstannyl)-4-pentenyl]morpholine, mp 142-144 °C; MS (ESI) m/z 467.1.
Example 2
4-[(2,4-dichlorophenyl)amino]-7-[(lE)-6-morpholin-4-ylhex-l-enyl]quinoline-3-
carbonitrile
[0056] The title compound is prepared using a procedure analogous to Method II
from 7-bromo-4-(2,4-dichloro-phenylamino)-quinoline-3-carbonitrile and 4-
[(5E)-6-(tributylstannyl)hex-5-enyl]morpholine, mp 139-140 °C; MS (ESI) m/z
481.2.
Example 3
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[(lE)-5-morpholin-4-
ylpent-l-enyl]quinoline-3-carbonitrile
[0057] The title compound is prepared using a procedure analogous to Method II
from 3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl
trifluoromethanesulfonate and 4-[(E)-5-(tributylstannyl)-4-pentenyl]morpholine,
mp 110-112 °C; MS (ESI) m/z 527.2.
Example 4
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-3-
hydroxyprop-1-enyl]quinoline-3-carbonitrile
[0058] The title compound is prepared using a procedure analogous to Method II
from 7-bromo-4-{3-chloro-4-[(1-methyl-lH-imidazol-2-yl)sulfanyl]anilino}-3-
quinolinecarbonitrile and 3-(E)-tributylstannanyl-prop-2-en-1-ol, mp 220-240 °C;
MS (ESI) m/z 448.

Example 5
4-( {3-chloro-4-[(1-methyl-1H-iraidazol-2-yl)thio]phenyl}airiino)-7-[(1E)-4-
hydroxybut-1-enyl]quinoline-3-carbonitrile
[00591 The title compound is prepared using a procedure analogous to Method II
firom 7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-
quinolinecarbonitrile and 4-(E)-tributylstannanyl-but-3-en-1-ol, mp 205-210 °C;
MS (ESI) m/z 462.2.
Example 6
(2E)-3-[4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}araino)-3-
cyanoquinolin-7-yl]prop-2-enyl acetate
[0060] The title compound is prepared as described in Method III from 4-({3-
chloro-4-[( 1 -methyl-1 H-irnidazol-2-yl)thio]phenyl} arnino)-7-[(1E)-3-
hydroxyprop-1-enyl]quinoline-3-carbonitrile, 181-193 °C; MS (ESI) m/z 490.1.
Example 7
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-3-
morpholm-4-ylprop-1-enyl]quinoline-3-carbonitrile
[0061] The title compound is prepared using a procedure analogous to Method
IV from (2E)-3-[4-({3-chloro-4-[(1-methyl-1H-imidazol-2-
yl)thio]phenyl}amino)-3-cyanoquinolm-7-yl]prop-2-enyl acetate and morphoine,
mp 235-240 °C; MS (ESI) m/z 517.1.
Example 8
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl} amino)-7-[(1E)-4-
(diethylamino)but-1-enyl]quinoline-3 -carbonitrile
[0062] The title compound is prepared using a procedure analogous to Method II
from 7-bromo-4-{3-chloro-4-[(1-methyI-1H-imidazol-2-yl)sulfanyl]anilino}-3-
quinolinecarbonitrile and N,N-diethyl-N-[(3E)-4-(tributylstannyl)but-3-
enyl]amine, mp 200-210 °C; MS (ESI) m/z 517.1.
Example 9
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-4-
(dimethylamino)but-1 -enyl]quinoline-3-carbonitrile
[0063] The title compound is prepared using a procedure analogous to Method
VI from toluene-4-sulfonic acid 4-{4-[3-chloro-4-(l-methyl-lH-imidazol-2-

ylsulfenyl)-phenylamino]-3-cyano-quinolin-7-yl}-but-3-enyl ester and
dimethylamine, mp 191-198 °C; MS (ESI) m/z 489.
Toluene-4-sulfonicacid4-{4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfenyl)-
phenylamino]-3-cyano-quinolin-7-yl}-but-3-eny] ester was prepared using a
procedure analogous to Method II from 7-bromo-4-{3-chloro-4-[(1-methyl-1H-
imidazol-2-yl)sulfanyl]anilmo}-3-quinolinecarbonitrile and E-4-
(Trfbutylstannyl)-3-buten-l-yl tosylate.
E-4-(Tributylstannyl)-3-buten-1-yl tosylate:
[0064] To a stirred solution E-(4-hydroxybuten-1-yl)tributylstannane (5.42 g, 15
mtnol, the preparation of which was disclosed in J. Qrg. Chem. 1998, 63, pp.
7811) in 30 ml of 2,6-lutidine was added tosyl chloride (8.58 g, 45 mmol) at
25°C. After 20 h the mixture was treated with 30 ml of H2O and 5 ml of pyridine
with cooling. After 15 minutes at 25°C the mixture was partitioned with DCM
and aqueous NaHCO3. The organic layer was washed with H2O, dried and
concentrated to give an oil; 1H NMR (DMSO-d6) 8 7.76 (d, J=8.0 Hz, 2H)5 7.48
(d, J=8.0 Hz, 2H).
Example 10
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-4-
morpholin-4-ylbut-1-enyl]quinoline-3-carbonitrile
[0065] The title compound was prepared using a procedure analogous to Method
nfrom7-bromo-4-{3-chloro-4-[(l-methyl-lH-imidazol-2-yl)sulfanyl]anilino}-3-
quinolinecarbonitrile and 4-[(E)-5-(tributylstannyl)-4-pentenyl]morpholine,
mp 232-238 °C; MS (ESI) m/z 531.
Example 11
4-({3-chloro-4-[(l-me1hyl-lH-imidazol-2-yl)thio]phenyl}amino)-7-[(lE)-3-
(diethylamino)prop-l-enyl]quinolihe-3-carbonitrile
[0066] The title compound is prepared using a procedure analogous to Method
IV from (2E)-3-[4-({3-chloro-4-[(l-methyl-1H-imidazol-2-
yl)thio]phenyl}amino)-3-cyanoquinolin-7-yl]prop-2-enyl acetate and
diethylamine, mp 223-228 °C; MS (ESI) m/z 503.

Example 12
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-4-
pyrrolidin-1-ylbut-l-enyl]quinoline-3-carbonitri]e
[0067] The title compound is prepared using a procedure analogous to Method
VI from toIuene-4-sulfonic acid 4-{4-[3-chloro-4-(1-methyl-1H-imidazol-2-
ylsulfanyl)-phenylamino3-3-cyano-quinolin-7-yl}-but-3-enyl ester and
pyrrolidine, mp 185-191 °C; MS (ESI) m/z 515.1.
Example 13
4-({3-chloro-4-[(1-methyl-1H-imidazoI-2-yl)thio]phenyl}amino)-7-[(1E)-3-
dimethylamino)prop-1-enyl]quinoline-3-carbonitrile
[0068] The title compound is prepared using a procedure analogous to Method
IV from (2E)-3-[4-({3-chloro-4-[(1-methyl-1H-imidazol-2-
yl)thio]phenyl} amino)-3-cyanoquinolin-7-yl]prop-2-enyl acetate and
dimethylamine, mp 157-165 °C; MS (ESI) m/z 475.
Example 14
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(lE)-4-
piperidin-1 -ylbut-1-enyl]quinoline-3-carbonitrile
[0069] The title compound is prepared using a procedure analogous to Method
VI from toluene-4-sulfonic acid 4-{4-[3-chloro-4-(1-methyl-1H-imidazol-2-
ylsulfanyl)-phenylamino]-3-cyano-quinolin-7-yl}-but-3-enyl ester and piperidine,
mp 205-210 °C; MS (ESI) m/z 529.
Example 15
4-({3-chloro-4-[(l-methyl-lH-imidazol-2-yl)thio]phenyl}amino)-7-[(lE)-3-
pyrrolidin-l-ylprop-l-enyl]quinoline-3-carbonitrile
[0070] The title compound is prepared using a procedure analogous to Method
IV from (2E)-3-[4-({3-chloro-4-[(l-methyl-lH-imidazol-2-
yl)thio]phenyl}amino)-3-cyanoquinolin-7-yl]prop-2-enyl acetate and pyrrolidine,
mp 182-190 °C; MS (ESI) m/z 501.1.
Example 16
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-4-
hydroxybut-l-enyl]-6-methoxyquinoline-3-carbonitrile

[0071] The title compound is prepared using a procedure analogous to Method II
from4-({3-chloro-4-[(1-methyl-1H-irnidazol-2-yl)thio]phenyl}amino)-3-cyano-
6-methoxyquinolin-7-yl trifluoromethanesulfbnate and 4-(E)-tributylstannanyI-
but-3-en-1-ol, mp 273-278 °C; MS (ESI) m/z 492.
Example 17
4-( {3-chloro-4-[( 1 -methyl-1 H-imidazol-2-yl)thio]phenyl} amino)-7-[(1E)-5-
pynrolidin- 1-ylpent-1-enyl]quinoline-3-carbonitrile
{0072] The title compound is prepared using a procedure analogous to Method
VI from toluene-4-sulfonic acid 4-{4-[3-chloro-4-(1-methyl-1H-imidazol-2-
ylsulfanyl)-phenyIarnino]-3-cyano-quinolin-7-yl}-pent-3-enyl ester and
pyrrolidine, mp 217-222 °C; MS (ESI) m/z 529.2.
Toluene-4-sulfonic acid 4-{4-[3-chloro-4-(l-methyl-lH-imidazol-2-ylsulfanyl)-
phenylamino]-3-cyano-quinolin-7-yl}-pent-3-enyl ester was prepared using a
procedure analogous to Method II from 7-bromo-4-{3-chloro-4-[(1-methyl-1H-
imidazol-2-yl)sulfanyl]anilino} -3-quinolinecarbonitrile and E-4-(triutylstannyl)-
3-pent-l-yl tosylate.
Example 18
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-4-
(diethylamino)but-1-enyl3-6-methoxyquinoline-3-carbonitrile
[0073] The title compound is prepared using a procedure analogous to Method
VI from toluene-4-sulfonic acid 4-{4-[3-chloro-4-(1-methyl-1H-imidazol-2-
ylsulfanyl)-phenylamino]-6-methoxy-3-cyano-quinolin-7-yl}-but-3-enyl ester
and diethylamine, mp 194-202 °C; MS (ESI) m/z 547.2.
Example 19
4-({3-chloro-4-((1-methyl-1H-imidazol-2-yl)thio]phenyl}amimo)-6-methoxy-7-
[(lE)-4-pyrrolidin-l-ylbut-l-enyl]quinoIine-3-caTbonitrile
[0074] The title compound is prepared using a procedure analogous to Method II
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-3-cyano-6-
methoxyquinolin-7-yl trifluoromethanesulfonate and l-methyl-4-(4-
tributylstannanyl-but-3-enyl)-piperazinemp 230-234 °C; MS (ESI) m/z 545.1.

Example 20
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-4-(4-
methylpiperazin-1-yl)but-l-eny]]quinoline-3-carbonitrile
[0075] The title compound was prepared using a procedure analogous to Method
H from 7-bromo-4-{3-chloro-4-[(1 -methyl-1H-imidazol-2-yl)sulfenyl]anilino}-3-
quinolinecarbonitrile and 1 -methyl-4-(E)-(4-tributylstannanyl-but-3-enyl)-
piperazine, mp 225-235 °C; MS (ESI) m/z 544.2.
Example 21
4-({3-chloro-4-[(1-niethyl-1H-imidazol-2-yl)thio]phenyl}amino)-6-methoxy-7-
[(1E)-4-(4-methylpiperazin-1-yl)but-1-enyl]quinoline-3-carbonitrile
[0076] The title compound is prepared using a procedure analogous to Method II
from 4-( {3-chloro-4-[( 1-m ethyl-1 H-imtdazol-2-yl)thio]phenyl} amino)-3 -cyano-
6-methoxyquinolin-7-yl trifluoromethanesulfonate and l-methyl-4-(E)-(4-
tributylstannanyl-but-3-enyl)-pipera2ine, mp 223-203 °C; MS (ESI) m/z 574.2.
Example 22
4-({3-chloro-4-[(l-methyl-l H-imidazol-2-yl)thio]phenyl}amino)-7-[(lE)-4-
(dimethylamino)but-l-enyl]-6-methoxyquinoline-3-carbonitrile
[0077] The title compound is prepared using a procedure analogous to Method II
from 4-( {3-chloro-4-[( 1 -methyl-lH-imidazol-2-yl)thio]phenyl) amino)-3-cyano-
6-methoxyquinolin-7-yl trifluoromethanesulfonate and dimethyl-4-(E)-
(triburylstannanyl-but-3-enyl)-amine, mp 215-225 °C.
Example 23
4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[(lE)-4-morpholin-4-ylbut-l-
enyl]quinoline-3-carbonitrile
[0078] The title compound is prepared using a procedure analogous to Method II
from 7-bromo-4-(2,4-dichloro-5-methoxyanilino)-3-quinolinecarbonitrile and 4-
[(E)-5-(tributylstannyl)-4-butenyl]morpholine, mp 88-89 °C; MS (ESI) m/z 483.1.

Example 24
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1E)-4-morpholin-4-
ylbut-1-enyl]quinoline-3-carbonitrile
[0079] The title compound is prepared using a procedure analogous to Method II
from 3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl
trifluoromethanesulfonate and 4-[(E)-5-(tributylstannyl)-4-butenyllmorpholine,
mp 141-143 °C; MS (ESI) m/z 513.1.
Example 25
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-5-
(diethylamino)pent-1-enyl]quinoline-3-carbonitrile
[0080] The title compound was prepared using a procedure analogous to Method
II from 7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfenyl]anilino}-3-
quinolinecarbonitrile and diethyl-(E)-(5-tributylstannanyl-pent-4-enyl)-arnine,
mp 220-225 °C; MS (ESI) m/z 531.1.
Example 26
4-({3-chloro-4-[(1-methyl- 1H-imidazol-2-yl)thio]phenyl} amino)-7-[(1E)-5-
(diethylamino)pent-1 -enyl]-6-methoxyquinoline-3-carbonitrile
[0081] The title compound is prepared using a procedure analogous to Method II
from 4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-3-cyano-
6-methoxyquinoIin-7-yI trifluoromethanesulfonate and diethyl-(E)-(5-
tributylstannanyl-pent-4-enyl)-amine, mp 229-233 °C; MS (ESI) m/z 561.1.
Example 27
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-5-(4-
metnylpiperazin-l-yl)pent-l-enyl]quinoline-3-carbonitrile
[0082] The title compound was prepared using a procedure analogous to Method
Ilfrom 7-bromo-4-{3-chIoro-4-[(1-metfiyl-1H-irnidazol-2-yl)sulfanyl]anilino}-3-
quinolinecarbonitrile and 1-methyl-4-(E)-(5-triburylstannanyl-pent-4-enyl)-
piperazine, mp 219-227 °C; MS (ESI) m/z 558.1.

Example 28
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-6-methoxy-7-
[(1E)-5-(4-methylpiperazin-1-yl)pent-1-enyl]quinoline-3-carbonitrile
[0083] The title compound is prepared using a procedure analogous to Method II
from 4-{{3-chloro-4-[(1 -methyl-1H-imidazol-2-yl)thio]phenyl}ammo)-3-cyano-
6-methoxyquinolin-7-yl trifluoromethanesulfonate and 1-methyl-4-(E)-(5-
tributylstannanyl-pent-4-enyl)-piperazine, mp 215-221 °C; MS (ESI) m/z 588.1.
Example 29
4-[(2,4-dichloro-5-methoxyphenyI)amino]-6-methoxy-7-[(1E)-4-(4-
methylpiperazin-1 -yl)but-l -enyl]quinolme-3-carbonitrile
[0084] The title compound was prepared as described in Method I from 3-cyano-
4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl
trifluoromethanesulfonate, 1-but-3-ynyl-4-methyl-piperazine and 4,4,5,5-
tetramethyl-[l,3,2]dioxaborolane or using a procedure analogous to Method II
from 3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl
trifluoromethanesulfonate and 1 -methyl-4-(E)-(4-tributylstannanyl-but-3-enyl)-
piperazine, mp 142-143 °C; MS (ESI) m/z 526.1.
Example 30
4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[(1E)-4-hydroxybut-1-enyl]-6-
methoxyquinoline-3-carbonitrile
[0085] The title compound was prepared using a procedure analogous to Method
I from 3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl
trifluoromethanesulfonate, tert-butyl-but-3-ynyloxy-dimethyl-silane and 4,4,5,5-
tetramethyl-[1,3,2]dioxaborolane followed by acidic hydrolysis, mp 186-188 °C;
MS (ESI) m/z 444.1.
Example 31
7-[(1E)-4-morpholin-4-ylbut-1-enyl]-4-[(3,4,5-
trimethoxyphenyl)amino]quinolme-3-carbonitrile
[0086] The title compound was prepared using a procedure analogous to Method
II from 7-bromo-4-(3,4,5-trimemoxyanilino)-3-quinolinecarbonitrile and 4-[(E)-
5-(tributylstannyl)-4-pentenyl]morpholine, mp 128-130 °C; MS (ESI) m/z 475.2.

Example 32
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1E)-3-tnoipholm-4-
ylprop-1 -enyl]quinoline-3-carbonitrile
[0087] The title compound was prepared as described in Method II from 3-
cyano-4-(2,4-dichloro-5-methoxyanilmo)-6-meihoxy-7-quinolinyl
trifluoromethanesulfonate and 4-[(E)-5-(tributylstannyl)-4-propenyl]morpholinc,
mp 105-106 °C; MS (ESI) m/z 499.1.
Example 33
6-methoxy-7-[(1E)-4-(4-methylpiperazin-1 -yl)but-1 -en-1 -yl]-4-[(3,4,5-
trimethoxyphenyl)amino]quinoline-3-carbonitriIe
[0088] The title compound was prepared as described in Method I from 3-cyano-
6-methoxy-4-[(3,4,5-trimethoxyphenyl)amino]quinolin-7-yl
trifluoromethanesulfonate, 1-but-3-ynyl-4-rnethyl-piperazine and 4,4,5,5-
tetraraethyl-[1,3,2]dioxaborolane, mp 122-124 °C; MS (ESI) m/z 518.2.
Example 34
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1E)-4-piperidin-1-
ylbut-1-enyl]quinoline-3-carbonitrile
[0089] The title compound is prepared using a procedure analogous to Method V
from 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[(1E)-4-hydroxybut-1-enyl]-6-
methoxyquinoline-3-carbonitrile and piperidine, mp 140-142 °C; MS (ESI) m/z
511.1.
Example 35
4-[(2,4-dichlorophenyl)amino]-7-[(1E)-4-morphoIin-4-ylbut-l-enyl]quinoline-3-
carbonitrile
[0090] The title compound is prepared using a procedure analogous to Method II
from 7-bromo-4-(2,4-dichloro-phenylamino)-quinoline-3-carbonitrile and 4-
[(5E)-6-(tributylstannyl)but-5-enyl]morpholine, mp 129-131 °C; MS (ESI) m/z
453.1
Example 36
4-[(2,4-dichlorophenyl)amino]-7-[(1E)-3-morpholin-4-ylprop-l-enyl]quinoline-
3-caibonitrile

|0091] The title compound is prepared using a procedure analogous to Method II
from 7-bromo-4-(2,4-dichoro-phenylaiuino)-qiunoline-3-carbonitrile and 4-
[(5E)-6-(tributy]stamiyl)prop-5-enyl3iiioipholine, mp 175-176 °C; MS (BSI) m/z
439.1.
Example 37
4-({3chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}ammo)-7-[(IE)-3-(4-
methyIpiperazin-1-yl)prop-1-enyl]quinoline-3-carbonitrile
(0092) The title compound is prepared using a procedure analogous to Method
IV from (2E)-3-[4-({3-chloro-4-[(1-methyl-1H-imidazol-2-
yl)thio]phenyl}amino)-3-cyanoquinolin-7-yl]prop-2-enyl acetate and N-
methylpiperazine, MS (ESI) m/z 530.
Example 38
4-[(2,4-dichlofo-5-methoxyphenyl)amino)-6-methoxy-7-[(1E)-6-morpholin-4-
ylhex-1 -enyl]quinoline-3-carbonitrile
[0093J The title compound is prepared using a procedure analogous to Method II
from 7-bromo-4-(2,4-dichloro-phenylamino)-qumoline-3-carbonitrile and 4-
[(5E)-6-(tributylstannyl)hex-5-enyl]morpholme, mp 99-100 °C; MS (ESI) m/z
541.1.
Example 39
4-[(2,4-dicchorophenyl)amino]-7-[(1E)-11-morpholin-4-ylundec-I-
enyl]quinoline-3-carbonitrile
[0094J The title compound is prepared using a procedures analogous to Method II
from 7-bromo-4-(2,4-dichloro-phenylamino)-quinoline-3-carbonitriie and 4-
[(5E)-6-(tributylstannyl)undec-5-enyl]morpholine,mp 105-106 °C; MS (ESI) m/z
551.2.
Example 40
44(2,4-dichloro-5-methoxyphenyl)amino3-6-methoxy-7-[(1E)-11-morpholin-4-
ylundec-l-enyl]quinoline-3-carbonitrile
[00951 The title compound is prepared using a procedure analogous to Method II
fiom 3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl

trifluoromethanesulfonate and 4-[(5E)-6-(tributylstannyl)undec-5-
enyl]morpholine, mp 98-99 °C; MS (ESI) m/z 611.3;
Example 41
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(]E)-3-
piperidin-l-ylprop-l-enyl]quinoline-3-carbonitrile
[0096J The title compound is prepared using a procedure analogous to Method
IV from (2E)-3-[4-({3-chloro-4-[(1-methyl-1H-imidazol-2-
yl)thio]phenyl}amino)-3-cyanoquinolm-7-yl]prop-2-enyl acetate and piperidine,
MS (ESI) m/z 515.1.
Example 42
4-({3-chloro-4-[(1-mettiyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-3-(4-
pyrrolidin-1 -ylpiperidin-1 -yl)prop-1 -enyl]quinoline-3 -carbonitrile
[0097] 'The title compound is prepared using a procedure analogous to Method
IV from (2E)-3-[4-({3-chloro-4-[(l-methyI-lH-imidazol-2-
yl)thio]phenyl}amino)-3-cyanoquinolm-7-y]]prop-2-enyl acetate and 4-
pyrrolidin-1-yl-piperidine, MS (ESI) m/z 584.1.
Example 43
4-({3-chloro-4-[(1-memyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-3-(4-
ethyl piperazin-1 -yl)prop-1 -enyl]quinoline-3 -carbonitrile
[0098] The title compound is prepared using a procedure analogous to Method
IV from (2E)-3-[4-({3-chloro-4-[(1-methyl-1H-imidazol-2-
yl)thio]phenyl}amino)-3-cyanoquinolin-7-yl]prop-2-enyl acetate and N-
ethylpiperazine, mp 232-236 °C; MS (ESI) m/z 544.1.
Example 44
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-4-(4-
ethylpiperazin-1 -yl)but-l -enyl]quinoline-3-carbonitrile
[0099] The title compound was prepared using a procedure analogous to Method
I from 7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-3-
quinolinecarbonitrile, l-but-3-ynyl-4-methyl-piperazine and 4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane, mp 194-204 °C; MS (ESI) m/z 558.1.

Example 45
4-( {3-chloro-4-[(l -methyl-1 H-imidazol-2-yl)thio]phenyl} amino)-7-[(l E)-4-
(tetrahydro-2H-pyran-2-yloxy)but-l-enyl]quinoline-3-carbonitrile
[00100] The title compound was prepared using a procedure analogous to
Method I from 7-bromo-4- {3-chloro-4-[(1-methyl-1 H-imidazol-2-
yl)sulfanyl]anilino}-3-quinolinecarbonitrileand2-{[(3E)-4-(4,4>5,5-tetramethyl-
l,3,2-dioxaborolan-2-yl)but-3-enyl]oxy}tetrahydro-2H-pyran, mp 217-220 °C;
MS (ESI) m/z 546.1.
Example 46
7-((lE)-4-{[tert-butyl(dimethyl)silyl]oxy}but-l-eny])-4-[(2,4-dichloro-5-
memoxyphenyl)amino]-6-methoxyquinoline-3-carbonitrile
[00101] The title compound was prepared using a procedure analogous to
Method I from 3-cyano-4-(2J4-dichloro-5-methoxyanilino)-6-methoxy-7-
quinolinyl trifluoromethanesulfonate, (3-butynyloxy)-(l,l-
dimethylethyl)dimethylsilane and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, mp
97-99 °C; MS (ES1+) nVz 558.1.
Example 47
4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-7-[(1E)-4-(4-
pyrrolidin-1 -ylpiperidin-1 -yl)but-1-enyl]quinoline-3- carbonitrile
[00102] The title compound was prepared using a procedure analogous to
Method I from 7-bromo-4-{3-chloro-4-[(1-methyl-1H-imidazol-2-
yl)suIfanyl]anilino}-3-quinolmecarbonitrile, l-but-3-ynyl-4-pyrrolidin-l-yl-
piperidine and 4,4J5,5-tetramethyl-[l,3,2]didxaborolane) mp 214-216 °C; MS
(ES1+) m/z 598.2.
Example 48
4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[(1E)-4-(4-methyIpiperazin-l-
yl)but-1 -enyl]quinoline-3-carbonitrile
[00103] The title compound is prepared using a procedure analogous to Method
II from 7-bromo-4-(2,4-dichloro-5-methoxyphenylamino)-quinoline-3-
carbonitrile and 1 -methyl-4-[(3E)-4-(trtbutylstannyl)but-3-enyl]piperazine, mp
152-154 °Q MS (ES1+) m/z 496.1.

Example 49
4-({3-ohloro-4-[(1-methyl-1H-imidazol-2-yr)thio]phenyl}amino)-6-fluoro-7-
[(1E)-4-(4-methylpiperazin-l-yl)but-l-enyl]quinoline--3-carbonitrile
[00104] The title compound is prepared using a procedure analogous to Method
ii from 4-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-3-
cyano~6-fluoroquinolin-7-yl trifluoromethanesulfonate and l-methyl-4-(E)-(4-
tributylstannanyl-but-3-enyl)-pipera2dne, mp 188-194 °C; MS (ES1+) m/z 562.1.
Example 50
4-[(2,4-dichloro-5-memoxyphenyl)arnmo]-7-[(1E)-4-(dimethylamino)but-1 -
enyl]-6-methoxyquinoline-3-carbonitrile
[00105] The title compound is prepared using a procedure analogous to Method
V from 4-[(2,4-dichlbro-5-methoxyphenyl)amino]-7-[(1E)-4-hydroxybut-l-enyl]-
6-methoxyquinoline-3-carbonitrile and dimethylamine, mp 119-121 °C; MS (ESI)
m/z 471.1.
Example 51
4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[(1E)-4-(4-ethylpiperazin-l-yl)but-
l-enyl]-6-methoxyquinoline-3-carbonitrile
[00106] The title compound is prepared using a procedure analogous to Method
V from 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[(1E)-4-hydroxybut-1-enyl]-
6-methoxyquinoline-3-carbonitrile and N-ethylpipeTazine, mp 129-131 °C; MS
(ESI) m/z 540.1.
Example 52
7-[(1E)-4-hydroxybut-l-en-l-yl]-6-methoxy-4-[(3,4!,5-
trimethoxyphenyl)amino]quinoline-3-carbonitrile
[00107] The title compound was prepared using a procedure analogous to
Method I from 4-[(3,4-5-trimethoxyphenyl)amino]-7-[(1E)-4-hydroxybut-l-
enyl]-6-methoxyquinoline-3-carbonitrile, tert-butyl-but-3-ynyloxy-dimethyl-
silane and 4,4,5,5-tetramethyl-[l,3,2]dioxaborolane followed by acidic
hydrolysis, mp 184-185 °C; MS (ESI) m/z 436.1.

Example 53
4-[(2,4-4iohloro-5-methoxyphenyl)amino3-6-methoxy-7-[(1E)-4-pyrrolidin-l-
ylbut-1 -en-1 -yl]quinoline-3-carbonitrile
[00108] The title compound is prepared using a procedure analogous to Method
V from 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[(1E)-4-hydioxybut-l -enyl]-
6-methoxyquinoline-3-carbonitrile and pyrcolidine, mp 158-159°C; MS (ESI) m/z
497.1.
Example 54
7-({3-chloro-4-[(l-methyl-lH-imidazol-2-yl)thio]phenyl}amino)-2-[(1E)-4-
pyrrolidin-1 -ylbut-1 -enyl]thieno[3,2-b]pyridine-6-carbonitrile
[00I09J The title compound was prepared using a procedure analogous to
Method I from 7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-
2-iodothienot3,2-b]pyridine-6-carbonitrile, l-but-3-ynyl-pyrrolidine and 4,4,5,5-
tefiramethyl-[1,3,2]dioxaborolane; MS (ESI+) m/z 521.1.
Example 55
7-{3-chloro-4-[(1-me1hyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[(1E)-4-(4-
pyrrolidin-l-ylpiperidin-l-yl)but-l-enyl]thieno[3,2-b]pyridine-6-carbonitrile
[00110] The title compound was prepared using a procedure analogous to
Method I from 7-({3-chloro-4-[(1-methyl-1H-imida2ol-2-yl)thio]phenyl}amino)-
2-iodomieno{3,2-b3pyridine-6-carbonitrile, 1 -but-3-ynyl-4-pyrrolidin-1 -yl-
piperidine and 4,4,5,5-tetramethyl-[1,3,2]dioxaborokneJ mp 213-216°C; MS
(ESI+) m/z 604.2.
Example 56
7-({3-chloro-4-f(1-methyl-1H-imidazol-2-y!)thio]phenyl}amino)-2-[(1E)-4-(4-
ethylpiperazin-1 -yl)but-1-enyl]mieno[3,2-b]pyridine-6-carbonitriIe
[00111] The title compound was prepared using a procedure analogous to
Method I from 7-({3-chloro-4-((1-methyl-1H-imidazol-2-yl)thio]phenyl>amino)-
2-iodothieno[3,2-b]pyridine-6-carbonitrile, 1 -but~3-ynyI-4-ethyl-piperazine and
4,4,5,5-tetramethyl-[1,3,2]dioxaboro]ane, mp 179-182°C (dec); MS (ESI4-) m/z
564.1.

Example 57
7-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[(1E)-4-(4-
methylpiperazin-1-yl)but-1-en-1-yl]thieno[3,2-b]pyridine-6-carbonitrile
[00112] The title compound was prepared using a procedure analogous to
Method I from 7-({3-chIoro-4-[(1-methyl-1H-imida2ol-2-yl)thio]phenyl}amino)-
2-iodothieno[3,2-b]pyridine-6-carbonitrile, 1 -but-3-ynyl-4-methyi-piperazine and
4,4J5,5-tetramethyl-[1,3,2]dioxaborolane,inp 160-163°C (dec.); MS (ES1+) m/z
550.1.
Example 58
7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-2-[(1E)-3-
(dimethylamino)prop-l -en-1 -yl]thieno[3,2-b3pyridine-6-carbonitrile
[00113] The title compound was prepared using a procedure analogous to
Method I from 7-({3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl}amino)-
2-iodothieno[3,2-b3pyridine-6-carbonitrile, but-3-ynyl-dimethyl-amine and
4,4,5,5-tetramethyl-[1,3,2]dioxaborokne, mp 208-210°C (dec); MS (ESi) m/z
481.1.
Example 59
4-[(2,4-dichloro-5-methoxyphenyl)amino]-8-[(1E)-4-morpholin-4-ylbut-l-
enyl]quinoline-3-carbonitrile
{00114] The title compound was prepared using a procedure analogous to
Method II from 8-bromo-4-(2,4-dicbloro-5-inethoxyphenylamino)-quinoline-3-
carbonitrileand4-[(E)-5-(tributylstannyl)-4-butenyl]jnorpholine, mp 176-179°C;
MS (ESI) m/z 483.1.
Example 60
4-[(254-dichlorophenyl)ammo]-6-[(1E)-4-morpholin-4-ylbut-l-enyl]qumoline-3-
carbonitrile
[0011S] The title compound was prepared using a procedure analogous to
Method H from 6-bromo-4-(2,4-dichlorophenyIamino)-quinoline-3-carbonitrile
and 4-[(E)-5-(tributylstannyl)-4-butenyl]morpholine, mp 115-116°C; MS (ESI)
m/z 453.1.

Example 61
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-[(1E)-4-inorpholin-4-ylbut-l-
enyl]quinoline-3-carbonitrile
[00116] The title compound was prepared using a procedure analogous to
Method II from 6-bromo-4-(2,4-dichIoro-5-methoxyphenyIamino)-quinoIine-3-
carbonitrile and 4-[(E)-5-(tributylstannyl)-4-butenyl]morplioline, mp 95-96°C;
MS (ESI) m/z 483.1.
Example 62
4-[(2,4-dichIorophenyI)amino3-6-[(1E)-4-(4-met3iylpiperazim-1-yl)but-1-
enyl]quinoline-3-carbonitrile
[00117] The title compound was prepared using a procedure analogous to
Method II from 6-bromo-4-(2,4-dichlorophenylamino)-quinoline-3-carbonitrile
and l-mefeyl-4-(E)-(4-tributylstarmanyl-but-3-enyl)-piperazine, mp 97-98°C; MS
(ESI) m/z 466.1.
Example 63
6-[(1E)-4-moipholin-4-ylbut-l-enyl]-4-[(3,4,5-
trimethoxyphenyl)amino]quinoline-3-carbonitrile
[00118] The title compound was prepared using a procedure analogous to
Method n from 6-bromo-4-(3,4,5-trimethoxyphenylamino)-quinoline-3-
carbonitrile and 4-[(E)-5-(tributylstannyl) 4-butenyljmorpholine, mp 86-87°C;
MS (ESI) m/z 475.2

WE CLAIM:
1. A process for preparing compounds of formula (I):

wherein:
R1 is independently selected from H, alkyl of 1 to 6 carbon atoms, C1-C12
alkoxy, F, Cl and CF3;
R2 is selected from the group H3 alkyl of 1 to 6 carbon atoms, OH, Cl, F,
acetyl, -OSO2- C6-C12 aryl, -OSO2- C1-C12 alkyl and -NRl9R20, where R19 and R20
can independently be H and alkyl of 1 to 6 carbon atoms, or R19 and R20 taken
together form a 3 to 8 membered heterocycle containing 1-3 heteroatoms selected
from O, S, or N, and where R19 and R20 can be substituted with groups selected
from C1-C6 alkylamino, C2-C12 dialkylamino, and a 3-8 membered heterocycle
containing 1-3 heteroatoms selected from O, S, or N;
A is aryl of 6 to 12 carbon atoms optionally substituted with 1 to 4
substituents which are independently selected from H, J, NO2J NH2, OH, SH, CN,,
COOH, CONH2, NHC(O)NH2, C(O)H, CF3, OCF3) R5, OR5, NHR5, Q, S(O)mR5,
NHSO2R5, R6OH, R5OR5, R6NHz, R6NHR5, R6Q, R6SH, R6S(O)mR5, NHR7OH,
NHR7ORS, N(R5)R7OH, N(R5)R7OR5, NHR7NH2, NHR7NHR5, NHR7Q,
N(R5)R7NH2, N(R5)R7NHR5, N(R5)R7Q, OR7OH, OR7OR5, OR7NH2, OR7NHR5,
OR7Q, OC(O)R5, NHC(O)R5, NHC(O)NHR5, OR6C(O)R5, NHR6C(O)R54 C(O)R5,
C(O)OR5, C(O)NHR5, C(O)Q, R6C(O)H, R6C(O)R5, R6C(O)OH, R6C(O)OR5,
R6C(O)KH2> R6C(O)NHR5, R6C(O)Q, R6OC(O)R5, R6OC(O)NH2, R6OC(O)NHR5,
R6OC(O)Q and YR8, wherein Y is independently selected from C(O), C(O)O,
OC(O), C(O)NH,NHC(O), NHSO2, SO2NH, C(OH)H, O(C(R9)2)q,
S(O)m(C(R9)2)q, NH(C(R9)2)q, NR10C(R9)2)q, (C(R9)2)q) (C)(R9)2)qO,

(C(R9)2)qS(O)m (C(R9)2)qNH, (C(R9)2)qNR10, C=C, cis and trans CH=CH and
cycioalkyl of 3 to 10 carbon atoms; or
A is a heteroaryl ring having 5 or 6 atoms containing 1 to 4 heteroatoms or
particularly 1 or 2 heteroatoms which may be the same or different, selected from
N, O and S wherein the heteroaryl ring may be optionally substituted with 1 to 4
substituents which may be the same or different selected from H, J, NO2, NH2, OH,
SH, CN, COOH, CONH2, NHC(O)NH2, C(O)H, CF3s OCF3, R5, OR5, NHRS, Q,
S(O)roR3, NHSO2R5, R6OH, R6OR5, R6NH2, R6NHR5:, R6Q, R6SH, R6S(O)mR5,
NHR7OH, NHR7OR5, N(R5)R7OH, N(R5)R7OR5, NHR7NH2, NHR7NHR5,
NHR7Q, N(R5)R7NH2, N(R5)R7NHR5, N(R5)R7Q, OR7OH, R7OR5, OR7NH2,
OR7NHR5, OR7Q, OC(O)R5, NHC(O)R5, NHC(O)NHR5, R6C(O)R5,
NHR6C(O)R5, C(O)R5, C(O)OR5, C(O)NHR5, C(O)Q, R6C(O)H, R6C(O)R5,
R6C(O)OH, R6C(O)OR5, R6C(O)NH2, R6C(O)NHR5, R6C(O)Q, R6OC(O)R5,
R6OC(O)NH2, R6OC(O)NHR5, R6OC(O)Q and YR8, wherein Y is independently
selected from C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHSO2, SO2NH,
C(OH)H, O(C(R9)2)q, S(O)m(C(R9)2)q,NH(C(R9)2)q, NR10(C(R9)2)q, (C(R9)2)qO,
(C(R9)2)qS(O)m, (C(R9)2)qNH, (C(R9)2)qNR10, C=C, cis and trans CH=CH and
cycloalkyl of 3 to 10 carbon atoms; or
A is a bicyclic heteroaryl ring system having 8 to 20 atoms containing 1 to
4 heteroatoms which may be the same or different selected from N, O and S
wherein the bicyclic heteroaryl ring system may be optionally substituted with 1 to
4 substituents which may be the same or different selected from H, J, NO2, NH2,
OH, SH, CN, COOH, CONH2, NHC(O)NH2, C(O)HB CF3, OCF3, R5, OR5, NHR5,
Q, S(O)mR5,NHSO2R5, R6OH, R6OR5, R6NH2, R6NHR5, R6Q, R6SH, R6S(O)mR5,
NHR7OH, NHR7OR5, N(R5)R7OH, N(R5)R7OR5, NHR7NH2, NHR7NHR5,
NHR7Q, N(RS)R7NH2, N(R5)R7NHR5, N(R5)R7Q, OR7OH, OR7OR5, OR7NH2,
OR7NHR5, OR7Q, OC(O)R5, NHC(O)R5, NHC(O)NHRS, OR6C(O)R5,
NHR6C(O)R5, C(O)R5, C(O)OR5, C(O)NHR5, C(O)Q, R6C(O)H, R6C(O)R5,
R6C(O)OH, R6C(O)OR5, R6C(O)NH2, R6C(O)NHR5, R6C(O)Q, R6OC(O)R5,
R6OC(O)NH2, R6OC(O)NHR5, R6OC(O)Q and YR8, wherein Y is independently
selected from C(O), C(O)O, OC(O), C(O)NH, NHC(O), NHSO2, SO2NH,
C(OH)H, O(C(R9)2)q, S(O)m(C(R9)2)q, NH(C(R9)2)q, NR10(C(R9)2)q, (C(R9)2)q,

(C(R9)2),O, (C(R9)2)qS(O)m (C(R9)2)qNH, (C(R9)2)qNR10, C=C, cis and trans
CH==CH and cycloalkyi of 3 to 10 carbon atoms; or
A and -YR8 may be taken together to form a tricyclic ring system;
J is selected from F and Cl;
m is 0,1 or 2;
q is 0, 1, 2, 3,4 or 5;
s is 0, 1,2 or 3;
t is 1,2, 3,4,5,6,7, 8,9,10,11, or 12;
R5 is a monovalent group wherein each Rs is independently selected from
alkyl of 1-6 carbons, alkenyl of 2-6 carbon atoms, or alkynyl of 2-6 carbon atoms,
or when two R5 ate present on a nitrogen atom they may together form a
hetrocyclic ring;
R6 is a divalent group selected from alkyl of 1-6 carbons, alkenyl of 2-6
carbon atoms, or alkynyl of 2-6 carbon atoms;
R7 is a divalent alkyl group of 2-6 carbon atoms;
R8 is a cycloalkyi ring of 3-7 carbons feat may be optionally substituted
with one or more alkyl groups of 1 to 6 carbons; or
R8 is a phenyl or heteroaryl ring, that can be fused to an additional phenyl
or heteroaryl ring, wherein heteroaryl is as previously defined, and may be
optionally substituted with I to 4 substituents selected from the group consisting of
-Ph, -CH2Ph, -NHGPh, OPh, -S(O)mPh, J, -NO2, -NH2, -OH, -SH, -CN, -COOH, -
CONH2, -MHC(O)NH2, -C(0)H, -CF3, - OCF3, -R5, -OR5, -NHR5, -NR5R5, -
S(O)mRs, -NHSOzRs, -R11, -OR11, -NHR11, -R6OH, -R6OR5, -R6NH2, -R6NHR5, -
R6NR5R5, -R6SH, -R6S(O)mR5, -NHR7OH5 -NHR7OR5, -N(R5)R7OH,
-N(R5)R7OR5, -NHR7NH2, -NHR7NHR5, -NHR7NR5R5, -N(R5)R7NH2,
-N(R5)R7NHR5, -N(R5)R7NHR5R5, -OR7OH, -OR7ORS, -OR7NH2, -OR7NHR5,
-OR7NR5R5, -OC(O)R5, -NHC(O)R5, -NHC(O)NHR5, -OR6C(O)R5,
-NHR6C(O)R5, -C(O)R5, -C(OpR5, -C(O)NHR5, C(O)NR5R5, -R6C(O)H,
-R6C(O)R5, -R6C(O)OH, -R6C(O)ORS, -R6C(O)NH2, -R6C(O)NHR5,
-R6C(O)NR5R5, -R6OC(O)R5, -R6OC(O)NE2, -R6OC(O)NHR5 and
-R6OC(O)NR5R5;
R9 is independently H, F or R5;

R10 is an alkyl of 1-6 carbon atoms;
R15 is independently selected from a group consisting of H, -Rs, -R11,
-(CR92)qPh, -(CR92)q - Cz-Cgheteroaryl, -(CR92)q C2-C9heterocycle, -(CR92)qOH, -
(CR92)qOR10, (CR92)qNH2, -(CR92)qNHR10, -(CR92)qR10, -(CR92)qS(O)raR10, -
(CR92)qCO2R10, -(CR92)qCONHR10, -(CR92)qCONRl0R10, -(CR92)qCOR10, -
(CR92)qCO2H, and -(CR92)qCONH2
Q is NR5R5 and further provided that when each R5 is independently
selected from C1-C12 alkyl and C2-C6 alkenyl, each R5 may optionally be token
together with the nitrogen atom to which they are attached to form a heterocyclic
ring of 3 to 8 atoms, optionally containing 1 or 2 additional heteroatoms which
may be the same or different selected from N, O and S;
comprising the step of reacting a reagent of formula (H):

in the presence of Pd(0) metal with a compound of formula (HI):

wherein:
X is selected from O-triflate,Br, I and Cl;
M is Sn or B;
Z is a bond, or an oxygen atom, with the proviso that Z can only be a bond
when M is Sn and Z can only be an oxygen atom when M is B;
u is 1, 2 or 3; and

R3 is independently selected from H, alkyl of 1 to 12 carbon atoms, or two
R3 groups taken together with Z and M can form a 3 to 8 membered ring, wherein
the atoms of the ring can be selected from carbon, nitrogen, oxygen and sulfur;
any of the substituents recited herein may be further subsitituted with
groups selected from C1C12 alkyl, F, Cl, C1-C12 fluoroalkyl, C1-C12chloroalkyl,
nitro, amino, hydroxyl, cyano, Ci-C8alkylamino, C2-Ci6dialkylamino, C1-C12
alkoxy, C1-C12 fluoroalkoxy, C1-C12chloroalkoxy, -S- C1-C12 alkyl, -SH, -S- C1-C12
fluoroalkyl, -S- C1-C12 chloroalkyl, C6-C12 aryl, C6-C12 aryloxy, -S- C6-C16aryl,
C2-C9 heteroaryl, C2-C9 heteroaryloxy, -S-C2-C9 heteroaryl and C1-C8 acyl;
or salts thereof.
2. The method of Claim 1, wherein A is phenyl or substituted phenyl.
3. The method of Claim 1, wherein R1 is selected from H, F, Cl and -OCH3.
4. The method of Claim 1, wherein R2 is selected from morpholinyl, OH,
CH3C(O)O-, pyrrolidinyl, piperidinyl, n-methyl piperazinyl, n-ethylpiperazinyl, 4-
(N-pyrrolidinyl)piperidinyI, 2-tetrahydropyranoxy, (CH3)3CSi(CH3)2O- and
-NR19R20.
5. The method of Claim 4, wherein R2 is -NR19R20.
6. The method of Claim 1, wherein M is Sn and Z is a bond.
7. The method of Claim 1, wherein M is B and Z is O.
8. The method of Claim 1, wherein the source of the Pd(0) metal is Pd(PPh3)4.

9. A method of preparing compounds of formula (TV):

wherein:
A is selected from phenyl and C2-C9 heteroaryl, any of which may be
substituted by substituents selected from H, F, Cl, alkoxy of 1 to 4 carbon atoms,
alky] of 1 to 4 carbon atoms, hydroxy], fluoroalkyl of 1 to 4 carbon atoms,
chloroalkyl of 1 to 4 carbon atoms, C6-C12aryloxy, C2-C9heteroaryloxy, -S-alkenyl
of 1 to 4 carbon atoms, -S- C6-C12 aryi, and -S- C2-C9 heteroaryl;
RA, RB and Rc are independently selected from H, alkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms, F, Cl and CF3;
t is 1, 2,3,4, 5,6, 7, 8,9 or 10;
R2 is selected from OH, C1-C4 alkyl -C(O)O-, alkylamino of 1 to 4 carbon
atoms, dialkylamino of 2 to 8 carbons, C6-C12aryl, cycloalkyl of 3 to 8 carbon
atoms, C1-C9heterocycloalkyl and (alkyl)3 Si-O- containing 3 to 12 carbon atoms;
comprising the step of reacting a reagent of formula (II):

in the presence of a source of Pd(0) metal with a compound of formula (V):


X is selected from O-triflate, Br, I and Cl;
M is Sn or B;
Z is a bond or an oxygen atom, with the proviso that Z is a bond when M is
Sn and Z is oxygen when M is B;
u is 1, 2 or 3; and
R3 is independently selected Scorn. H and alkyl of 1 to 12 carbon atoms, or
two R3 groups taken together with Z and M can form a 3 to 8 membered ring,
wherein the atoms of the ring are selected from carbon, nitrogen, oxygen and
sulfur;
or salts thereof.
10. The method of Claim 9, wherein A is phenyl, which may be substituted.
11. The method of Claim 10, wherein RA and Rc are H.
12. The method of Claim 11, wherein A is substituted by H, Cl, OCH3 or
-S-heteroaryl.
13. The method of Claim 9, wherein R2 is dialkylamino.
14. The method of Claim 9, wherein M is Sn and Z is a bond.
15. The method of Claim 9, wherein M is B and Z is oxygen.
16. The method of Claim 9, wherein the source of Pd(O) is Pd(PPh3)4.
17. A method of preparing compounds of formula (VI):


wherein:
A is selected from phenyl and C2-C9 heteroaryl, any of which may be
substituted by substituents selected from H, F, Cl, alkoxy of 1 to 4 carbon atoms,
alkyl of 1 to 4 carbon atoms, hydroxyl, fluoroalkyl of I to 4 carbon atoms,
chloroalkyl of 1 to 4 carbon atoms, C6-C12 aryloxy, C2-C9 heteroaryloxy, -S-alkenyl
of 1 to 4 caifcon atoms, -S-C6-C12 aryl, and -S-C2-C9 heteroaryl;
RB is selected from H, F, Cl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4
carbon atoms, fluoroalkyl of 1 to 4 carbon atoms, chloroalkyl of 1 to 4 carbon
atoms, OH, SH and -S-alkyl of 1 to 4 carbon atoms;
t is 1 or 2;
R2 is selected from OH, C1-C4 alkyl-C(O)O-, alkylamino of 1 to 4 carbon
atoms, dialkylamino of 2 to 8 carbons, aryl, cycloalkyl of 3 to 8 carbon atoms,
C1-C9 heterocycloalkyl and (alkyl)3 Si-O- containing 3 to 12 carbon atoms;
comprising the step of reacting a reagent of formula (II):

in the presence of a source of Pd(O) metal with a compound of formula
(VII):

wherein:
X is selected from O-triflate, Br, I and Cl;
M is Sn or B;
Z is a bond or an oxygen atom, with the proviso that Z is a bond when M is
Sn and Z is oxygen when M is B;
u is 1, 2 or 3; and

R3 is independently selected from H and alkyl of 1 to 12 carbon atoms, or
two R3 groups taken together with Z and M can form a 3 to 8 membered
heterocyclic ring; or salts thereof.
18. The method of Claim 17, wherein A is phenyl, which may be substituted.
19. The method of Claim 17, wherein RB is H.
20. The method of Claim 18, wherein A is substituted by H, Cl, OCH3 or
-S-heteroaryl.
21. The method of Claim 17, wherein M is Sn and Z is a bond.
22. The method of Claim 17, wherein M is B and Z is oxygen.
23. The method of Claim 17, wherein the source of Pd(0) is Pd(PPh3)4.
24. The method of any of Claims 1,9 or 17 further comprising using a solvent
selected from the group consisting from NMP, toluene, benzene,
toluene/ethanol/water (10:1:1), DMF, THF, and DMF/THF (1:1)
25. The method of Claim 24, wherein the solvent is toluene/ethanol/water
(10:1:1).
26. The method of Claim 24, wherein the solvent is NMP.
27. The methods of any of Claims 1, 9 or 17 further comprising the step of
heating the reaction to a temperature in the range of about 80°C to about 120°C.
28. The method of Claim 27, wherein the temperature is at least 90°C.
29. The method of Claim 27, wherein the temperature is at least 105°C.

The present invention is directed to a process for preparing
compounds of formula (I): wherein A, R -R , X, s, t, u, m and Z are defined herein, comprising the step of reacting a reagent of formula (II): in the
presence of Pd(O) metal with a compound of formula (III): or salts thereof.
Another aspect of this invention is a method of preparing compounds of
formula (VI).