BACKGROUND OF THE INVENTION
Until recently, theories regarding the pathophysiology of migraine have been
dominated since 1938 by the work of Graham and Wolff. Arch. Neurol. Psychiatry,
39:737-63, 1938- They proposed that the cause of migraine headache was vasodilatation
of extracranial vessels. This view was supported by knowledge that ergot alkaloids and
sumatriptan, a hydrophilic 5-HT, agonist which does not cross the blood-brain barrier,
induce contraction of cephalic vascular smooth muscle and are effective in the treatment
of migraine. Humphrey, et al, Arm. NY Acad. Sci., 600:587-600, 1990. Recent work by
Moskowitz has shown, however, that the occurrence of migraine headaches is
independent of changes in vessel diameter. Cephalalgia, 12:5-7, 1992.
Moskowitz has proposed that currently unknown triggers for pain stimulate
trigeminal ganglia that innervate vasculature within the cephalic tissue, giving rise to
release of vasoactive neuropeptides from axons on the vasculature. These released
neuropeptides then activate a series of events, a consequence of which is pain. This
neurogenic inflammation is blocked by sumatriptan and ergot alkaloids by mechanisms
involving 5-HT receptors, believed to be closely related to the 5-HT1D subtype, located on
the trigeminovascular fibers. Neurology, 43(suppl. 3):S16-S20 1993. Sumatriptan, in
fact, has high affinity for the 5-HT1B and 5-HT1D receptors, K1 = 10.3 nM and 5.1 nM,
respectively, which activity may be indicative of vasoconstrictive activity. Sumatriptan
and similar compounds previously advanced for the treatment of migraine had tended to
be selected on the basis of this vasoconstrictive activity under the premises of the prior art
models for migraine.

Serotonin (5-HT) exhibits diverse physiological activity mediated by at least seven
receptor classes, the most heterogeneous of which appears to be 5-HT1. A human gene
which expresses one of these 5-HT1 receptor subtypes, named 5-HT 1F, was isolated by
Kao and coworkers. Proc. Natl Acad. Sci. USA, 90:408-412, 1993. This 5-HT1F
receptor exhibits a pharmacological profile distinct from any serotonergic receptor yet
described. It was found that sumatriptan, in addition to the above mentioned strong
affinities for the 5-HT1B and 5-HT1D receptors, also has affinity for the 5-HT1F receptor
subtype, with a Ki of about 23 nM. This suggests a possible role for the 5-HT1F receptor
in migraine.
Various 5-HT1F receptor agonists have subsequently been developed which have
shown relative selectivity for the 5-HT1F receptor subclass and it has been shown that
such selectivity generally reduces the vasoconstrictive activity characteristic of other
compounds advanced as potential agents for the treatment of migraine and associated
disorders.
Included among these 5-HT1F receptor agonists are compounds disclosed in the
following:
U.S. Patents 5.708,187 and 5,814,653, describing a family of 6-substituted-3-
amino(alkyl)-tetrahydrocarbazoles and 7-substituted-4-
amino(alkyl)cyclohepta[7,6b]Indoles;
U.S. 5,521,196, U.S. 5,721,252, U.S. 5.521.197, and WO 96/29075, describing
various families of 5-substituted piperidin-3-yl-indoles and 5-substituted
1,2,3,6 tetrahydropyridin-3-yl-indoles;
WO 97/13512 describing a family of 5-substituted 3-aminoethylindoles:
WO 98/46570 describing a family of 5-substituted indoles, pyrrolo[3.2-
b]pyridines, benzofurans, and benzothiophenes, having the 3-position
substituted with octahydroindoiizinyl, octahydro-2H-quinolizinyl,
decahydropyrido[1,2-a]azepinyl, 1,2,3,5.8,8a-hexabydroindolizinyl,
1,3,4,6,9,9a-hexahydro-2H-quinolizinyl, or 1,4,6,7,8,9,10,10a-
octahydropyrido[1,2-a]azepinyl;
WO 98/20875 and WO 99/25348 describing two families of 5-substituted
piperidin-3-yl-azaindoles and 5-substituted 1,2,3,6-tetrahydropyridin-3-yl-
azaindoles:
WO 00/00487 describing a family of 5-substituted (piperidin-3-yl or 1.2.3,6-
tetrahydropyridin-3-yl)indoles, azaindoles. benzofurans, and benzothiophenes:

WO 98/08502 describing a family of 8-substituted-1,2,3,4-tetrahydro-2-
dibenzofuranamines and 9-substituted-2-aminocyclohepta[b]benzofurans;
WO 98/55115 describing a family of 3-amino-1,2,3,4-tetrahydro-9H-carbazole-6-
carboxamides and 4-amino-10H-cyclohepta[7,6-b]indole-7-carboxamides;
WO 98/15545 describing a select family of 3,5-disubstituted indoles and
benzofurans;
WO 00/00490 describing a family of 5-allyl-substituted (piperidin-3-yl or 1,2,3,6-
tetrahydropyridin-3-yl)indoles, azaindoles, benzofurans, and benzothiophenes;
WO 00/47559 describing a family of 4-(3-substituted-benzoyl)piperidines;
WO 00/50426 describing a family of 3,5-disubstituted azabenzofurans; and
WO 00/34266 describing a family of 3-heteroaryl-5-(2-(aryl or heteroaryl)-2-
oxoethyl)indoles.
Continued research has now surprisingly yielded a new and unexpected class of
novel selective 5-HT1F agonists having distinct chemical and receptor binding properties,
which inhibit peptide extravasation, while avoiding significant vasoconstrictive activity,
and are therefore useful for the treatment of migraine and other 5-HT1F receptor
associated disorders.
SUMMARY OF THE INVENTION
The present invention relates to substituted 2-carbonylamino-6-
piperidinaminopyridines and substituted l-carbonylamino-3-piperidinaminobenzenes
compounds of the general formula I:

or a pharmaceutically acceptable acid addition salt thereof, where;
X is-C(R3c)= or -N=;
R1 is C2-C6 alkyl, substituted C2-C6 alkyl, C3-C7 cycloalkyl, substituted C3-C7
cycloalkyl, phenyl, substituted phenyl, heterocycle, or substituted heterocycle;

R2 is hydrogen, C1-C3 n-alkyl, C3-C6 cycloalkyl-C1-C3 alkyl, or a group of formula
II

provided that when R1 is C2-C6 alkyl or substituted C2-C6 alkyl, R2 is hydrogen or
methyl;
R3a, R3b, and, when X is -C(R3c)=.R3c, are each independently hydrogen, fluoro,
or methyl, provided that no more than one of R3a, R3b, and R3c may be other than
hydrogen;
R4 is hydrogen or C1-C3 alkyl;
R5 is hydrogen, C1-C3 alkyl, or C3-C6 cycloalkylcarbonyl, provided that when R3a
is other than hydrogen, R3 is hydrogen;
R6 is hydrogen or C1-C6 alkyl; and
n is an integer from 1 to 6 inclusively.
The present invention also relates to pharmaceutical compositions comprising a
compound of formula 1, or a pharmaceutically acceptable acid addition salt thereof, and a
pharmaceutically acceptable carrier, diluent, or excipient. In another embodiment, the
present invention relates to pharmaceutical compositions adapted for the activation of
5-HT1F receptors, for the inhibition of neuronal protein extravasation, and/or for the
treatment or prevention of migraine in mammals, particularly humans, containing a
compound of formula i, or a pharmaceutically acceptable acid addition salt thereof, and a
pharmaceutically acceptable carrier, diluent, or excipient.
In addition, the present invention relates to a method for activating 5-HT1F
receptors in mammals, particularly humans, comprising administering to a mammal in
need of such activation an effective amount of a compound of formula 1, or a
pharmaceutically acceptable acid addition salt thereof.
Moreover, the present invention relates to a method for inhibiting neuronal protein
extravasation in mammals, particularly humans, comprising administering to a mammal
in need of such inhibition an effective amount of a compound of formula I, or a
pharmaceutically acceptable acid addition salt thereof.

Additionally, the present invention relates to a method for treating or preventing
migraine in mammals, particularly humans, comprising administering to a mammal in
need of such treatment or prevention, an effective amount of a compound of formula 1, or
a pharmaceutically acceptable acid addition salt thereof.
Another aspect of the present invention relates to the use of a compound of
formula I as a medicament, and in particular a medicament adapted for the activation of
5-HT1F receptors, for the inhibition of neuronal protein extravasation, and/or for the
treatment or prevention of migraine in mammals, particularly humans. That is to say, the
present invention relates to the use of a compound of formula 1 for the activation of
5-HT1F receptors, for the inhibition of neuronal protein extravasation, and/or for the
treatment or prevention of migraine in mammals, particularly in humans.
Additionally, the present invention relates to the use of one or more compounds of
formula 1 in the manufacture of a medicament for the activation of 5-HTIF receptors, for
the inhibition of neuronal protein extravasation, and/or for the treatment or prevention of
migraine in mammals, particularly in humans.
Furthermore, the present invention provides for methods for the treatment and/or
prevention of 5-HT1F-mediated disorders comprising administering to a mammal in need
of such treatment or prevention, particularly a human, an effective amount of a compound
of formula I, or a pharmaceutically acceptable acid addition salt thereof. In preferred
embodiments, the 5-HT1F-mediated disorder is neuronal protein extravasation and/or
migraine,
DETAILED DESCRIPTION OF THE INVENTION
The following detailed description is provided to aid those skilled in the art in
practicing the present invention. Even so, the following description should not be
construed to unduly limit the present invention in that modifications and variations in the
embodiments discussed herein can be made by those of ordinary skill in the art without
departing from the spirit or scope of the present inventive discovery. Such modifications
and variations are contemplated as being within the scope of the invention.
One embodiment of the present invention is a method for increasing activation of
5-HTIF receptors, while avoiding vasoconstrictive activity, for treating a variety of
disorders that have been linked to decreased neurotransmission of serotonin in mammals.
Included among these disorders are migraine, general pain, trigeminal neuralgia, dental
pain or temperomandibular joint dysfunction pain, anxiety, general anxiety disorder, panic

disorder, depression, disorders of sleep, chronic Fatigue syndrome, premenstrual syndrome
or late luteal phase syndrome, post-traumatic syndrome, memory loss, dementia including
dementia of aging, social phobia, autism, attention deficit hyperactivity disorder,
disruptive behavior disorders, impulse control disorders, borderline personality disorder,
obsessive compulsive disorder, premature ejaculation, erectile dysfunction, bulimia,
anorexia nervosa, alcoholism, tobacco abuse, mutism, and trichotillomania. The
compounds of this invention are also useful as a prophylactic treatment for migraine. Any
of these methods employ a compound of formula I. In preferred embodiments, the
mamma! to be treated by the administration of the compounds of formula I is human.
In those instances where the disorders which can be treated by serotonin agonists
are known by established and accepted classifications, their classifications can be found in
various sources. For example, at present, the fourth edition of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV™) (1994, American Psychiatric
Association, Washington, D.C.), provides a diagnostic tool for identifying many of the
disorders described herein. Also, the International Classification of Diseases, Tenth
Revision (ICD-10), provides classifications for many of the disorders described herein.
The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and
classification systems for disorders described herein, including those as described in the
DSM-IV and ICD-10, and that terminology and classification systems evolve with
medical scientific progress.
The use of a compound of formula I for the activation of the 5-HT1F receptor, for
the inhibition of neuronal peptide extravasation, in general or due to stimulation of the
trigeminal ganglia specifically, and/or for the treatment of any of the disorders described
above, are all embodiments of the present invention. In one preferred embodiment, the
invention provides a method for the treatment of migraine in a mammal, as for example a
human, comprising administering to a mammal in need of such treatment, a
pharmaceutically effective amount of a compound of formula I. In another preferred
embodiment, the invention provides a method for the prevention of migraine in a
mammal, as for example a human, comprising administering to a mammal in need of such
treatment, a pharmaceutically effective amount of a compound of formula I.
Likewise, the use of a compound of formula I, or a combination of more than one
compound of formula i, in the manufacture of a medicament for the activation of the
5-HT1F receptor, for the inhibition of neuronal peptide extravasation, in general or due to

stimulation of the trigeminal ganglia specifically, and/or for the treatment of any of the
disorders described above, are also all embodiments of the present invention.
The general chemical terms used throughout have their usual meanings. For
example, the term alkyl refers to a branched or unbranched saturated hydrocarbon group.
The term "n-alkyl" refers to an unbranched alkyl group. By way of illustration, but
without limitation, the term "C1-C2 alkyl" refers to methyl and ethyl. The term "C1-C3 n-
alkyl" refers to methyl, ethyl, and n-propyl The term "C1-C3 alkyl" refers to methyl,
ethyl, n-propyl, and isopropyl. The term "C1-C4 alkyl" refers to methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. The term "C1-C6 alkyl" refers to all
branched and unbranched alkyl groups having from one to six carbon atoms. The term
"C2-C6 alkyl" refers to all branched and unbranched alkyl groups having from two to six
carbon atoms. The term "C3-C6 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexyl. The term "C3-C7 cycloalkyl" also includes cycloheptyl. Cycloalkylalkyl
refers to a cycloalkyl moiety linked through an n-alkyl chain, as for example, but not
limited to, "C3-C6 cycloalkyl-C1-C3 alkyl," which refers to a C3-C6 cycloalkyl moiety
linked through a 1. to 3 carbon n-alkyl chain. Each alkyl, cycloalkyl, and cycloalkylalkyl
group may be optionally substituted as provided for herein. Among compounds wherein
R1 is cycloalkyl, compounds wherein X is -N= are preferred over compounds wherein X
is -C(R3C)=.
The terms "alkoxy", "phenyloxy", "benzyloxy" and "pyrimidinyloxy" refer to an
alkyl group, phenyl group, benzyl group, or pyrimidinyl group, respectively, each
optionally substituted as provided for herein, that is bonded through an oxygen atom.
The terms "alkylthio", "phenylthio", and "benzylthio" refer to an alkyl group,
phenyl group, or benzy) group, respectively, each optionally substituted as provided for
herein, that is bonded through a sulfur atom.
The term "C1-C1 acyl" refers to a formyl group or a C1-C3 alkyl group bonded
through a carbonyl moiety. The term "C1-C4 alkoxycarbonyl" refers to a C1-C4 alkoxy
group bonded through a carbonyl moiety. The term C3-C6 cycloalkylcarbonyl refers to a
C3-C6 cycloalkyl group bonded through a carbonyl moiety.
The term "halo" refers to fluoro, chloro, bromo, or iodo. Preferred halo groups are
fluoro, chloro, and bromo, More preferred halo groups are fluoro and chloro.
The term "heterocycle" is taken to mean a saturated or unsaturated 5- or 6-
membered ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and
sulfur, said ring optionally being benzofused. Exemplary heterocycles, for the purposes

of the present invention, include furanyl, thiophenyl, pyrrolyl, pyrrolidinyl, pyridinyl, N-
methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, thiazolyl, thiazolidinyl, N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, and the like. Exemplary benzofused heterocycles, for the purposes of the
present invention, include isoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl,
quinolinyl, benzofuranyl, benzothiophenyl, indolyi, and the like, all of which may be
optionally substituted, which also includes optionally substituted on the benzo ring when
the heterocycle is benzofused.
In one embodiment, preferred heterocycles include furanyl, thiophenyl, pyrrolyl,
pyridinyl, N-methylpyrrolyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,
benzothiophenyl, benzodioxolyl, and thiazolidinyl, all of which may be optionally
substituted.
In yet another embodiment, preferred heterocycles include pyridinyl, thiophenyl,
and furanyl, all of which may be optionally substituted.
Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio, means an alkyl,
cycloalkyl, cycloalkylalkyl, alkoxy, or alkythio group, respectively, substituted one or
more times independently with a substituent selected from the group consisting of halo,
hydroxy, and C1-C3 alkoxy. Substitutions on cycloalkylalkyl moieties may be on the ring
portion or the alkyl linker portion or both. Preferred substitutions include substitution 1 -5
times with halo, each independently selected, or substituted 1-3 times with halo and 1-2
times independently with a group selected from hydroxy and C1-C3 alkoxy, or substituted
1-3 times independently with a group selected from hydroxy and C1-C3 alkoxy, provided
that no more than one hydroxy and/or alkoxy substituent may be attached through the
same carbon.
The terms "substituted phenyl" and "substituted heterocycle" are taken to mean
that the cyclic moiety in either case is substituted with one or more halo substituents,
preferably one to five, more preferably one to three, each independently selected; or
substituted with one or more substituents, preferably one to two substituents,
independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, C1-
C4 alkylthio, cyano. and nitro, wherein each alkyl, alkoxy and alkylthio substituent can be
further substituted independently with C1-C2 alkoxy or with one to five halo groups
selected from fluoro and chloro; or substituted with one substituent selected from the
group consisting of phenyloxy, benzyloxy, phenyithio, benzyithio, and pyrimidinyloxy,
wherein the phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy moiety

can be further substituted with one to two substituents selected from the group consisting
of halo, C1-C2 alkyl, and C1-C2 alkoxy, wherein each alkyl and alkoxy group can be
further substituted with 1 to 3 fluoro groups; or substituted with one substituent selected
from the group consisting of C1-C4 acyl and C1-C4 alkoxycarbonyl, and further substituted
with zero to one substituent selected from the group consisting of halo, C1-C4 alkyl, C1-C4
alkoxy, and C1-C4 alkylthio. When a substituent is halo, preferred halo groups are fluoro,
chloro, and bromo.
In another embodiment, preferred substitutions for "substituted phenyl" and
"substituted heterocycle" include substitution with one or more halo substituems,
preferably one to five, more preferably one to three, each independently selected; or
substituted with one or more substituents, preferably one to two substituents,
independently selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy,
cyano, and nitro, wherein each alkyl and alkoxy substituent can be further substituted
independently with one to five halo groups selected from fluoro and chloro.
In another embodiment, preferred substitutions for "substituted phenyl" include
substitution with one or three independently selected halo substituents; or substituted with
one to two substituents, independently selected from the group consisting of halo, methyl,
methoxy, trifluoromethyl, trifluoromethoxy, and cyano.
Abbreviations used herein are defined as follows:
BINAP means 2,2'-bis(diphenylphosphino)-1,1'binaphthyl.
DMF means N,N-dimethytformamide.
DMSO means dimethylsulfoxide.
Pd2(dba)3 means tris(dibenzylideneacetorte)dipalladium(0)
Pd(OAc)2 means palladium diacetate.
THF means tetrahydrofuran.
The term "amino protecting group" as used in this specification refers to a
substituent commonly employed to block or protect the amino functionality while reacting
other functional groups on the compound. Examples of such amino-protecting groups
include the formyl group, the trityi group, the phthalimido group, the acetyl group, the
trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type
blocking groups such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC"),
t-butoxycarbonyl (t-BOC), and the like; and like amino protecting groups. The species of
amino protecting group employed is not critical sc long as the derivatized amino group is

stable to the conditions of subsequent reactions on other positions of the molecule and can
be removed at the appropriate point without disrupting the remainder of the molecule.
The selection and use (addition and subsequent removal) of amino protecting groups is
well known within the ordinary skill of the art. Further examples of groups referred to by
the above terms are described by T.W. Greene and P. G. M. Wuts, "Protective Groups in
Organic Synthesis"', 3rd edition, John Wiley and Sons. New York. NY, 1999. chapter 7.
hereafter referred to as "Greene".
The term "pharmaceutical" or "pharmaceutically acceptable" when used herein as
an adjective, means substantially non-toxic and substantially non-deieterious to the
recipient.
By "pharmaceutical composition" it is further meant that the carrier, solvent,
excipients and salt must be compatible with the active ingredient of the composition (e.g.
a compound of formula I). It is understood by those of ordinary skill in this art that the
terms "pharmaceutical formulation'' and "pharmaceutical composition" are generally
interchangeable, and they are so used for the purposes of this application.
The term "acid addition salt" refers to a salt of a compound prepared by reaction
of the compound with a mineral or organic acid. The compounds of the present invention
form pharmaceutically acceptable acid addition salts with a wide variety of organic and
inorganic acids and include the physiologically acceptable salts which are often used in
pharmaceutical chemistry. Such salts are also embodiments of this invention. A
"pharmaceutically-acceptable (acid) addition salt" is formed from a pharmaceutically-
acceptable acid as is well known in the art. Such salts include the pharmaceutically
acceptable salts exemplified in Berge, S.M, Bighley, L.D., and Monkhouse, D.C.,./
Pharm. Sci., 66:1, (1977), which are well known to those skilled in the art.
Inorganic acids commonly employed to form such salts include hydrochloric acid,
hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Organic
acids commonly employed to form such salts include g-toluenesulfonic acid,
methanesulfonic acid, oxalic acid, g-bromophenylsulfonic acid, carbonic acid, succinic
acid, citric acid, benzoic acid, acetic acid and the like. Examples of such
pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite,
bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate,
acrylate, formate, isobutyrate, caproate, heptanoate, propiolale, oxalate, malonate,
succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,

benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate,
metboxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate,
phenylbutyrate, citrate, lactate, p-hydroxybutyrate, glycollate, tartrate, methanesulfonate,
propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the
like. It is well known that such compounds can form salts in various molar ratios to
provide for example the hemi-acid, mono-acid, di-acid salts, etc.
The term "effective amount" means an amount of a compound of formula I which
is capable of activating 5-HT1F receptors and/or inhibiting neuronal protein extravasation.
The term "suitable solvent" refers to any solvent, or mixture of solvents, inert to
the ongoing reaction that sufficiently solubitizes the reactants to afford a medium within
which to effect the desired reaction.
It is understood that compounds of the present invention may exist as
stereoisomers. As such, all enantiomers, diastereomers, and mixtures thereof, are
included within the scope of the present invention. Where specific stereochemistries are
identified in this application, the Cahn-Prelog-lngold designations of (R)- and (S)- and the
cis and trans designation of relative stereochemistry are used to refer to specific isomers
and relative stereochemistry. While all enantiomers, diastereomers, and mixtures thereof,
are contemplated within the present invention, preferred embodiments are single
enantiomers and single diastereomers.
While all of the compounds of the present invention are useful as 5-HT1F agonists,
certain classes are preferred, as for example, compounds having any of the following
enumerated selections of substituents: Compounds wherein
1) R1 is phenyl, substituted phenyl, heterocycle, or substituted heterocycle;
2) R1 is substituted phenyl;
3) R1 is mono- or di- substituted phenyl wherein the substituents are
independently selected from halo, C1-C4 alkyl, C1-C4 alkoxy,
trifluoromethyl, trifluoromethoxy, trifluoroethoxy, phenyloxy, benzyloxy,
cyano, and nitro;
4) R1 is mono- or di- substituted phenyl wherein the substituents are
independently selected from halo, C1-C2 alkoxy, trifluoromethyl,
trifluoromethoxy, and trifluoroethoxy;
5) R1 is mono- or di-substituted phenyl wherein the substituents are
independently selected from halo, trifluoromethyl, and trifluoromethoxy;
6) R1 is mono-, di- or tri-halo substituted phenyl;

7) R1 is heterocycle or substituted heterocycle;
8) R1 is heterocycle or substituted heterocycle wherein the heterocycle is
selected from the group consisting of furanyl, thiophenyl, pyrrolyl,
pyrrolidinyl, pyridinyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl,
imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, N-
acetylthiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoquinolinyl,
benzoxazolyl, benzodioxolyl, benzothiazolyl, quinolinyl, benzofuranyl,
benzothiophenyl, and indolyl;
9) R' is a substituted or unsubstituted heterocycle wherein the heterocycle is
selected from the group consisting of pyridinyl, indolyl, furanyl,
benzofuranyi, thiophenyl, benzodioxolyl, and thiazolidinyl;
10) R1 is a substituted or unsubstituted heterocycle wherein the heterocycle is
selected from the group consisting of pyridinyl. thiophenyl, and furanyl;
11) R1 is mono-, di-, or tri- halo-substituted heterocycle, each halo group being
independently selected;
12) R1 is mono- or di- substituted heterocycle, wherein one of the substituents is
selected from the group consisting of C1-C2 alkoxy, phenoxy. and
phenylthio;
13) R1 is mono-substituted heterocycle, wherein the substituents is halo or nitro;
14) R1 is mono-halo substituted heterocycle;
15) R1 is unsubstituted heterocycle;
16) R1 is C2-C6 alkyl;
17) R1 is C2-C6 alkyl substituted one to five times with halo;
18) R1 is C3-C7 cycloalkyl;
19) R1 is C3-C7 cycloalkyl and X is -N=;
20) R1 is cyclopropyl;
21) R2 is hydrogen or C1-C3 n-alkyl;
22) R2 is hydrogen or methyl;
23) R2 is pyrazolylalkyl or N-substituted pyrazolylalkyl;
24) R2 is pyrazol-4-yl-ethyl;
25) R2 is 1-(C1-C3 alkyl)pyrazol-4-yl-ethyl;
26) R2 is cyclopropylmethyl;
27) R3a, R3b , and R3c if present, are each hydrogen;
28) One of R3b or R3c if present, is fluoro;

29) R4 is hydrogen;
30) When X is -C(R3C)=, R4 is methyl;
31) R5 is hydrogen;
32) R5 is methyl;
33) R3a, R3b, and R3c if present, are hydrogen or fluoro, provided no more than
one of R3a, R3b, and R3c may be other than hydrogen;
34) R3a, R3b, and R3c if present, are hydrogen or fluoro, provided no more than
one of R3a, R3b, and R3c may be other than hydrogen, and R4 is hydrogen;
35) R3a, R3b, and R3c if present, are hydrogen or fluoro, provided no more than
one of R3a, R3b, and R3c may be other than hydrogen, R4 is hydrogen, and R3
is hydrogen or methyl;
36) R3b, and R3c if present, are hydrogen or fluoro, provided no more than one of
R3b and R3c may be other than hydrogen, R4 is hydrogen, and R= is hydrogen
or methyl;
37) R2 is hydrogen or methyl, R3a, R3b, and R3c if present, are each hydrogen or
fluoro, provided no more than one of R3a. R3b, and R3c may be other than
hydrogen, R4 is hydrogen, and R5 is hydrogen or methyl;
38) R1 is mono-, di-, or tri-substituted phenyl wherein the substituents are
independently selected from halo, C1-C2 alkoxy, trifluoromethyl.
trifluoromelhuxy, and trifluoroethoxy, R2 is hydrogen or methyl. R3a, R3b,
and R3c if present, are each hydrogen or fluoro, provided no more than one
of R3a, R3b, and R3C may be other than hydrogen, R4 is hydrogen, and R5 is
hydrogen or methyl;
39) R1 is mono-, di-. or tri-substituted phenyl wherein the substituents are
independently selected from halo, R2 is hydrogen or methyl, R3a, R3b, and
R3c if present, are each hydrogen or tluoro, provided no more than one of
R3a, R3b, and R3c may be other than hydrogen, R4 is hydrogen, and R5 is
hydrogen or methyl;
40) R1 is a substituted or unsubstituted heterocycle selected from the group
consisting of pyridinyl. indolyl, benzofuranyl, furanyl, thiophenyl,
benzodioxolyl, and thiazolidinyl, R2 is hydrogen or methyl, R3a, R3b, and R3c
if present, are each hydrogen or fluoro, provided no more than one of R3a,
R3b, and R3c may he other than hydrogen, R4 is hydrogen, and R5 is
hydrogen or methyl;

41) R1 is a substituted or unsubstituted heterocycle selected from the group
consisting of pyridinyl, thiophenyl. and furanyl, R2 is hydrogen or methyl.
R3a, R3b, and R3c if present, are each hydrogen or fluoro, provided no more
than one of R3a, R3b, and R3c may be other than hydrogen, R4 is hydrogen,
and R5 is hydrogen or methyl;
It will be understood that the above classes may be combined to form additional
preferred classes, as for example the combination of preferred selections for two or more
substituents. Illustrative examples of combinations of preferred classes forming
additional preferred classes are:
42) the combination of any one of preferred classes 1) through 20) with any one of
preferred classes 21) through 26);
43) the combination of any one of preferred class 42) with preferred class 27) or
28);
44) the combination of any one of preferred classes 42) or 43) with preferred class
29) or 30);
45) the combination of any one of preferred classes 42). 43), or 44) with preferred
class 31) or 32);
The compounds of the present invention may be synthesized through a number of
alternative routes. Schemes 1-7 relate to the synthesis of compounds wherein X is
-C(R3c)=. Schemes 8 and 9 relate to the synthesis of compounds wherein X is -N=.
Suitable reaction conditions for the steps of these schemes are well known in the art and
appropriate substitutions of solvents and co-reagents are within the skill of the art.
Likewise, it will be appreciated by those skilled in the art that synthetic intermediates may
by isolated and/or purified by various well known techniques as needed or desired, and
that frequently, it will be possible to use various intermediates directly in subsequent
synthetic steps with little or no purification. All substituents, unless otherwise indicated,
are as previously defined, and all reagents are well known and appreciated in the art.
Scheme 1:


Compounds of the present invention wherein X is -CH= can be synthesized by
methods according to Scheme 1, above, wherein R7 is C1-C3 n-alkyl, C3-C6 cycloalkyl-C1-
C3 alkyl, or a group of formula II, above, or a suitable nitrogen protecting group. The
scheme comprise."; a reductive amination of an optionally R3-substituted 3-
aminonitrobenzene with the appropriate piperidin-4-one reagent, followed by reduction of
the nitro group, and finally acylation of the primary amine with the appropriate R1-
acylchloride. Optionally, another reductive amination can then be done to obtain
compounds wherein R5 is other than hydrogen. Where R7 is a protecting group, removal
of the protecting group provides compounds of the present invention wherein R2 is
hydrogen. Further compounds wherein R2 is other than hydrogen can then be made in a
straight forward manner by alkylation of the piperidinyl nitrogen.
Reductive amination of 3-aminonitrobenzene with the appropriate piperidin-4-one
reagent can be done in an inert solvent like dichloromethane. THF, toluene, or the like, at
temperatures typically between about 0 - 40°C in the presence of a borohydride such as
sodium borohydride, soduim triacetoxyborohydride, sodium cyanoborohydride, or the
like. Preferrably, the reaction is performed in dichloromethane at ambient temperature in
the presence of soduim triacetoxyborohydride. Reduction of the nitro function by
catalytic hydrogenation in the presence of Pd/C is performed in an appropriate solvent,
such as methanol, ethanol, isopropanol, or the like, at temperatures typically between
about 20 - 40oC. Preferrably, the hydrogenation is performed in methanol at ambient
temperature. Finally, the acylation of the primary amine is run with an excess of the acid
chloride, typically between about 1.1-1.3 equivalents, in the presence of an organic base,
such as triefhylamine. Hunig's base, or the like, in an appropriate solvent such as THF,
CH2Cl2, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane, DMF, toluene,

ethylacetate, acetone, or the like, .at temperatures typically between about 0 - 40°C.
Preferrably, the acylation is performed in THF, acetone or ethyl acetate with 1.1
equivalent of the acid chloride at ambient temperature in presence of 2.2 equivalents of
triethylamine.
Compounds wherein R3 is C1-C3 alkyl can by made by reductive amination with
the appropriate aldehyde, in the presence of an organic acid and a suitable borohydride.
Preferrably, this second amination is performed in methanol, with acetic acid and sodium
cyanoborohydride at ambient temperature. Compounds wherein R5 is C3-C6
cycloalkylcarbonyl can by made by reaction with the appropriate cycloalkylcarbonyl
chloride reageant under similar acylation conditions as described above.
Scheme 2:

Alternatively, compounds of the present invention wherein X is -CH= can be
synthesized by methods according to Scheme 2, above, wherein the condesation of the
optionally R3-substituted 3-aminonitrobenzene with the appropriate R1-acylchloride is
conducted first, followed by reduction of the nitro group and reductive amination with the
appropriate piperidin-4-one reagent. As with Scheme 1, compounds wherein R5 is other
than hydrogen may he obtained through another reductive amination at the linker
nitrogen. Also as with Scheme 1, where R7 is a protecting group, removal of the
protecting group provides compounds of the present invention wherein R2 is hydrogen.
Further compounds wherein R2 is other than hydrogen can then be made in a
straightforward manner by alkylation of the piperidinyl nitrogen.
Typically, combine the optionally R3-substituted 3-aminonitrobenzene with an
appropriate solvent, such as dioxane, pyridine, THF, N,N-dimethylacetamide, or the like.
Treat the mixture with the appropriate acid chloride (1.0 to 2.0 equivalents). Stir the
reaction for between about 2 - 48 hr. at between about 0 - 40°C, say room temperature for

about 16 hr. Transfer the reaction mixture into ethyl acetate or other suitable solvent, and
wash successively with aqueous HCl (1N), aqueous NaOH (1N), saturated aqueous NaCl,
Normal workup procedures on the organic layer provide the benzamide intermediate.
Add the benzamide intermediate to a warm solution (about 35 - 70°C, say about
55°C) of SnCl2.2H2O in ethanol. Add concentrated HCl and then stir and heat the
mixture at between about 50 - 65°C, say about 60°C, for between about 20 - 60 min., say
about 30 min. Cool the reaction mixture and then basify the mixture to about pH 14 with
aqueous NaOH. Extract the product with an appropriate solvent, such as ethyl acetate or
the like. Normal workup procedures on the combined organic layers provide the.
aminobenzamide intermediate.
Stir a mixture of the aminobenzamide intermediate, N-protected-4-piperidone, and
powdered molecular sieve (4A), in an appropriate solvent such as THF, dichloroethane.
methylene chloride, or the like, under an inert atmosphere. Add glacial acetic acid. After
between about 1 - 8 hr., say about 1 hr., add NaBH(OC(O)CH3)3. Allow the mixture to
react for about 8-24 hr., at about 0°C - 40°C, say about room temperature. Pour the
reaction mixture into a suitable solvent such as methylene chloride, ethyl acetate, or the
like, and wash with aqueous NaOH. Normal workup procedures on the organic layer
provides the desired piperidinylbenzamide.
As with Scheme 1, the linker nitrogen can optionally be substituted if desired to
provide compounds wherein R5 is other than hydrogen.
Scheme 3:


Compounds of the present invention wherein X is -CH= may also be synthesized
by methods according to Scheme 3, above, comprising protection of one amino group of
1,3 diaminobenzene, reductive animation with an appropriate piperidin-4-one reagent,
deprotection, and finally acylation of the primary amine with an appropriate R1
acytchloride. Reaction conditions are similar to those in Schemes 1 and 2. above. Note
also that substitution of the linker nitrogen may be performed before or after the acylation
step, as desired.
Scheme 4:


Compounds of the present invention wherein R3c is fluoro can be synthesized as
shown in Scheme 4. An initial reductive animation of 3-amino-1-chloro-2-fluorobenzene
with an appropriately substituted 4-piperidone is followed by conversion of the chloro
group to an amino group, and subsequent condensation with the appropriate R1-acylhalide
compound. Reaction conditions are similar to those in Schemes 1 - 3. above. Note also
that substitution of the linker nitrogen may be performed before or after the acylation step,
as desired.


Compounds wherein R3c is fluoro and R5 is C1-C3 alkyl can be synthesized as
shown in Scheme 5 showing R5 = methyl as an example. An initial condensation of 1 -
bromo-2-fluorobenzene with an appropriately substituted 4-aminopiperidine is followed
by halogenation of the benzyl ring, conversion of the halo group to an amino group, and
subsequent condensation with the appropriate R1-acylhalide compound.
Scheme 6:

Compounds of the present invention wherein R3b is fluoro and R5 is C1-C3 alkyl
can be synthesized as shown in Scheme 6 showing R5 = methyl as an example. An initial
condensation of 1,3-dibromo-5-fluorobenzene with an appropriately substituted
4-aminopiperidine is followed by conversion of the remaining bromo group to an amino
group, and subsequent condensation with the appropriate R1-acylhalide compound.
Alternatively, 1,3-difluoro-5-nitrobenzene can be used in the initial condensation with an
appropriately substituted 4-aminopiperidine, followed by reduction of the nitro group to
an amino group, and subsequent condensation with the appropriate R1-acylhalide
compound.
Typically the 1,3-dibromo-5-fluorobenzene dissolved in an appropriate solvent,
such as toluene, benzene, or the like, is combined with methyl-(1-methylpiperidin-4-
yl)amine, sodium t-butoxide, Pd2dba3, and BINAP, and heated, as for example, hetween

50°C and 100°C, say about 80°C, for between about 1 - 3 hr., say about 2 hr. The reaction
is quenched, as for example by addition of water or other suitable means. The (3-bromo-
5-fluorophenyl)-methyl-(1-methylpiperidin-4-yl)-amine intermediate may be worked up
by common procedures, as for example, solvent removal, extraction procedures, and/or
further purification by chromatography, etc.
The (3-bromo-5-fluorophenyl)-methyl-(1-methylpiperidin-4-yl)-amine
intermediate is then aminated at the benzo 3-position, as for example, by reacting the
intermediate with BINAP, Pd2dba3, benzhydrylideneamine, and sodium t-butoxide, in a
suitable solvent, such as toluene or the like, under an inert atmosphere for about 1 - 3 hr.,
say about 2 hr., at about 50°C to 100°C. say about 80°C. The resulting intermediate is
treated with 1M HCl or the like in a suitable solvent, such as THF at 0°C to ambient
temperature, preferably ambient temperature for 1-2 hours, say about 1 hr. The resulting
intermediate, 5-Fluoro-N-methyl-N-(1-methylpiperidin-4-yl)benzene-1,3-diaminc may
then be isolated and purified by common procedures such as, but not limited to. solvent
removal, extraction and/or chromatography, etc.
Final compounds can then be synthesized by condensation with the R1-
acylchloride. Typically, the 5-fluoroaminobenzene intermediate is reacted with the
appropriate R1-acylchloride, in an appropriate solvent, such as dioxane, pyridine, DMF. or
the like, at between ambient temperature and about 100°C. preferably between about 50 -
100°C, until the reaction is complete, as for example between about 1 - 4 hr., say about 2
hr. The reaction is then quenched by addition of water and the final product purified by
normal work-up procedures.
Alternatively, the 5-fluoro-N-mcthyl-N-(1-methylpiperidin-4-yl)benzene-1,3-
diamine intermediate may be prepared by reacting the 1,3-difluoro-5-nitro benzene with
methyl-(l-methylpiperidin-4-yl)amine in the presence of sodium acetate in a suitable
solvent, such as ethanol or the like, for between about 8-16 hr., say about 12 hr., at 80 -
120°C, say about 100°C in a sealed tube The reaction is then quenched by the addition of
water or the like and the (3-Fluoro-5-nitrophenyl)-methyl-(l-methylpipendin-4-yl)amine
intermediate is purified by normal work-up procedures. The nitro group is then reduced
to an amino group, as for example, by treatment with iron and 1M HCl in a suitale
solvent, such as methanol or the like, for between about 8 hr. to overnight, say about 16
hours, at between about 80 - 100°C, say about 100°C. The 5-fluoro-N-methyl-N-(1 -
methylpiperidin-4-yl)benzene-1,3-diamine intermediate may then be isolated and purified
by common procedures.


Compounds of the present invention wherein R3b is fluoro and R5 is hydrogen can
be synthesized as shown in Scheme 7, where 1,3-dibromo-5-fluorobenzene is converted to
a 1,3-diamino compound, condensed with the appropriate R1-acylhalide compound,
followed by reductive amination with an appropriately substituted 4-aminopiperidine.
Typically, 1,3-dibromo-5-fluorobenzene, benzophenone imine, Pd2(dba)3, BINAP
and sodium t-butoxide are mixed in a suitable solvent, such as toluene, xylene. 1,4-
dioxane, or the like, and heated, as for example between 60-130°C for about 8-20 hr., say
about 15 hr. The reaction is quenched with saturated NaHCO3 solution extracted several
times with an organic solvent, such as ethylacetate, methylene dichloride. or the like. The
organic layers are combined and the solvent removed. The residue is dissolved in a
suitable solvent, such as THF, ether, methanol, or the like, and aqueous HCl is added, as
for example, between 1-6 N HCl, say about 5 N HCl. The reaction mixture is stirred for
about 1 -3 hr. at between about 0-60°C, say about ambient temperature. The reaction
mixture is then diluted with dilute aqueous HCl and extracted with an ethyl
acetate/hexanes solvent system, or equivalent. The organic layer is washed with dilute
aqueous HCl and the aqueous layer is then basifled with NaOH and extracted with an
organic solvent such as methylene dichloride or the like. The extract is dried, filtered,
concentrated, and further purified by chromatography to give the diamino intermediate.
A mixture of the diamino intermediate and the desired R1-acylchloride in an
appropriate solvent, such as dioxane, pyridine, THF, or DMF, with an appropriate tertiary
amine, such as triethylamine, N-methylmorpholine, or diisopropylethylamine is stirred at
between about 0-40°C until the reaction is complete, as for example, between about 2-20
hr., say about 12 hr. The reaction is then quenched by addition of dilute aqueous NaOH.
Norma! work up and purification procedures provides the amide intermediate. Sodium

triacetoxyborohydride is then added to a mixture of the amide intermediate, the
appropriate 1 -substituted or N-protected 4-piperidone, acetic acid, and a molecular sieve
(typically about 4 A), in anappropriate solvent, such as THF, dicloroethane. methylene
dichloride, or the like. The reaction mixture is stirred for about 8-20 hr., say about 12 hr.,
at about 0-40°C, say about ambient temperature. The reaction is then quenched with
dilute aqueous NaOH, extracted with a suitable organic solvent, such as methylene
dichloride, ethylacetate, or the like. The organic layer is dried, filtered, concentrated, and
further purified, as for example, by chromotogrphy, to provide the desired product. When
R7 is a protecting group, an appropriate unprotecting method is used to provide
compounds wherein R2 is hydrogen. If desired, the unsubstituted piperidinyl moiety can
then be alkylated by common reductive alkylation methods to provide compounds having
R2 other than hydrogen.
Scheme 8:

2,6-Dihaiopyridine (X = Cl or Br) is alkylated with an appropriately substituted 4-
(methylamino)piperidine in the presence of a base such as potassium carbonate,
n-butyllithium, sodium hydride, etc. in DMF, acetonitrile, THF, or like solvent.
Alternatively, the 2.6-dihalopyridine can be treated with BINAP (or other acceptable
ligand), Pd(OAc)2, the piperidine, and sodium tert-butoxide (or other suitable base) in
toluene (or like solvent) to yield the intermediate 1-methyl-4-(N-(6-
halopyridinyl)methylaminopiperidine. The halopyridine is then treated with BINAP (or
other acceptable ligand), Pd(OAc)2, benzophenone imine (or other amine equivalent), and
sodium tert-butoxide (or other suitable base) in toluene (or like solvent) to yield the
intermediate substituted 4-(N-(6-aminopyridinyI)methylaminopiperidine. This amine is
then acylated with a variety of acid chlorides in pyridine, THF, 1,4-dioxane, or like

solvent to yield the final product.Similarly, compounds wherein R5 is ethyl or propyl can
be made using the appropriate 4-(ethylamino)piperidine or 4-(propylamino)piperidine.
Scheme 9:

Typically, a mixture of R1-acyl chloride and 2,6-diaminopyridine in a suitable
solvent, such as dioxane, THF, DMF. or the like, is stirred at about ambient temperature
to about 100°C for between about 2-20 hr., say about 12 hr. Normal work procedures,
such as extraction, filtration, and/or chromatography, provides the N-(6-aminopyridin-2-
yl)amide intermediate.
Sodium tiacetoxyborohydride is then added to a mixture of the above intermediate
with the appropriate 1-substituted 4-piperidone. acetic acid, and a molecular sieve, in an
appropriate solvent, such as THF, dichloroethane, methylene dichloride, or the like. The

reaction mixture is stirred at between about 0 - 40°C. say about ambient temperature, for
about 8-20 hr.. say about 12 hr, Typically another aliquot of the piperidone reagent and
sodium triaeetoxyborohydride is added and allowed to react with any remaining N-(6-
aminopyridin-2-yl)amide intermediate. The reaction is then quenched with diliute
aqueous NaOH. Routine work-up and purification procedures provide the N-(5-
pipieridin-4-ylamino)amide compound. When R7 is the desired R2 moiety, then normal
final purification procedures are used to provide the end product. When R is a protecting
group, the protecting group is removed by appropriate procedures to provide compounds
wherein R2 is hydrogen. These compounds may, if desired, then be further alkylated by
well know procedures to provide end products wherein R2 is other than hydrogen.
The following Preparations and Examples are provided to better elucidate the
practice of the present invention and should not be interpreted in any way so as to limit
the scope thereof.
Preparations
Preparation 1. N-(3-Aminophenyl)-2-chloro-4-fluorobenzamide

Combine 3-nttroaniline (3.0 g, 21.7 mmol), dichloromethane (100 mL), pyridine
(2.11 mL, 26.0 mmol) and 2-chloro-4-fluorobenzoyl chloride (3.07 mL, 23.9 mmol). Stir
at room temperature overnight. Filter the white precipitate, rinse with ether (2x10 mL),
and dry under vacuum to provide 2-chloro-4-fluoro-N-(3-nitrophenyl)benzamide (4.92 g,
77%). Combine the 2-chloro-4-fluoro-N-(3-nitrophenyl)benzamide (4.92 g, 16.7 mmol)
with ethanol (150 mL), SnCl2H2O (18.9 g, 83.6 mmol) and concentrated hydrochloric
acid (8.24 mL, 83.6 mmol). Stir at reflux under a nitrogen atmosphere for 2 hr.
Neutralize with ammonium hydroxide (15 mL). Filter through celite, wash with
dichloromethane (2x15 mL), separate the filtrate, extract with dichloromethane (2 x 80
mL), and dry the combined organic layers over magnesium sulfate. Filter and concentrate
to dryness to provide the title intermediate as an off-white solid (3.04 g, 69%): mass
spectrum (ion spray): m/z = 265.0(M+1); 1H NMR (DMSO-d6): 10.16 (bs, N-H), 7.60 (dd,
J= 6.2 Hz, 8.6 Hz, 1H), 7.54 (dd, J = 2.5 Hz, 9.0 Hz, 1H), 7.30 (td, J = 2.5 Hz, 8.5 Hz,

1H), 7.04 (t, J = 2.0 Hz. 1 H), 6.93 (t, J = 8.0 Hz, 1H), 6.74 (bd, J = 7.9 Hz, 1H), 6.29 (dd,
J= 2.2 Hz, 7.9 Hz, 1H). 5.10(bs, 2H).
Preparation 2. N-(3-Aminophenyl)-2-chloro-6-fluorobertzamide

Using a method similar to Preparation 1, using 2-chloro-6-fluorobenzoyl chloride
(1.0 g, 3.39 mmol) gives the title intermediate (820 mg, 91%): mass spectrum (ion
spray): m/z = 265.1 (M +1); 1H NMR (DMSO-d6): 10.42 (bs, N-H), 7.50 (td, J = 6.2 Hz,
8.2 Hz, 1H), 7.40 (d, J =8.0 Hz, 1H), 7.34 (t. J = 8.7 Hz, 1H), 7.03 (t, J= 2.1 Hz, 1H),
6.94(t, J=8.0Hz, 1H), 6.71 (dd, .7=2.1 Hz, 8.0 Hz, 1H),6.31 (dd, J=2.1 Hz, 8.0 Hz,
1H), 5.13 (bs, 2H).
Preparation 3. N-(3-AminophenyI)-2,6-difluorobenzamide

Using a method similar to Preparation 1, using 2,6-difluorobenzoyl chloride (1.0
g, 3.59 mmol) gives the title intermediate (723 mg, 81%): mass spectrum (ion spray); m/z
= 248.9 (M-H); 1H NMR (DMSO-d6): 10.44 (bs, N-H), 7.58 - 7.50 (m, 1H), 7.24 - 7.17
(m, 2H), 7.02 (t, J= 2.0 Hz, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.72 (bd, J = 8.0 Hz, 1H), 6.31
(dd,.7=2.1 Hz, 8,0 Hz, 1H), 5.14 (bs, 2H).
Preparation 4. N-(3-Aminophenyl)-2,4-
difluorobenzamide
Using a method similar to Preparation 1, using 2,4-difluorobenzoyl chloride (1.0
g, 3.59 mmol) gives the title intermediate (664 mg, 74%): mass spectrum (ion spray): m/z
= 248.9(M+1); 1HNMR(DMSO-d6): 10.08 (bs, N-H), 7.68 (dd. J = 8.1 Hz, 15.1 Hz, 1H),

7.38 (td, J=2.5 Hz, 10.2 Hz, 1H), 7.18 (td. J-2.5 Hz. 8.5 Hz, 1H). 7.01 (bs. 1H), 6.93
(t, J=7.8Hz, 1H), 6.76 (bd, J = 7.8 Hz, 1H), 6.29 (dd, J= 1.9 Hz. 8.0 Hz, 1H), 5.10 (bs.
2H).
Preparation 5. N-(3-Aminophenyl)-2,4,6-

trifluorobenzamide
Using a method similar to Preparation 1, using 2.4,6-trifluorobenzoyl chloride (1.0
g, 3.37 mmol) gives the title compound (485 mg, 54%): mass spectrum (ion spray): m/z -
266.9 (M+1); 1H NMR (DMSO-d6): 10.43 (bs, N-H). 7.34 (t. J= 8.5 Hz. 2H). 6.99 (d, J =
1.5 Hz, 1H), 6.94 (t, , J = 7.9 Hz, 1H), 6.70 (d, J= 8.2 Hz. 1H). 6.31 (d, J=8.2 Hz, 1H).
5.l5(bs,2H).
Preparation 6. N-(3-Aminophenyl)-2-bromobenzamide

Using a method similar to Preparation 1, using 2-bromobenzoyl chloride (1.0 g.
3.11 mmol) gives the title intermediate (744 mg, 82%): mass spectrum (ion spray): m./z =
293.0 (M+1); 1H NMR (DMSO-d6): 10.14 (bs, N-H), 7.68 (d. J= 8.0 Hz. 1 H). 7.50 - 7.43
(m, 2H), 7.37 (td, J=2.5 Hz, 7.3 Hz, 1H), 7.07 (bs, 1H). 6.92 (t. J= 7.8 Hz. 1H), 6.74
(bd, J= 8.0 Hz, 1H), 6.29 (bd, J = 8.0 Hz, 1H), 5.10 (bs. 2H).
Preparation 7. N-(3-Arninopheny!)-2-chlorobenzamide

Using a method similar to Preparation 1, using 2-ch!orobenzoyl chloride (4.0 g,
14.5 mmol) gives the title intermediate (2.8 g, 78%): mass spectrum (ion spray): m/z =
247.0 (M+l); 1H NMR (DMSO-d6): 10.16 (bs, N-H), 7.54 - 7.39 (m, 4H). 7,06 (bs, 1H),

6.92 (t, J = 8.0 Hz, 1H), 6.74 (bd, J= 8.0 Hz, 1H), 6.28 (bd, J = 8.3 Hz, 1H), 5.10 (bs.
2H).
Preparation 8. N-(3-Aminophenyl)-2-trifluoromethoxybenzamide

Using a method similar to Preparation I, using 2-trifluoromethoxybenzoyl
chloride (300 mg, 1.01 mmol) gives the title intermediate (274 mg, 69%) as a white foam;
mass spectrum (ion spray): m/z = 394.2 (M+1); 1H NMR (CDCl3): 8.18 (bs, N-H), 8.07
(d, J =7.5 Hz, 1H), 7.55(t, J=7.7Hz, 1H), 7.45 (t, J= 7.5 Hz, 1H), 7,34 (d, J= 8.0 Hz,
1H), 7.21 (s, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.68 (d, J= 7.7 Hz, 1H),6.41 (d. J =8.0 Hz,
1H), 3.70 - 3.63 (bm, 1H), 3.38 - 3.28 (bm, 1H), 3.85 - 3.77 (bm, 2H), 2.30 (s, 3H), 2.21
- 2.04 (bm, 4H), 1.57-1.46 (bm, 2H).
Preparation 9. (3-(1-Methylpiperidin-4-ylarnino)phenyl)carbamic acid tert-butyl ester

Add a solution of di-tert-butyl dicarbonate (5.04 g, 23.11 mmol) in chloroform
(100 mL+ 100 mL rinse) to a solution of 1,3-phenylenediamine (5.0 g, 46.23 mmol) in
chloroform (100 mL). Stir at room temperature overnight. Wash with sodium hydroxide
(t N aq., 200 mL) and separate the organic layer. Purify through flash chromatography
(ethylacetate/hexanes 1/4 to 1/1) to provide (3-amino-phenyl)-carbamic acid tert-butyl
ester (4.17 g, 87%).
Combine (3-aminophenyl)carbamic acid tert-butyl ester (0.156 g, 0.756 mmol), 1-
methylpiperidin-4-one (0.093 mL, 0,756 mmol), sodium triacetoxyborohydride (208 mg,
0.982 mmol), acetic acid (0.043 mL. 0.756 mmol) and dichloromethane (8 mL). Stir at
room temperature overnight. Dilute with dichloromethane (5 mL) and wash twice with
sodium hydroxide (10 mL 1N aq.). Combine the organic layers and wash with saturated
aqueous NaCl (10 mL). Dry over magnesium sulfate, filter under reduced pressure and
concentrate to dryness. Purify by flash chromatography on a Biotage® silica cartridge

eluting with a 20/1 mixture of dichloromethane and 2N ammonia in methanol to give the
free base of the title compound. Dissolve the residue in diethyl ether and treat with
ethereal hydrogen chloride. Triturate the resulting gum with ether to give the title
compound as a white solid: mp 124-5°C; mass spectrum (ion spray): m/z = 306.2 (M+1),
1H NMR(CDCl3):7.06(t, J =8.0Hz, lH),6.86(bs, 1H),6.51 -6.48(m, 1H),6.42(bs,
1H), 6.30 -6.27 (m, 1H), 3.60 (bs, 1H), 3.30(bs, 1 H), 2.80 (bd, J= 11.8 Hz, 2H), 2.31 (s,
3H), 2.19-2.02 (m,4H), 1.89(bs. 2H), 1.52 (s, 9 H).
Preparation 10. (3-(Methyl-(1-methylpiperidin-4-yl)aminG)phenyl)carbamic acid tert-
butyl ester

Combine (3-(1-methylpiperidin-4-yiamino)pheny1)carbamic acid tert-butyl ester
(Preparation 9, 1.15 g, 3.77 mmol), methanol (15 mL) and formaldehyde (37% aq., 0.92
mL, 11.3 mmol). Stir at room temperature for 45 min. Cool to 0°C. Add acetic acid
(0.22 mL, 3.77 mmol) and sodium cyanoborohydride (414 mg, 6.59 mmol). Stir at room
temperature overnight. Concentrate to dryness. Dissolve the residue in a 2/1 mixture of
ethyl acetate and hexanes (20 mL) and wash with sodium hydroxide (1N aq., 2 x 20 mL).
Separate the organic layer and dry over magnesium sulfate. Filter and concentrate under
reduced pressure. Purify through flash chromatography eluting with a 20/1 mixture of
dichloromethane and 2M ammonia in methanol to provide the title compound (990 mg,
82%): mass spectrum (ion spray): m/z = 320.3 (M+1).
Preparation 11. 1-methyl-4-(N-(3-aminophenyl)-N-methylamino)piperidine
trihydrochloride

Combine acetyl chloride (5 mL) with dried methanol (10 mL) at 0°C under
nitrogen atmosphere. Stir for 1 hr. at 0°C. Add a solution of (3-(methyl-(1-

methylpiperidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester (Preparation 10, 990
mg, 3.1 mmol) in methanol (2 mL). Stir overnight. Concentrate under reduced pressure.
Triture with diethyl ether (1 mL) to provide the title intermediate (671 mg, 66%): mass
spectrum (free base, ion spray): m/z = 220.3 (M+1). Analysis calculated for
C13H24Cl3N3Cl3: C, 47.50; H, 7.36; N, 12.78. Found: C, 47.28; H, 7.28; N. 12.46.
Preparation 12. 4-(2-Hydroxyethyl)-1-isopropyl-1H-pyrazole

Combine 2,3-dihydrofuran (25 mL, 0.33 mol) and triethylorthoformate (93.3 mL,
0.56 mol) and then slowly add boron trifluoride diethyl etherate (2.0 mL, 0.017 mol)
while stirring rapidly. Allow the reaction to continue for 18 hr. Distill the reaction at
60°C under 8 mm Hg vacuum to remove excess 2,3-dihydrofuran and
triethylorthoformate. Heat a portion of the remaining residue (10 g, 45 mmol) at reflux, in
1 N HCl with isopropyl hydrazine (3.4 g, 45 mmol). After 2 hr, the temperature is
reduced to S0°C and the reaction is stirred for 18 hr. After cooling to room temperature,
the mixture is basified with 1 N NaOH to a pH > 12 and diluted with CH2Cl2, Separate
and extract the aqueous layer with CH2Cl2 (two times), combine organic layers, dry over
MgSO4, and concentrate. Chromatography on silica gel, eluting with a gradient of 0-10%
(2M NH3 in methanol) in CH2Cl2 provides the title intermediate as a brown solid (3.6 g,
52%). Mass spectrum (ion spray): m/z = 155.2 (M+1); 1H NMR (DMSO, ppm) 7.52 (s.
1H), 7,24 (s,1H), 4.59 (t,J= 5.5, 10.6 Hz, 1H),4.39(m, 1H), 3.51 (m,2H),2.51 (m, 2H),
1.38 (s,3H). 1.35 (s,3H)
Preparation 13. 2-Chloro-4-fIuoro-N-(4-fluoro-3-
nitrophenyl)benzamide
Combine 4-fluoro-3-nitroaniline (1.0 g, 6.4 mmol) with dioxane (20 mL). Treat
mixture with 2-chloro-4-fluorobenzoyl chloride (1.6 g, 8.3 mmol). Stir the reaction

overnight at room temperature. Transfer the reaction mixture into ethyl acetate (220 mL),
then wash successively with aqueous HCl (1N, 50 mL), aqueous NaOH (1N, 50 mL),
saturated aqueous NaCl (50 mL). Dry the organic layer over anhydrous sodium sulfate,
then evaporate the solvent under reduced pressure. Further purify the residue by
chromatography on silica gel, using a gradient of 10-30% ethyl acetate in hexanes to
obtain the title intermediate (1.7 g, 85% yield): mass spectrum (ion spray): m/z = 313.0
(M+1).
Preparation 14. N-(3-Amino-4-fluorophenyl)-2-chloro-4-
fluorobenzamide
Add 2-chloro-4-fIuoro-N-(4-fluoro-3-nitrophenyl)benzamide (Preparation 11. 1 g,
3.2 mmol) to a warm solution (55°C) of SnCl2 2H2O (3.6 g, 16 mmol) in ethanol (25 mL).
Add concentrated HCl (25 mL), Stir and heat the mixture at 60°C for 30 min. Cool and
then basicify the mixture to pH 14 with aqueous NaOH. Extract the product three times
with ethyl acetate (3 x 150 mL). Combine the organic layers and dry over anhydrous
sodium sulfate. Evaporate the solvent under reduced pressure. Further purify the residue
by chromatography on silica gel, using a gradient of 10-50% ethyl acetate in hexanes to
obtain the title intermediate (800 mg, 89% yield): mass spectrum (ion spray): m/z = 283.0
(M+1).
Preparation 15. 2,4-Difluoro-N-(4-fluoro-3-
nitrophenyl)benzamide
Using a method similar to Preparation 13, using 4-fluoro-3-nitroaniline (1.0 g, 6.4
mmol), dioxane (20 mL), and 2,4-difluorobenzoyl chloride (1.46 g, 8.3 mmol) gives the
title intertermediate (1.6 g, 84% yield): mass spectrum (ion spray): m/z = 297.0 (M+1).

Preparation 16. 2,4-DifIuoro-N-(3-amino-4-

fluorophenyl)benzamide
Using a method similar to Preparation 14 using 2,4-Difluoro-N-(4-fluoro-3-
nitrophenyl)benzamide (Preparation 13) (1.0 g, 3.38 mmol), SnCl2-2H2O (3.8 g, 16.9
mmol), ethanol (25 mL), and concentrated HCl (25 mL), gives the title intermediate (803
mg. 89% yield): mass spectrum (ion spray): m/z = 267.0 (M+1).
Preparation 17. 1 -Methyl-4-(3-nitrophenylamino)piperidine

Combine 3-nitroaniline(25.0 g, 180.0 mmol), 1-methyl-4-piperidone (40.9 mL,
360.0 mmol), and acetic acid (21.7 mL, 360.0 mmol) in 350 mL of dichloroethane. Stir at
room temperature for 0.5 hr. Add sodium triacetoxyborohydride (76.4 g, 360.0 mmol) in
several portions, and stir the reaction mixture at room temperature for 2 days. Quench the
reaction mixture by the addition of saturated aqueous NaHCO3, and partition between
CH2Cl2 and water. Adjust aqueous phase to about pH 8, and extract 3 times with CH2Cl2,
Combine the organic fractions and wash with saturated aqueous NaCl, dry over MgSO4,
and concentrate. Further purify by chromatography over silica gel, eluting with a gradient
of 1-10% methanol in ethylacetate, to obtain the title intermediate (23.8 g, 56% yield):
mass spectrum (ion spray): m/z = 236.2 (M+1); Anal calc'd for C12H17N3O2 0.3 H2O:
Theory: C, 59.88; H, 7.37; N, 17.45. Found: C, 60.07; H, 7.18; N, 17.09.
Alternatively, to a solution of 3-nitroaniline (360 g, 2.6 mol) in dichloromethane
(7.2 L) under nitrogen, add sodium triacetoxyborohydride (1.38 kg, 6.5 mol) by portion
over 1 hr. Then add acetic acid (370 mL, 6.5 mol) at a rate such that Tmass does not
exceed 25°C, followed by 1-methyl 4-piperidone (450g, 3.98 mol), which is introduced
over 150 min., keeping the temperature below 25°C. Stirr the mixture at room
temperature for 3 hr. Add additional sodium triacetoxyborohydride (280 g, 1.32 mol),
acetic acid (74 mL, 1.29 mol), and 1-methyl 4-piperidone (90 g, 0.8 mol) and stir the
mixture overnight at room temperature. Quench the reaction mixture with water (4 L) and
adjust the pH to between 8-9 with 30% sodium hydroxide. Extract the organic layer and

wash the aqueous layer with dichloromethane (2 L), Wash the combined organic layers
with water (1 L), dry over MgSO4 (100g) and concentrate (2X). Filter the resulting
suspension, wash with dichloromethane (500 mL), and concentrate the filtrates under
reduced pressure (40°C) to provide the crude 1-methyl-4-(3-nitrophenylamino)piperidine
as an orange solid (620 g). Suspend the crude 1-methyl-4-(3-nitrophenylamino)piperidine
(590 g) in a mixture of water (5.9 L) and isopropanol (590 mL). Stirr the mixture at room
temperature for 5 hr. Filter the resulting yellow crystals, rinse with a mixture of water
(600 mL) and isopropanol (60 mL) and the dry under reduce pressure at room temperature
overnight to provide 1-methyl-4-(3-nitrophenylamino)piperidine (524 g, 94% yield).
Preparation 18. 1-Methyl-4-(3-aminophenylamino)piperidine
triacetate
Combine 1-methyl-4-(3-nitrophenylamino)piperidine (Preparation 17) (8.2 g. 34.8
mmol), acetic acid (6.3 g, 110 mmol), and palladium on carbon (10%, 2.1 g) in 300 mL of
ethanol. Evacuate the reaction flask, charge with H2 gas (atmospheric pressure) and stir at
room temperature for 18 hr. Filter through celite, rinse with ethylacetate, and concentrate
to provide 13.1 g of the title intermediate, which is typically used in subsequent reactions
without further purification. A small sample of the free base amine further purified by
dissolving the triacetate salt was dissolved in methanol, placing on a 1 g SCX column
(mega bond clut®, Varian), and washing with methanol, eluting with 2 M NH3 in
methanol, and concentrated in vacuo: mass spectrum (ion spray): m/z = 206.2 (M+1); 1H
NMR δ (CDCl3, ppm) 6.93 (t, J = 7.9, 15.8 Hz, 1H), 6.03 (d, J = 7.9 Hz, 2H). 5.94 (s,
1H), 3.46 (bs, 3H), 3.24 (bs, 1H). 2.79 (m, 2H), 2.28 (s, 3H), 2.10 (m, 4H). 1.40 (m, 2H).
Alternatively, charge a 2 L Parr bottle with 1-methyl-4-(3-
nitrophenylammo)piperidine(100 g; 0.425 mol), 10% Pd/C (5 g) and methanol (1 L).
Shake the mixture overnight under an initial hydrogen pressure of 4 atm, keeping the
temperature below 35°C. Filter off the catalyst and wash with methanol (100 mL).
Concentrate the filtrates under reduced pressure to provide 1-methyl-4-(3-
aminophenylamino)piperidine as a red oil(95.7g, 100% yield) which crystallizes upon
standing at room temperature.

Preparation 19. 1 -Methyl-4-(3-chloro-2-

fluorophenylamino)piperidine
Combine 3-chloro-2-fluoroaniline (4.37 g, 30 mmol), 1-melhylpiperidin-4-one
(3.39 g, 30 mmol), sodium triaceloxyborohydride (5.26 g, 33 mmol), and acetic acid (5.4
g, 90 mmol) and stir at room temperature overnight. Partition the reaction mixture
between dichloromethane and saturated aqueous NaCl containing NH4OH, dry over
anhydrous sodium sulfate, evaporate and purify on a silica gel columnn (110 g), using a
gradient of diChloromethane-2M NH3 in methanol to give 2.34 g of the title compound
(32% yield): mass spectrum (ion spray): m/z = 243 (M+1); 1H NMR (CDCl3): 6.88
(ddd,1H), 6.63 (ddd, 1H), 6.56 (dd, 1H), 3.85 (brd, 1H), 3.28 (m, 1H), 2.80 (m, 2H), 2.30
(s, 3H), 2.13 (m, 2H), 2.04 (m, 1H), 1.53 (m , 2H). (file: mn4-b6k-284-2)
Preparation 20. 2-Fluoro-N-(1-Methylpiperidin-4-yl)benzene-1,3-diamine

Combine 1-Methyl-4-(3-Chloro-2-fluorophenylarnino)piperidine (Preparation 19)
(0.439 g, 1,8 mmol), benzophenone imine (0.393 g), Pd2(dba)3 (4.1 mg),
2-(dicyclohexylphosphino)biphenyl (4.7 mg), and sodium t-butoxide (0.242 g) with
toluene (5 mL) and heat at reflux overnight. Dissolve the reaction mixture in methanol
and filter through a SCX column (10 g). wash with methanol, elute the product with 2M
NH3 in methanol, evaporate the solvent, and further purify on a silica gel column (35 g,
using a dichloromethane-2M NH3 in methanol gradient) to give crude 1-methyl-4-(3-
benzhydrylideneamino-2-fluorophenylamino)piperidine (0.372 g). Add 1N HCl (2 mL)
into a solution of the benzhydrylidenyl intermediate in THF (10 mL) and stir at room
temperature for 30 minutes. Basicify with NH4OH, extract with ethyl acetate, dry over
anhydrous sodium sulfate, evaporate and purify on a silica gel columnn (10 g), using a
gradient of dichloromethane-2M NH3 in methanol to give the title intermediate (0.08 g):
mass spectrum (ion spray): m/z = 224 (M+1); 1H NMR (CDCl3): 6.75 (ddd,1H), 6.12 (m,
2H), 3.70 (br d, 1H), 3.62 (br s, 2H), 3.25 (m, 1H), 2.80 (m, 2H), 2.29 (s, 3H), 2.10 (m,
4H), 1.53 (m, 2H).

Preparation 21. 1 -Methyl-4-(N-(3-chloro-2-fluorophenyl)methylamino)piperidine

Mix 1-methyl-4-(3-chloro-2-fluorophenylamino)piperidine (Preparation 19)
(0.961 g), formaldehyde (37%)(0.973 g). sodium cyanoborohydride (0.917 g) and acetic
acid (t ,66 g) in methanol (50 mL) and stir at room temperature overnight. Add
formaldehyde (37%)(0.973 g), sodium cyanoborohydride (0.917 g) and acetic acid (2 mL)
and stir at room temperature overnight. Partition the reaction mixture between
dichloromethane and saturated saturated aqueous NaCl, dry over anhydrous sodium
sulfate, evaporate and purify on a silica gel column, using a gradient of dichloromethane-
2M NH3 in methanol to give 1.06 g of the title intermediate.
Preparation 22. 1-Methyl-4-(N-(3-amino-2-f!uorophenyl)methylamino)piperidine

Heat a mixture of 1-Methyl-4-(N-(3-chloro-2-
fluorophenyl)methylamino)piperidine (Preparation 21) (0.77 g), benzophenone imine
(0.652 g), Pd2(dba)3 (6.9 mg), racemic BINAP (7.9 mg) and sodium r-butoxide (0.404 g)
in toluene (10 mL) for 44 hours. Dilute the reaction mixture with methanol, load on a
SCX column (10 g), wash with methanol, elute the product with 2M NH3 in methanol,
evaporate and purify on a silica gel columnn (110 g), using a gradient of dichloromethane-
2M NH3 in methanol to give 0.21 g of 1-methyl-4-(N-(3-benzhydrylidenylamino-2-
fluorophenyl)methylamino)piperidine.
Add 2 mLof 1N HCl into a solution of the diamine (0.21 g) and stir for 30 min,
basicity with NH4OH, extract with ethyl acetate, dry over anhydrous sodium sulfate,
evaporate and purify on a silica gel column (10 g), using a gradient of dichloromethane-
2M NH3 in methanol to give 44 mg of the title intermediate.
Preparation 23. 1 -Methyl-4-(N-(2-fluorophenyl)Methylamino)piperidine


Mix 1-bromo-2-fluorobenzene (3.50 g), 1-methyl-4-(methylamino)piperidine
(2.56 g), Pd2(dba)3 (0.366 g), racemic BINAP (0.498 g) and sodium t-butoxide (2.70 g) in
toluene (40 mL) and heat at reflux for two days. Filter through a Celite bed. partition
between dichloromethane and saturated aqueous NaCl, dry over anhydrous sodium
sulfate, evaporate and purify on a silica gel column (35 g). using a gradient of
dichloromethane-2M NH3 in methanol to give 1.1 g of the title intermediate.
Preparation 24. 1-Methyl-4-(N-(2-fluoro-3-bromophenyi)methylamino)piperidine

Add n-butyl lithium (1,6 M in hexanes. 4.3 mL) into a solution of 2.2.6.6-
tetramethyl-piperidine(0.97 g) in THF(10 mL)at -78°C and stir for 30 minutes. Add a
solution of 1-methyl-4-(N-(2-fluorophenyl)methylamino)piperidine (Preparation 23. 1.02
g) in THF (10 mL) portionwise and stir for 10 minutes. Add 1,2-dibromo-1, 1, 2, 2-
tetrachloroethane (1.50 g) in THF (10 mL) dropwise and stir for 1 hr. Remove the
cooling bath and stir for 30 minutes. Partition between ethyl acetate and saturated
aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel
column (110 g), using a gradient of dichloromethane-2M NH3 in methanol to give 0.49 g
of the title intermediate.
Preparation 25. 1 -Methyl-4-(N-(2-fluoro-3-aminophenyl)methylamino)piperidine

Mix 1-methyl-4-(N-(2-fluoro-3-bromophenyl)methylamino)piperidine
(Preparation 24. 0.42 g), benzophenone imine (0.303 g), Pd2(dba)3 (25 mg). racemic
BINAP (35 mg) and sodium t-butoxide (0.187 g) in toluene (10 mL) and heat at reflux for
3 hours. Dilute the reaction mixture with methanol (5 mL), load on a SCX column (10 g),
wash with methanol, elute the with 2M NH3 in methanol, evaporate and further purify on

a silica gel column (10 g), using a gradient of dichloromethane-2M NH3 in methanol to
give 0.44 g of the title intermediate.
Preparation 26. 1-Methyl-4-CN-(2-fluoro-3-chlorophenyl)ethylamino)piperidine

Add acetaldehyde (0.817 g) to a solution of 1-methyl-4-(3-Chloro-2-
fluorophenylamino)piperidine (Preparation 19) (0.4.5 g), sodium cyanoborohydride
(0.123 g) and trifluoroacetic acid (0.633 g) in methanol (20 mL) and heat in a sealed tube
at 80°C for three days. Load on a SCX column (10 g), wash with methanol, elute with
2M NH3 in methanol, evaporate, and further purify on a silica get column (35 g), using a
gradient of dichloromethane-2M NH3 in methanol to give 0.50 g of the title intermediate
as a colorless oil: mass spectrum (electric spray) m/z = 271 (M+1); 1H NMR (CDCl3):
6.94 (m, 3H), 3.14 (q. J= 7.0 Hz, 2H). 3.06 (m, 1H), 2.84 (br d, 2H), 2.22 (s. 3H). 1.93
(m, 2H), 1.74 (m. 4H), 0.95 (t, .1= 7.0 Hz, 3H).
Preparation 27. 1-Methyl-4-(N-(2-fluoro-3-aminophenyl)ethylamino)piperidine

Mix 1 -Methyl-4-(N-(2-fluoro-3-chlorophenyl)ethylamino)piperidine (Preparation
26) (0.367 g), benzophenone imine (0.295 g), Pd2(dba)3 (50 mg), 2-(di-t-
butylphosphino)biphenyl (32 mg), and sodium t-butoxide (0.182 g) in toluene (10 mL)
and heat at reflux for three days. Dilute with methanol (5 mL), 30 minutes after adding 2
mL of 5N HCl, load on a SCX column (10 g), wash with methanol, elute the product with
2M NH3 in methanol, evaporate and purify on a silica gel column (35 g), using a gradient
of dichloromethane-2M NH3 in methanol to give 39 mg of the title compound: mass
spectrum (electric spray) m/z = 252 (M+1).

Preparation 28. 1-Methyl-4-(N-(3-nitro-5-fluorophenyl)methylamino)piperidine

Combine 1,3-difluoro-5-nitro-benzene (1.78 mL, 15.7mmol), 1-methyl-4-
(methylamino)piperidine (2.74 mL, 18.85 mmol), sodium acetate (2.45 g, 29.8 mmol) and
absolute ethanol (10 mL) in a sealed tube. Heat and stir at 100°C for 16 hr. Cool the
reaction mixture to ambient temperature and pour into water (100 mL). Extract with ethyl
acetate (2x100 mL). Wash combined organic layers with saturated aqueous NaCl solution
(100mL), dry over sodium sulfate, filter, and concentrate. Purify residue by silica gel
flash chromatography eluting with 10% (2M NH3 in methanol) in CH2Cl2 to obtain 0.06 g
(1.4%)of the title intermediate: 1H NMR (CDCl3): 7.3 (m, 1H), 7.2 (m, 1H),6.7(m, 1H),
3.6 (m, 1H), 3.0 (m, 2H), 2.8 (s, 3H), 2.3 (5, 3H), 2.2 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Preparation 29. 1 -Methyl-4-(N-(3-amino-5-fluorophenyl)methylamino)piperidine

Combine 1-Methyl-4-(N-(3-nitro-5-fluoropheny])methylamino)piperidine
(Preparation 28) (0.06 g. 0.22 mmole), iron dust (0.06 g. 1.12 mmol), methanol (5 mL)
and 1M HCl (0.22 mL, 0,22 mmol), stir, and heat at reflux for 18 hr. Cool the reaction
mixture to ambient temperature, dilute with ethyl acetate (50 mL), and add 1N sodium
hydroxide solution until basic (pH=9). Separate organic layer, wash with saturated
aqueous NaCl solution, dry over sodium sulfate, filter, and concentrate to obtain 0.036 g
(69%) of the title intermediate: 1H NMR(CDCl3): 5.9 (m, 1H), 5.7 (m, 2H). 3.6 (bs, 2H),
3.4 (m, 1H), 2.9 (m, 2H), 2.7 (s, 3H), 2.3 (s, 3H), 2.0 (m, 2H), 1.8 (m, 2H), 1.7 (m, 2H).
Preparation 30. 1-Methyl-4-(N-(3-bromo-5-fluorophenyl)methylamino)piperidine


Combine l,3-dibromo-5-fluorobenzene (5.0 g, 19.7 mmol), 1-methyl-4-
(methylamino)piperidine(2.58 mL, 17.7 mmol), 2,2'-bis(diphenylphosphino)-1,1'-
binaphthyl (0.49 g, 0.79 mmol), sodium t-butoxide (2.57 g, 27.58 mmole) and toluene
(100 mL). stir and heat at 80°C. After 10 minutes, add Pd2(dba)3 (0.49 g, 0.79 mmol).
After 3 hr. at 80°C, cool to ambient temperature. Dilute with ethyl acetate (100 mL) and
wash with water (50 mL). Dry the organic layer over sodium sulfate, filter, and
concentrate to an oil. Purify the residue by silica gel flash chromatography eluting with
10% (2M NH3-methanol) in CH2Cl2 to obtain 2.95 g (55%)of the title intermediate: 1H
NMR (CDCl3): 6.6 (s, 1H), 6.5 (m, 1H), 6.3 (m, 1H), 3.5 (m, 1H), 2.9 (m, 2H), 2.7 (s,
3H), 2.3 (s, 3H), 2.0 (m, 2H), 1.8 (m, 2H), 1.7 (m, 2H).
Preparation 31. 1-Methyl-4-(N-(3-amino-5-fluorophenyl)methylamino)piperidine

Combine 3 -methyl- 4-(N-(3-bromo-5-fluorophenyl)methylamino)piperidine
(Preparation 30, 2.90g. 9.63 mmol), benzophenone imine (1.94 mL, 11.55 mmol), 2,2'-
bis(diphenylphosphino)-1,1'-binaphthyl (0.24 g, 0.39 mmol), sodium t-butoxide (1.26 g,
13.48 mmol), and toluene (60 mL), stir and heat to 80°C. After 10 minutes, add Pd2(dba)3
(0.17 g, 0.19 mmol). After 3 hr at 80°C. cool to ambient temperature. Dilute with ethyl
acetate (100 mL)and wash with water (50 mL). Separate organic layer, dry over sodium
sulfate, filter and concentrate. Dissolve this material in tetrahydrofuran (120 mL) and
treat with 1M aqueous hydrochloric acid solution (40 mL). After stirring at ambient
temperature for 1 hr, add 2M sodium hydroxide solution until basic (21 mL). Extract
with ethyl acetate (2 x 100 mL). Wash organic layer with saturated aqueous NaCl
solution (75 mL), dry over sodium sulfate, filter and concentrate to an oil. Purify residue
by silica gel flash chromatography eluting with 10% (2M NH3 in methanol) in CH2Cl2 to
obtain 1.96 g (86%) of the title compound.
Preparation 32. 1.3-Diamino-5-fluorobenzene


Add 1,3-dibromo-5-fluorobenzene (5.078 g, 20 mmol), benzophenone imine
(8.700 g, 48 mmol), Pd2(dba)3 (366 mg, 0.4 mmol), BINAP (747 mg. 1.2 mmol) and
sodium t-butoxidc (4.998 g, 52 mmol) to toluene (100 mL). Heat the reaction mixture at
80°C for 15 hr. Quench the reaction with saturated NaHCO3 solution. Extract the
mixture with ethylacetate three times. Wash the combined organic layers with saturated
NaCl solution, dry over Na2SO4, filter and concentrate to give a residue. Dissolve the
residue in THF (80 mL), add 5N HCl (14 mL), and stir for 2 hr. Dilute the reaction
mixture with 0.1N HCl and extract with ethylacetate/hexanes (1:2) twice. Wash the
combined organic layer once with 0.1N HCl, combine the aqueous layers, adjust to
pH>11 with 5N NaOH. Extract the turbid mixture with CH2Cl2 three times. Combine the
organic layers, dry over Na2SO4, filter, and concentrate to give an orange-color oil. Purify
by chromatography on silica gel. eluting with 30-60% ethylacetate in hexanes to obtain
the title intermediate as a yellow oil (1.955 g, 77%): mass spectrum (ion spray): m/z =
127.1 (M+1); 1H NMR (CDCl3, ppm): 5.82 (m, 3H), 3.67 (s, br. 2H).
Preparation 33. 1 -Methyl- 4-(N-(6-bromopyridinyl)methylaminopiperidine

Dissolve 2,6-dibromopyridine (5.0 g, 21.1 mmol), (±)-BINAP (1.09 g, 1.76
mmol), and Pd2(dbab (805 mg. 0.88 mmol) in toluene (50 mL). Stir and add 1 -methyl-4-
(methylamino)piperidine (2.56 mL, 17.6 mmol) followed by sodium t-butoxide (2.37 g,
24.6 mmol). Heat the reaction mixture to 80°C for 40 hr. Cool the reaction mixture to
room temperature and partition between ethyl acetate and water. Separate the organic
layer and extract the aqueous layer with dichloromethane (2 x 50 mL). Combine the
organic extracts, dry over MgSO4, filter, and concentrate in vacuo. Load residue onto an
SCX column and wash with methanol. Elute with with 2M ammonia in methanol and
concentrate in vacuo. Further purify the product by column chromatography on silica gel
using a gradient of 2%-10% (2MNH3 in methanol) in CH2Cl2) to give of the title
intermediate (632 mg. 13%): mass spectrum (ion spray): m/z 286.0 (M+1): 1H NMR: δ
(CDCl3, ppm) 7.25 (m, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 8.4 Hz. 1H), 4.37 (m,
1 H). 2.94 (m, 2H). 2.85 (s, 3H), 2.30 (s, 3H). 2.13 (m, 2H), 1.85 (m, 2H). 1.68 (m, 2H).

Preparation 34. 1-Methyl- 4-(N-(6-aminopyridinyl)rnethylaminopiperidine

Mix 1-methyl- 4-(N-(6-bromopyridinyl)Methylaminopiperidine (1.02 g, 3.59
mmoi) (Preparation 33), (±)-BIMAP (224 mg, 0.36 mmol), and Pd2(dba)3 (164 mg, 0.18
mmol) in toluene (20 mL). Add benzophenone imine (723 µL, 4.31 mmol) and sodium
tert-butoxide (483 mg, 5.03 mmol) to the reaction and heat to 80°C for 19 hr. Cool the
reaction mixture to room temperature and partition between ethyl acetate and water.
Separate the organic layer, and extract the aqueous layer with dichloromethane (2 x 50
mL). Combine the organic extracts, dry (MgSO4), filter, and concentrate in vacuo.
Dissolve the residue in 50 mL of 1:1 THF/H2O and treat with 50 mL of aqueous 1N HCl
for 2 hr. Load the solution onto an SCX column, and wash successively with 1:1
THF/H2O, methanol, and finally with 2M ammonia in methanol. Concentrate the basic
wash in vacuo, and purify the residue by column chromatography on silica gel using a
gradient of 2%-10% (2M NH3 in methanol) in CH2Cl2 to give of the title intermediate
(459 mg, 58%): mass spectrum (ion spray): m/z =221.2 (M+1); Analysis Calcd for
C12H20N4 0.1 CH2Cl2: C, 63.51; H, 8.90; N, 24.49. Found: C, 63.42; H, 8.56; N, 24.25.
Preparation 35. 1 -Methyl-4-(N-(6-chloropyridin-2-yl)methylamino)piperidine

Dissolve 1-methyl-4-(methylamino)piperidine (10 mL, 68.8 mmol) in
tetrahydrofuran (50 mL) and cool to -78°C. Slowly add n-butyllithium (1.6 N in hexane,
43 mL, 68.8 mmol) to the reaction mixture and stir at -78°C for 30 min. Warm the
reaction mixture to room temperature and stir for 30 min. Then cool the reaction mixture
to -78°C and add 2,6-dichloropyridine (11.2 g, 75.7 mmol) in tetrahydrofuran (50 mL).
Stir the reaction mixture at -78°C for 15 min, warm to room temperature, and then heat to
60°C for 19 hr. Cool the reaction mixture to room temperature and partition between
ethyl acetate and water. Separate the organic layer and extract the aqueous layer with

dichloromethane (2 x 50 mL). Combine organic extracts, dry (MgSO4), filter, and
concentrate in vacuo. Purify the. residue by column chromatography on silica gel using a
gradient of 2%-10% (2M NH3 in methanol) in CH2Cl2 to give of the title intermediate
(11.91 g, 72%): mass spectrum (ion spray): m/z =240.1 (M+1); 1H NMR: δ (CDCl3, ppm)
7.34 (t, J=7,6, 16.0 Hz, 1H), 6.50 (d, J= 8.0 Hz, 1H), 6.33 (d, J = 8.8 Hz, 1H), 4.41 (m,
1H), 2.94 (m, 2H), 2.86 (s, 3H), 2.32 (s, 3H), 2.15 (m, 2H), 1.84 (m, 2H), 1.68 (m, 2H).
Preparation 36. 1-Methyl-4-(N-(6- aminopyridine)methylamino)piperidine

Place 1-methyl-4-(N-(6-chloropyridin-2-yl)methylamino)piperidine (Preparation
35, 1.62 g, 6.76 mmol), (±)-BINAP (420 mg, 0.68 mmol), and Pd2(dba)3 (310 mg, 0.34
mmol) in toluene (15 mL). Add benzophenone imine (1.36 mL, 8.11 mmol) and sodium
tert-butoxide (910 mg, 9.46 mmol) to the reaction and heat to 80°C for 20 hr. Cool the
reaction to room temperature and partition between ethyl acetate and water. Separate the
organic layer, and extract the aqueous layer with dichloromethane (2 x 50 mL). Combine
the organic extracts, dry over MgSO4, filter, and concentrate in vacuo. Load the residue
on an SCX column, wash with methanol, elute with 2M ammonia in methanol, and
concentrate in vacuo. Dissolve the residue in 50 mL of 1:1 THF/H2O and treat with 50
mL of IN HCl for 2 hr. Load the solution onto an SCX column, and wash successively
with 1:1 THF/H2O, methanol, and finally with 2M ammonia in methanol. Concentrate
the basic wash in vacuo, and purify the residue by column chromatography on silica gel
using a gradient of 2%-10% (2M NH3 in methanol) in CH2Cl2 to give of the title
intermediate (l.38g, 93%): mass spectrum (ion spray): m/z =221.1 (M+1); 1H NMR: δ
(CDCl3, ppm) 7.23 (t, J = 9.2, 17.2 Hz, 1H), 5.86 (d, J= 8.0 Hz, 1H), 5.78 (d, J = 7.2 Hz,
1H), 4.46 (m, 1H), 4.13 (bs, 2H), 2.94 (m, 2H), 2,81 (s, 3H), 2.31 (s, 3H), 2.11 (m, 2H),
1.84 (m, 2H), 1.65 (m, 2H).
Preparation 37. N-(6-Aminopyridin-2-yl)-4-fluorobenzamide


Combine tricthylamine (15.8 mL, 111.0mmol) and 2,6-diaminopyridine (6.5 g,
59.6 mmol) in dioxane (200 mL). Add 4-fluorobenzoyl chloride (5.46 mL. 44.7 mmol) in
small increments. After complete addition, stir at room temperature for 18 hr. Pour into
water and dilute with ethyl acetate and water. Separate and extract twice the aqueous
layer with CH2Cl2, combine the organic fractions, dry over MgSO4, and concentrate.
Chromatograph on silica gel, eluting with a gradient of 0%-10% (2M NH3 in methanol) in
CH2Cl2 to give the title intermediate (8.91 g, 86.3%): mass spectrum (ion spray): m/z
=232.3 (M+1); Analysis calc'd for C12H10N3OF-0.1 H2O: C, 61.85; H, 4.41; N, 18.03.
Found: C, 61.75; H, 4.08; N, 17.66.
Preparation 38. N-(6-Aminopyridin-2-yl)-2-chloro-4-fluorobenzamide

Using a method similar to Preparation 37, using 2-chloro-4-fluorobenzoyl
chloride, gives the title intermediate as a tan solid: mass spectrum (ion spray): m/z = 266.2
(M+1); Analysis calc'd for C12H9N3OClF: C, 54.25; H, 3.41: N, 15.82. Found: C, 53.98;
H, 3.23; N, 15.54.
Preparation 39. 4-(6-(4-F1uorobenzoylamino)pyridin-2-ylamino)piperidine-1-carboxylic
acid t-butyl ester

Place N-(6-aminopyridin-2-yl)-4-fluorobenzarnide (Preparation 37) (2 g, 8.3
mmol)and 1-boc-4-piperidone (15.0 g, 83 mmol) in 1,2-dichloroethane (20 mL). Stir for
1 hr. then add sodium triacetoxyborohydride (4.38 g, 20.8 mmol). After stirring for 36
hr., quench with 1 N NaOH and dilute with CH2Cl2. Separate and extract the aqueous
layer twice with CH2Cl2, combine organics, dry over MgSO4, and concentrate. Take up

the residue in CH2Cl2, and place on two 10 g SCX columns. Wash the
columnssuccessively with CH2Cl2 and then with methanol. Elute the product with 2M
NH3 in methanol. Concentrate and chromatograph on silica gel, eluting with a gradient of
0-10% (2M NH3 in methanol) in CH2Cl2) to give the title intermediate 3.11 g (90%):
mass spectrum (ion spray): m/z 415.4 (M+1); mp 82.7°C.
Preparation 40. 4-(6-(2-Chloro-4-fluorobenzoylamino)pyridin-2-ylamino)piperidine-1-
carboxylic acid tert-butyl ester

Using a method similar to Preparation 39, using N-(6-aminopyridin-2-yl)-2-
chloro-4-fluorobenzamide (Preparation 38, 2.0g, 7.5mmol), gives the title intermediate as
a white solid: mass spectrum (ion spray): tn/z = 449.4 (M+1); mp 82.0°C.
Preparation 41. 4-((6-(4-FIuorobenzoylamino)pyridin-2-yl)methylamino)piperidine-1-
carboxylic acid tert-butyl ester

Place 4-(6-(4-fluorobenzoyiamino)pyridin-2-ylamino)piperidine-1 -carboxylic acid
t-butyl ester (Preparation 39) (3.1 g, 7.4 mmol) and formaldehyde (37% in water) (6.1
mL, 74 mmol) in methanol (10 mL) and stir for 36 hr. Add sodium cyanoborohydride
(2.3 g, 37.0 mmol) and stir for 2 hr. Quench the reaction with 1N NaOH and dilute with
CH2Cl2, Separate and extract the aqueous layer twice with CH2Cl2, and once with 3:1
CHCl3:isopropanol. Combine the organic fractions, dry over MgSO4. and concentrate.
Chromatograph on silica gel. eluting with a gradient of 0-10% (2M NH3 in methanol) in
CH2Cl2 to give the title intermediate (0.97 g, 30.6%): mass spectrum (ion spray); m/z
=429.4 (M+1);mp 77.7°C.

Preparation 42. 4-((6-(2-Chloro-4-fluorobenzoylamino)pyridin-2-
yl)methylamino)piperidine-1-carboxylic acid tert-butyl ester

Using a method similar to Preparation 41, using 4-(6-(2-chloro-4-
fluorobenzoylamino)pyridin-2-ylamino)piperidine-1-carboxylic acid t-butyl ester
(Preparation 40, 2.11g, 4.6mmol), gives the title intermediate as a white solid: mass
spectrum (ion spray): m/z - 463.3 (M+1); mp 79.1°C.
Preparation 43. N-(6-Aminopyridin-2-yl)-2,4,6-trifluorobenzamide

Combine 2,4,6-trifluorobenzoyI chloride (3.891 g, 20 mmol), 2,6-diaminopyridine
(6.548 g, 60 mmol) and dioxane (25 mL) and stir for 1 hr. at room temperature followed
by heating at 40°C overnight. Dilute the reaction mixture with CH2Cl2 (100 mL), and
wash with 0.1N NaOH solution. Extract the aqueous layer three times with CH2Cl2-
Combine the organic layers, dry over Na2SO4, filter, and concentrate to a residue.
Chromatography on silica gel, eluting with a gradient of 40-50% ethylacetate in hexanes
gives the title intermediate (3.95 g, 74%): mass spectrum (ion spray): m/z = 267.9 (M+1);
1H NMR(CDCl3, ppm):8.28(s, br, 1H), 7.66 (d, 1H), 7.52 (t, 1 H), 6.78 (m, 2H), 6.3 1 (d,
lH),4.36(s, br, 2H).
Preparation 44. N-(6-Amino-pyridin-2-yl)acetamide

Dissolve 2,6-diaminopyridine (9.822 g, 90 mmol) in dioxane (100 mL) and cool to
0°C. Add acetyl chloride (2.355 g, 2.1 mL, 30 mmol) slowly and stir for 1 hr. at 0°C.
Remove the ice bath and stir at room temperature overnight. Quench the reaction mixture
with saturated NaHCO3 solution, extract with ethylacetate three times. Combine the

organic layers, dry over Na2SO4, filter, and concentrate to give a solid. Chromatography
on silica gel, eiuting with a gradient of 60-70% ethytacetate in hexanes affords the title
intermediate (3,45 g, 76%): mass spectrum (ion spray): m/z = 152.1 (M+1); 1H NMR
(CDCl3, ppm): 7.49 (m. 3H), 6.28 (d, 1H),4.31 (s, br, 2H), 2.19 (s, 3H).
Preparation 45. N-(6-Aminopyridin-2-yl)-2-chlorobenzamide

Using a method similar to Preparation 44, using 2-Chlorobenzoyl chloride (875
mg, 5.0 mmol) gives the title intermediate of as a white solid (1.172 g, 95%): mass
spectrum (ion spray) m/z = 247.9 (M+1): 1H NMR (CDCl3, ppm): 8.37 (s, 1H), 7.72 (m,
2H), 7.44 (m. 4H), 6.31 (d, 1H), 4.36 (s. br, 2H).
Preparation 46. N-(6-Amino-pyridin-2-yl)-2-bromobenzamide

Using a method similar to Preparation 44, using 2-bromobenzoyl chloride (1.097
g, 5.0 mmol) gives the title intermediate as a white solid (1.445 g, 99%): mass spectrum
(ion spray): m/z - 291.9 (M+1); 1H NMR (CDCl3, ppm): 8.27 (s, br. 111), 7.65 (m, 4H).
7.34 (m, 2H). 6.29 (d, 1H). 4.36 (s, br, 2H).
Preparation 46. Cyclohexanecarboxylic acid (6-aminopyridin-2-yl)amide

Using a method similar to Preparation 44, using cyclohexanecarbonyl chloride
(733 mg, 5.0 mmol) gives the title intermediate as a white solid (1.137 g, 100%): mass
spectrum (ion spray): m/z = 242.0 (M+Na); 1H NMR (CDCl3, ppm): 7.97 (s, 1 H), 7.56 (d,
1H), 7.43 (dd, 1H),6.23(dd, 1H), 4.40 (s, br, 2H), 2.18 (m, 1H), 1.81 (m, 4H), 1.66(1H),
1.46 (2H), 1.20 (m, 3H).

Preparation 48. N-(6-Aminopyridin-2-yl)-2-chloro-6-fluorobenzamide

Dissolve 2,6-diaminopyridine (1.3 g, 12 mmol) in dioxane (30 mL). Add 2-
Chloro-6-fluorobenzoyl chloride (768 mg, 4 mmol). Stir under nitrogen (40oC, 64 hr.).
Transfer the reaction mixture into ethyl acetate (150 mL). Wash with saturated sodium
bicarbonate solution (80 mL). Dry over anhydrous sodium sulfate. Remove the solvent
under reduced pressure and clean by chromatography (silica gel, 10% ethyl
acetate/hexanes) to give the title intermediate (820 mg, 78% yield): mass spectrum (ion
spray): m/z = 266.0 (M+1).
Preparation 49. N-(6-Aminopyridin-2-yl)-3-chloro-2,6-difluorobenzamide

Using a method similar to Preparation 48. using 3-chloro-2,6-difluorobenzoyl
chloride (840 mg, 4 mmol) gives the title intermediate (761 mg, 67% yield): mass
spectrum (ion spray): m/z = 284,0 (M+1).
Preparation 50. N-(6-Aminopyridin-2-yl)-2,6-difiuoro-3-Methylbenzamide
Using a method similar to Preparation 48, using 2,6-difluoro-3-methylbenzoyl

chloride (760 mg, 4 mmol) gives the title intermediate (669 mg, 64% yield): mass
spectrum (ion spray): m/z = 264.1 (M+1).
Preparation 51. N-(6-Aminopyridin-2-yl)-2,4-difluorobenzamide


Using a method similar to Preparation 48. using 2,4-difluorobenzoyl chloride (704
mg, 4 mmol, stir at 25°C for 16 hr.) gives the title intermediate (625 mg, 63% yield): mass
spectrum (ion spray): m/z = 250,0 (M+1).
Preparation 52. N-(6-Aminopyridin-2-yl)-2,6-dichlorobenzamide

Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6 g, 24
mmol), dioxane (75 mL), and 2,6-dichlorobenzoyl chtoride (1.68 g, 8 tnmol)(stir at 25°C
for 16 hr.) gives the title intermediate (i .5 g, 66% yield): mass spectrum (ion spray): m/z
= 282.0 (M+1)
Preparation 53. N-(6-Aminopyridin-2-yl)-2,6-difluorobenzamide

Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6 g, 24
mmol), dioxane (75 mL), and 2,6-difluorobenzoyl chloride (1.4 g, 8 mmol)(stir at 25°C
for 16 hr.), gives the title intermediate (1.5 g, 75% yield): mass spectrum (ion spray): m/z
= 250.1 (M+1).
Preparation 54, N-(6-Aminopyridin-2-yl)-2,4-dichlorobenzamide


Using a method similar to Preparation 48, using 2,4-dichlorobenzoyl chloride (838
mg, 4 mmol)(stir at 0-25°C for 16 hr.), gives the title intermediate (621 mg, 56% yield):
mass spectrum (ion spray): m/z = 282.0 (M+1).
Preparation 55. N-(6-Aminopyridin-2-yl)-2,4,6-trichlorobenzamide

Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6 g, 12
mmol), dioxane (80 mL), and 2,4,6-trichlorobenzoyl chloride (1.95g, 8 mmol)(stir at 0-
25°C for 16 hr.) gives the title intermediate (1.0 g, 39% yield): mass spectrum (ion spray):
m/z = 316.0 (M+1).
Examples
Example t. 2-Chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide
dihydrochloride

Combine 2-chloro-4-fluoro-N-(3-aminophenyl)benzamide (Preparation 1, 200 mg,
0.756 mmol), 1-methylpiperidin-4-one (0.093 mL, 0.756 mmol), sodium
triacetoxyborohydride (208 mg, 0.982 mmol), acetic acid (0.043 mL, 0.756 mmol) and
dichloromethane (8 mL). Stir at room temperature overnight. Dilute with
dichloromethane (5 mL) and wash twice with sodium hydroxide (10 mL 1N aq.).
Combine the organic layers and wash with saturated aqueous NaCl (10 mL). Dry over
magnesium sulfate, filter under reduced pressure and concentrate to dryness. Purify by
flash chromatography on a Biotage® silica cartridge eluting with a 20/1 mixture of
dichloromethane and 2N ammonia in methanol to give the free base of the title compound
(239 mg, 87%). Dissolve the residue in diethyl ether and treat with ethereal hydrogen
chloride. Triturate the resulting gum with ether to give the title compound as a white
solid (31 mg): mp 180°C; mass spectrum (free base, ion spray): m/z = 362.1 (M+H ), 1H
NMR (free base, CDCl3): 7.80 - 7.75 (m, 2H), 7.23 (bs, 1H), 7.19 (dd, J - 2.4 Hz, 8.3 Hz,

1H). 7.13 (t, J= 8.2 Hz, 1H). 7.08 (dd. J= 2.4 Hz, 8.3 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H),
6.41 (dd, J =2.0Hz.8.3 Hz, 1H), 3.68 (bd, J = 7.9 Hz, 1H),3.36(bs, 1H). 2.92 - 2.81
(bm, 2H), 2.35(s, 3H), 2.82-2.17(bm. 2H), 2.10(bd, J = 13.0 Hz, 2H), 1.64- 1.51 (bm,
2H). Analysis calc'd for C19H23Cl3FN3O: C. 51.95; H. 5.39; N. 9.57. Found: C, 52.03;
H, 5.46; N, 9.17.
Alternatively, to a solution of 1-methyl-4-(3-aminophenylamino)piperidine (92 g,
17mmol) and triethylamine (156 mL, 39 mmol) in dry THF (1 L), add dropwise 2-Chloro-
4-fluorobenzoyl chloride (3.6 g, 18,6 mmol), under nitrogen, over 1 hr., keeping the Tmass
between 20°C and 26aC. Agitate the suspension at room temperature for t hr. Quench
the reaction mixture with water (100 mL) and 30% NaOH (40 mL) to obtain a biphasic
solution (pH~8-9). Extract with methyl t-butyl ether (500 mL), wash the organic layer
with water (100mL), dry over MgSO4, and concentrate under reduced pressure to obtain
2-Chloro-4-fluoro-N-(3-(1-metbylptperidin-4-ylamino)phenyl)benzamide as an
amorphous solid. Suspend the solid with methyl t-butyl ether (400 mL) and warm the
mixture under reflux for 2 hr. Cool the mixture to room temperature, add cyclohexane
(100 mL) and methyl t-butyl ether (250 mL). Filter the resulting crystals, rinse with
methyl t-butyl ether (160 mL) and dry under reduced pressure at 50°C overnight to obtain
2-Chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide as a white
powder (123 g, 76% yield).
Example 1 A. 2-Chloro-4-fluoro-N-(3-(1 -methylpiperidin-4-ylamino)phenyl)benzamide
fumarate salt.
Fumaric acid (170 mg; 1.46 mmol) is added to a suspension of 2-Chloro-4-fluoro-
N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide (free base of Example 1, 500 mg,
1.38 mmol) in isopropanol (5 mL) at room temperature. The suspension is heated under
reflux for I hr., cooled down to room temperature and post-agitated for 2 hr. The crystals
are filtered, washed with isopropanol (2 x 0.5 mL) and dried under reduced pressure at
40°C to give a white solid (665mg, 100% yield). These crystals (100 mg; 0.21 mmol) are
resuspended in water (1 mL) and stirred at room temperature. After 5 min. of stirring.
The suspension becomes an orange homogeneous solution (after about 5 min.) and then
fine crystals appear (after about 10 min.). The mixture is post-agitated overnight. The
suspension is then Filtered, the solid washed with water (0.1 mL) and dried under reduced
pressure to give the title compound as a pure white solid (76mg, 76% yield).

Example 2. 2-Chloro-4-fluoro-N-(3-(N-cyclopropylcarbonyl-N-( 1-methylpiperidin-4-
yl)amino)phenyl)benzamide hydrochloride

Combine 2-Chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide
dihydrochloride (Example 1, 48 mg, 0.134 mmol), dioxane (1 mL) and
cyclopropylcarbonyi chloride (0.013 mL, 0.148 mmol). Shake and heat (106°C) in a J-
Kem® Reaction Block for 2 hr. Load onto a SCX column (Varian) and elute with 2 M
ammonia methanol to give the free base of the title compound (54 mg, 93%). Following a
salt formation method similar to that described in Example 1 gives the title compound as
a white solid (47 mg): mp 133-6°C; mass spectrum (freebase, ion spray): m/z- 430.1
(M+1), 1H NMR (freebase, CDCl3): 8.31 (bs, N-H), 7.76 (dd, J = 6.0 Hz, 8.6 Hz, 1H),
7.61 - 7.56 (m, 2H), 7.38 (t, J= 8.0 Hz, 1H), 7.19 (dd, J = 2.4 Hz, 8.3 Hz, 1H), 7.09 (td, J
= 2.4 Hz, 8.2 Hz, 1H). 6.96 (d, J = 8.2 Hz, 1H), 4.62 -4.53 (m, 1H), 2.80 (bd, J = 11.5
Hz, 2H),2.20(s, 3H), 2.05 (td, J = 2.2 Hz, 12.1 Hz, 2H), 1.83- 1.69(bm, 2H), 1.59-
i.37(bm,2H), 1.2! - 1.13 (m, 1H), 0.99 -0.89 (bm, 2H), 0.56 (bd, J = 7.4 Hz, 2H).
Analysis calc'd for C23H26Cl2FN3O2 0.8H2O: C, 57.46; H, 5.79; N, 8.74. Found: C, 57.16;
H, 5.73; N, 8.70.
Example 3. 2-Chloro-4-fluoro-N-(3-(N-cyclobutanecarbonyl-N-(1-methylpiperidin-4-
yl))arnino)phenyl)benzamide hydrochloride

Using a method similar to Example 2, using cyclobutylcarbonyl chloride (0.017
mL, 0.148 mmol) gives the title compound as a white solid (freebase, 46 mg, 78%;
hydrochloride, 30 mg): mass spectrum (freebase, ion spray): m/z - 444.2 (M+1), 1H
NMR (freebase, CDCl3): 8.29 (bs, N-H), 7.77 (dd, 7-6.0 Hz, 8.8 Hz, 1H), 7,54 (d, J =
8.2 Hz, 1H), 7.50 - 7.48 (bs, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.19 (dd, J = 2.4 Hz, 8.5 Hz,
1H). 7.09 (td, J =2.3 Hz. 8.2 Hz, 1H), 4.56 (tt, J = 4.2 Hz, 12.1 Hz, 1H), 2.89 - 2.76 (m,
3H), 2.32 -2.18 (m, 5H), 2.06 (td, J= 2.1 Hz, 12.1 Hz, 2H), 1.82- 1.64 (bm. 6H). 1.54-

1.32 (bm, 2H). Analysis calculated for C24H28Cl2FN3O2 1.0H2O: C, 57.83: H, 6.07; N,
8.43. Found: C, 57.77; H, 5.97; N, 8.36.
Example 2. 2-Chloro-6-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide
dihydrochloride

Using a method similar to Example 1, using 2-chloro-6-fluoro-N-(3-
aminophenyl)benzamide (Preparation 2. 300 mg, 1.133 mmol) gives the title compound
as a white solid (free base 358 mg, 87%; dihydrochloride 415 mg): mp 192-4°C; mass
spectrum (freebase, ion spray): m/z = 362.0 (M+1), 1H NMR (freebase, CDCl3): 7.41 (bs,
N-H), 7.38-7.32 (m, 1 H), 7.24 (bs, 1H), 7.13 (t, J = 8.2 Hz, 1H), 7.08 (td. J=0.9 Hz.
8.5 Hz, 1H), 6.66 (dd, J = 2.0 Hz, 8.0 Hz. 1H). 6.41 (dd, J=2.1 Hz, 8.0 Hz. 1H), 3.69
(bd, J = 7.9 Hz, !H), 3.35 (bs, N-H), 2.88 - 2.80 (bm, 2H), 2.33 (s, 3H), 2.19 (bt, J = 11.2
Hz, 2H), 2.12 - 2.05 (bm, 2H), 1.61 - 1.50 (bm, 2H). Analysis calc'd for
C19H23Cl3FN3O: C, 52.49; H, 5.33; N, 9.66. Found: C, 52.24; H, 5.43; N, 9.27.
Example 5. 2,6-Difluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamidc
dihydrochloride

Using a method similar to Example 1. using 2,6-difluoro-N-(3-
aminophenyl)benzamide (Preparation 3, 300 mg, 1.208 mmol) gives the title compound
as a white solid (freebase 355 mg, 85%; dihydrochloride 411 mg): mp 198°C (dec); mass
spectrum (freebase, ion spray): m/z = 346.0 (M+1), 1H NMR (freebase, CDCl3): 7.55 (bs,
N-H), 7.45 - 7.36 (m, 1H), 7.24 (t, J = 1.9 Hz, 1H), 7.12 (t, J= 8.0 Hz, 1H). 6.99 (t, J=
8.1 Hz,2H). 6.66 (dd, J= 1.4 Hz, 7.8 Hz, 1H), 6.40 (dd, J = 2.0 Hz, 8.0 Hz. 1H), 3.67
(bd,y= 8.1 Hz, 1H), 3.34 (bs,N-H), 2.83 (bd, J= 11.0 Hz, 2ht), 2.32 (s, 3H). 2.18 (bt, J =
11.6 Hz, 2H), 2.08 (bd, J = 12.7 Hz, 2H), 1.59 - 1.48 (m, 2H). Analysis calc'd for
C19H23Cl2F2N3O: C, 54.55; H, 5.54; N, 10.04. Found: C, 54.78; H, 5.69; N, 9.78.

Example 6: 2,4-Difluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide
dihydrochloride

Using a method similar to Example 1. using 2.4-difluoro-N-(3-
aminophenyl)benzamide (Preparation 4, 307 mg, 1.236 mmol) gives the titie compound
as a white solid (freebase 394 mg, 92%; dihydrochloride 394 mg): mp 262°C (dec); mass
spectrum {freebase, ion spray): m/z = 346.0 (M+1), 1H NMR (freebase, CDCl3): 8.20 -
8.02 (m, 2H), 7.14(t, J = 1.9 Hz, JH), 7.05 (t, J = 8.0 Hz, 1H), 7.00- 6.93 (m, 1H), 6.92
- 6.80 (m, 1H), 6.63 (dd, J=1.3 Hz, 7.9 Hz, 1H), 6.33 (dd, J = 1.9 Hz, 7.9 Hz, 1H). 3,58
(bd, J=8.1 Hz, 1H), 3.27 (bs, N-H), 2.73 (bd, J = 11.8 Hz, 2H), 2.22 (s, 3H). 2.07(bt. J =
11.1 Hz, 2H), 2.01 (bd,J = 12.9 Hz, 2H), 1.50 - 1.35 (m, 2H).
Example 7. 2,4,6-Trifluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide
dihydrochloride

Using a method similar to Example 1, using 2,4,6-trifluoro-N-(3-
aminophenyl)benzamide (Preparation 5, 290 mg, 1.089 mmol) gives the title compound
as a white solid (freebase 355 mg, 90%; dihydrochloride 355 mg): mp 257°C (dec); mass
spectrum (freebase, ion spray): m/z = 364,0 (M+1), 1H NMR (freebase, CDCl3): 7.43 (bs,
N-H), 7.1 3 (t,J= 2.0 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6,69 (t, J= 8.2 Hz, 2H). 6.57 (dd,
J = 1.4 Hz, 7.8 Hz, 1H), 6.33(dd, J = 1.9 Hz, 8.1 Hz, 1H), 3.59 (bd, J= 8.0 Hz, 1H), 3.25
(bs, N-H), 2.72 (bd, J= 11.8 Hz, 2H), 2.22 (s, 3H), 2.06 (bt, J= 11.2 Hz, 2H). 2.00 (bd, J
= 11.7 Hz, 2H), 1.50- 1.35 (m, 2H).
Example 8. 2-Bromo-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzarnide
dihydrochloride


Using a method similar to Example 1, using 2-bromo-N-(3-
aminophenyl)benzamide (Preparation 6, 304 mg, 1.044 mmol) gives the title compound
as a white solid (free base 377 mg, 93%; dihydrochloride 395 mg): mp 192-3°C; mass
spectrum (free base, ion spray); m/z = 388.1 (M+1), 1H NMR (free base, CDCl3): 7.65 -
7.60 (m,2H), 7.57 (bs, N-H), 7.40 (td, J = 1.1 Hz, 7.5 Hz, 1H), 7.31 (td, J = 1.7 Hz, 7.8
Hz, 1H), 7.24 (bt, J=2.1 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.67 (dd, J= 1.5 Hz. 7.9 Hz.
1H), 6.40 (dd, J = 2.0 Hz, 8.1 Hz, 1H), 3.68 (bd, J = 7.9 Hz, 1H), 3.38-3.29 (bm. 1H).
2.82 (bd, J = 11.2 Hz, 2H), 2.31 (s, 3H). 2.17 (bt, J= 11.2 Hz, 2H), 2.08 (bd, J = 12.9 Hz,
2H), 1.58 - 1.47 (m, 2H). Analysis calc'd for C19H24BrCl2N3O 0.25H2O C, 49.00; H,
5.30; N, 9,02. Found: C, 49.11; H, 5.36; N, 8.69.
Example 9. 2-Chloro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide
dihydrochloride

Using a method similar to Example 1, using 2-chloro-N-(3-
aminophenyl)benzamide (Preparation 7, 300 mg, 1.216 mmol) gives the title compound
as a white solid (free base 331 mg, 79%: dihydrochloride 333 mg): mp 206-8°C; mass
spectrum (free base, ion spray): m/z = 344.0 (M+1), 1H NMR (free base. CDCl3): 7.75 (bs.
N-H), 7.73 (dd, J = 2.0 Hz, 7.3 Hz, 1H). 7.46 - 7.34 (m, 3H), 7.25 (bt, J = 2.1 Hz, 1H),
7.13 (t, J =8.1 Hz, 1H). 6.68 (dd, J= 1.3 Hz, 7.9 Hz, 1H), 6.40 (dd. J = 2.0 Hz. 8.2 Hz,
1H), 3.67 (bd, J =7.7 Hz. 1H). 3.39 -3.29(bm. 1H), 2.83 (bd, J = 11.0 Hz, 2H), 2.32 (s,
3H), 2.18 (bt, J = 11.5 Hz,2H),2.09(bd, J= 12.5 Hz, 2H), 1.59- 1.48 (bm, 2H),
Analysis calc'd for C19H24Cl3N3O 0.5H2O: C, 53.60; H, 5.92; N, 9.87. Found: C, 53,94;
H, 5.91; N, 9.70.
Example 10. 2-Trifluoromethoxy-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide
dihydrochloride


Using a method similar to Example 1, using 2-trifluoromeihoxy-N-(3-
aminophenyl)benzamide (Preparation 8. 300 mg, 1.053 mmol) gives the title compound
as a white solid (free base 274 mg, 69%; dihydrochloride 325 mg); mp 1 59-62°C; mass
spectrum (free base, ion spray): m/z = 394,2 (M+1), 1H NMR (free base, CDCl3): 8.18 (bs,
N-H), 8.07 (d, J = 7.5 Hz, 1H), 7.55 (t, J= 7.5 Hz, 1H), 7.45 (t, J= 7.5 Hz, 1H), 7.34 (d, J
= 8.0 Hz, 1H), 7.21 (bs, 1H), 7.13 (t, J= 8.0 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1 H), 6.41 (d, J
= 7.5 Hz, 1H). 3.67 (bd, J=7.1 Hz, 1H), 3.38-3.28 (bm, 1H), 2.81 (bd, ,7=9.5 Hz, 2H),
2.30 (s, 3H), 2.22 - 2.04 (bm, 4H), 1.58 - 1.46 (bm, 2H).
Example 11. 2,6-Difluoro-N-(3-(N-methyl-N-(1-methylpiperidirt-4-
yl)amino)phenyl)benzamide dihydrochloride

Combine 1-methyl-4-(N-(3-aminophenyl)-N-methylamino)piperidine (Preparation
11, 101 mg, 0.307 mmol), dichloromcthanc (6 mL) and pyridine (0.125 mL, 1.535 mmol)
at 0°C. Add 2,6-difluorobenzoyl chloride (0.048 mL, 0.384 mmol) neat and continue
stirring for 1 hr. Dilute with dichloromethane (5 mL) and wash with sodium hydroxide
(1N aq., 2x8 mL). Combine the organic layers, dry over magnesium sulphate, filter
under reduced pressure and concentrate to dryness. Purify by flash chromatography,
eluting with a 20/1 mixture of dichloromethane/(2N ammonia in methanol) to give the
free base of the title compound (88 mg, 80%). Following a salt formation method similar
to that described in Example 1 gives the title compound as a yellow solid (89 mg): mass
spectrum (free base, ion spray): m/z = 360.1(M+1), 1H NMR (free base, CDCl3): 7.56 (bs,
1H), 7.44 - 7.34 (m, 2H). 7.20 (t, J = 8.2 Hz, 1H), 7.00 (t,J= 8.2 Hz, 2H), 6.78 (d. J =
8.0 Hz, 1H), 6.59 (dd, J =2.2 Hz. 8.2 Hz, 1H), 3.71 -3.63(bm, 1 H), 3.14 - 3.04 (bm,
2H), 2.82 (s, 3H), 2.41 (bs, 3H), 2.11 - 1.97 (bm, 2H), 1.79 (bd, J=13 Hz, 2H).
Example 12. 2-Chloro-4-fluoro-N-(3-(N-methyl-N-(1-methylpiperidin-4-
yt)amino)phenyl)benzamide dihydrochloride


Using a method similar to Example i 1, using 2-chloro-4-fluorobenzoyl chloride
(0.049 mL, 0.384 mmol) gives the title compound (free base 102 mg, 89%;
dihydrochloride 67 mg, white solid): mp (72°C; mass spectrum (free base, ion spray):
m/z = 376.1(M+1), 1H NMR (free base, CDCl3): 7.80 - 7.76 (m, 2H), 7.30 (bs, N-H), 7.22
- 7.18 (m, 2H), 7.09 (td, J = 2.4 Hz, 8.1 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.60 (dd, J =
2.1 Hz, 8.4 Hz, 1H), 3.68-3.58 (m, 1H), 3.03 (bd, J= 11.0 Hz, 2H), 2.82 (s, 3H), 2.36 (s,
3H), 2.23-2.15 (bm.2H), 2.01 - 1,89 (bm, 2H), 1.76(bd, J= 12.0 Hz, 2H). Analysis
calc'd for C20H23Cl3FN3O 0.25H2O: C, 53.53; H, 5.61; N, 9.36. Found: C, 53.19; H, 5.79;
N, 9.36.
Example 13. 2,4,6-Trifluoro-N-(3-(N-methyl-N-(1-methylpiperidin-4-
yl)amino)phenyl)benzamide dihydrochloride

Load 1 -methyl-4-(N-(3-aminophenyl)-N-methylamino)piperidine trihydrochloride
(Preparation 11, 240 mg, 1.094 mmol) in methanol (2 ml) onto a SCX column (2 g
cartridge, Varian). Elute with ammonia (2.0 M in methanol) to obtain the corresponding
free base. Concentrate to dryness. Dissolve the resulting brown oil in dioxane (2 mL)
and divide the solution into two aliquots (2 x 1 mL). Take one of the aliquots and add
dioxane (1 mL). Add 2,4.6-trifluoro-benzoyl chloride (0.052 mL, 0.401 mmol) neat.
Shake and heat at 106.5°C for 2 hr. Cool to ambient temperature and load onto a SCX
column (1 g cartridge. Varian), Elute with ammonia (2.0 M in methanol). Purify further
by flash chromatography using 20/1 mixture of dichloromethane and 2.0 M ammonia in
methanolto provide the free base of the title compound (86 mg, 62%). Following a salt
formation method similar to Example 1 gives the title compound as a white solid (99 mg);
mp 199-200°C; mass spectrum (free base, ion spray): m/z = 378.2 (M+1), 1H NMR (free
base, CDCl3): 7.44 (bs, N-H), 7.31 (bs, 1H), 7.19 (t, J= 8.3 Hz, 1H), 6.80-6.73 (m, 3H),
6.60 (dd, J = 2.2 Hz. 8.3 Hz. 1H), 3.64 (it, J = 4.0 Hz, 11,9 Hz, 1H). 3.05 (bd. J = 10.8
Hz, 2H), 2.81 (s, 3H), 2.38 (s, 3H), 2.28 - 2.17 (bm, 2H), 2.06 - 1.92 (bm, 2H), 1.76 (bd,
1 = 12.2 Hz, 2H).

Example 14. 2-Chloro-6-fluoro-N-(3-(N-methyl-N-(1-methylpiperidin-4-
yl)amino)phenyl)benzamide dihydrochloride

Using a method similar to Example 13, using 2-chloro-6-fluorobenzoyl chloride
(0.052 ml, 0.401 mmol) gives the title compound as a white solid (free base 100 mg,
73%; dihydrochloride 114 mg): mp 214-7°C; mass spectrum (free base, ion spray): m/z =
376.2 (M+1), 1H NMR (free base, CDCl3): 7044 (bs, N-H), 7.39 - 7.32 (m. 2H), 7.27 -
7.24 (m, 1H), 7.21 (t, ,7-8.1 Hz, 1H), 7.09 (t, J = 8.5 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H),
6.60 (dd, J = 2.3 Hz, 8.4 Hz, 1H), 3.72 - 3.63 (m, 1H), 3.09 (bd. J= 10.1 Hz. 2H), 2.82
(s, 3H), 2.41 (s, 3H), 2.33 - 2.22 (bm, 2H), 2.12 - 1.99 (bm, 2H), 1.79 (bd, J = 11.9 Hz,
2H). Analysis calculated for C20H25Cl3FN3O: C, 53.53; H, 5.61; N, 9.36. Found: C.
53.85; H, 5.72; N, 8.99.
Preparation 56. 4-(3-(2-Chloro-4-fluorobenzoylamino)phenylamino)pipeHdine-i-
carboxylic acid t-butyl ester

Using a method similar to Example 1, using 1-t-butoxycarbonyl-4-piperidone(158
mg, 0.793 mmol) gives the title free base compound (288 mg. 97%) as an off-white foam:
mass spectrum (ion spray): m/z = 446,2 (M-1); lH NMR (CDCl3): 7.81 (bs. N-H), 7.76
(dd, J = 6.1 Hz, 8.4 Hz, 1H), 7.27 (bs, 1H), 7.19 (dd, J = 2.3 Hz, 8.4 Hz, 1H). 7.15 (t, J =
8.0 Hz, 1H), 7.09 (td, J = 2.3 Hz, 8.2 Hz, 1H), 6.72 (bd, J= 7.7 Hz, 1H), 6.45 (M,J= 8.0
Hz, 1H), 4.09-3.99 (bm, 1H), 3.50 - 3.41 (bm, 1H), 2.92 (bt, J= 11.7 Hz. 2H), 2.09-
2.01 (bm,2H), 1.46 (s,9H), 1.71 - 1.54(bm,2H), 1.39 - 1.33 (bm, 2H).

Example 15. 2-Chloro-4-fluoro-N-(3-(pipendin-4-ylamino)phenyl)benzamide
dihydrochloride

Combine acetyl chloride (5 mL) and dried methanol (10 mL) at 0°C under a
nitrogen atmosphere. Stir for 1 hr. at 0°C. Add a solution of 4-(3-(2-Chloro-4-
fluorobenzoylamino)phenylamino)piperidine-1-carboxylic acid t-butyl ester (Preparation
56, 72 mg, 0.161 mmol) in methanol (2 mL). Stir overnight. Concentrate under reduced
pressure. Triturate with diethyl ether (1 mL) to provide a pale yellow foam of the title
compound: mp255-7°C; mass spectrum (ion spray): m/z = 348.2 (M+1). Analysis calc'd
for C18H21Cl3FN3O 1.0H2O: C, 49.28; H, 5.28; N, 9.58. Found: C, 49.15; H, 4.96; N,
9.56.
Example 16. 2-Chloro-N-(3-(N-methyl-N-(1-methylpiperidin-4-
y!)amino)phenyl)benzamide dihydrochloride

Combine 2-chloro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide
dihydrochloride (Example 9, 100 mg, 0.240 mmol), methanol (3 mL) and formaldehyde
(37% aq., 0.195 mL, 2.39 mmol). Stir at room temperature for 45 min. Cool to 0°C.
Add acetic acid (0.412 mL, 7.20 mmol) and sodium cyanoborohydride (26 mg: 0.420
mmol). Stir at room temperature overnight. Concentrate to dryness. Dissolve the residue
in a 2/1 mixture of ethyl acetate and hexanes (8 mL) and wash with sodium hydroxide
(1N aq., 2x6 mL). Separate the organic layer and dry over magnesium sulfate. Filter
and concentrate under reduced pressure. Purify through flash chromatography eluting
with a 20/1 mixture of diChloromethane and 2M ammonia in methanol to provide the free
base of the title compound (69 mg, 80%). Following a salt formation method similar to
Example 1 gives the title compound as a white solid (83 mg, white solid): mass spectrum
(free base, ion spray): m/z = 358.2 (M+1), 1H NMR (free base, CDCl3): 7.97 (bs, N-H),
7.66 (dd, J =1.7 Hz, 7.5 Hz, 1H), 7.42 - 7.27 (m, 4H), 7.17 (t, J = 8.2 Hz, 1 H). 6.82 (dd,
J= 1.5 Hz, 8.2 Hz, 1H), 6.57 (dd, J = 2.3 Hz, 8.4 Hz, 1H), 3.59 (tt, J = 3.9 Hz, 11.7 Hz,

1H), 2.90 (bd, J = 11.7 Hz, 2H), 2.78 (s, 3H), 2.26 (s, 3H), 2.05 (td, J=2.3 Hz. 12.0 Hz,
2H), 1.82 (qd, J=3.9 Hz. 12.0 Hz, 2H), 1.70 (bd, J = 12.0 Hz, 2H). Analysis calc'd for
C20H26Cl3N3O 0.25H2O: C, 55.18: H, 6.14; N, 9.65. Found: C, 55.03; H, 6.11; N, 9.26.
Example 17. 2-Bromo-N-(3-(N-methyl-N-(1-methylpiperidin-4-
yl)amino)phenyl)benzamide dihydrochloride

Using a method similar to Example 16, using 2-bromo-N-(3-(1-methylpiperidin-4-
ylamino)phenyl)benzamide dihydrochloride (Example 8, 100 ing, 0.217 mmol) gives the
title compound as a white solid (free base 62 mg, 71%; dihydrochloride 73 mg): mp 196-
7°C; mass spectrum (free base, ion spray): m/z = 402.2 (M+1), 1H NMR (free base,
CDCl3):7.76(bd, J = 11.3 Hz, N-H), 7.66 - 7.57 (m, 2H), 7.42 - 7.16 (m, 4H), 6.88 -
6.81 (m, 1H), 6.63 - 6.56 (m, 1H), 3.67 - 3.55 (bm, 1H), 2.98 - 2.89 (bm, 2H), 2.79 (bs,
3H), 2.27 (bs, 3H), 2.13 - 2.02 (bm, 2H), 1.92 - 1.78 (bm, 2H), 1.77 - 1.68 (bm, 2H),
Analysis calc'd for C20H26BrCl2N3O 0.5H2O: C, 49.61; H. 5.62; N. 8.68. Found: C,
49.84; H, 5.85; N, 8.36.
Example 18. 2,4-Difluoro-N-(3-(N-methyl-N-(1-methylpiperidin-4-
yl)amino)phenyl)benzamide dihydrochloride

Using a method similar to Example 16, using 2,4-difluoro-N-(3-(1-
methylpiperidin-4-ylamino)phenyl)benzamide dihydrochloride (Example 6, 100 mg,
0.239 mmol) gives the title compound as a white solid (free base 79 mg, 92%;
dihydrochloride 94 mg): mp 165-8°C; mass spectrum (free base, ion spray): m/z = 360.3
(M+1), 1H NMR (free base, CDCl3): 8.28 (bd, J= 13.8 Hz, N-H), 8.21 - 8.12 (bm, 1H),
7.29 - 7.23 (bm, 1H), 7.19 (t, J = 8.2 Hz, 1H), 7.06 - 6.77 (bm, 3H). 6,60 (d, J = 7.9 Hz.
1H), 3.65 - 3.53 (bm. 1H). 2.99 - 2.88 (bm, 2H), 2.81 (bs, 3H). 2.30 (bs, 3H), 2.09 (bt, J
= 11.0Hz, 2H), 1.92- 1.78 (bm,2H), 1.73(bd, J = 11,0 Hz. 2H). Analysis calc'd for
C20H25Cl2F2N3O: C, 55.56; H, 5.83; N, 9.72. Found: C, 55.62: H. 5.95: N, 9.69,

Preparation 57. 4-(N-(3-(2-Chloro-4-
fluorobenzoylamino)phenyl)methylamino)piperidine-1-carboxylic acid t-butyl ester

Using a method similar to Example 16, using 4-(3-(2-chloro-4-
fluorobenzoylamino)phenylamino)pipendine-1-carboxytic acid t-butyl ester (Preparation
56, 165 mg. 0.368 mmol) gives the title free base compound (169 mg, 99%): mass
spectrum (ion spray): m/z = 462.2 (M+I), 1H NMR (CDCl3): 8.(3 (bs. N-H), 7.67 (dd, J
= 6.0 Hz, 8.6 Hz, 1H), 7.31 (bt, J=2.0 Hz, 1H), 7.18 (t, J = 8,2 Hz, 1H), 7.13 (dd, J= 2.3
Hz, 8.6 Hz, 1H), 7.01 (td, J = 2.3 Hz, 8.2 Hz, 1H), 6.83 (bd, J = 8.0 Hz, )H). 6.59 (dd, J =
2.3 Hz, 8.4 Hz, 1H), 4.24 -4,14 (bm, 2H), 3.72 (tt, J = 3.8 Hz, 11.5 Hz, 1H), 2.76 - 2.73
(m, 5H), 1.74- 1.56 (bm, 4H), 1.45 (s,9H).
Example 19. 2-Chloro-4-fluoro-N-(3-(N-piperidin-4-yl)methylamino)phenyl)benzamide
dihydrochloride

Using a method similar to Example 15, using 4-(N-(3-(2-Chloro-4-
fluorobenzoylamino)phenyl)methylamino)piperidinc-1-carboxylic acid t-butyl ester
(Preparation 57, 169 mg, 0.366 infnoi) gives the title compound as an off-white solid:
mass spectrum (ion spray): m/z = 362.1 (M+1); 1H NMR (free base, CDCl3): 7.84 (bs, N-
H), 7.68 (dd, J = 6. i Hz, 8.6 Hz, 1H). 7.21 - 7.19 (m, 1H), 7.15 - 7.09 (m, 2H), 7.00 (td, J
= 2.3 Hz, 8.2 Hz. 1H), 6.75 (bd, J = 8.0 Hz, 1H), 6.54 (dd. J = 2.1 Hz, 8.4 Hz, 1 H), 3.68 -
3.59 (bm, 1H), 3.25-3.08 (bin, 2H), 2.74 (s,3H), 2.73-2.62 (bm,2H), 1.81 - 1.60 (bm,
4H), Analysis calc-d for C19H23Cl3FN3O 0.1H2O: C. 52.27; H, 5.36; N, 9.63. Found: C,
52.60; H, 5.75; N, 9.29.

Example 20. 2-Chloro-4-fluoro-N-(3-(1-ethylpiperidin-4-ylamino)phenyl)benzamide
dihydrochloride
Using a method similar to Example 1, using )-ethylpiperidin-4-one (0.102 mL,
0.756 mmol) gives the title compound as a white solid (143 mg, 50%): mass spectrum
(free base, ion spray): m/z = 376.1 (M+1); 1H NMR (free base, CDCl3): 7.77 (bs. N-H),
7.76 (dd, .7-6.1 Hz, 8.7 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.18 (dd, J= 2.5 Hz. 8.3 Hz,
1H), 7.12 (t, J=8.1 Hz. 1H), 7.08 (td, , J =2.5 Hz. 8.3 Hz, 1H), 6.67 (bd, J= 8.0 Hz, 1H),
6.40 (dd, J=2.0 Hz, 8.1 Hz, 1H), 3.67 (bd, J = 8.0 Hz, 1H), 3.39 - 3.29 (bm, 1H), 2.92-
2.85 (bm, 2H), 2.42 (q, J=7.2 Hz, 2H), 2.16-2.05 (bm, 4H), 1-55-1.44 (bm, 2H), 1.09
(t, J= 7.2 Hz, 3H).
Example 21. 2-Chloro-4-fluoro-N-(3-(1-propylpiperidin-4-ylamino)phenyf)benzamide
dihydrochloride

Using a method similar to Example 1, using 1-propylpiperidin-4-one (0.1 14 mL,
0.756 mmol) gives the title compound as a white solid (262 mg, 89%): mass spectrum
(free base, ion spray): m/z = 390.2 (M+1); 1H NMR (free base, CDCl3): 7.89 (bs. N-H),
7.7! (dd, J = 6.0 Hz, 8.7 Hz, 1H), 7.19 (bt, J = 2.0 Hz, 1H), 7.16 (dd, J = 2.5 Hz. 8.6 Hz,
1H), 7.11 (t,J=8.0Hz, 1H), 7.05 (td, J =2.5 Hz, 8.1 Hz, 1H), 6.68 (bd, J = 8.0 Hz. 1H),
6.39 (dd, J = 2.0 Hz, 8.0 Hz, 1H), 3.67 (bd, J= 7.8 Hz, 1H), 3.36 - 3.26 (bm, 1H). 2.86
(bd, J = 11.6 Hz, 2H), 2.32 - 2.27 (m, 2H). 2.14- 2.02 (bm. 4H), 1.56-1.43 (bm, 4H).
0.89(t, J =7.4 Hz, 3H).

Example 22. 2-Chloro-4-fluoro-N-(3-(N-(1-propylpiperidin-4-
yl)Methylamino)phenyt)benzamide

dihydrochloride
Using a method similar to Example 16, using 2-chloro-4-fluoro-N-(3-(1-
propylpiperidin-4-ylamino)phenyl)benzamide dihydrochloride (Example 21.71 mg, 0.153
mmol) gives the title compound as a white solid (43 mg, 69%): mass spectrum (free base,
ion spray): m/z = 404.1 (M+H); 1H NMR (free base, CDCl3): 7.87 (bs, N-H), 7.64 (dd, J =
6.1 Hz, 8.6 Hz, 1H), 7.20 (s, 1H), 7.14 - 7.07 (m, 2H), 6.97 (td, J = 2.3 Hz. 8.2 Hz, 1H),
6.75 (d, J=8.2 Hz, 1H), 6.51 (dd, J= 2.1 Hz, 8.6 Hz, 1H), 3.54 (tt, J = 3.8 Hz. 11.7 Hz.
1 H). 2.97 (bd. J = 11.4 Hz. 2H), 2.73 (s, 3H), 2.27 - 2.22 (m, 2H), 1.98 (bt, J=11.7 Hz.
2H), 1.80 (bqd, J=3.5 Hz, 12.5 Hz, 2H), 1.66(bd, J = 11.7 Hz, 2H), 1.51-1.41 (m, 2H),
0.83 (t, J =7.4 Hz, 3H).
Example 23. 2-Chlaro-4-fluoro-N-(3-(N-(1-(2-(1 -isopropyl-1H-pyrazol-4-
yl)ethyt)piperidin-4-yl)methylamino)phenyl)benzamide

dihydrochloride
Combine 1-isopropyl-2-hydroxyethyl-1H-pyrazole (Preparation 10, 2 g. 12.9
mmol), and triethylamine (3.6 mL, 25.9 mmol) in 30 mL of THF. Add methanesulfonyl
chloride (1.3 mL, 15.6 mmol) and stir for 36 hr. Dilute with water and ethyl acetate.
Separate and extract the aqueous layer with CH2Cl2 (2 times). Combine organics, dry
over MgSO4, and concentrate in vacuo. Take a portion of this crude mixture (55 mg,
0.237 mmol) and combine with 2-Chloro-4-fluoro-N-(3-(N-piperidin-4-
y!)methylamino)phenyl)benzamide dihydrochloride (Example 19, 78 mg. 0.179 mmol),
potassium carbonate (99 mg, 0.716 mmol) and acetonitrile (3 mL). Stir and heat at 80°C

overnight. Cool to room temperature and filter through a silica plug. Concentrate the
filtrate. Purify through flash chromatography eluting with a 20/1 mixture of CH2Cl2 and
2.0 M ammonia in methanol. Dissolve the residue in diethyl ether and treat with ethereal
hydrogen chloride. Triturate the resulting gum with ether to give the title compound as an
off white solid (53 ing, 60%): mass spectrum (free base, ion spray): m/z = 498.1 (M+1);
1H NMR (free base. CDCl3): 7.79 (bs, N-H). 7.78 (dd, J = 6.0 Hz, 8.7 Hz, 1H), 7.35 (s,
lH),7.29(bs, 1H), 7.24(s, 1H), 7.23 - 7.18(m, 2H), 7.09 (td. J =2.5 Hz, 8.2 Hz, 1H),
6.80 (bd, J=7.8 Hz, 1H), 6.61 (dd, J= 2.3 Hz, 8.3 Hz, 1H), 4.44 (septet, J= 6.4 Hz, 1H),
3.69-3.60 (bin, 1H), 3.11 (bd, J = 11.0 Hz, 2H), 2.83 (s, 3H), 2.71 - 2.64 (bm, 2H), 2.60
- 2.55 (bm, 2H), 2.2 1-2.11 (bm, 2H). 1.94 - i .83 (bm, 2H), 1.81 - 1.74 (bm, 2H), 1.48
(d, J = 6.4 Hz, 6H).
Example 24, 2-Chloro-4-fluoro-N-(3-( 1-methylpiperidin-4-ylamino)-4-
fluorophenyl)benzamide hydrochloride

Under an inert atmosphere, stir a mixture of 2-chloro-4-fluoro-N-(3-amino-4-
fluorophenyl)benzamide (Preparation 14.481 mg, 1.7 mmol). 1-methyl-4-piperidone (384
mg, 42 ml, 3.4 mmol), 1,2-dichloroethane (15 mL), powdered molecular sieves 4Å (1 g)
for 15min. Add glacial acetic acid ( 306 mg, 0.3 mL. 5.1 mmol). After 1 hr., add sodium
triacetoxyborohydride (900 mg, 4.25 mmol). Allow the reaction to go overnight. Pour
the reaction mixture into ethyl acetate (200 mL), and wash once with aqueous NaOH (2N.
30 mL). Separate the organic layer, dry over anhydrous sodium sulfate, remove the
solvent under reduced pressure. Further purify the residue by chromatography on silica
gel using a 4%-6% gradient of (2M NH3 in methanol) in CH2Cl2 to obtain the free base of
the title compound (443 mg, 69% yield). Convert the product To its HCl salt by dissolving
it in CH2Cl2 and treating with excess 1 .OM HCl in diethyl ether. Add more ether to
precipitate the title compound as a white solid: mass spectrum (ion spray): m/z = 380.2
(M+1); Analysis calc'd for C19H20ClF2N3O HCl H2O: C, 52.54; H, 5.34; N, 9.68. Found:
C, 52.93; H, 5.29; N, 9.65; LY 653915: 1H NMR 8(methanol-d4) 7.72(dd, 1H), 7.60(m,
1H), 7.37(dd, 1H), 7.14(m, 3H), 3.74(m, 1H), 3.62(d, 2H), 3.30(dd, 2H), 2.88(s, 3H),
2.36(d. 2H), 1.93(m. 2H)

Example 25. 2,4-Difluoro-N-(3-(1-methylpiperidin-4-ylamino)-4-
fluorophenyl)benzamide hydrochloride

Using a procedure similar Example 24 using 2,4-difluoro-N-(3-amino-4-
fluorophenyl)benzamide (Preparation 16, 452 mg, 1.7mmol), 1-methyl-4-piperidone(384
mg, .42 mL, 3.4 mmol), 1,2-dichloroethane(15 mL), powdered molecular sieves 4Å (1 g),
glacial acetic acid (306 mg, 0.3 mL, 5.1 mmol), sodium triacetoxyborohydride (900 mg,
4.25 mmol) to obtain the free base of the title compound (434 mg, 70% yield) and the title
compound: mass spectrum (ion spray): m/z = 364.1 (MM); analysis calc'd for
C19H20F3N3O HCl H2O:C, 54.61 ;H, 5.55; N, 10.06. Found: C, 54.48; H, 5.36; N, 9.93:
1H NMR8(methanol-d4)7.79(m, III). 7.63(d, 1H), 7.1 l(m, 4H), 3.74(m, 1H), 3.62(d,
2H), 3.30(dd, 2H), 2.88(s, 3H). 2.36(d, 2H), 1.93(m, 2H)
Example 26. 3-Methyl-N-(3-(1-methylpiperidin-4-ylamino)phenyl)butyramide
hydrochloride
Combine 1-methyl-4-(3-aminophenylamino)piperidine triacetate (Preparation 18,
460 mg, 1.17 mmol) and CH2Cl2 (13 mL); stir and cool to 0°C. Add isovalcryl chloride
(135 µL, 1.05 mmol), and stir at room temperature for 18 hr. Load onto a 5 g SCX
cartridge (mega bond elut, Varian). Wash resin with methanol, then elute product with 2
M ammonia in methanol, Concentrate in vacuo, and chromatograph on silica gel, eluting
with a gradient of 1-15% (2M ammonia in methanol) in CH2Cl2, Concentrate in vacuo.
Dissolve the purified oil (115 mg, 38% isolated yield) in methanol, add solid NH4Cl (21.2
mg, 1 eq) and sonicate the solution at room temperature for 15 min. Concentrate in vacuo
to provide the title compound: mass spectrum (ion spray): m/z = 290.2 (M+1): Anal calc'd
for C17H28CIN3O 0.1 H2O: Theory: C, 62.31; H, 8.67; N, 12.82. Found: C. 62.32; H,
8.78; N, 12.56.

Example 27. 4-Fluoro-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)benzamide
hydrochloride

A method similar to Example 26, using 4-fluorobenzoyl chloride, gives the title
compound as a white solid (127 mg): mass spectrum (ion spray): m/z = 328.1 (M+1);
Anal calc'd for C19H23ClFN3O 0.1 H2O: Theory: C, 62.41; H, 6.39; N, 11.49. Found: C,
62.13; H, 6.55; N, 11.14.
Example 28. Cyclopropane-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)carboxamide
hydrochloride

A method similar to Example 26, using cyclopropanecarbonyl chloride, gives the
title compound as a white solid (80 mg): mass spectrum (ion spray): m/z = 274.1 (M+1):
Ana! calc'd for C16H24CIN3O 1.0H2O: Theory: C, 58.62; H, 7.99; N. 12.82. Found: C,
58.47; H, 8.00; N, 12.73.
Example 29. 2-Methyl-N-(3-(1-Methyl-piperidin-4-ylarnino)phenyl)benzamide
hydrochloride

A method similar to Example 26, using 2-Methylbenzoy! chloride, gives the title
compound as a white solid (32 mg): mass spectrum (ion spray): m/z = 324.2 (M+1); 1H
NMRS(DMSO, ppm) 10.02 (s, 1H), 7.37 (in, 1H), 7.25 (in, 4H), 7.02 (t, J = 8.1. 16.1
Hz, 1 H), 6.82 (d, J = 7.7 Hz, 1H), 6.34 (d, J = 8.4 Hz, 1H), 5.76 (m. 1H), 3.40 (m, 2H),
3.11 (bs, 2H), 2.71 (s. 3H), 2.36 (s,3H), 2.29 (s, 1 H), 2.05 (m, 2H), 1.70 (m, 2H)

Example 30. N-(3-(1 -Methyl-piperidin-4-ylamino)phenyl)isonicotinamide

A method similar to Example 26, but not making the HCl salt, using isonicotinyl
chloride, gives the title compound as a yellow oil (30 mg): mass spectrum (ion spray): m/z
= 310.0 (M+1).
Example 31. 2,6-Dichloro-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)benzamide
hydrochloride

A method similar to Example 26, using 2,6-dichlorobenzoyl chloride, gives the
title compound as a white solid (174 mg): mass spectrum (ion spray): m/z = 378.0 (M+1);
1H NMR 5 (DMSO, ppm) 10.45 (s, 1H), 7.52 (m. 2H), 7.22 (m, 2H), 7.05 (t, J = 8.1, 16.1
Hz, 1H), 6.76 (d. J =8.1 Hz, 1H), 6.38 (d, J = 8.1 Hz, 1H), 5.84 (d, J = 7.0 Hz, 1H), 3.40
(m, 2H), 3.17 (bs, 2H), 2.72 (s, 3H), 2.30 (s, 1H), 2.06 (m, 2H), 1.69 (m, 2H).
Example 32. N-(3-(1-Methyl-piperidin-4-ylamino)phenyl)-2-trifluoromethyl-benzamide
hydrochloride

********************A method similar to Example 26, using 2-trifluoromethylbenzoyl chloride, gives
the title compound as a white solid (147 mg): mass spectrum (ion spray): m/z = 378.1
(M+1); 1H NMR δ (DMSO, ppm) 10.29 (s, 1H). 7.75 (m. 2H), 7.21 (m. 3H), 7.04 (t, J =
8.1. 16.1 Hz, 1H). 6.77 (d. J =7.7 Hz, 1H), 6.37 (d, J= 7.7 Hz, 1H), 5.81 (d. J=7.3 Hz. 1H), 3.40 (m, 2H), 3.10 (bs. 2H), 2.72 (s. 3H), 2.30 (s, 1H). 2.06 (m, 2H), 1-71 (m, 2H).

Example 33. 4-Fluoro-N-(3-{l-methyl-piperidin-4-ylamino)phenyl)-2-trifluoromethy)-
henzamide hydrociiloride

A method similar to Example 26, using 4-fluoro-2-trifluoromethylbenzoyl
chloride, gives the title compound as a white solid (174 mg): mass spectrum (ion spray):
m/z= 396.1 (M+1); Anal calc'd forC2oHJ2CIF4NjO-0.5 H2O: Theory: C, 54,49; H, 5.26:
N, 9.53. Found: C, 54.88; H, 5.56; N, 9.89.
Example 34. 2,6-DiChloro--(3-(methyl-(1-methyl-piperidin-4-yl)-
amino)phenyl)benzam ide hydrochloride

Dissolve 2,6-dichloro-N-(3-(1-methyl-piperidin-4-ylamino)phenyl)benzamide
hydrochloride (Example 31, 168 mg, 0.40 mmol) in 5 mL of methanol. Add an excess of
50% aqueous formaldehyde solution. (600 uL), and stir the reaction for 0.5 hr. Adjust the
solution to pH = 5 by the addition of acetic acid, add sodium cyanoborohydride (100 mg),
and stir the reaction for an additional 18 hr. Load onto a 5 g SCX cartridge (mega bond
elut, Varian), Wash the resin with methanol, then remove the product with 2M
NH3/methanol. Dissolve the resulting oil (153 mg, 98% isolated yield) in methanol, add
NH4CI (20.9 mg, I eq) as a solid, and sonicate the solution at room temperature for 15
min. Concentrate in vacuo to provide the title compound: mass spectrum (ion spray): m/z
= 392.3 (M+1); mp 164.2°C.
Example 35. 4-Fluoro-N-(3-(Methyl-(I-methyl-piperidiri-4-yl)-amino)phenyl)benzamide
hydrochloride


A method similar to Example 34, using 4-fluoro-N-(3-(1-methyl-piperidin-4-
ylamino)phenyl)benzamide hydrochloride (Example 27 ), gives the title compound as a
white solid (102 mg): mass spectrum (ion spray): m/z = 342.4 (M-f-I); mp 76.1°C
Example 36. 2-Methyl-N-(3-(methyl-(1-methyl-piperidin-4-yl)-amino}pheny!)benzamide
hydrochloride

A method similar to Example 34, using 2-methyl-N-(3-(!-methyl-piperidin-4-
ylamino)phenyl)benzamide hydrochloride (Example 39), gives the title compound as a
white solid (25 mg): mass spectrum (ion spray):, m/z = 338.4 (M+1); mp 82.4°C.
Example 37. 4-Fluoro-N-(3-(Methyl-(!-methyl-piperidin-4-yl)-atnino)phenyl)-2-
trifluoromethyl-benzamide hydrochloride

A method similar to Example 34, using 4-fluoro-N-(3-(1-methyl-piperidin-4-
ylamino)phenyl)-2-trifluoroMethyl-benzamide hydrochloride (Example 33), gives the title
compound as a white solid (1 14 mg): mass spectrum (ion spray): m/z = 410.4 (M+1); mp
113.8°C.
Example 38. N-(3-(Methyl-(1-methyl-piperidin-4-yl)-amino)phenyl)-2-trifluoromethyl-
benzamide hydrochloride


A method similar to Example 34. using N-(3-(1-methyl-piperidin-4-
ylamino)phenyl)-2-trifluoromethyl-benzamide hydrochloride (Example 32), gives the title
compound as a white solid {125 mg): mass spectrum (ion spray): m/z = 392.4 (M+I); mp
84.5°C.
Preparation 58. (2S.4S)-4-(3-(2-Chloro-4-fluoro-benzoylamino)-phenylamino)-2-methyl-
piperidine-1 -carboxylic acid /4), filter, and concentrate in vacuo, Purify
by column chromatography (0%-l 0% 2M NH3 in methanol/CH^Cb) to yield an oil. Make
the hydrochloride salt by sonication with one equivalent of ammonium chloride dissolved
in methanol to yield 21 mg (68%) of the title compound. Mass spectrum (ion spray): m/z
=376.4 (M+1); mP 159-62°C.

Example 43. 2-Chloro-4-fluoro-N-(2-fluoro-3-(1-methyl-piperidinylamino)-phenyl)-
benzamide

Mix 2-fluoro-N-(I-methyl-piperidin-4-yl)-benzcne-l,3-diamine (Preparation 20)
(0.08 g) and 2-Chloro-4-fluorobenzoy1 chloride (83 mg) in 1,4-dioxane (5 ml) and heat at
reflux for 2 hr. Partition the reaction mixture between ethyl acetate and saturated
saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a
silica gel column (10 g) (dichloromethane-2M NH3 in methanol, gradient) to give 0.106 g
of the title compound (78% yield): mass spectrum (ion spray): m/z = 380 (M+1); !H NMR
(CDCl3): 8.19 (brs, 1H), 7.83 (dd, 1H), 7.66 (dd, 1H), 7.19 (dd, 1H), 7.09 (ddd,IH), 7.00
(dd, 1H), 6.52 (ddd, I H), 3.76 (br d, 1H), 3.29 (m, 1H), 2.81 (br d, 2H), 2.29 (s, 311). 2.1 3
(m. 2H), 2.05 (in. 2H), 1.52 (m , 2H).
Dissolve the benzamidc in methanol, add 0.28 ml of 1 N HCl in ether and
evaporate to give its mono-hydrochloric acid salt.
Example 44. 2-Chloro-4-fluoro-N-(2-fluoro-3-(methyl-(1-methyl-piperidin-4-yl)-amino)-
phenyl)-benzam ide

Heat2-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-l.3-diamine
(Preparation 22, 44 nig) with 2-chloro-4-fluorobenzoyl chloride (40 mg) in 1,4-dioxane (5
mL) at reflux for 2 hr. Dilute the reaction mixture with methanol (5 mL) and load on a
SCX column (10 g). After wash with methanol, elute the product with 2 M NH3 in
methanol, evaporate to give 73 mg of the title compound: mass spectrum (electric spray)
m/z-394(M+1); !H NMR (CDCl3): 8.29 (br d, 1H), 7.94 (t, 1H), 7.81 (dd, 1H), 7.18
(dd, 1H), 7.05 (m, 2H). 6.77 (ddd, 1H), 3.15 (m. 1H), 2.72 (s, 3H), 2.26 (s, 3H). 1.96 (m,
2H), 1.83 (m. 2H), 1.70 (m, 2H).
The benzamide is dissolved in methylene chloride and 0.185 mL of IN HCl in
ether is added and evaporated, dried in vacuum to give its monohydrochloric acid salt.

Example 45. 2,4,6-Trifluoro-N-(2-fluoro-3-(methyl-{l-methyl-piperidin-4-yl)-amino)-
phenyl)-benzamide

Heat a mixture of 2-fluoro-N-methyl-N-(!-methyl-piperidin-4-y1)-benzene-l,3-
diamine (Preparation 22, 60 mg) and 2,4,6-trifluorobenzoyl chloride (59 mg) in 1,4-
dioxane (5 mL) for 2 hr. Dilute the reaction mixture with methanol (5 mL) and load on a
SCX column (10 g). After wash with methanol, elute the product with 2M NH3 in
methanol, evaporate and purify on a silica gel column (4 g, solvent: dichloromethane-2M
NH3 in methanol, gradient) to give 94 mg of the title compound: mass spectrum (electric
spray) m/z = 396 (M+i); !H NMR (CDCl3): 7.96 (in, 1H), 7.84 (br s, I H), 7.05 (m, 1H),
6.79 (m, 3H). 3.48 (d, 1H), 3.16 (m, 3H), 2.91 (br d, 2H), 2.74 (s, 3H), 2.27 (s, 3H), 1.97
(m, 2H), 1.84 (m, 2H), 1.72 (m, 2H).
Dissolve the benzamide in methanol (2 mL), add IN HCl in ether (0.24 mL),
evaporate to give its mono-hydrochloric acid salt.
Example 46. 2,4-Difluoro-N-(2-fluoro-3-(methyl-(1-methyl-piperidin-4-yl)-amino)-
phenyl)-benzamide

Using a method similar to example 45, using 2.4-difluorobenzoyl chloride gives
the title compound: mass spectrum (electric spray) m/z = 378 (M+1); 1H NMR (CDCl3):
8.67 (brd, 1H), 8.21 (m, 1H), 8.00 (m, 1H), 7.04 (m, 1H),6.94(m, lH),6.77(m, 1H),
3.17 (m, 1H), 2.90 (brd,2H), 2.75 (s,3H), 2.26 (s,3H), 1.97(m, 2H), 1.84 (m, 2H), 1,72
(m, 2H).Using a method similar to the above example, provides the mono hydrochloride
salt.

Example 47, 2-Chloro-N-(3-(ethyl-(1-methyl-piperidii>4-y!)-amino)-2-fluoio-pheny])-4-
fluoro-benzamide

Heat a mixture ofN-ethyl-2-fluoro-N-(1-Methyl-piperidin-4-yl)-benzene-l,3-
diamine (Preparation 27) and 2-chloro-4-fluorobenzoy! chloride (23 mg) in 1,4-dioxane (5
mL) at reflux for 1 hour. Dilute with methanol (5 mL), load on a SCX column (10 g),
wash with methanol, elute the product with 2M NH3 in methanol, evaporate to give the
title compound: mass spectrum (electric spray) mfz = 408 (M+i), Purify further by HPLC
to give the di-trifluoroacetic acid salt.
Example 48. 2-Chtoro~4-fluoro-N-(3-fl(Joro-5-(methyl-(]-methyl-piperidin-4-yl)-amino)-
pheny!)-berrzam ide

Combine 5-fluoro-N-Methyl-N-(1-methyl-piperidin-4-yl)-benzene-!,3-diamine
(Preparation 29, 0.036 g, 0.15 mmo!\ 2-chloro-4-fluoro-benzoyl chloride (0.044 g, 0.23
mmol) and 1,4-doxanc (2 mL), stir and heat at reflux. After 3 hr, cool to ambient
temperature. Load on a SCX column (10 g), wash with methanol, elute with 2M
ammonia-methanol. Concentrate eluent to obtain 0.059 g (100%) the title compound as a
free base. Dissolve this material in dichloromethane (5 mL) and treat with 1M
hydrochloric acid in ether (0.15 mL. 0.15 mmol). Concentrate to give the title compound
as a brown powder: high resolution mass spectrum: Obs. m/z 394.1495; Calc. mfz
394.1497; lH NMR (CDClj)of free base: 7.8 (bs, 1H), 7.7 (m, lH),7.2(m, I H), 7.1 (m.
1 H), 6.8 (s, 1H), 6.7 (m, 1H), 6.2 (m, 1H), 3.5 (m, 1H), 2.9 (m, 2H), 2.8 (s. 3H). 2.3 (s,
3H), 2.1 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).

Examples 49-52

Using methods similar to Example 48, the following compounds are prepared,
isolated and converted to mono hydrochloric acid salts



Example 53. 4-Fluoro-N-(3-fluoro-5-(1-mcthyl-piperidin-4-ylamino)-phenyl)-benzamide
dihydrochloride salt

Add slowly 4-fluorobenzoyl chloride (403 mg, 2.54 mmol) to a solution of 5-
f!uoro-benzene-l,3-diamine (Preparation 32 320 mg, 2.54 mmol) in iriethylamine (514
mg, 0,7! mL. 5.08 mmol) and THF (10 mL) atO°C. Stir the mixture overnight and
gradually raise to room temperature. Quench the reaction with 0.1N NaOH solution, and
extract the mixture with ethylacetate three times. Combine the organic layers and wash
with saturated NaCl solution, dry over Na2SO4, filter and concentrate to give a solid.
Purify by chromatography (silica gel, eluting with 25-40% ethylacetate in hexanes) gives
379 mg (60%) of N-(3-amino-5-fluoro-phenyl)-4-fluoro-benzamide.
Combine the above benzamide (379 mg, 1.53 mmol), 1 -metbyl-4-piperidone (345
mg, 3.06 mmol). THF (1.5 mL), 1,2-dichloroethane (!5 mL), molecular sieve 4A (0.7 g)
and acetic acid (276 mg. 0.26 mL, 4.59 mmol). Add sodium triacetoxyborohydride
portionwise and stir the mixture at room temperature overnight. Quench the reaction with
0.1N NaOH solution, extract the mixture with CH2Cl2 three times. Combine the organic
layers, dry over Na2SO4, filter and concentrate to give a crude residue. Purify by
chromatography (silica gel, eluting with 5.5% 2M NH3-methanol in CH2Cl2) provides 434
mg (82%) of thefree base of the title compound: Free base: mass spectrum (ion spray):
m/z - 346.1; 1H NMR (CDCl3, ppm): 7.86 (m, 3H), 7.14 (t, 2H), 6.88 (s, br, 1H), 6.60 (dt.
lH),6.10(dt, 1H). 3.79 (d. 1H),3.24(m, I H), 2.78 (m, 2H), 2.31 (s, 3H), 2.1 7-2.03 (m,
4H), 1.42 (m, 2H).Dissolve the free base in methanol and add 2 equivalents of 1 N HCl in
diethylether. Remove the solvent and wash with diethylether. Remove the solvent to
obtain the title compound: Di-hydrochloride salt: Anai cald for C19H21 F2N3O.2HCI: C,
54.55; H, 5.54; N, 10.04. Found: C, 54.58; H, 5.45; N, 9.84.

Example 54. 2,6-Difluoro-N-(3-fluoro-5-(I-methyl-piperidin-4-y!amino)-pheny!)-
benzamide dihydrochloride salt

Using methods similar to example 53, using 2,6-dif!uorobenzoyl chloride (448
mg, 2.54 mmol) gives 515 mg (56% two-step yield) of thefree base of the title compound.
Using a salt formation method similar to that described in Example 59 gives the title
compound: Free base: mass spectrum (ion spray): m/z - 364.1 (M+1); 'H NfvfR (CDCh,
ppm): 7.63 (s, br, 1H), 7.55 (m, I H), 7.40 (s, 1H). 7.13 (t. 2H). 7.02 (s, br, 1H), 6.67 (dt,
I If), 6.24 (dt, 1H), 3.90 (m, 1H), 3.41 (m, 1H), 2,92 (m, 2H), 2.43 (s, 3H), 2.22 (m, 4H),
l.60(ni, 2H). Di-hydrochloride salt: Analcalc'd for C19H20F3N3O.2HCl.C. 52.31: H.
5.08; N, 9.63. Found: C, 52.65; H, 4.96; N, 9.44.
Example 55. 2,4,6-Trifluoro-N-(3-f!uoro-5-(J-methyl-pLperidin-4-ylamino)-phenyl)-
benzamide hydrochloride salt

Using methods similar to example 53, using 2,4,6-trifluorobenzoyl chloride (494
mg, 2.54 mmol) gives 525 mg (54% two-step yield) of thefree base of the title compound.
Using a salt formation method similar to thai described in Example 59, using 1 equivalent
of HCl gives obtain the title compound: Free base: mass spectrum (ion spray): m/z =
382.1 (M+1); ' H NMR (CDCl3, ppm): 7.87 (s, br, 1H), 6.85 (s, br, 1H), 6.70 (m, 2H),
6.54 (m, 1H), 6.11 (dt, 1H),3.80(d, 1H), 3.25 (m, 1H), 2.75 (m, 2H), 2.30 (s. 3H), 2.16-
2.02 (m, 4H), 1.49 (m, 2H). Mono-hydrochioride salt: Anal calc'd for
C19H19F4N3O-HC.H2O: C, 52.36; H, 5.09; N, 9.64. Found, C, 52.71; H, 4.78; N. 9.62.
Example 56. 2-Chloro-6-f!uoro-N-(3-fluoro-5-( 1-Methyl-piperidin-4-ylamino)-phenyl)-
benzamide dihydrochloride salt


Using methods similar to example 53, using 2-chloro-6-fluorobenzoyl chloride
(490 mg, 2.54 mmol) gives 667 mg (69% two-step yield) of the free base of the title
compound. Using a salt formation method similar to that described in Example 59 gives
the title compound: Free base: mass spectrum (ion spray): m/z = 380.0 (M+1); 1H NMR
(CDCl3, ppm): 7.38 (m, 2H), 7.28 (m, lH)m7.12(m, 1H), 6.91 (s, br, 1H), 6.56 (dt, 1H),
6.14 (dt, 1H), 3.83 (d, 1H), 3.29 (m, 1H). 2.77 (m, 2H), 2.33 (s, 3H), 2.20-2.06 (m, 4H),
1.55 (m, 2H). Di-hydrochloride salt: Anal calc'd for d19H20CIF2N3O.2HCl.0.4H2O: C,
49.61; H, 5.00; N, 9.14. Found: C. 49.27; H. 4.55; N, 9.08.
Example 57. 2-Chloro-4-fluoro-N-(3-fluoro-5-(1-methyl-piperidin-4-ylamino)-phenyl)-
benzamide dihydrochloridc salt

Using methods similar to example 53, using 2-chloro-4-fluorobenzoyl chloride
(490 mg, 2.54 mmol) gives 654 mg (68% two-step yield) of the free base of the title
compound. Using a salt formation method similar to that described in Example 59 gives
the title compound: Free base: mass spectrum (ion spray): m/z = 380,0 (M+1); 1H NMR
(CDCl3, ppm): 7.82 (m, 2H), 7.24 (dd. 1H), 7.17 (m, 1H), 6.90 (s, br, 1H), 6.60 (m, 1H),
6.15 (dt, 1H), 3.83 (d, 1H), 3.31 (m, 1H), 2.85 (m, 2H), 2.35 (s, 3H), 2.23-2.08 (m, 4H),
1.53 (m,2H). Di-hydrochloride salt: Anal.calc'd. for C19H20ClF2N3O.2HCl: C, 50.40; H,
4.89; N, 9.28. Found: C. 50.43; H, 4.60; N, 9.29.


Examples 58-65 are synthesized by heating 5-fluoro-N-methyl-N-(1-methyl-
piperidin-4-yl)-benzene-l,3-diamine(Prepartion 31, 200 μLof 0.5M solution in dioxane)
and the appropriate R-acid chloride (0.10 mmol) to 90°C for 2hr. The reaction mixture is
diluted with 10% acetic acid/methanol (0.5 mL). The resulting solution is directly applied
to a 2 g SCX column. After thoroughly washing with methanol, the column is eluted with
1M ammonia-methanol and the eluant is concentrated and further purified by high-
throughput mass guided chromatography. The compounds are characterized by
chromatography using a Metachem™ C18 column (monochrom 3 micron, 2.5 x 25 cm)
using a 10-90% solvent B gradient in 4.5 min., where solvent A is 0.1% trifiuoroacetic
acid in water and solvent B is 0. f % trifiuoroacetic acid in acetonitrile. The procedure is
repeated in parallel for Examples 64-71



Example 66. 4-Cyano-N-(6-(1-methylpipendin-4-ylamino)pyridin-2-yl)benzamide
hydrochloride

Combine 4-cyanobenzoyl chloride (300 μL, 1.80 mmol), 2,6-diaminopyridine
(600 mg, 5.5 mmol, and dioxane (10 mL); stir at room temperature for 2 hr. Pour into
water and adjust to pH>12 by the addition of 5N NaOH. Extract with CH2Cl2 twice,
combine organics, dry over MgSO4, and concentrate. Chromatograph (silica gel, eluting
with 0-10% methanol/CH2Cl2). Dissolve the purified intermediate N-(6-amino-pyridin-
2-yl)-4-cyano-benzamide (202 mg. 0.84 mmol, 47%) in THF(10 mL). Add to this I-
Methyl-4-piperidone (77 mg, 0.68 mmoi), acetic acid (150 μL, 2.5 mmol), and sodium
triacetoxyborohydride (440 mg, 2.10 mmol). Stir the reaction at room temperature for 18
hr, and quench by the addition of saturated aqueous NaHCO3. Extract the aqueous layer
with ethylacetate twice, wash the combined organics with saturated aqueous NaCl, dry
over MgSO4, and concentrate. Chromatograph the material (silica gel, eluting with 0-
20% 2M NH3 in methanol/CH2Cl2). Dissolve the clean material (10.4 mg, 5%) in
methanol and add 1 equivalent (1.7 mg) of NH4Cl. Sonicate the reaction at room
temperature for 15 min, then concentrate to provide the title compound: mass spectrum
(ion spray): m/z = 336.0 (M+1).

Example 67. 4-FIuoro-N-(3-(methyl-(1-methyl-piperidin-4-yl)-amino)phenyl)-2-
trifluoromethyl-benzam.ide hydrochlj£'fe

A method similar to Example 66, using 4-fluoro-2-trifluoromethylbenzoyi
chloride, gives the title compound as a white solid (42 mg): mass spectrum (ion spray):
m/z = 397.0 (M + 1); mp 84.9°C.
Example 68. N-(3-(methyl-(1-methyl-piperidin-4-yl)-amino)phenyl)-2,3.4-trifluoro-
benzamide hydrochloride

A method similar to Example 66. using 2,3,4-trifluorobenzoyl chloride gives the
title compound as a white solid (32 mg): mass spectrum (ion spray): m/z - 365.3 (M+1);
mp 231.4°C(dec).
Example 69. 2-Chloro-4-fluoro-N-(6-(methyl-(I-methyl-piperidin-4-yl)-amino)-pyridin
2-yl)-berizamide hydrochloride

Prepare according to procedure in Example 66 starting with N-methyl-N-( 1-
methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0,907 mmol) and
2-chloro-4-fluorobenzoyl chloride (263 mg, 1.36 mmol), and using pyridine as the
solvent, to yield 185 mg (49%) of the title compound: mass spectrum (ion spray): m/z
=377.2 (M+1); Analysis calc-d for C19,H23N4OFCl2.0-6 H2O: C, 53.80; H. 5.75: N, 13.21.
Found: C, 53.55; H, 5.66; N, 13.28; mp 229-31 °C.

Example 70. 4-Fluoro-N-(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-
benzamide hydrochloride

Prepare according to Example 69 starting with N-Methyl-N-(1-methyl-piperidin-4-
yI)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.91 mmol) and 4-fiuorobenzoyl
chloride (160 μL, 1.36 mmol) to yield 309 mg (90%) of the title compound: mass
spectrum (ion spray): m/z =343.3 (M+1); Analysis calc d for C19H24N4OFCI-0.6 H2O: C.
58.56; H, 6.52: N, 14.38. Found: C, 58.31; H, 6.37; N, 14.39: mp 250-2°C.
Example 71. N-(6-(Methyl-(1-methylpiperidin-4-yl)amino)pyridin-2-yl)isonicotinamide
hydrochloride

Prepare according to procedure in Example 69 starting with N-rnethyl-N-(1-
mcthyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (175 mg, 0.794 mmol).
isonicotinoyl chloride hydrochloride (212 mg, 1.19 mmol), and pyridine (15 mL) to yield
247 mg (86%) of the title compound: mass spectrum (ion spray): m/z =326.1 (M+1);
Analysis Caicd for C,8H24N5OC1.0.5 H2O: C, 58.29; H, 6.79; N, 18.88. Found: C, 58.49;
H, 6,79; N, 19.22. mp 274-7°C.
Example 72. Furan-2-carboxylic acid (6-(methyl-(1-Methyl-piperidin-4-yl)-amino)-
pyridin-2-yl)-amide hydrochloride


Prepare according to procedure in Example 69 starting with N-methyl-N-(1-
Methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34, 175 ing, 0.794 mmoi), 2-
furoyl chloride (117 μL, 1.19 mmol), and pyridine (15 mL) to yield 243 mg (87%) of the
title compound: mass spectrum (ion spray): m/z =315.1 (M+1); Analysis calc'd for
C17H23N4O2C1.0.2 HI2O:C, 57.60; H, 6.65; N, 15.81. Found: C, 57.31; H. 6.72; N, 15.81.
mp lI6-9°C,
Example 73. Thiophene-2-carboxylic acid (6-(methy|-(1-methyl-piperidin-4-y!)-amino)-
pyridirt-2-yl)-thiophenamide hydrochloride

Prepare according to procedure in Example 69 starting with N-meth>i-N-(1-
Methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (175 mg, 0.794 mmol),
thiophene-2-carbonyl chloride (127 \xL, [.19 mmoi), and pyridine (15 mL) to yield 238
mg (82%) of the title compound: mass spectrum (ion spray): m/z =331. J (M+I): Analysis
Calcd for CI7H23N4OSCl: C, 55.65; H, 6.32; N. 15.27. Found: C, 55.46, H. 6.49, N.
15.41 mp 126-8°C.
Example 74. N-(6-(Methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-propionamide
hydrochloride


Prepare according to procedure in Example 69 starling with N-methyl-N-( 1 -
methy1-piperidin-4-yl)-pyridine-2.6-diamine (Preparation 34, 175 mg, 0.794 mmol),
propionic anhydride (152μL, 1.19 mmol). and pyridine (15 mL) to yield 134 mg (54%) of
the title compound: mass spectrum (ion spray): m/z =211.1 (M+1); Analysis Calcd for
C,sH2sN4OCl.0.2 H2O: C, 57.11; H, 7.80; N, 17.76. Found: C, 56.73: H, 8.16;N, 17.94.
mp216-8°C.
Example 75. Cyclobutanecarboxylic acid (6-(methyl-(1-methyl-piperidin-4-yl)-amino)-
pyridin-2-yl)-amide hydrochloride

Prepare according to procedure in Example 69 starting with N-Methyl-N-([-
methyl-piperidin-4-yl)-pyridine-2,6-diainine (Preparation 34) (175 mg, 0.794 mmol),
cyclobutanecarbonyl chloride (136 μL, 1.19 mmol), and pyridine (15 mL) to yield 237 mg
(88%) of the title compound: mass spectrum (ion spray): m/z =303.1 (M+1): Analysis
Calcd fbr C12H27N4OCl.0.1 H2O: C, 59.93; H, 8.05; N. 16.45. Found: C, 59.81. H, 7.93,
N, 16.45. mp 258-60°C.
Example 76. Cycloliexanecarboxylic acid (6-(methyl-(1-methyl-piperidin-4-yl)-amino)-
pyridin-2-yl)-amide hydrochloride

Prepare according to procedure in Example 69 starting with N-methyl-N-(1-
Methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34, !75 mg, 0.794 mmol),
cyclohexanecarbonyl chloride (159 μL, 1.19 mmol), and pyridine (15 mL) to yield 257
mg (88%) of the title compound. Mass spectrum (ion spray): m/z 331.2 (M+1): Analysis
Calcd for C,9H31N4OCl: C, 62.19; H, 8.51; N, 15.27. Found: C, 61.22; H. 8.44; N, 15.39.
mp 250-2°C.

Example 77. Cyclopropanecarboxylic acid (6-(methyl-(1-methyl-piperidin-4-yl)-amino)
pyridin-2-yl)-amide hydrochloride

Prepare according to procedure in Example 69 starting with N-methyl-N-(1-
methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34, 175 nig, 0.794 mmol),
cyclopropanecarbonyl chloride (108 μL, 1.19 mmol), and pyridine (15 ml.) to yield 190
mg (74%) of the title compound: mass spectrum (ion spray): m/z 289.1 (M+1): Analysis
Calc'd for C16H:25Nt OCl.0.l H2O: C 58,83; H, 7.78; N, 17.15. Found: C. 58.69; H, 7.71;
N, 17.31. mp258-60°C.
Example 78. 2.6-Difluom-N-(6-(methyl-( 1 -methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-
benzamide hydrochloride

Prepare according to procedure in Example 66 starting with N-Methyl-N-(i-
methyl-piperidin-4-yt)-pyridine-2,6-diamine (Preparation 34, 200 mg, 0,907 mmol), 2,6-
difluorobenzoyl chloride (125 μL, 0.998 mmol), and 1,4-dioxane (10 mL) to yield 289 mg
(80%) of the title compound: mass spectrum (ion spray); m/z =361,3 (M+1); Analysis
Calcd for C19H23N4OF2C1.0.5 H2O: C, 56.22; H, 5.96; N, 13.80. Found: C. 56.49; H,
5.80; N, 14.15. mp 308°C (dec).
Example 79. 2,4,6-Trifluoro-N-(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-
yl)-benzamide hydrochloride


Prepare according to procedure in Example 66 starting with N-methyl-N-(1-
methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.907 mmol),
2,4,6-trifluorobenzoyl chloride (130 μL, 0.998 mmol), and !,4-dioxane (10 mL) to yield
302 mg (80%) of the title compound: mass spectrum (ion spray): m'z =379.2 (M+1);
Analysis caie d for C19H22N4OF3Cl.0.5 H2O: C, 53.84; H. 5.47; K 13.22. Found: C,
54.02; H, 5.32; N, 13.56. mp 302°C (dec).
Example 80. 2-Chloro-N-(6-(methyl-(l -methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-
benzamide hydrochloride

Prepare according to procedure in Example 66 starting with N-methyl-N-(1-
methyl-piperidin-4-yl)-pyridine-2,6-diainine (Preparation 34) (200 mg, 0.907 mmol), 2-
chlorobenzoyl chloride (126 μL, 0.998 mmol), and l,4-dioxane (10 mL) to yield 340 mg
(95%) of the title compound: mass spectrum (ion spray): m/z =359.3 (M+1); Analysis
calc d for C19H24N,OCl20.5 H2O: C, 56.44: H, 6.23; N, 13.86. Found: C, 56.21; H, 5.91;
N, 14.23. mp90-2cC.
Example 81. 2-Chloro-6-fluoro-N-(6-(methyl-(1 -methyl-piperidin-4-yl)-amino)-pyridin-
2-yl)-benzamide hydrochloride


Prepare according to procedure in Example 66 starting with N-methyl-N-(1-
methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.907 mmol), 2-
chloro-6-fluorobenzoyl chloride (179 mg, 0.998 mmol), and 1,4-dioxane (10 mL) to yield
310 mg (85%) of the title compound: mass spectrum (ion spray): m/z =377.2 (M+1);
Analysis calc'd for C19H23N4OCl2F.0.5 H2O: C, 54.03; H, 5.73; N, 13.27. Found: C,
53.71; H, 5.71; N, 13.45. mp283-6oC.
Example 82. 4-Fluoro-N-(6-(methyl-(1-methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-2-
trifluoromethyl-benzamide hydrochloride

Prepare according to procedure in Example 66 starting with N-methyl-N-( l -
methyl-piperidin-4-yl)-pyridine-2.6-diarnine (Preparation 34) (200 mg, 0.907 mmol). 4-
fluoro-2-(trifluoromethyl)benzoyl chloride (165 μL, 1.09 mmol), and 1,4-dioxane (10 mL)
to yield 332 mg (82%) of the title compound; mass spectrum (ion spray): m/z =410.8
(M+1); Analysis calc'd for C20H23N4OClF4.1.5 H2O: C, 50.69; H, 5.53; N. 11.82. Found:
C, 50.66; H, 5.17; N, 12.01. mp 100-2°C.
Example 83. N-(6-(Methyl-( 1 -methyl-piperidin-4-yl)-amino)-pyridin-2-yl)-2-
rtifluoromethoxy-benzamide hydrochloride

Prepare according to procedure in Example 66 starting with N-methyl-N-(i-
Methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.907 mmol), 2-
(trifluoromethoxy)benzoyI chloride (175 μL. 1.09 mmol), and 1,4-dioxane (10 mL) to
yield 357 mg (88%) of the title compound: mass spectrum (ion spray): m/z =408.8 (M+1):

Analysis calc'd for C20H24N4O2F3Cl.1.0 H2O: C, 51.89; H, 5.66; N, 12.10. Found: 51.64;
5.50; 12.48. mp 102-4°C.
Example 84. 4-Bromo-N-(6-(methyl-(1-Methyl-piperidin-4-yl)-aniino)-pyridin-2-yl)-
benzamide hydrochloride

Prepare according to procedure in Example 66 starting with N-methyl-N-(1-
methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.907 mmol). 2-
bromobenzoyl chloride (142 μL, 1.09 mmol), and 1.4-dioxane (10 mL) to yield 335 mg
(84%) of the title compound: mass spectrum (ion spray): m/z =404.3 (M+1); Analysis
Calcd for C19H24N4OBrCl.1.l H2O: C, 49.65; H, 5.75; N. 12.19. Found: C. 49.39; H,
5.5 1 ;N, 12.46.; mp 121-3°C
Example 85. 4-Fluoro-N-(6-Methyl-piperidin-4-yl-amino)-pyridin-2-yl)-benzanide
hydrochloride

Place 4-(N-(6-14-fluorobenzoylamino)pyridin-2-yl)-N-methylamino)piperidine-1-
carboxylic acid tert-buiyl ester (Preparation 41. 0.94 g, 2.2 mmol) in 20 ml. of CH2Cl2
and add trifluoroacetic acid (3.16 mL, 21.9 mmol). Stir for 2 hr then pour directly on a 10
g SCX column and wash with methanol. Remove the product with 2M NH3 in methanol
and concentrate in vacuo. Chromatograph (silica gel, eluting with 0-20% 2M NH3 in
methanol/CH2Cl2) to give 0.54 g (75%) of product. Dissolve the clean material in
methanol and add 1 equivalent (87.9 mg) of NH4Cl. Sonicate the reaction at room
temperature for 15 mm. then concentrate to provide the title compound: mass spectrum
(ion spray): m/z =329.3 (M+1); mp 152.4°C.
Example 86. 2-Chloro-4-fluoro-N-(6-methyl-piperidin-4-yi-amino)-pyridin-2-yl)-
benzamide hydrochloride


A method similar to Example 85 , using 4-((6-(2-chloro-4-fluoro-benzoylamino)-
pyridin-2-yl)-methyl-amino)-piperidine-1-carboxyIic acid tert-butyl ester, (Preparation
42), gives the title compound as a white solid (720 mg): mass spectrum (ion spray): m/z =
363.25 (M+1);mp 152.1°C.
Example 87. N-(6-(( 1 -Ethyl-piperidin-4-yl)-methyl-amino)-pyridin-2-yl)-4-fluoro-
benzamide hydrochloride

Place 4-fluoro-N-(6-methyl-piperidin-4-yl-amino)-pyridin-2-yl)-benzamide (free-
based of Example 85. 0.19 g, 0.57 mmol) in 6 ml_ of 1,2-dichloroethane and add
acetaldehyde (0.1 1 mL, 2.3 mmol). Stir for 1 hrthen add sodium triacetoxyborohydride
(0.31 g, 1.4 mmol) and stir for 18 hr. Quench with IN NaOH and dilute with water and
CH2Cl2. Separate and extract the aqueous layer with CH2Cl2 (2 times), combine organics,
dry over MgSO4, and concentrate. Chromatograph (silica gel, eluting with 0-10% 2M
NH3 in methanol/CH2Cl2) to give 0.119 g (60%) of product. Dissolve the clean material
in methanol and add 1 equivalent (17.9 mg) of NH4Cl. Sonicate the reaction at room
temperature for 15 min, then concentrate to provide the title compound: mass spectrum
(ion spray): m/z =357.3 (M+1); mp 75.6°C,
Example 88. 2-Chloro-N-(6-((l-ethyl-piperidin-4-yl)-Methyl-amino)-pyridin-2-yl)-4-
fluoro-benzamide hydrochloride

A method similar to Example 87. using 2-chloro-4-fluoro-N-(6-methyl-piperidin-
4-yl-amino)-pyridin-2-yl)-benzamide (free-based of Example 86). gives the title

compound as a yellow-white solid (102 mg): mass spectrum (ion spray): m/z = 391.3
(M+1);mp 132.9°C.
Example 89. 4-Fluoro-N-(6-(methyl-(1-propyl-piperidin-4-yl)-amino)-pyridin-2-yl)-
benzamide hydrochloride

A method similar to Example 87, using 4-fluoro-N-(6-methyl-piperidin-4-yl-
amino)-pyridin-2-y!)-benzamide (free-based of Example 85), and propionaldehyde in
place of acetaldehyde, gives the title compound as a white solid (77 mg): mass spectrum
(ion spray): m/z = 371.4 (M+1); mp 84.7°C.
Example 90. 2-Chloro-4-fluoro-N-(6-(methyl-(1-propyl-pipen'din-4-yl)-amino)-pyridin-
2-yl)-bertzamide hydrochloride

A method similar to Example 87, using 2-chloro-4-fluoro-N-(6-methyl-pipcridin-
4-yl-amtno)-pyridin-2-yl)-benzamide (free-based of Example 86), and propionaldehyde in
place of acetaldehyde, gives the title compound as a white solid (41 mg): mass spectrum
(ion spray): m/z = 405.32 (M+1); mp 258oC (dec).
Example 91. N-(6-((1-Cyclopropylmethyl-piperidin-4-yl)-methyl-amino)-pyridin-2-yl)-4-
fluoro-benzamide hydrochloride


A method similar to Example 87, using 4-fluoro-N-(6-methyl-piperidin-4-yl-
amino)-pyridin-2-yl)-benzarnide (free-based of Example 85), and cyclopropane
carboxaldehyde in place of acetaldehyde, gives the title compound as a white solid (130
mg): mass spectrum (ion spray) m/z = 383.2 (M+1); mp 81.6°C.
Example 92. 2-Chloro-N-{6-((l-cyclopropylmcthyl-piperidin-4-yl)-methyl-amino)-
pyridin-2-yl)-4-fluoro-benzamide hydrochloride

A method similar to Example 87, using 2-chloro-4-fluoro-N-(6-methyl-piperidin-
4-yl-amino)-pyridin-2-yl)-benzamide. the free-based product from Example 86, and
cyclopropane carboxaldehyde, in place of acetaldehyde, gives the title compound as a
white solid (143 mg): mass spectrum (ion spray): m/z = 417.3 (M+1); mp 257.5°C.
Example 93. 4-Fluoro-N-(6-((l-(2-(1-isopropyl-1H-pyrazol-4-yl)-ethyl)-piperidin-4-yl)-
Methyl-amino)-pyridin-2-yl)-benzamide hydrochloride

Combine 2-(1-isopropyl-1H-pyrazol-4-yl)-ethanol {Preparation 12, 2 g, 12.9
mmol) and triethylamine (3,6 mL, 25.9 mmol) in 30 mL of THF. Add methanesulfonyl
chloride (1 .3 mL, 15.6 mmol) and stir for 36 hr. Dilute with water and ethyl acetate.
Separate and extract the aqueous layer with CH2CI2 (2 times). Combine organics, dry
over MgSO4, and concentrate in vacuo. Take a portion of this crude mixture (0.17 g, 0.73
mmol) and combine with 4-fluoro-N-(6-methyl-piperidin-4-yl-amino)-pyridin-2-yl)-
benzamide (free-based of Example 85,0.20 g, 0.60 mmol) in 4 ml of DMF. Add
potassium carbonate (0.25g, 1.8 mmol) and heat at 80°C for 18 hr. Cool and dilute with
water and CH2Cl2. Separate and extract the aqueous layer with CH2Cl2 (2 times).

Combine organics, dry over MgSO4, and concentrate in vacuo. Chromatograph (silica get,
eluting with 0-10% 2M NH3-methanol/CH2Cl2) to give 0.1 58 g of product (57%).
Dissolve the purified oil in methanol, add NH4Cl (18.2 mg, 1 eq) as a solid, and sonicate
the solution at room temperature for 15 min. Concentration provides the title compound:
mass spectrum (ion spray): m/z = 465.4 (M+1): mp 85.8°C.
Example 94. 2-Chloro-4-fluoro-N-(6-((l-(2-(1-isopropyl-1H-pyrazol-4-yl)-ethyl)-
piperidin-4-yl)-methyl-amino)-pyridin-2-yl)-benzamide hydrochloride

Using a method similar to Example 93, using 2-Chloro-4-fluoro-N-(6-
methylpiperidin-4-ylamino)pyridin-2-yl)benzamide (Example 86, 150 mg, 0.4 mmol),
gives the title compound as a white solid (114 mg): mass spectrum (ion spray)' m/z =
49936 (M+l );mp96.7°C.
Example 95. 2,4,6-Trifluoro-N-(6-( 1 -methyl-piperidin-4-ytamino)-pyridin-2-yl)-
benzamide dihydrochloride

Combine N-(6-amino-pyridin-2-yl)-2,4,6-trifluoro-benzamide (Preparation 43,
668 mg, 2.5 mmol). 1-methyl-4-piperidone (566 mg, 5.0 mmol), acetic acid (450 mg, 0.43
mL, 7.5 mmol), molecular sieves 4A (1 g) and 1,2-dichloroethane, stir for 30 min at room
temperature, then add sodium triacetoxyborohydride (1.325 g, 6.25 mmol) portionwise.
Add another batch of 1-methyl-piperidone (566 mg, 5.0 mmol) and sodium
triacetoxyborohydride (1.325 g, 6.25 mmol) if starting benzamide is still present after
overnight reaction. Quench the reaction with 0.IN NaOH solution. Extract the mixture
with ethyjacetate three times. Combine organic layers, dry over Na2SO4, filter and
concentrate to afford a residue. Chromatography (silica gel, 4% 2M NH3-methanol in

CH2Cl2) provides 571 mg (63%) of the free base of the title compound. Dilute the free
base in CH2Cl2 (1 mL), add 1M HCl/Et2O (5.6 mL, 5.6 mmol), remove the supernatant,
wash the white solid with ether four times and dry in vacuum oven to afford 600 mg
(88%) of thefree base of the title compound. Using a salt formation method similar to
that described in Example 53 gives the title compound: Free base: mass spectrum (ion
spray): m/z = 365.0 (M+1); 1H NMR (CDCl3, ppm): 8.50 (1H, s), 7.49 (m, 2H), 6.70 (m,
2H), 6.14 (d. 1H). 4.38 (d, 1H), 3.48 (m, 1H), 2.78 (m, 2H), 2.28 (s, 3H), 2.05 (m, 4H),
1 .51 (m, 2H). Di-hydrochloride salt: Anal calc'd for C18H19F3N4O.2HCl: C, 49.44; H,
4.84; N, 12.81. Found: C 49.31; H, 4.96; N. 12.49.
Example 96. 4-Fluoro-N-(6-( 1 -mcthyl-piperidin-4-ylamino)-pyridin-2-yl)-benzamide
dihydrochloride salt

Dissolve 2,6-diaminopyridine (1.637 g, 15 mmol) in dioxane (15 mL) and cool to
0°C for 10 min. Add 4-fluorobenzoyl chloride (793 mg, 0.59 mL. 5.0 mmol) slowly.
After 40 min, remove ice bath and stir the reaction at room temperature. Use the work-up
and purification procedures described in Preparation 43 to provide N-(6-Amino-pyridin-2-
yl)-4-fluoro-benzamide as a slightly yellow solid (1,1 70 g, 100%): mass specturm (ion
spray): m/z = 232.0 (M+1).
Using a method similar to Preparation 43, using the above benzainide (580 mg,
2.51 mmol, 493 mg) gives 493 mg (60%) of the title compound as a white solid. Using a
salt formation method similar to that described in Example 53 gives the title compound:
Free base: mass spectrum (ion spray): m/z = 329.2 (M+1); 1H NMR (CDCl3, ppm): 8.16
(s, 1H), 7.93 (m. 2H), 7.53 (m, 2H), 7.22 (m, 2H), 6.20 (d, 1H), 4.30 (d, 1H), 3.62 (m,
1H), 2.80 (m, 2H). 2.33 (s. 3H), 2.16 (m, 4H), 1.53 (m, 2H). Di-hydrochioride salt: Anal
calc'd for C18H21FN4O.2HCl-H2O: C, 51.56; H, 6.01;N, 13.36. Found: C, 51.78; H, 5.65;
N, 13.36.

Example 97. N-(6-(I-Methyl-piperidin-4-yiamirso)-pyridin-2-yl,)-acetamide
dihydrochloride salt

Using a method similar to Example 95 and THF as the reaction solvent (40 mL).
using N-(6-amino-pyridin-2-yl)-acetamide (Preparation 44, 1.5 12 g, 10 mmol) gives 597
mg (24%) of the free base of the title compound. Using a salt formation method similar
to that described in Example 53gives the title compound: Free base: mass spectrum (ion
spray): m/z = 249.1 (M+1); 1H NMR (CDCl3, ppm): 7.60 (s, br, 1H), 7.44 (m, 2H), 6.14
(m, 1H), 4.25 (d, 1H), 3.58 (m, 1H), 2.554 (m, 2H), 2.34 (s, 3H), 2.19 (s, 3H), 2.13 (m,
4H), 1.56 (m 2H). Di-hydrochloride salt: Anal calc'd for C13H20N4O.2HCl.0.25H2O: C.
47.93; H, 6.96; N, 17.20. Found: C, 47.94; H, 7.18; N, 16.77.
Example 98. 2-Chloro-N-(6-(1-Methyl-piperidin-4-ylamino)-pyridiiv2-yl)-
benzamidedihydrochloride salt

Using a method similar to Example 95 with 1,2-dichloroethane/THF as solvent
(1:1, 20 mL), using N-(6-amino-pyridin-2-yl)-2-chloro-benzamide (Preparation 45, 500
mg, 2.02 mmol) gives 285 mg (34%) of the free base of the title compound as a white
solid. Using a salt formation method similar to that described in Example 53 gives the
title compound: Free base: mass spectrum (ion spray): m/z = 345.1 (M+1); fH NMR
(CDCl3, ppm): 8.21 (s, 1H), 7.70 (m, 1H), 7.62 (m. I H), 7.40 (m, 4H), 6.19 (d. 1H). 4.32
(d, 1H), 3.57 (m, 1H), 2.79 (m, 2H), 2.31 (s, 3H), 2.10 (m, 4H), 1.5 I (m, 2H). Di-
hydrochloridesalt: Anal calc'd for C,SH2|CIN402HC1: C, 51.75; H, 5.55; N, 13.41.
Found: C, 51.47; H, 5.38; N, 13.18.

Example 99. 2-Bromo-N-(6-(1-methyl-piperidin-4-ylamino)-pyridin-2-yl)-
bcnzamidedihydrochloride salt

Using a method similar to Example 98, using N-(6-amino-pyridin-2-yl)-2-bromo-
bcnzamidc (Preparation 46, 495 mg, 1.69 mmol) gives 195 mg (25%) of the free base of
the title compound as a white solid. Using a salt formation method similar to that
described in Example 53 gives the title compound: Free base: mass spectrum (ion spray):
m/z = 389.1 (M+1); 1H NMR (CDCl3, ppm): 8.09 (s, 1H), 7.64 (m, 3H), 7.40 (m, 3H),
6.19(d, 1H), 4.31 (d, lH),3.58(m, 1H), 2.80 (m, 2H), 2.30 (s, 3H), 2.07 (m. 4H), 1.54
(m, 2H). Di-hydrochloride salt: Anal calc'd for Cl8H21BrN4O.2HCl.0.5H2O: C. 45.88; H.
5.13: N, 11.89. Found: C, 45.95; H. 5.10; N, 11.73.
Example 100. Cyclohexanecarboxylic acid (6-(1-methyl-piperidin-4-yIamino)-pyridin-2-
yl)-amide dihydrochloride salt

Using a method similar to Example 98, using cyclohexanecarboxylic acid (6-
amino-pyridin-2-yl)-amide (Preparation 47, 510 mg, 2.33 mmol) gives 352 mg (39%) of
the free base of the title compound. Using a salt formation method similar to that
described in Example 53 gives the title compound: Free base: mass spectrum (ion spray):
m/z- = 3l7.2(M+1); 1H NMR (CDCl3, ppm): 7.52 (s, br, 1H), 7.46 (m. 2H). 6.13 (dd. 1H).
4.24 (d. 1 H), 3.58 (m, 1H), 2.82 (m, 2H), 2.33 (s, 3H), 2.24-1.94 (m, 7H), 1.83 (m. 2H),
1.74 (m, 1H), 1.58 (m, 4H), 1.27 (in, 3H). Di-hydrochloride salt: Anal cald for
C18H2SN4O.2HCl.0.5H2O: C, 54.27; H, 7,84; N, 14.06. Found: C. 54.36; H. 7.83: N,
13.91.
Example 101. 2-Chloro-6-fluoro-N(6-(1-methylpiperidin-4-ylarnino)pyridin-2-
yl)benzamide, free base and dihydrochloride salt


Under an inert atmosphere, stir a mixture of N-(6-aminopyridin-2-yl)-2-chloro-6-
fluorobenzamide (Preparation 48, 810 mg, 3.0 mmol), 1-methyl-4-piperidone (339 mg,
0.37 mL, 3,0 mmol), anhydrous THF (50 mL), glacial acetic acid (0.52 mL. 9.2 mmol) at
room temperature for 45 min. Add sodium triacetoxyborohydride (1 g, 4.6 mmol). Allow
the reaction to go for 4 days. Transfer the reaction mixture into ethyl acetate (200 mL),
then wash once with aqueous NaOH (2N, 30 mL). Separate the organic layer, dry over
anhydrous sodium sulfate. Remove the solvent under reduced pressure. Clean the residue
by chromatography (silica gel; 4%-6% (2M NH3 in methanol)/CH2Cl2). Collect the free
base product and convert to its dihydrochloride salt by treating it in CH2Cl3 with excess
solution of 1.0M HCl in diethyl ether and adding more ether to cause its precipitation as a
white solid (268 mg, 20% yield): mass spectrum (ion spray): m/z = 363.2 (M+1); Anal,
calc'd. for C18H20CIFN4O.2HCl H2O: C, 47.64; H, 5.33; N, 12.35. Found: C. 47.69; H.
5.59; N, l1.85;1H NMR δ (methanol-d4)8.01(dd, 1H), 7.60(q, 1H), 7.44(d. 1H), 7.3 l(t.
1H), 6.9l(d. 1H), 6.65(d, 1 H), 3,98(m, 1H). 3.64(d, 2H), 3.30(dd, 2H). 2.91 (s. 3H).
2.37(d, 2H), l.93(m, 211)
Example 102. 3-Chloro-2,6-dir1uoro-N-(6-(1-methylpiperidin-4-ylamino)pyridin-2-
yl)benzamide and dihydrochloride salt

Using a method similar to Example 101, using N-(6-Aminopyridin-2-yl)-3-chloro-
2.6-difluorobenzamide (Preparation 49, 764 mg, 2.7 mmol), i-methyl-4-piperidone (305
mg, .3 mL, 2.7 mmol), anhydrous THF (50 mL), glacial acetic acid ( 0.46 mL. 8.1 mmol),
sodium triacetoxyborohydride (848 mg, 4.0 mmol) gives the title compound
(dihydrochloride salt: 335 mg. 27% yield): mass spectrum (ion spray): m/z =381.0
(M+1); Anal, calc'd. for C1RH19CIF2N4O2HCl H2O: C, 45.83; H, 4.91; N. 11 .88. Found:
C. 46.33; H, 5.02; N, 11.36; (LY 635 146) 1H NMR δ (methanol-d4) 7.99(dd. 1 H), 7,77(m,
1H).7.23(t, 1H),6.91(d, lH),6.69(d, 1H), 3.98(m, 1H), 3.64(d. 2H), 3.30(dd. 2H). 2.91(s,
3H), 2.37(d. 2H). 1.93(m, 2H).

Example 103. 2,6-Difluoro-3-nethyl-N-(6-(1HTiethytpiperidin-4-ylamino)pyridinn-2-
yl)benzarnide and dihydrochloride salt

Using a method similar to Example 101, using N-(6-Aminopyridin-2-yl)-2,6-
difiuoro-3-methylbenzamide (Preparation 50, 662 mg, 2.5 mmol), I-methyl-4-piperidone
(282 mg, .26 mL. 2.5 mmol), anhydrous THF (50 mL), glacial acetic acid ( 0.42 mL, 7.5
mmol),sodium triacetoxyborohydride (795 mg, 3.75 mmol) gives the title com pound
(dihydrochloride salt: (208 mg, 19% yield): mass spectrum (ion spray): m/z = 361.1
(M+1); Anal, caic'd. for C19H22F2N4O.2HCl: C, 52.66; H, 5.58; N, 12.93. Found: C,
52.70; H, 5.46; N, 12.75; 1H NMR δ (methano1-d4) 8.02(dd, 1H),7.51(q, 1H),7.09(t, 1H).
6.90(d, 1H), 6.63(d, 1H), 3.98(m, 1H), 3.64(d, 2H), 3.30(dd, 2H), 2.9l(s, 3H), 2.37(d,
2H), 2.31(s, 3H), 1.93(m,2H)
Example 104. 2-Chloro-4-fluoro-N-(6-(1-Methylpipendin-4-ylarnino)pyridin-2-
yl)benzamide and dihydrochloride salt

Under an inert atmosphere, stir a mixture of N-(6-ammopyridin-2-yl)-2-chloro-4-
fluorobenzamide (Preparation 38, 433 mg, 1.63 mmol), 1-Methyl-4-piperidone (369.5 mg,
0.4 mL, 3.27 mmol), 1,2-dichloroethanc (20 mL), powdered molecular sieves 4A (1 g) for
15 min. Add glacial acetic acid ( 294 mg. 0.28 mL, 4.89 mmol). After 1 hr. add sodium
triacetoxyborohydride (869 mg, 4.1 mmol). Allow the reaction to go overnight, transfer
the reaction mixture into ethyl acetate (200 mL), then wash once with aqueous NaOH
(2N. 30 mL). Separate the organic layer, dry over anhydrous sodium sulfate, pull off the
solvent under reduced pressure. Clean the residue by chromatography (silica gel: 5%-6%
(2M NI l3, in methanol)/CH2CI2). Collect the free base product (226 mg, 38% yield).
Convert the product to its dihydrochloride salt by treating it in CH2Cl2 with excess
solution of 1.0M HCl in diethyl ether and adding more ether to cause its precipitation as a
white solid: mass spectrum (ion spray): m/z = 363.0 (M+1): Anal, ealc'd, for

C18H20ClFN4O.2HC10.5H2O: C, 48.61; H, 5.21; N. 12.60. Found: C. 48.43; H, 5.11; N,
12.28; (LY 635148)1H NMRS(methanol-d4)8.00(dd. lH),7.77(m, lH).7.45(d, 1H),
7.29(m, lH),6.90(d, 1H). 6.65(d, 1H),3.98(m, 1H), 3.64(d, 2H), 3.30(dd. 2H), 2.91(s,
3H), 2.37(d, 2H). 1.93(m, 2H)
Example 105. 2,4-Difluoro-N-(6-(1-mcthylpipcridin-4-ylamino)pyridin-2-yl)benzamide
and dihydrochloride salt

Using a method similar to Example 101, using N-(6-aminopyridin-2-yl)-2,4-
difluorobenzamide (Preparation 51, 617 mg, 2.48 mmol), 1-methyl-4-piperidone (280 mg,
0.3 mL, 2.48 mmol), anhydrous THF (50 mL), glacial acetic acid ( 0.42 mL. 7.4 mmol),
sodium triacetoxyborohydride (784 mg, 3.7 mmol) gives the title compound
(dihydrochloride salt: 56.4 mg, 5% yield): mass spectrum (ion spray): m/z = 347.3
(M+1); Anal, calc'd. for C18H20F2N4O.2HCl.0.SH2O: C. 50.48, H, 5.41. N. 13.08.
Found: C, 50.63, H, 5.43, N, 12.84; (LY 635150) 1H NMR δ (methanol-d4) 7.95(m, 2H),
7.20(m,2H), 6.86(d, 1 H), 6.73(d, 1H), 3.98(m, 1H), 3.64(d, 2H), 3.30(dd, 2H), 2.91(s,
3H), 2.37(d, 2H). 1.93(m, 2H)
Example 106. 2,6-Dichloro-N-(6-(1-methylpiperidin-4-ylamino)pyridin-2-yl)benzamide
and its dihydrochloride salt

Using a method similar to Example 104 using N-(6-aminopyridin-2-yl)-2,6-
dichlorobenzamide (Preparation 52, 569 mg, 2.0 mmol), 1-methyl-4-piperidone 450 mg,
0.5 mL, 4.0 mmol), 1,2-dichloroethane (15 mL), powdered molecular sieves 4A (1 g),
glacial acetic acid ( 360 mg, 0.34 mL, 6.0 mmol), sodium triacetoxyborolndride (1.06 g,
5.0 mmol) gi ves the title compound (491 mg, 66% yield): dihydrochloride salt: mass
spectrum (ion spray): m/z = 379.2 (M+1): Anal, calc'd. for Ci8H2oCI2N40-2HCI: C.
47.81; H, 4.90; N, 12.39. Found: C, 47.59; H, 5.21; N, 12.00; (LY 641053) 1H NMR δ

(CDCl3)7.79(s, 1H), 7.59(d, 1H), 7.47(t, 1H), 7.34(m, 3H), 6.18(d, 1H),4.26(d, 1H).
3.55(m, 1H). 2.73(d, 2H). 2.28(s, 3H). 2.11 (m, 4H), 1.50(m. 2H)
Example 107. 2,6-Difluoro-N-(6-(1-methylpiperidin-4-ylamino)pyridin-2-yl)benzamide
Free base and dihydrochloride salt

Using a method similar to Example 104 using N-(6-aminopyridin-2-yl)-2,6-
difluorobenzamide (Preparation 53, 536 mg, 2.2 mmol), 1-methyl-4-piperidone (486 mg,
.53 mL, 4.3mmol), 1,2-dichloroethane (15 mL), powdered molecular sieves 4A (1 g).
glacial acetic acid (396 mg, 0.38 mL, 6.6 mmol), sodium triacetoxyborohydride (1.16 g,
5.5 mmol) gives the title compound (596 mg, 78% yield): dihydrochloride salt: mass
spectrum (ion spray): m/z = 347.2 (M+1); Anal, calc'd. for C18H20F2N4O.2HCl.0.5H2O:
C, 50.48, H, 5.41, N. 13.08. Found: C, 50.76, H, 5.77, N, 12.70; 1H NMR δ (CDCl3)
7.94(s, 1H), 7.55(d, 1H), 7.41 (m, 2H), 6.97(t, 2H), 6.18(d, lH),4.26(d, 1H),3.55(m, 1H).
2.73(d, 2H), 2.28(s, 3H), 2.1 l(m, 4M), 1.50(m, 2H)
Example 108. 2,4-Dichloro-N-(6-(1-methyl-piperidin-4-ylamino)-pyridin-2-yl)-
benzamide Free base and dihydrochloride salt

Using a method similar to Example 104 using N-(6-aminopyridin-2-yl)-2,4-
dichlorobenzamide (Preparation 54, 621 mg, 2.24 mmol), 1-methyl-4-piperidone (510
mg, 0.55 mL, 4.48mmoI), 1,2-dichloroethane (15 mL), powdered molecular sieves 4A (1
g), glacial acetic acid ( 403.5 mg, 0.38 mL, 6.72 mmol), sodium triacetoxyborohydride
(1.2 g, 5.6 mmol) gives the title compound (397 mg, 46% yield): dihydrochloride salt:
mass spectrum (ion spray): m/z = 379.0 (M+1); Anal, calc'd. for
C18H20Cl2N4O.2HCl.0.4H2O: C, 47.06; H, 5.00; N, 12.20. Found: C, 47.49: H, 5.31: N.
11.72; 1H NMR δ (methano1-d4) 8.01 (dd, 1H), 7.69(m, 2H), 7.53(d. 1H), 6.90(d. 1H),
6.67(m, 1H), 3.98(m, 1H), 3.64(d, 2H), 3.30(dd, 2H), 2.9l(s, 3H), 2.37(d, 2H), l.93(m.
2H).

Example 109. 2,4,6-TriChloro-N(6-(1-methylpiperidin-4-ylamino)pyridin-2-yl)benzamide
Free base and HCl salt

Using a method similar to Example 104 using N-(6-amino-pyridin-2-yl)-2,4,6-
trichloro-benzamide (Preparation 55, 375 mg, 1.18 mmol), 1-methyl-4-piperidone (270
mg, 0.29 mL, 2.37 mmol), 1,2-dichloroethane (15 mL), powdered molecular sieves 4A (1
g), glacial acetic acid ( 0.21 g, 0.20 mL, 3.54 mmol), sodium triacetoxyborohydride (625
mg, 2.95 mmol) gives the title compound (187 mg, 45% yield): dihydrochloride salt:
mass spectrum (ion spray): m/z = 412.0 (M+1), lH NMR 5 (CDCl3) 7.78(s, 1H), 7.56(d,
1H), 7.45(t, 1H), 7.36(s, 2H), 6.18(d, lH),4.26(d, 1H), 3.55(m, 1H), 2.73(d. 2H), 2.28(s,
3H), 2.1l(m, 4H), 1.50(m, 2H).

For Examples 110-115, heat N-methyl-N-(1-methylpiperidin-4-yl)-pyridine-2,6-
diamine(Preparation 34, 200 μL of 0.5M solution in dioxane) and the appropriate R-acid
chloride (0.10 mmol) to 90°C for 2 hr. The reaction mixture is diluted with 10% acetic
acid/methanol (0.5 mL). The resulting solution is directly applied to a 2 g SCX column.
After thoroughly washing with methanol, the column is eluted with 1M ammonia-
mcthanol and the cluant is concentrated and further purified by high-throughput mass
guided chromatography. The compounds are characterized by chromatography using a
Metachem™ CI8 column (monochrom 3 micron, 2.5 x 25 cm) using a 10-90% solvent B
gradient in 4.5 min„ where solvent A is 0.1% trifluoroacetic acid in water and solvent B is
0.1% trifluoroacetic acid in acetonitrile. The procedure is repeated in parallel for
Examples 110-115.


The compounds of this invention are useful for increasing activation of the 5-HT1F
receptor. An increase in the activation of the 5-HT1F is useful fortreating a variety of
disorders which have been linked to decreased neurotransmission of serotonin in
mammals, e.g., migraine headaches. See U.S. Patent No. 5,708,008 demonstrating the
nexus between activation of the 5-HT1F receptor and migraine. 5-HT1F receptor binding
affinity is determined to demonstrate the use of the compounds of the present invention in
the treatment of migraine. The ability of the compounds of this invention to bind to the
5-HT1F receptor subtype is measured essentially as described in N. Adham. et al.
Proceedings of the National 15 Academy of Sciences (USA), 90:408-412, 1993.

Membrane Preparation:
Prepare membranes from transfected Ltk- cells (transfected with the human 5-HT1F
receptor sequence) that have grown to 100% confluency. Wash the cells twice with
phosphate-buffered saline, scrape them from the culture dishes into 5 ml. of ice-cold
phosphate-buffered saline, and centrifuge at 200 x g for 5 min. at 4°C. Resuspend the
pellet in 2.5 ml of ice-cold Tris buffer (20 mM Tris HC1, pH 7.4 at 23°C. 5 mM EDTA)
and homogenize with a Wheaton tissue grinder. Centrifuge the lysate at 200 x g-for 5
min. at 4°C to pellet large fragments which are discarded. Collect the supernatant and
centrifuge at 40,000 x g for 20 min. at 4°C. Wash the resulting pellet once in ice-cold
Tris wash buffer and resuspend in a final buffer containing 50 mM Tris HCl and 0.5 mM
EDTA, pH 7.4 at 23°C. Maintain the membrane preparations on ice and utilize them for
the radioligand binding assays within two hr. of preparation. Determine protein
concentrations by the method of Bradford. Anal. Biochem., 72:248-254. 1976.
Radioligand Binding:
[3H]5-HT binding is performed using slight modifications of the 5-HT|D assay
conditions reported by Herrick-Davis and Titeler (J. Neurochem., 50:1624-1631, 1988)
with the omission of masking ligands. Conduct radioligand binding studies at 37°C in a
total volume of 250 uX of buffer (50 mM Tris, 10 mM MgCl2, 0.2 mM EDTA, 10 μM
pargyline, 0.1% ascorbate, pH 7.4 at 37°C) in 96 well microtiter plates. Perforin
saturation studies using [3H] 5-HT at 12 different concentrations ranging from 0.5 nM to
100 nM. Perform displacement studies using 4.5-5.5 nM [3H] 5-HT. Use 6-12
concentrations of compound to obtain binding profiles of drugs in competition
experiments. Incubations are for 30 minutes for both saturation and displacement studies
based upon initial investigations which determined equilibrium binding conditions.
Define nonspecific binding in the presence of 10 μM 5-HT. Initiate binding by the
addition of 50 μL membrane homogenate (10-20 μg). Terminate the reaction by rapid
filtration through presoaked (0.5% poylethyleneimine) filters using 48R Brandel Cell
Harvester (Gaithersburg, MD). Wash the filters for 5 seconds with ice cold buffer (50
mM Tris HC1, pH=7.4 at 4°C), dry the filters, and place them individually into vials
containing 2.5 mL Readi-Safe (Beckman, Fullerton, CA) and radioactivity was measured
using a Beckman LS 5000TA liquid scintillation counter. The efficiency of counting of
[3H] 5-HT averages between 45-50%. Analyze the binding data by computer-assisted
nonlinear regression analysis (Accufit and Accucomp, Lunden Software, Chagrin Falls.

OH). Convert the IC50 values to Ki values using the Cheng-Prusoff equation. Biochem.
Pharmacol, 22:3099-3108 (1973). Perform experiments in triplicate. Representative
compounds of the present invention were assayed essentially as described above and were
found to have high affinity for the 5-HT1F receptor, as for example Ki's of less than or
equal to about 600 nM. Preferred compounds of the present invention have Ki's of less
than or equal to about 300 nM. Yet more preferred compounds are those having a Ki of
less than or equal to about 200 nM. Particularly preferred compounds are those having a
Ki of less than or equal to about 50 nM. Exemplified compounds have Ki's of less than or
equal to about 200 nM.
Measurement of cAMP formation
As was reported by R.L. Weinshank, et al, W093/14201, the 5-HT1F receptor is
functionally coupled to a G-protein as measured by the ability of serotonin and
serotonergic drugs to inhibit forskolin stimulated cAMP production in NIH3T3 cells
transfected with the 5-HT1F receptor. Adenylate cyclase activity is determined using
standard techniques. A maximal effecl is achieved by serotonin. An Emax is determined
by dividing the inhibition of a test compound by the maximal effect and determining a
percent inhibition. N. Adham, et al, supra,; R.L. Weinshank, et a/., Proceedings of the
National Academy of Sciences (USA), 89:3630-3634, 1992; and the references cited
therein.
Incubate human 5-H7V receptor transfected NIH3T3 cells (estimated Bmax from
one point competition studies = 488 fmol/mg of protein) in DMEM, 5 mM theophylline.
10 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) and 10 μM
pargyline for 20 minutes at 37°C, 5% CO2. Use a range of 6 final concentrations of test
compound in parallel incubations to obtain drug dose-effect curves. Obtain a dose-
response curve for 5-HT measured in parallel, using a fixed dose of methiothepin (0.32
μM), for use in demonstrating competitive antagonism. Add the test compound or 5-HT
to the cells, and follow immediately with the addition of forskolin (10 μM) to initiate
stimulated cAMP production. Incubate the cells for 10 minutes at 37°C, 5% CO2.
Aspirate the medium and quench the reaction with 100 mM HC1. Cool the plates at 4°C
for 15 min., centrifuge to pellet cellular debris (5 min., 500 x g), aliquot the supernatant
into vials and store at -20°C until assessment of cAMP formation by radioimmunoassay
(cAMP radioimmunoassay kit; Advanced Magnetics, Cambridge, MA). Quantify
radioactivity using a Packard COBRA Auto Gamma counter, equipped with data

reduction software. Representative compounds of the present invention were assayed
essentially as described above and found to be agonists of the 5-HT1F receptor.
Protein extravasation assay
The inhibition of neuronal protein extravasation is a functional assay for the
neuronal mechanism of migraine, A compound's ability to inhibit neuronal protein
extravasation can be tested as described in the following assay.
Anesthetize Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles
River Laboratories (225-325 g) with sodium pentobarbital (intraperitoneal injection, 65
mg/kg or 45 mg/kg, respectively). For each animal, place the animal in a stereotaxic
frame (David Kopf Instruments) with the incisor bar set at -3.5 mm for rats or -4.0 mm for
guinea pigs. Make a midline sagital scalp incision, and drill two pairs of bilateral holes
through the skull (6 mm posterially, 2.0 and 4.0 mm laterally on both sides of the mid-line
in rats; 4 mm posteriorly and 3.2 and 5.2 mm laterally on both sides of the mid-line in
guinea pigs, all coordinates referenced to bregma.). Lower pairs of stainless steel
stimulating electrodes, insulated except at the ends (Rhodes Medical Systems, Inc.),
through the holes in both hemispheres, one electrode to a hole, to a depth of 9 mm (rats)
or 10.5 mm (guinea pigs) from dura.
Expose the femoral vein and inject a dose of the test compound or saline negative
control intravenously (1 mL/kg). Approximately 7 min. later, inject a 50 mg/kg dose of
Evans Blue intravenously. The Evans Blue is a fluorescent dye which complexes with
proteins in the blood and functions as a marker for protein extravasation. Exactly 10 min.
post-injection of the test compound, stimulate the left trigeminal ganglion for 3 min. at a
current intensity of 1.0 in A (5 Hz, 4 msec duration) with a Model 273 polentiostat/
galvanoslal (EG&G Princeton Applied Research).
Fifteen minutes following stimulation, kill the animal by exsanguination with 20
mL of saline. Remove the top of the skull to facilitate the collection of dura! membrane
samples. Remove the membrane samples from both hemispheres, rinse with water,
spread flat on microscope slides, dry the tissue on a microscope slide warmer, and apply a
coverslip with a 70% glycerol/water solution.
Quantify the amount of Evans Blue dye in each sample using a fluorescence
microscope (Zeiss) equipped with a grating monochronomator, a spectrophotometer, a
computer-driven motorized stage, and an interface to a personal computer. For each dural
membrane sample, measure fluorescence at 25 points (500 μm steps covering a 2.5 x 2.5

mm square area) using an excitation wavelength of approximately 535 nm and measuring
the emission intensity at a wavelength of 600 nm. Determined the mean and standard
deviation of these measurements.
The extravasation induced by the electrical stimulation of the trigeminal ganglion
is an ipsilateral effect (i.e. occurs only on the side of the dura in which the trigeminal
ganglion was stimulated). This allows the stimulated dura to be used as the test tissue and
the unstimulated half of the dura to be used as a control. The ratio of the amount of
extravasation in the dura from the stimulated side compared to the unstimulated side is
calculated. Saline controls yield a ratio of approximately 2.0 in rats and 1.8 in guinea
pigs. In contrast, a compound which effectively prevents the extravasation in the dura
from the stimulated side will have a ratio of approximately 1.0. Using a range of
compound doses and multiple animals at each dosage level, generate a dose-response
curve for the test compound and approximate the dose that inhibites the extravasation by
50% (ID50). Representative compounds of the present invention were assayed essentially
as described above. The compounds were found to significantly inhibit neuronal protein
extravasation and are thus efficatious in the neurogenic plasma protein extravasation
model for migraine.
Rabbit Saphenous Vein Contraction
Sacrifice male New Zealand White rabbits (3-6 lbs) (Hazleton, Kalamazoo, Ml)
by a lethal dose of sodium pentobarbital (325 mg) injected into the ear vein. Dissect
saphenous vein tissue free of connective tissue, cannulate in situ with polyethylene tuning
(PE50, outside diameter = 0.97 mm) and place in petri dishes containing modified Kreb's
solution (118.2 mMol NaCl, 4.6 mMol KC1, 1.6 mMol CaCI2.H2O. 1.2 mMol KH2PO4.
1.2 mMol MgSO4, 10.0 mMol dextrose and 24.8 mMol NaHCO3). Bend the tips of two
30-gauge stainless steel hypodermic needles into an L-shape and slip them into the lumen
of the polyethylene tubing. Gently push vein tissue from the cannula onto the needles.
Separate the needles and attach the lower needle with thread to a stationary glass rod and
the upper needle with thread to a force transducer (Statham UC-3).
Mount the tissues in organ baths containing 10 ml of modified Krebs' solution.
Maintain tissue bath solutions at 37°C and aerate with 95% O2 and 5% CO2. Apply an
initial optimum resting force of 4 grams to the vein tissue. Record isometric contractions
as changes in grams of force on a Beckman Dynograph with Statham UC-3 transducers
and microscale accessory attachments. Allow tissues to equilibrate 1 to 2 hr. before

exposure to test compound. Add 67 mM KCI to the bath and record the maximal
contraction. Flush the bath, allow the tissue to re-equilibrate under a 4 gram force, add
test compound and record the force of contraction. Add additional compound to achieve
the next concentration in a range of compound concentrations to generate cumulative
agonist concentration-response curves for each test compound. Tissues can be used to
generate up to two agonist concentration-response curves. Calculate the mean EC50 and
the maximal compound response, which maximum is expressed as a percentage of the
maximal contraction for the tissue in response to the 67 mM KCI administered initially to
each tissue.
Two important parameters can be measured with this vasoconstriction assay,
saphenous vein contraction (EC50) and maximal contraction as a percentage of the
maximal KCI response (%mas KCI). The saphenous vein contraction (EC50) is a measure
of the dose required to contract tissue to 50% of the maximal response that the specific
compound is capable ofmediating. The maximal response that the saphenous vein is
capable of exhibiting is measured after administration of a high concentration (67 mM) of
KCI. The %max KCI contraction is the ratio of the maximal response that the specific
compound is capable ofmediating divided by the maximal response that the tissue can
produce upon stimulation with KCI. For purposes of this application, a compound may be
considered to not have significant vasoconstrictive activity if it produces a maximal
contraction of less than or equal to 5% of the contraction produced by the 67 mM KCI
positive control at a compound concentration of up to 100 μM, when assayed essentially
as described above.
Representative compounds of the present invention were tested for
vasoconstrictive activity in the rabbit saphenous vein assay essentially as described above
and were found to not be significantly vasoconstrictive. All compounds of the present
invention that were tested had a %max KCI less than or equal to 10%. This contrasts
greatly with prior art compounds for the treatment of migraine targeting the neural
vasoconstrictive model for migraine treatment, which compounds were selected on the
basis of strong vasoconstrictive activity, as for example, sumatriptan, which has an EC50
of 0.66 mM and a %max KCI of 64.20 when tested essentially as described above.
Selectivity for the S-HT1F receptor
Compounds of the prevent invention are relatively selective for the 5-HT1F
receptor, particularly in comparison to other 5-HT receptor subtypes, specifically other

receptors in the 5-HT1 subclass, as for example, but without limitation, the 5-HT1A,
5-HT1B, 5-HT1D, and 5-HT1E receptor subtypes. Affinity for these other receptor subtypes
can readily be determined by slight modification of the above described radioligand
receptor binding assays using cells transfected with the desired receptor subtype in place
of cells transfected with the 5-HT1F receptor subtype. The binding affinities of
representative compounds of the present invention were determined by such assays and
were found to be selective for the 5-HT1F receptor; that is the affinity of the compounds
for the 5-HT1F receptor was on the whole, higher than for other receptor subtypes,
particular for the 5-HT1B and 5-HT1D receptor subtypes.
Specificity Index
The specificity of compounds of the present invention for 5-HT1F mediated
inhibition of neuronal protein extravasation versus vasoconstrictive activity can be
expressed with a Specificity Index, which is the ratio of vasoconstriction to efficacy in
inhibiting neuronal protein extravasation:

The Corrected Vasoconstriction takes into consideration the maximal contraction
relative to KC1 for each individual compound, and is defined as the vasoconstriction
EC50 value divided by the %max KCI.
For example, sumatriptan has a corrected vasoconstriction EC50 of 1.03x10-8 M
(0.66 mM EC50 ÷ 64.20 %max KCI) and an extravasation inhibition [D50 of 2.6x10-8
mMol/Kg, giving a Specificity Index of 0.40.
Thus the procedure for determining the Specificity Index of any given compound
is as follows:
1. Measure the affinity of the compound for the 5-HTIF receptor using the
radioligand binding method described above;
2. Once affinity for the 5-HTIF receptor is established, determine whether the
compound is an agonist, partial agonist or antagonist of the 5-HT1F receptor by its
response in the above described cAMP assay;
3. If the compound is shown to be an agonist or partial agonist with an Emax of at
least about 50%, measure efficacy of the compound in inhibition of protein extravasation
and saphenous vein contraction using the above described assays; and

4. Calculate the Specificity Index as shown above.
While compounds with a Specificity Index greater than 1 are useful for the
methods and uses of the present invention, larger values for the Specificity Index are
preferred. A larger Specificity Index indicates greater specificity for efficacy in inhibition
of neuronal protein extravasation over vasoconstriction. Thus, preferred compounds have
a Specificity Index of greater than or equal to 10 (at least 10), preferably greater than or
equal to 100 (at least 100). More preferred compounds have a Specificity Index of greater
than or equal to 1000 (at least 1000), and yet more preferred compounds have Specificity
Indexes greater than or equal to 5000 (at least 5000).
Pharmaceutical Compositions
The type of pharmaceutical composition used for the administration of the
compounds employed in the methods of the present invention may be dictated by the
particular compounds selected, the type of pharmacokinetic profile desired from the route
of administration, and the state of the patient.
Pharmaceutical compositions amenable to oral, sublingual, nasal or injectable
administration are prepared in a manner well known in the pharmaceutical art and
comprise at least one active compound. See, e.g., REMINGTON'S PHARMACEUTICAL
SCIENCES, (16th ed. 1980)
In general, a pharmaceutical composition of the present invention includes an
active ingredient (a compound of formula I) and is usually mixed with an excipient,
diluted by an excipient or enclosed within such a carrier which can be in the form of a
capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be
a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the
active ingredient. Thus, the pharmaceutical compositions can be in the form of tablets,
pills, powders, lozenges, sachets, cachets, elixirs, suspensions, Emulsions, solutions,
syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up
to 10% by weight of the active compound, soft and hard gelatin capsules, gels,
suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a pharmaceutical composition, it may be necessary to mill the active
compound to provide the appropriate particle size prior to combining with the other
ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a
particle size of less than 200 mesh. If the active compound is substantially water soluble,
the particle size is normally adjusted by milling to provide a substantially uniform

distribution in the pharmaceutical composition, e.g., about 40 mesh. In one embodiment
of the present invention, the particle size range is between about 0.1 μm to about 100 μm.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol,
mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and
methyl cellulose. The pharmaceutical compositions can additionally include: lubricating
agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and
suspending agents; preserving agents such as Methyl- and propylhydroxybenzoates;
sweetening agents; and flavoring agents. The compounds of the invention cart be
formulated so as to provide quick, sustained or delayed release of the active ingredient
after administration to the patient by employing procedures known in the art.
While it is possible to administer a compound employed in the methods of this
invention directly without any formulation, the compounds are usually administered in the
form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient
and at least one active ingredient. These formulations can be administered by a variety of
routes including oral, buccal, rectal, intranasal, transdermal, subcutaneous intravenous,
intramuscular, and intranasal. Many of the compounds employed in the methods of this
invention are effective as both injectable and oral compositions.
In order to administer transdermally, a transdermal delivery device ("patch") is
needed. Such transdermal patches may be used to provide continuous or discontinuous
infusion of a compound of the present invention in controlled amounts. The construction
and use of transdermal patches for the delivery of pharmaceutical agents is well known in
the art See, e.g., U.S. Patent No. 5,023,252. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical
composition to the brain, either directly or indirectly. Direct techniques usually involve
placement of a drug delivery catheter into the host's ventricular system to bypass the
blood-brain barrier. One such implantable delivery system, used for the transport of
biological factors to specific anatomical regions of the body, is described in U.S. Patent
5,011,472, which is herein incorporated by reference. The delivery of hydrophilic drugs
may be enhanced by intra-arterial infusion of hypertonic solutipns, which can transiently
open the blood-brain barrier.
In one preferred embodiment of the present invention, there is provided a
pharmaceutical composition coin prising at lest one compound as described above in a

pharmaceutical composition adapted for buccal and/or sublingual, or nasal administration.
This embodiment provides administration of the active compound in a manner that avoids
gastric complications, such as first pass metabolism by the gastric system and/or through
the liver. This administration route may also reduce adsorption times, providing more
rapid onset of therapeutic benefit. The compounds of the present invention may provide
particularly favorable solubility profiles to facilitate sublingual/buccal pharmaceutical
compositions. Such pharmaceutical compositions typically require relatively high
concentrations of active ingredients to deliver sufficient amounts of active ingredients to
the limited surface area of the sublingual/buccal mucosa for the relatively short durations
the pharmaceutical composition is in contact with the surface area, to allow the absorption
of the active ingredient. Thus, the very high activity of the compounds of the present
invention facilitate their suitability for sublingual/buccal pharmaceutical compositions.
A compound of formula 1 is preferably formulated in a unit dosage form, each
dosage containing from about 0.001 to about 100 mg, more usually about 1.0 to about 30
mg, of the active ingredient. The term "unit dosage form" refers to physically discrete
units suitable as unitary dosages for human subjects and other mammals, each unit
containing a predetermined quantity of active material calculated to produce the desired
therapeutic effect, in association with a suitable pharmaceutical excipient as described
above.
The compounds of the present invention are generally effective over a wide
dosage range. For examples, dosages per day normally fall within the range of about
0.0001 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of
about 0,1 to about 1 5 mg/kg/day, in single or divided dose, is especially preferred.
However, it will be understood that the amount of the compound actually administered
will be determined by a physician, in the light of the relevant circumstances, including the
condition to be treated, the chosen route of administration, the actual compound or
compounds administered, the age, weight, and response of the individual patient, and the
severity of the patient's symptoms, and therefore the above dosage ranges are not intended
to limit the scope of the invention in any way. In some instances dosage levels below the
lower limit of the aforesaid range may be more than adequate, while in other cases still
larger doses may be employed without causing any harmful side effect, provided that such
larger doses are first divided into several smaller doses for administration throughout the
day.

WE CLAIM:
1. A compound of formula I:

or a pharmaceutically acceptable acid addition salt thereof, where;
X is-C(R3c)=or-N=;
R1 is C2-C6 alkyl, substituted C2-C6 alkyl, C3-C7 cycloalkyl, substituted C3-C7
cycloalkyl, phenyl, substituted phenyl, heterocycle, or substituted heterocycle;
R2 is hydrogen, C1-C3 n-alkyl, C3-C6 cycloalkyl-C1-C3 alkyl, or a group of formula

provided that when R1 is C2-C6 alkyl or substituted C2-C6 alkyl, R2 is hydrogen or
methyl;
R3a, R3b, and, when X is -C(R3c)=, R3c, are each independently hydrogen, fluoro,
or methyl, provided that no more than one of R3a, R3b3 and R3c may be other than
hydrogen;
R4 is hydrogen or C1-C3 alkyl;
R5 is hydrogen, C1-C3 alkyl, or C3-C6 cycloalkylcarbonyl, provided that when R3a
is other than hydrogen, R5 is hydrogen;
R6 is hydrogen or C1-C6 alkyl; and
n is an integer from 1 to 6 inclusively.
2. The compound according to Claim 1 wherein R4 is hydrogen.

3. The compound according to either Claim 1 or Claim 2 wherein R3a, R3b,
and when X is -C(R3c)=, R3c are each independently hydrogen or fluoro, provided no
more than one of R3a, R3b and R3c may be other than hydrogen.
4. The compound according to any one of Claims 1-3 wherein R5 is
hydrogen or methyl.
5. The compound according to any one of Claims 1-4 wherein R2 is
hydrogen or methyl.
6. The compound according to any one of Claims 1-5 wherein R1 is phenyl,
substituted phenyl, heterocycle, or substituted heterocycle.
7. The compound according to any one of Claims 1 - 5 wherein R1 is phenyl,
substituted phenyl, heterocycle, or substituted heterocycle, wherein heterocycle is selected
from the group consisting of furanyl, thiophenyl, pyrrolyl, pyrrolidinyl, pyridinyl, N-
methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl,
thiadiazolyl, thiazolyl, thiazolidinyl, N-acetyltbiazolidinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, isoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, quinolinyl,
benzofuranyl, benzothiophenyl, and indolyl; and
wherein substituted phenyl and substituted heterocycle are taken to mean the ring
moiety is:
i. substituted with one to three halo substituents; or
ii. substituted with one to two substituents independently selected from the group
consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, cyano, and nitro, wherein
each alkyl, alkoxy and alkylthio substituent can be further substituted independently with
C1-C2 alkoxy or with one to five halo groups each independently selected from fluoro and
chloro; or
iii. substituted with one substituent selected from the group consisting of
phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy, wherein the
phenyloxy, benzyloxy, phenylthio, benzylthio, or pyrimidinyloxy moiety can be further
substituted with one to two substituents selected from the group consisting of halo, C1-C2

alkyl, and C1-C2 alkoxy, wherein each alkyl and alkoxy group can be further substituted
with 1 to 3 fluoro groups; or
iv. substituted with one substituent selected from the group consisting of C1-C4
acyl and C1-C4 alkoxycarbonyl, and optionally further substituted with one substituent
selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4
alkyltihio, wherein each alkyl, alkoxy, and alkylthio group can be further substituted with
1 to 3 fluoro groups.
8. The compound according to Claim 7 wherein R1 is phenyl, substituted
phenyl, heterocycle, or substituted heterocycle, wherein heterocycle is selected from the
group consisting of furanyl, thiophenyl, pyrrolyl, pyridinyl, N-Methylpyrrolyl,
pyrirnidinyl, pyrazinyl, indolyl, benzofuranyl, benzothiophenyl, benzodioxolyl, and
thiazolidinyl; and
wherein substituted is taken to mean the ring moiety is:
i. substituted with one to three halo substituents; or
ii. substituted with one to two substituents independently selected from the group
consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, cyano, and nitro, wherein
each alkyl, alkoxy and alkylthio substituent can be further substituted independently with
one to five fluoro groups.
9. The compound according to Claim 7 wherein R1 is phenyl, substituted
phenyl, heterocycle, or substituted heterocycle, wherein heterocycle is selected from the
group consisting of pyridinyl, thiophenyl, and furanyl and
wherein substituted phenyl is taken to mean the ring moiety is:
i. substituted with one to three halo substituents; or
ii. substituted with one to two substituents independently selected from the group
consisting of halo, methyl, methoxy, trifluoromethyl, trifluoromethoxy, and cyano; and
wherein substituted heterocycle is taken to mean the ring moiety is mono-
substituted with halo.
10. A pharmaceutical composition comprising a compound according to any
one of Claims 1 - 9 and a pharmaceutical carrier, diluent, or excipient.

11. A method for the treatment or prevention of migraine in a mammal
comprising administering to a mammal in need of such treatment or prevention an
effective amount of a compound of formula I:

or a pharmaceutically acceptable acid addition salt thereof, where;
X is-C(R3c)=or-N=;
R1 is C2-C6 alkyl, substituted C2-C6 alkyl, C3-C7 cycloalkyl, substituted C3-C7
cycloalkyl, phenyl, substituted phenyl, heterocycle, or substituted heterocycle;
R2 is hydrogen, C1-C3 n-alkyl, C3-C6 cycloalky]-C1-C3 alkyl, or a group of formula
II

provided that when R1 is C2-C6 alkyl or substituted C2-C6 alkyl, R2 is hydrogen or
methyl;
R3a, R3b, and, when X is -C(R3c)=, R3c, are each independently hydrogen, fluoro,
or methyl, provided that no more than one of R3a, R3b, and R3c may be other than
hydrogen;
R4 is hydrogen or C1-C3 alkyl;
Rs is hydrogen, C1-C3 alkyl, or C3-C6 cycloalkylcarbonyl, provided that when R3a
is other than hydrogen, R5 is hydrogen;
R6 is hydrogen or C1-C6 alkyl; and
n is an integer from 1 to 6 inclusively.
12 The method according to Claim 11 wherein the mammal is a human.

13. A compound according to any one of Claims 1 - 9 for use as a
pharmaceutical,
14. A compound according to any one of Claims 1 - 9 for me in the treatment
or prevention of migraine in a mammal.
15. A compound according to Claim 14 wherein the mammal is a human.
16. The use of a compound according to any one of Claims 1 - 9 in the
manufacture of a medicament for the treatment or prevention of migraine in a mammal.
17. The use according to Claim 16 wherein the mammal is a human.
18. A pharmaceutical composition adapted for the treatment or prevention of
migraine comprising a compound according to any one of Claims 1 - 9 in combination
with one or more pharmaceutically acceptable excipients, carriers, or diluents therefor.

ABSTRACT
The present invention relates to compounds of formula I:

or a pharmaceutically acceptable acid addition salt thereof, where;
X is C(R3c= or -N=;
R1 is C2-C6 alkyl, substituted C2-C6 alkyl, C3-C7 cycloalkyl, substituted C3-C7
cycloalkyl, phenyl, substituted phenyl, heterocycle, or substituted heterocycle;
R2 is hydrogen, C1-C3 n-alkyl, C3-C6 cycloalkyl-C1-C3 alkyl, or a group of
formula II

provided that when R1 is C2-C6 alkyl or substituted C2-C6 alkyl, R2 is hydrogen or
methyl; R3a, R3b, and, when X is C(R3c)=, R3c, are each independently hydrogen, fluoro,
or methyl, provided that no more than one of R3a, R3b, and R3c may be other than
hydrogen;
R4 is hydrogen or C1-C3 alkyl;
R5 is hydrogen, C1-C3 alkyl, or C3-C6 cycloalkylcarbonyl, provided that when R3a
is other than hydrogen, R5 is hydrogen;
R6 is hydrogen or C1-C6 alkyl;
and n is an integer from 1 to 6 inclusively. The compounds of the present
invention are useful for activating 5-HT1F receptors, inhibiting neuronal protein
extravasation, and for the treatment or prevention of migraine in a mammal.