INDOLYL-PIPERIDINYL BENZYLAMINES AS BETA-TRYPTASE INHIBITORS
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a series of substituted indolyl-piperidinyl
benzylamines. The compounds of this invention are inhibitors of -tryptase and are,
therefore, useful as pharmaceutical agents. Additionally, this invention also relates to
methods of preparation of substituted indolyl-piperidinyl benzylamines and
intermediates therefor.
Description of the Art
Mast cell mediated inflammatory conditions, in particular asthma, are a
growing public health concern. Asthma is frequently characterized by progressive
development of hyper-responsiveness of the trachea and bronchi to both
immunospecific allergens and generalized chemical or physical stimuli, which lead to
the onset of chronic inflammation. Leukocytes containing IgE receptors, notably mast
cells and basophils, are present in the epithelium and underlying smooth muscle
tissues of bronchi. These leukocytes initially become activated by the binding of
specific inhaled antigens to the IgE receptors and then release a number of chemical
mediators. For example, degranulation of mast cells leads to the release of
proteoglycans, peroxidase, arylsulfatase B, chymase, and tryptase, which results in
bronchiole constriction.
Tryptase is stored in the mast cell secretory granules and is the major
protease of human mast cells. Tryptase has been implicated in a variety of biological
processes, including degradation of vasodilatory and bronchodilatory neuropeptides
(Caughey, et al., J. Pharmacol. Exp. Ther., 1988, 244, pages 133-1 37; Franconi, et
al., J. Pharmacol. Exp. Ther., 1988, 248, pages 947-951 ; and Tarn, et al., Am. J.
Respir. Cell Mol. Biol., 1990, 3, pages 27-32) and modulation of bronchial
responsiveness to histamine (Sekizawa, et al., J. Clin. Invest., 1989, 83, pages 75-
179).
As a result, tryptase inhibitors may be useful as anti-inflammatory agents (K
Rice, P.A. Sprengler, Current Opinion in Drug Discovery and Development, 1999,
2(5), pages 463-474) particularly in the treatment of chronic asthma (M.Q. Zhang, H.
Timmernnan, Mediators Inflamm., 1997, 112, pages 3 11-31 7), and may also be useful
in treating or preventing allergic rhinitis (S. J. Wilson et al, Clin. Exp. Allergy, 1998,
28, pages 220-227), inflammatory bowel disease (S.C. Bischoff et al, Histopathology,
1996, 28, pages 1- 13), psoriasis (A. Naukkarinen et al, Arch. Dermatol. Res., 1993,
285, pages 341-346), conjunctivitis (A.A.Irani et al, J. Allergy Clin. Immunol., 1990,
86, pages 34-40), atopic dermatitis (A. Jarvikallio et al, Br. J. Dermatol., 1997, 136,
pages 871 -877), rheumatoid arthritis (L.C Tetlow et al, Ann. Rheum. Dis., 1998, 54,
pages 549-555), osteoarthritis (M.G. Buckley et al, J. Pathol., 1998, 186, pages 67-
74), gouty arthritis, rheumatoid spondylitis, and diseases of joint cartilage destruction.
In addition, tryptase has been shown to be a potent mitogen for fibroblasts,
suggesting its involvement in the pulmonary fibrosis in asthma and interstitial lung
diseases (Ruoss et al., J. Clin. Invest., 1991 , 88, pages 493-499).
Therefore, tryptase inhibitors may be useful in treating or preventing fibrotic
conditions (J.A. Cairns and A.F. Walls, J. Clin. Invest., 1997, 99, pages 131 3-1 321 )
for example, fibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial
fibrosis, neurofibromas and hypertrophic scars.
Additionally, tryptase inhibitors may be useful in treating or preventing
myocardial infarction, stroke, angina and other consequences of atherosclerotic
plaque rupture (M. Jeziorska et al, J. Pathol., 1997, 182, pages 115-1 22).
Tryptase has also been discovered to activate prostromelysin that in turn
activates collagenase, thereby initiating the destruction of cartilage and periodontal
connective tissue, respectively.
Therefore, tryptase inhibitors could be useful in the treatment or prevention of
arthritis, periodontal disease, diabetic retinopathy, and tumour growth (W.J. Beil et al,
Exp. Hematol., ( 1998) 26, pages 158-1 69). Also, tryptase inhibitors may be useful in
the treatment of anaphylaxis (L.B. Schwarz et al, J. Clin. Invest., 1995, 96, pages
2702-271 0), multiple sclerosis (M. Steinhoff et al, Nat. Med. (N. Y.), 2000, 6(2), pages
151-1 58), peptic ulcers and syncytial viral infections.
Such a compound should readily have utility in treating a patient suffering from
conditions that can be ameliorated by the administration of an inhibitor of tryptase,
e.g., mast cell mediated inflammatory conditions, inflammation, and diseases or
disorders related to the degradation of vasodilatory and bronchodilatory
neuropeptides, and have diminished liability for semicarbazide-sensitive amine
oxidase (SSAO) metabolism.
-tryptase is located solely in mast cell granules as the most abundant serine
protease and is released following stimulation of the IgE receptor by allergen. In
experimental animals, -tryptase release provokes inflammation and
bronchoconstriction characteristic of human asthma. It is also thought to cause
fibroblast activation and therefore to have a role in airways remodeling. Levels of -
tryptase are elevated in bronchoalveolar lavage fluid (BALF) from asthmatic patients.
Clinical proof-of-concept (bronchial allergen challenge) for asthma has been reported
with an inhaled -tryptase inhibitor (APC-366 - since terminated due to bronchial
irritation) -tryptase inhibitors have the potential to impact the symptoms and
pathogenesis of a number of proinflammatory indications, in particular, asthma and
potentially COPD.
Benzylamine containing tryptase inhibitors, as one popular class of serine
protease inhibitors, are also recognized as substrates for amine oxidases, especially
SSAO.
All of the references described herein are incorporated herein by reference in
their entirety.
Accordingly, it is an object of this invention to provide a series of substituted
indolyl-piperidinyl benzylamines that are inhibitors of -tryptase.
It is also an object of this invention to provide processes for the preparation of
the substituted indolyl-piperidinyl benzylamines as disclosed herein.
Other objects and further scope of the applicability of the present invention will
become apparent from the detailed description that follows.
SUMMARY OF THE INVENTION
The present invention provides substituted indolyl-piperidinyl benzylamines of
formula (I), and the stereoisomers, enantiomers, racemates and tautomers of said
compounds and the pharmaceutically acceptable salts thereof, as inhibitors of -
tryptase, and methods of using the compounds of formula (I) as pharmaceutical
agents for the treatment of diseases and disorders.
Thus in accordance with the practice of this invention there is provided a
compound of formula (I):
(I)
wherein
R 1 is F, CI, Br, OCH2CO2CH3, OCH2CONW1 W2, CH2OH or optionally
substituted alkyl, haloalkyl, alkoxy or haloalkoxy; wherein
W1 and W2 are independently H or alkyl;
R2 is H, F, CI, Br, OH, CH2OH, alkyl or alkoxy;
provided R 1 and R2 are not H at the same time; and
R3 is aryl or heteroaryl.
This invention further includes various salts of the compounds of formula (I)
including various enantiomers or diastereomers of compounds of formula (I).
A further embodiment of the present invention relates to a method for inhibiting
-tryptase activity in a patient comprising administering to said patient a
therapeutically effective amount of an inhibitor of -tryptase.
Another embodiment of the present invention relates to a method for inhibiting
-tryptase activity in a patient comprising administering to said patient a
therapeutically effective amount of a compound of formula (I).
Another embodiment of the present invention relates to a method for treating a
patient suffering from a disease or disorder ameliorated by inhibition of -tryptase
comprising administering to said patient a therapeutically effective amount of a
compound of formula (I).
In other aspects of this invention there are also provided various
pharmaceutical compositions comprising one or more compounds of formula (I) as
well as their therapeutic use in alleviating various diseases which are ameliorated by
inhibition of -tryptase.
DETAILED DESCRIPTION OF THE INVENTION
The terms as used herein have the following meanings:
As used herein, the expression "(Ci-C 4)alkyl" includes methyl and ethyl
groups, and straight-chained or branched propyl, and butyl groups. Particular alkyl
groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. Derived expressions such
as "(Ci-C 4)alkoxy", "(C C4)alkoxy(Ci-C 4)alkyl", or "hydroxy(C C4)alkyl" are to be
construed accordingly.
As used herein, the expression "(CrC 6)perfluoroalkyl" means that all of the
hydrogen atoms in said alkyl group are replaced with fluorine atoms. Illustrative
examples include trifluoromethyl and pentafluoroethyl, and straight-chained or
branched heptafluoropropyl, nonafluorobutyl, undecafluoropentyl and
tridecafluorohexyl groups. Derived expression, "(Ci-C6)perfluoroalkoxy", is to be
construed accordingly.
"Halogen" or "halo" means chloro, fluoro, bromo, and iodo.
As used herein, "patient" means a warm blooded animal, such as for example
rat, mice, dogs, cats, guinea pigs, and primates such as humans.
As used herein, the expression "pharmaceutically acceptable carrier" means a
non-toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed
with the compound of the present invention in order to permit the formation of a
pharmaceutical composition, i.e., a dosage form capable of administration to the
patient. One example of such a carrier is pharmaceutically acceptable oil typically
used for parenteral administration.
The term "pharmaceutically acceptable salts" as used herein means that the
salts of the compounds of the present invention can be used in medicinal
preparations. Other salts may, however, be useful in the preparation of the
compounds according to the invention or of their pharmaceutically acceptable salts.
Suitable pharmaceutically acceptable salts of the compounds of this invention include
acid addition salts which may, for example, be formed by mixing a solution of the
compound according to the invention with a solution of a pharmaceutically acceptable
acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfamic acid, sulfuric
acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid,
fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid,
glutaric acid, acetic acid, propionic acid, salicylic acid, cinnamic acid, 2-
phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic
acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid,
carbonic acid or phosphoric acid. The acid metal salts such as sodium
monohydrogen orthophosphate and potassium hydrogen sulfate can also be formed.
Also, the salts so formed may present either as mono- or di- acid salts and can exist
substantially anhydrous or can be hydrated. Furthermore, where the compounds of
the invention carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth
metal salts, e.g. calcium or magnesium salts, and salts formed with suitable organic
ligands, e.g. quaternary ammonium salts.
The expression "stereoisomers" is a general term used for all isomers of the
individual molecules that differ only in the orientation of their atoms in space.
Typically it includes mirror image isomers that are usually formed due to at least one
asymmetric center, (enantiomers). Where the compounds according to the invention
possess two or more asymmetric centers, they may additionally exist as
diastereoisomers, also certain individual molecules may exist as geometric isomers
(cis/trans). Similarly, certain compounds of this invention may exist in a mixture of
two or more structurally distinct forms that are in rapid equilibrium, commonly known
as tautomers. Representative examples of tautomers include keto-enol tautomers,
phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is
to be understood that all such isomers and mixtures thereof in any proportion are
encompassed within the scope of the present invention.
As used herein, 'R' and 'S' are used as commonly used terms in organic
chemistry to denote specific configuration of a chiral center. The term 'R' (rectus)
refers to that configuration of a chiral center with a clockwise relationship of group
priorities (highest to second lowest) when viewed along the bond toward the lowest
priority group. The term 'S' (sinister) refers to that configuration of a chiral center with
a counterclockwise relationship of group priorities (highest to second lowest) when
viewed along the bond toward the lowest priority group. The priority of groups is
based upon sequence rules wherein prioritization is first based on atomic number (in
order of decreasing atomic number). A listing and discussion of priorities is contained
in Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and
Lewis N. Mander, editors, Wiley-lnterscience, John Wiley & Sons, Inc., New York,
994.
In addition to the (R)-(S) system, the older D-L system may also be used
herein to denote absolute configuration, especially with reference to amino acids. In
this system a Fischer projection formula is oriented so that the number 1 carbon of
the main chain is at the top. The prefix 'D' is used to represent the absolute
configuration of the isomer in which the functional (determining) group is on the right
side of the carbon at the chiral center and 'L', that of the isomer in which it is on the
left.
In a broad sense, the term "substituted" is contemplated to include all
permissible substituents of organic compounds. In a few of the specific embodiments
as disclosed herein, the term "substituted" means substituted with one or more
substituents independently selected from the group consisting of (Ci-C6 )alkyl, (C2-
C6)alkenyl, (Ci .C6 )perfluoroalkyl, phenyl, hydroxy, -CO 2H , an ester, an amide, (C
C6)alkoxy, (CrC 6)thioalkyl, (CrC 6)perfluoroalkoxy, -NH2, C I, Br, I, F, -NH-lower alkyl,
and -N(lower alkyl)2 . However, any of the other suitable substituents known to one
skilled in the art can also be used in these embodiments.
"Therapeutically effective amount" means an amount of the compound which
is effective in treating the named disease, disorder or condition.
The term "treating" refers to:
(i) preventing a disease, disorder or condition from occurring in a patient
that may be predisposed to the disease, disorder and/or condition, but has not yet
been diagnosed as having it;
(ii) inhibiting the disease, disorder or condition, i.e., arresting its
development; and
(iii) relieving the disease, disorder or condition, i.e., causing regression of
the disease, disorder and/or condition.
Thus, in accordance with the practice of this invention there is provided a
compound of formula (I):
(I)
wherein
R 1 is F, CI, Br, OCH2CO2CH3, OCH2CONW1 W2, CH2OH or optionally
substituted alkyl, haloalkyl, alkoxy or haloalkoxy; wherein
W1 and W2 are independently H or alkyl;
R2 is H, F, CI, Br, OH, CH2OH, alkyl or alkoxy;
provided R 1 and R2 are not H at the same time; and
R3 is aryl or heteroaryl.
This invention further includes various salts of the compounds of formula (I)
including various enantiomers or diastereomers of compounds of formula (I). As
noted hereinabove and by way of specific examples hereafter all of the salts that can
be formed including pharmaceutically acceptable salts are part of this invention. As
also noted hereinabove and hereafter all of the conceivable enantiomeric and
diastereomeric forms of compounds of formula (I) are part of this invention.
In one of the embodiments, there is provided the compounds of formula (I)
wherein R 1 is F, CI, Br, OCH2CO2CH3, OCH2CONW1W2 o CH2OH.
In another embodiment of this invention there is also provided a compound of
formula (I), wherein R2 is H, F, CI, Br, OH or CH2OH.
In yet another embodiment of this invention there is also provided a compound
of formula (I), wherein
wherein
R4 is alkyl optionally substituted by one or more groups selected from hydroxy,
alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, optionally
substituted aryl and heteroaryl, or optionally substituted heteroaryl; and
R5 is H, halo, alkoxy, haloalkoxy, alkyl, amido, carboxyl, ureyl, sulfonyl amido,
sulfonyl urea, alkyl optionally substituted by one or more groups
selected from hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl.
In yet another embodiment of this invention there is also provided a compound
of formula (I), wherein R3 is indolyl that is optionally substituted.
In a further aspect of this invention the compounds encompassed by the scope
of this invention without any limitation may be enumerated as shown in the Examples
section. All of these compounds may also include corresponding salts wherever
possible including the pharmaceutically acceptable salts thereof.
This invention describes a novel alternative scaffold which can be used to
generate a series of compounds with beta tryptase inhibitory activity. Based on the
structure activity relationship (SAR) of piperidinyl benzylamines several P4 groups
were chosen to determine whether this conformationally restricted scaffold would
orient the P4 and P 1 groups such that the molecules would have utility as beta
tryptase inhibitors.
The compounds of this invention can be synthesized by any of the procedures
known to one skilled in the art. Specifically, several of the starting materials used in
the preparation of the compounds of this invention are known or are themselves
commercially available. The compounds of this invention and several of the
precursor compounds may also be prepared by methods used to prepare similar
compounds as reported in the literature and as further described herein. For
instance, see R. C. Larock, "Comprehensive Organic Transformations," VCH
publishers, 1989.
It is also well known that in various organic reactions it may be necessary to
protect reactive functional groups, such as for example, amino groups, to avoid their
unwanted participation in the reactions. Conventional protecting groups may be used
in accordance with standard practice and known to one of skilled in the art, for
example, see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic
Chemistry" John Wiley and Sons, Inc., 1991 . For example, suitable amine protecting
groups include without any limitation sulfonyl (e.g., tosyl), acyl (e.g.,
benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g., benzyl), which may be
removed subsequently by hydrolysis or hydrogenation as appropriate. Other suitable
amine protecting groups include trifluoroacetyl [-C(=O)CF 3] which may be removed by
base catalyzed hydrolysis, or a solid phase resin bound benzyl group, such as a
Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker) or a 2,6-dimethoxy-
4-[2-(polystyrylmethoxy)ethoxy]benzyl, which may be removed by acid catalyzed
hydrolysis, for example with TFA. .
In another aspect of this embodiment, a specific disease, a disorder or a
condition that can be prevented and/or treated with the compound of this invention
include, without any limitation the following: ., joint inflammation, arthritis, rheumatoid
arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis,
psoriatic arthritis, and other chronic inflammatory joint diseases. Other embodiments
of physiological conditions that can be treated by the present invention include
physiological conditions such as chronic obstructive pulmonary disease (COPD),
COPD exacerbations, joint cartilage destruction, ocular conjunctivitis, vernal
conjunctivitis, inflammatory bowel disease, asthma, allergic rhinitis, interstitial lung
diseases, fibrosis, sceleroderma, pulmonary fibrosis, acute macular degneration,
macular degeneration, wet macular degeneration, liver cirrhosis, myocardial fibrosis,
neurofibromas, hypertrophic scars, various dermatological conditions, for example,
atopic dermatitis and psoriasis,
myocardial infarction, stroke, angina and other consequences of atherosclerotic
plaque rupture, as well as periodontal disease, diabetic retinopathy, tumor growth,
anaphylaxis, multiple sclerosis, peptic ulcers, and syncytial viral infections.
As described hereinbelow by way of specific examples, the compounds of
formula (I) bind to the -tryptase and demonstrate the ability to inhibit it. The
compound of formula I possesses tryptase inhibition activity according to tests
described in the literature and described hereinafter, and which test results are
believed to correlate to pharmacological activity in humans and other mammals. In
addition the compound in formula one is a prodrug of a compound that possesses invitro
typtase activity according to test described in the literature. Thus, in a further
embodiment, the present invention is directed to the use of formula I or a composition
comprising it for treating a patient suffering from, or subject to, a condition that can be
ameliorated by the administration of an inhibitor of tryptase. For example, the
compound of formula I is useful for treating an inflammatory disease, for example,
joint inflammation, including arthritis, rheumatoid arthritis and other arthritic condition
such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis,
psoriatic arthritis, osteoarthritis or other chronic inflammatory joint disease, or
diseases of joint cartilage destruction, ocular conjunctivitis, vernal conjunctivitis,
inflammatory bowel disease, asthma, allergic rhinitis, interstitial lung diseases,
fibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis,
neurofibromas, hypertrophic scars, various dermatological conditions, for example,
atopic dermatitis and psoriasis, myocardial infarction, stroke, angina or other
consequences of atherosclerotic plaque rupture, as well as periodontal disease,
diabetic retinopathy, macular degeneration, acute macular degeneration, wet ,
macular degeneration, tumor growth, anaphylaxis, multiple sclerosis, peptic ulcers, or
a syncytial viral infection.
According to a further feature of the invention there is provided a method for
the treatment of a human or animal patient suffering from, or subject to, conditions
which can be ameliorated by the administration of an inhibitor of tryptase, for example
conditions as hereinbefore described, which comprises the administration to the
patient of an effective amount of compound of the invention or a composition
containing a compound of the invention. Therefore, the compounds of this invention
may have utility in the treatment of diseases or conditions ameliorated by inhibition of
-tryptase. Accordingly, the differential activities of these compounds may allow for
utility to ameliorate multiple disease states as specifically enumerated above.
Thus in one aspect of this invention there is provided a method of treating a
disease in a patient, said disease selected from the group consisting of ., joint
inflammation, arthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis,
traumatic arthritis, rubella arthritis, psoriatic arthritis, and other chronic inflammatory
joint diseases. Other embodiments of physiological conditions that can be treated by
the present invention include physiological conditions such as chronic obstructive
pulmonary disease (COPD), COPD exacerbations, joint cartilage destruction, ocular
conjunctivitis, vernal conjunctivitis, inflammatory bowel disease, asthma, allergic
rhinitis, interstitial lung diseases, fibrosis, sceleroderma, pulmonary fibrosis, acute
macular degneration, macular degeneration, wet macular degeneration, liver
cirrhosis, myocardial fibrosis, neurofibromas, hypertrophic scars, various
dermatological conditions, for example, atopic dermatitis and psoriasis,
myocardial infarction, stroke, angina and other consequences of atherosclerotic
plaque rupture, as well as periodontal disease, diabetic retinopathy, tumor growth,
anaphylaxis, multiple sclerosis, peptic ulcers, and syncytial viral infections;
comprising administering to said patient a therapeutically effective amount of a
compound of formula (I).
One of skill in the art readily appreciates that the pathologies and disease
states expressly stated herein are not intended to be limiting rather to illustrate the
efficacy of the compounds of the present invention. Thus it is to be understood that
the compounds of this invention may be used to treat any disease caused by the
effects of -tryptase. That is, as noted above, the compounds of the present
invention are inhibitors of -tryptase and may be effectively administered to
ameliorate any disease state which is mediated all or in part by -tryptase.
All of the various embodiments of the compounds of this invention as disclosed
herein can be used in the method of treating various disease states as described
herein. As stated herein, the compounds used in the method of this invention are
capable of inhibiting the effects of -tryptase and thereby alleviating the effects and/or
conditions caused due to the activity of -tryptase.
In another embodiment of the method of this invention, the compounds of this
invention can be administered by any of the methods known in the art. Specifically,
the compounds of this invention can be administered by oral, intramuscular,
subcutaneous, rectal, intratracheal, intranasal, intraperitoneal or topical route.
Finally, in yet another embodiment of this invention, there is also provided a
pharmaceutical composition comprising a pharmaceutically acceptable carrier and a
compound of formula (I), including enantiomers, stereoisomers, and tautomers of said
compound and pharmaceutically acceptable salts, solvates or derivatives thereof,
with said compound having the general structure shown in formula (I) as described
herein.
As described herein, the pharmaceutical compositions of this invention feature
-tryptase inhibitory activity and thus are useful in treating any disease, condition or a
disorder caused due to the effects of -tryptase in a patient. Again, as described
above, all of the preferred embodiments of the compounds of this invention as
disclosed herein can be used in preparing the pharmaceutical compositions as
described herein.
Preferably the pharmaceutical compositions of this invention are in unit dosage
forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions
or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector
devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal
administration, or for administration by inhalation or insufflation. Alternatively, the
compositions may be presented in a form suitable for once-weekly or once-monthly
administration; for example, an insoluble salt of the active compound, such as the
decanoate salt, may be adapted to provide a depot preparation for intramuscular
injection. An erodible polymer containing the active ingredient may be envisaged.
For preparing solid compositions such as tablets, the principal active ingredient is
mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as
corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate,
dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form
a solid preformulation composition containing a homogeneous mixture of a compound
of the present invention, or a pharmaceutically acceptable salt thereof. When
referring to these preformulation compositions as homogeneous, it is meant that the
active ingredient is dispersed evenly throughout the composition so that the
composition may be readily subdivided into equally effective unit dosage forms such
as tablets, pills and capsules. This solid preformulation composition is then
subdivided into unit dosage forms of the type described above containing from 0.1 to
about 500 mg of the active ingredient of the present invention. Flavored unit dosage
forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the
active ingredient. The tablets or pills of the novel composition can be coated or
otherwise compounded to provide a dosage form affording the advantage of
prolonged action. For example, the tablet or pill can comprise an inner dosage and
an outer dosage component, the latter being in the form of an envelope over the
former. The two components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permits the inner component to pass intact
into the duodenum or to be delayed in release. A variety of materials can be used for
such enteric layers or coatings, such materials including a number of polymeric acids
and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and
cellulose acetate.
The liquid forms in which the novel compositions of the present invention may
be incorporated for administration orally or by injection include aqueous solutions,
suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with
edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as
elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents
for aqueous suspensions include synthetic and natural gums such as tragacanth,
acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl
pyrrolidone or gelatin.
The pharmaceutical compositions of this invention can be administered by any
of the methods known in the art. In general, the pharmaceutical compositions of this
invention can be administered by oral, intramuscular, subcutaneous, rectal,
intratracheal, intranasal, intraperitoneal or topical route. The preferred
administrations of the pharmaceutical composition of this invention are by oral and
intranasal routes. Any of the known methods to administer pharmaceutical
compositions by an oral or an intranasal route can be used to administer the
composition of this invention.
In the treatment of various disease states as described herein, a suitable
dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg
per day, and especially about 0.05 to 20 mg/kg per day. The compounds may be
administered on a regimen of 1 to 4 times per day.
This invention is further illustrated by the following examples which are
provided for illustration purposes and in no way limit the scope of the present
invention.
Examples (General)
As used in the examples and preparations that follow, the terms used therein
shall have the meanings indicated: "kg" refers to kilograms, "g" refers to grams, "mg"
refers to milligrams, Vg" refers to micrograms, "pg" refers to picograms, "lb" refers to
pounds, "oz" refers to ounces, "mol" refers to moles, "mmol" refers to millimoles,
mole" refers to micromoles, "nmole" refers to nanomoles, "L" refers to liters, "ml_" or
"ml" refers to milliliters, "_" refers to microliters, "gal" refers to gallons, "°C" refers to
degrees Celsius, "Rf " refers to retention factor, "mp" or "m.p." refers to melting point,
"dec" refers to decomposition, "bp" or "b.p." refers to boiling point, "mm of Hg" refers
to pressure in millimeters of mercury, "cm" refers to centimeters, "nm" refers to
nanometers, "abs." refers to absolute, "cone." refers to concentrated, "c" refers to
concentration in g/mL, "DMSO" refers to dimethyl sulfoxide, "DMF" refers to N,Ndimethylformamide,
"CDI" refers to 1, 1 '-carbonyldiimidazole, "DCM" or "CH2CI2"
refers to dichloromethane, "DCE" refers to 1,2-dichloroethane, "HCI" refers to
hydrochloric acid, "EtOAc" refers to ethyl acetate, "PBS" refers to Phosphate Buffered
Saline, "IBMX" refers to 3-isobutyl-1 -methylxanthine, "PEG" refers to polyethylene
glycol, "MeOH" refers to methanol, "MeNH2" refers to methyl amine, "N2" refers to
nitrogen gas, "iPrOH" refers to isopropyl alcohol, "Et O" refers to ethyl ether, "LAH"
refers to lithium aluminum hydride, "heptane" refers to n-heptane, "HMBA-AM" resin
refers to 4-hydroxymethylbenzoic acid amino methyl resin, "PdCI2(dppf)2" refers to
1, 1 '-bis(diphenylphosphino)ferrocene-palladium (II) dichloride DCM complex, "HBTU"
refers to 2-(1 H-benzotriazol-1yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate,
"DIEA" refers to diisopropylethylamine, "CsF" refers to cesium fluoride, "Mel" refers to
methyl iodide, "AcN," "MeCN" or "CH3CN"refers to acetonitrile, "TFA" refers to
trifluoroacetic acid, "THF" refers to tetrahydrofuran, "NMP" refers to 1-methyl-2-
pyrrolidinone, "H O" refers to water, "BOC" refers to t-butyloxycarbonyl, "brine" refers
to a saturated aqueous sodium chloride solution, "M" refers to molar, "mM" refers to
millimolar, "" refers to micromolar, "nM" refers to nanomolar, "N" refers to normal,
"TLC" refers to thin layer chromatography, "HPLC" refers to high performance liquid
chromatography, "HRMS" refers to high resolution mass spectrum, "L.O.D." refers to
loss on drying, "'\" refers to microcuries, "i.p." refers to intraperitoneally, "i.v." refers
to intravenously, anhyd = anhydrous; aq = aqueous; min = minute; hr = hour; d = day;
sat. = saturated; s = singlet, d = doublet; t = triplet; q = quartet; m = multiplet; dd =
doublet of doublets; br = broad; r.t. = room temperature; LC = liquid chromatograph;
MS = mass spectrograph; ESI/MS = electrospray ionization/mass spectrograph; RT =
retention time; M = molecular ion, "~" = approximately.
Reactions generally are run under a nitrogen atmosphere. Solvents are dried
over magnesium sulfate and are evaporated under vacuum on a rotary evaporator.
TLC analyses are performed with EM Science silica gel 60 F254 plates with
visualization by UV irradiation. Flash chromatography is performed using Alltech
prepacked silica gel cartridges. The 1H NMR spectra are run at 300 MHz on a
Gemini 300 or Varian Mercury 300 spectrometer with an ASW 5 mm probe, and
usually recorded at ambient temperature in a deuterated solvent, such as D2O,
DMSO-D6 or CDCI3 unless otherwise noted. Chemical shifts values () are indicated
in parts per million (ppm) with reference to tetramethylsilane (TMS) as the internal
standard.
High Pressure Liquid Chromatography-Mass Spectrometry (LCMS)
experiments to determine retention times (RT) and associated mass ions are
performed using one of the following methods:
Mass Spectra (MS) are recorded using a Micromass mass spectrometer. Generally,
the method used was positive electro-spray ionization, scanning mass m/z from 100
to 1000. Liquid chromatography was performed on a Hewlett Packard 1100 Series
Binary Pump & Degasser; Auxiliary detectors used were: Hewlett Packard 1100
Series UV detector, wavelength = 220 nm and Sedere SEDEX 75 Evaporative Light
Scattering (ELS) detector temperature = 46°C, N2 pressure = 4 bar.
LCT: Grad (AcN+0.05% TFA):(H 2O+0.05% TFA) = 5:95 (0 min) to 95:5 (2.5 min) to
95:5 (3 min). Column: YMC Jsphere 33x2 4 , 1 ml/min
MUX: Column: YMC Jsphere 33x2, 1 ml/min
Grad (AcN+0.05% TFA):(H2O+0.05% TFA) = 5:95 (0 min) to 95:5 (3.4 min) to 95:5
(4.4 min).
LCT2: YMC Jsphere 33x2 4 , (AcN+0.05%TFA):(H2O+0.05%TFA) = 5:95 (0 min)
to 95:5 (3.4 min) to 95:5 (4.4 min)
QU: YMC Jsphere 33x2 I ml/min, (AcN+0.08% formic acid):(H2O+0.1 % formic acid) =
5:95 (0 min) to 95:5 (2.5min) to 95:5 (3.0min)
The following examples describe the procedures used for the preparation of
some of the compounds of this invention.
Example 1
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
trifluoromethoxy-1 H-indol-3-yl]-methanone hydrochloride
A. (2-Trifluoromethoxy-phenyl)-carbamic acid ethyl ester
To a solution of 2-(trifluoromethoxy)aniline ( 15.9 g, 0.09 mol) in DME (300 ml_)
at -5 °C (ice/salt bath) is added sodium hydride (3.6 g, 60% by weight, 0.09 mol) in
portions. The suspension is warmed to r.t. and ethyl chloroformate (7.5 ml_, 0.08
mol) is added dropwise. The reaction mixture is stirred for 2 h at r.t. then heated to
reflux for 1.5 h. The mixture is then cooled to r.t. and water (150 ml_) is slowly added
to quench the reaction. The phases are separated and the water layer is extracted
with EtOAc (2x1 00 ml_). The combined organic layers are washed with brine, dried
over MgSO4, filtered and concentrated in vacuo. The crude material is purified on
silica gel with EtOAc/heptanes (1-5%) as eluent to afford the title product ( 1 1.0 g,
49%) as an amber oil.
1H NMR (300 MHz, CDCI3) 8.20 (d, J = 8.1 Hz, 1H), 7.30-7.22 (m, 2H), 7.07 (app t ,
1H), 6.90 (br s, 1H), 4.25 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H);
19F NMR (300 MHz, CDCI3) -57.32 (s, 3F);
LC Rt: 2.96 min; MS 250 (M+1 , 94%).
B. (2-lodo-6-trifluoromethoxy-phenyl)-carbamic acid ethyl ester
To a solution of (2-trifluoromethoxy-phenyl)-carbamic acid ethyl ester ( 11.0 g
44.2 mmol) in THF (200 mL) at -78 °C is added sec-BuLi ( 1 .3 M in cyclohexane, 7 1.4
mL, 92.8 mmol) dropwise. After 1 h, a solution of I2 ( 1 1.22 g, 44.2 mmol) in THF (42
mL) is added dropwise. The resulting orange mixture is stirred at -78 °C for 40 min
then saturated NH CI (200 mL) is added, and the cooling bath is removed. The
reaction mixture is partitioned between H2O and diethyl ether. The two layers are
separated, and the organic layer is washed with 50% Na2SO3, H2O and brine, dried
over MgSO , filtered, and concentrated in vacuo to yield a yellow/orange solid as the
title product (14.9 g, 90%).
1H NMR (300 MHz, CDCI3) 7.81 (d, J = 8.1 Hz, 1H), 7.29 (m, 1H), 7.05 (app t , 1H),
6.1 0 (br s, 1H), 4.24 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H);
19F NMR (300 MHz, CDCI3) -57.28 (s, 3F);
LC Rt 2.93 min; MS 375 (M+1 , 97%).
C. (2-Trifluoromethoxy-6-trimethylsilanylethynyl-phenyl)-carbamic acid ethyl ester
Bis(triphenylphosphine)palladiunn (II) dichloride (21 0 mg, 0.30 mmol) and Cul
(57 mg, 0.30 mmol) is added to TEA ( 1 10 ml_) and heated to 80 °C for 20 min. The
mixture is cooled to r.t. then (2-iodo-6-trifluoromethoxy-phenyl)-carbamic acid ethyl
ester ( 11.2 g, 29.9 mmol) is added and stirred for 30 min. TMS-acetylene (4.0 ml_,
28.4 mmol) is then added dropwise to the reaction mixture and the resulting solution
is stirred at r.t. for 1.5 h. Triethylamine is removed in vacuo and the residue is
partitioned between water and Et2O. The organic layer is washed with 1N HCI, brine
and dried over MgSO4, filtered and concentrated in vacuo. The crude material is
purified on silica gel with EtOAc/heptane (5-6 %) as eluent to give the titled product
(8.4 g, 8 1%) as a yellow solid.
1H NMR (300 MHz, CDCI3) 7.41 (d, J = 7.5 Hz, 1H), 7.29-7.1 3 (m, 2H), 6.32 (br s,
1H), 4.23 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.26 (s, 9H);
LC Rt 3.56 min; MS 346 (M+1 , 92%).
D. 7-Trifluoromethoxy-1 H-indole
KOH ( 1 .95 g, 34.8 mmol) is heated to 80 °C in t-butanol (55 ml_) for 2 hr during
which time the solution becomes homogeneous and clear. (2-Trifluoromethoxy-6-
trimethylsilanylethynyl-phenyl)-carbamic acid ethyl ester (5.214 g, 15.1 mmol) is
added to the solution and heated at 80 °C for 2 h. The solvent is removed in vacuo
and the residue partitioned between Et2O and water. The organic layer is washed
with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material
is purified on silica gel with EtOAc/heptane ( 1-5%) as eluent to yield the title product
( 1 .82 g, 60%) as a yellow liquid.
H NMR (300 MHz, CDCI3) 8.40 (br s, 1H), 7.58-7.55 (m, 1H), 7.25 (m, 1H), 7.09-
7.07 (m, 2H), 6.62-6.60 (m, 1H);
9F NMR (300 MHz, CDCI3) -57.50 (s, 3F);
CHN: Theoretical: C 53.74%, H 3.01 %, N 6.96%. Found: C 53.86%, H 3.14%, N
6.97%.
E. 1-(2-Methoxy-ethyl)-7-trifluoromethoxy-1 H-indole
Powder KOH (3.422 g, 6 1.1 mmol) in DMSO (45 mL) is stirred at r.t. for 5 min
under N2 then 7-trifluoromethoxy-1 H-indole (3.071 g, 15.3 mmol) in DMSO (5 mL) is
added dropwise to the reaction mixture. After 45 min at r.t., 2- methoxyethyl bromide
(2.9 mL, 30.6 mmol) is added dropwise and the mixture is stirred at r.t. overnight.
LC/MS indicates the reaction is completed. The mixture is partitioned between H2O
and Et2O. The two layers are separated, and the aqueous layer is extracted with
Et2O (2X). The combined organic layers are washed with H2O and brine, dried over
MgSO , filtered, and concentrated in vacuo. The crude material is purified on silica
gel with EtOAc/heptane (5-1 0%) as eluent to afford the title product (3.486 g, 88%) as
a yellow oil.
H NMR (300 MHz, CDCI3) 7.50 (d, 1H), 7.1 5 (d, J = 3.0 Hz, 1H), 7.05-7.03 (m, 2H),
6.51 (d, J = 3.3 Hz, 1 H), 4.46 (t, J = 5.4 Hz, 2H), 3.70 (t, J = 5.4 Hz, 2H), 3.30 (s,
3H);
9F NMR (300 MHz, CDCI3) -56.45 (s, 3F);
MS 260 (M+1 ) .
F. 2,2,2-Trifluoro-1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indol-3-yl]-ethanone
O
To a mixture of 1-(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole ( 1 .898 g,
7.32 mmol) in DMF (14 ml_) at 0 °C is added TFAA ( 1 .2 ml_, 8.63 mmol) dropwise.
After addition is completed, the reaction mixture is stirred at 0 °C for 3.5 h and then
poured into ice water (50 ml_). The solid precipitate is collected and can be used in
subsequent steps or taken up in water/EtOAc and further worked up as follows. The
two layers are separated, and the organic layer is washed with water, brine, dried
over MgSO4, filtered, and concentrated in vacuo. The crude orange solid (2.6 g,
100%) can be taken on to the next step without further purification.
H NMR (300 MHz, CDCI3) 8.35 (d, J = 9 Hz, 1H), 8.01 (s, 1H), 7.33 (app t , 1H),
7.26 (m, 1H), 4.55 (t, J = 6 Hz, 2H), 3.75 (t, J = 6 Hz, 2H), 3.32 (s, 3H);
9F NMR (300 MHz, CDCI3) -56.41 (s, 3F), -72.1 6 (s, 3F);
LC Rt 3.59 min; MS 356 (M+1 ) .
G. 1-(2-Methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carboxylic acid
2,2,2-Trifluoro-1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indol-3-yl]-
ethanone ( 1 .655 g, 4.66 mmol) in 5 N NaOH (20 ml_) is heated at 90 °C for two days.
The reaction mixture is cooled to room temperature, and then washed with CH2CI2
(3x30 ml_). The aqueous layer is slowly acidified to pH ~4 with cone. HCI and the
white powder is collected by suction filtration and air-dried to give the title product
(0.923 g, 65%).
H NMR (300 MHz, CDCI3) 8.1 7 (d, J = 6 Hz, 1H), 7.97 (s, 1H), 7.27-7.22 (m, 1H),
7.1 8-7.1 5 (m, 1H), 4.52 (t, J = 6 Hz, 2H), 3.74 (t, J = 6 Hz, 2H), 3.32 (s, 3H);
9F NMR (300 MHz, CDCI3) -56.34 (s, 3F);
LC Rt 3.1 7 min; MS 345 (M+CH3CN+1 ) , 304 (M+1 , 100%).
H. 2,2,2-Trifluoro-N-(4-fluoro-3-pyridin-4-yl-benzyl)-acetamide hydrochloride
A flask is charged with NaHCO3 ( 126 g, 1.5 mol), 3-bromo-4-
fluorobenzylamine hydrochloride ( 120 g, 0.5 mole) and pyridine-4-boronic acid (67.6
g, 0.55 mmol) and isopropyl alcohol (750 mL) and water (375 mL) at r.t. The
suspension is degassed with N2 for 1.0 h at 10 °C. Into the mixture is added 1, 1 '-
bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex
(PdCl2dppf-CH 2Cl2, 16.4 g, 20 mmol). The reaction mixture is ramped to 80 °C while
some part is distilled off until the internal temperature reached to 80 °C, and stirred
for 10 h. After the reaction is completed (HPLC analysis), the mixture is cooled to r.t.,
and aqueous 2 N HCI (750 mL) is added, and stirred for 0.5 h. The solution is
washed with CH2CI2 (750 mL and 500 mL). To the aqueous phase is charged 50%
aqueous NaOH (100 mL) to adjust pH >13. After adding n-BuOAc (2.0 L), activated
carbon (50 g) is added into the organic layer. This mixture is filtered through a pad of
Celite (50 g). Azeotropic distillation is performed. After adding an additional n-
BuOAc ( 1 .0 L), the reaction is cooled to 5 °C. Trifluoroacetic anhydride ( 157 g, 0.6
mol) is slowly added into the solution at 5 °C. After the reaction is completed (HPLC
analysis), the reaction mixture is washed with aqueous 10% Na2CO3 ( 1 .0 L). A
solution of 5-6 N HCI in isopropanol (120 mL) is introduced into the crude organic
layer at 10 °C. Additional n-BuOAc ( 1 .0 L) is then added, the suspension is left
overnight at r.t. The resultant solid is filtered at 10 °C, and dried in oven at 50 °C to
give the desired product ( 124 g, 75%) as a white solid: mp = 220 °C.
Anal. Calcd for C14H10F4N2O-HCI: C, 50.24; H, 3.31 ; N, 8.37. Found: C, 50.1 6; H,
3.08; N, 8.38.
H NMR (300 MHz, D2O) 8.70 (d, J = 6.9 Hz, 2H), 8.14 (d, J = 6.9 Hz, 2H), 7.56-
7.20 (m, 3H), 4.51 (s, 2H);
MS (ESI) m/z 299 (M+H).
I . 2,2,2-tnfluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride
A Parr flask is charged with 2,2,2-trifluoro-N-(4-fluoro-3-pyridin-4-yl-benzyl)-
acetamide hydrochloride ( 123 g, 0.37 mol) and MeOH (740 ml_) at room temperature.
Then, 5% Pt/C (36.9 g, 30 w/w%) is added. The reaction flask is placed in a Parr
hydrogenation system and charged with H at 50-60 psi. The mixture is shaken for
>48 h while charging H until the pressure reached a steady state (H2 was refilled to
50-60 psi every 2-3 hours during day time while 10-20 psi is observed without any
further refill after overnight). When HPLC analysis shows completion of the reaction,
the reaction mixture is filtered through a pad of Celite. The filtrate is distilled at 40-50
°C while adding n-BuOAc ( 1 .25 L). After completion of distillation of MeOH, additional
n-BuOAc ( 1 L) is added. The resultant suspension is allowed to cool to r.t. overnight.
The suspension is cooled to 10 °C, filtered, and dried in oven at 50 °C to give the
desired product ( 1 12 g, 89%) as white solid: mp = 134 °C.
Anal. Calcd for C14H10F4N2O-HCI: C, 50.24; H, 3.31 ; N, 8.37. Found: C, 50.1 6; H,
3.08; N, 8.38;
H NMR (300 MHz, D2O) 7.1 6-6.98 (m, 3 H), 4.34 (s, 2H), 3.42 (d, J = 12.9 Hz, 2H),
3.14-2.99 (m, 3H), 1.98-1 .81 (m, 4H);
MS (ESI) m/z 305.4 (M+H).
J. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of 1-(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carboxylic
acid (0.81 8 g, 2.70 mmol), Et3N (0.9 mL, 6.5 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-
piperidin-4-yl-benzyl)-acetamide hydrochloride (0.91 9 g, 2.70 mmol), and EDCI
(0.620 g, 3.2 mmol) in CH2CI2 (30 mL) is stirred at r.t. overnight. Both TLC and
LC/MS indicate that the reaction is completed. The mixture is diluted with EtOAc (60
mL) and the organic layer is washed with saturated NH CI solution, water and brine.
The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The
crude material is purified on silica gel with MeOH/CH 2Cl2 ( 1-5%) as eluent to give the
title product ( 1 .368 g, 86%) as a white foamy solid.
H NMR (300 MHz, CDCI3) 7.68 (d, J = 9 Hz, 1H), 7.46 (s, 1H), 7.1 5-7.13 (m, 4H),
7.1 5-7.01 (m, 1H), 6.89 (br s, 1H), 4.52 (br s, 3H), 4.48 (t, J = 5.2 Hz, 2H), 3.71 (t, J =
5.2 Hz, 2H), 3.30 (s, 3H), 3.20-3.00 (m, 4H), 1.90-1 .65 (m, 4H);
9F NMR (300 MHz, CDCI3) -56.52 (s, 3F), -75.40 (s, 3F), - 1 18.98 (s, 1F);
LC Rt 3.52 min; MS 590 (M+1 , 100%).
K. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
trifluoromethoxy-1 H-indol-3-yl]-methanone hydrochloride
2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (21 .574 g, 36.6 mmol) and
K2CO3 (65.5 g, 474 mmol in H2O/MeOH (290 mL/730 mL)) is stirred at r.t. overnight
during which time the suspension becomes homogeneous. The reaction mixture is
concentrated in vacuo to remove most of the methanol and the residue is partitioned
between H2O and EtOAc. The two layers are separated, and the organic layer is
washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo to
yield the title product ( 17.520 g, 97%) as a clear colorless sticky gum.
H NMR (300 MHz, CDCI3) 7.70 (d, 1H), 7.48 (s, 1H), 7.20-7.1 3 (m, 4H), 7.00-6.99
(m, 1H), 4.60 (br s, 2H), 4.49 (t, J = 5.1 Hz, 2H), 3.86 (br s, 2 H), 3.72 (t, J = 5.1 Hz,
2H), 3.30 (s, 3H), 3.20-3.00 (m, 3H), 1.95-1 .80 (m, 2H), 1.80-1 .63 (m, 4H);
9F NMR (300 MHz, CDCI3) -56.69 (s, 3F), - 12 1.96 (s, 1F);
LC 2.47 min; MS 494 (M+1 , 98%).
To a solution of the above material (2.856 g, 5.59 mmol) in Et2O (30 mL) is
added 2.0 N HCI/Et20 (3.0 mL, 6.0 mmol) dropwise. A solid precipitate forms and the
ethereal solution is decanted off. The solid is collected by vacuum filtration and
washed with additional Et O. The white product (2.475 g, 4.52 mmol) is dried under
high vacuum to removal any residual solvents.
H NMR (300 MHz, DMSO-c/6) 8.35 (br s, 2H), 7.82 (s, 1H), 7.74-7.70 (m, 1H), 7.58
(d, J = 5.7 Hz, 1H), 7.39-7.35 (m, 1H), 7.26-7.1 9 (m, 3H), 4.49 (t, J = 5.1 Hz, 2H),
4.44 (br s, 1H), 4.00 (br s, 2H), 3.68 (t, J = 5.1 Hz, 2H), 3.32 (s, 3H), 3.14 (m, 2H),
1.83-1 .78 (m, 2H), 1.69-1 .66 (m, 2H);
9F NMR (300 MHz, DMSO-c/6) -55.64 (s, 3F), - 1 19.95 (s, 1F);
LC 2.65 min; MS 494 (M+1 , 99%);
CHN: Theoretical: C 56.14%, H 5.38%, N 7.86% (calc'd as 0.27 H2O). Found: C
55.91 %, H 5.1 6%, N 7.53%.
EXAMPLE 2
[4-(3-Aminomethyl-phenyl)-piperidin-1 -yl]-[7-methyl-1 -(2-morpholin-4-yl-ethyl)-1 Hindol-
3-yl]-methanone hydrochloride
A. 4-Oxo-piperidine-1 -carbox lic acid 2-trimethylsilanyl-ethyl ester
A solution of 4-piperidone monohydrate hydrochloride (25 g, 88.22 mmol), 2-
trimethylsilylethyl p-nitrophenylcarbonate (50 mL, 359.7 mmol), triethylamine (50 mL,
0.345 mol) and DMAP ( 10.78 g, 88.24 mmol) in acetonitrile (300 mL) is warmed
under reflux for 2 hours and then allowed to cool to room temperature. The mixture is
diluted with dichloromethane (300 mL) and washed with 1 M HCI (3x1 00 mL) and 1M
NaOH (4 X 100 mL) until all of the yellow color is removed from the organic phase.
The organic phase is then washed with brine and dried over MgSO4. The organic
phase is concentrated in vacuo to afford the title compound ( 19.35 g, 90%) as a
colorless oil.
H NMR (300 MHz, CDCI3) 4.22 (m, 2H), 3.75 (t, J = 6.2 Hz, 4H), 2.44 (t, J = 6.2
Hz, 4H), 1.02 (m, 2H), 0.04 (s, 9H).
B. 4-(3-Cyanophenyl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid 2-trimethylsilanylethyl
ester
To a flask containing tetrahydrofuran (50 mL) at -70 °C is added 1 M lithium
hexamethyldisilazide (60 mL, 60 mmol) dropwise. A solution of 4-oxo-piperidine-1 -
carboxylic acid 2-trimethylsilanyl-ethyl ester ( 13.3 g, 55 mmol) is then added via
dropping funnel over 20 minutes keeping the internal temperature between -65 °C
and -70 °C. The solution is stirred at -70 °C for 45 minutes then a solution of
phenyltrifluoromethane sulfonamide ( 19.65 g, 55 mmol) in tetrahydrofuran (75 mL) is
added dropwise over 20 minutes. The solution is allowed to warm to 0 °C and stirred
for 3 hours. The reaction is then concentrated in vacuo and the residue, 4-
trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1 -carboxylic acid 2-trimethyl
silanyl-ethyl ester, is used without further purification.
To a solution of 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1 -
carboxylic acid 2-trimethyl-silanyl-ethyl ester (20.65 g, 55 mmol) in acetonitrile (300
mL) is added 3-cyanophenylboronic acid (8.9 g, 60.6 mmol) followed by 2 M sodium
carbonate (82.5 mL, 165 mmol), lithium chloride (6.98 g, 165 mmol) and
tetrakistriphenylphosphine palladium (0) (3.18 g, 2.8 mmol). The mixture is warmed
under reflux for 90 minutes then allowed to cool to room temperature and filtered.
The filtrate is concentrated and diluted with 2 M Na2CO3 (300 mL) then extracted
dichloromethane (3X). The organic phase is washed with brine then separated and
dried over MgSO4. The organic phase is concentrated in vacuo and the crude
residue is flash chromatographed over S1O2 using heptane:EtOAc:DCM (5:1 :1 ) as
the eluent to give the title compound ( 10.46 g, 58%) as a yellow oil.
H NMR (300 MHz, CDCI3) 7.65-7.52 (m, 3H), 7.44 (t, J = 7.7 Hz, 1H), 6.1 1 (bs, 1
H), 4.23 (m, 2H), 4.1 5 (m, 2H), 3.70 (t, J = 5.6 Hz, 2H), 2.52 (m, 2H), 1.04 (m, 2H),
0.06 (s, 9H).
C. 4-(3-Aminomethyl-phenyl)-piperidine-1 -carboxylic acid 2-trimethylsilanyl-ethyl
ester
To a slurry of 10% wet Pd/C (5 g) in ethanol (250 mL) is added concentrated
HCI (2.9 mL, 34.8 mmol) and 4-(3-cyanophenyl)-3,6-dihydro-2H-pyridine-1 -carboxylic
acid 2-trimethylsilanyl-ethyl ester ( 10.4 g, 3 1.7 mmol). The mixture is hydrogenated
at 50 psi for 4 hours. The mixture is then filtered over a cake of Celite and the cake is
washed with excess ethanol. The filtrate is then concentrated in vacuo and the
residue is triturated with Et2O/pentane and filtered to give the title compound (7.1 g,
67%) as a white solid.
1H NMR (300 MHz, CD3OD) 7.41 -7.27 (m, 4H), 4.26 (dm, J = 13.5 Hz, 2H), 4.20
(m, 2H), 4.09 (s, 2H), 2.92 (bm, 2H), 2.79 (tt, J = 12.1 , 3.6 Hz, 1H), 1.84 (dm, J = 12.9
Hz, 2H), 1.62 (qd, J = 12.6, 4.1 Hz, 2H), 1.02 (m, 2H), 0.06 (s, 9H);
MS (APCI, MeOH/H 2O) m/z 336, 335 (M++ 1, 100), 19 1 .
D. 4-[3-(tert-Butoxycarbonylamino-methyl)-phenyl]-piperidine-1 -carboxylic acid 2-
-ethyl ester
To a solution of 4-(3-aminomethyl-phenyl)-piperidine-1-carboxylic acid 2-
trimethylsilanyl-ethyl ester ( 1 1.1 g, 29.93 mmol) in dichloromethane (150 mL) and
saturated NaHCO 3 (50 mL) is added boc-anhydride (6.54 g, 29.96 mmol). The
mixture is stirred overnight at r.t. The organic phase is then separated and washed
with water and brine. The organic phase is then separated, dried over MgSO and
concentrated in vacuo to give the title compound (13.41 g, 100%) as an oil.
1H NMR (300 MHz, CDCI3) 7.26 (m, 1H), 7.1 0 (m, 3H), 4.85 (bs, 1H), 4.29 (d, J =
5.8 Hz, 4H), 4.1 9 (m, 2H), 2.83 (t, J = 12.5 Hz, 2H), 2.64 (tt, J = 12.0, 3.6 Hz, 1H),
1.81 (m, 2H), 1.60 (m, 2H), 1.45 (s, 9H), 1.01 (t, J = 8.4 Hz, 2H), 0.04 (s, 9H).
E. (3-Piperidin-4-yl-benzyl)-carbamic acid tert-butyl ester
To a solution 4-(3-tert-butoxycarbonylaminonnethylphenyl)-pipehdine-1 -
carboxylic acid 2-thmethylsilanyl-ethyl ester (13.41 g, 30.9 mmol) in tetrahydrofuran
(200 ml_) is added tetra-n-butyl ammonium fluoride ( 1 M, 34 ml_, 34 mmol). The
mixture is warmed to 50 °C for 2 hours then allowed to cool to room temperature and
stand overnight. To complete the reaction the mixture is heated for an additional 3 h
at 50 °C. The mixture is then concentrated in vacuo, diluted with 1M HCI and
extracted with Et2O. The aqueous phase is made basic with 1 N NaOH and extracted
with EtOAc (3X). The organic phases are combined, washed with brine, separated
and dried over MgSO4. The organic phase is filtered and concentrated in vacuo to
afford the title compound (8.3 g, 93%) as a yellow oil which is used without further
purification.
1H NMR (300 MHz, CDCI3) 7.25 (m, 1H), 7.07-7.13 (m, 3H), 4.85 (bs, 1H), 4.29 (d,
J = 5.1 Hz, 2H), 3.1 7 (dm, J = 12.0 Hz, 2H), 2.72 (td, J = 12.0, 2.4 Hz, 2H), 2.60 (tt, J
= 12.0, 3.6 Hz,1 H), 1.81 (m, 2H), 1.55-1 .70 (m, 3H), 1.46 (s, 9H).
F. 7-Methyl-1-(2-morpholin-4-yl-ethyl)-1 H-indole
To a solution of 7-methylindole ( 1 .01 g, 7.70 mmol) in N,N-dimethylacetamide
at r.t. is added sodium hydride (21 7 mg, 10.73 mmol). The resulting mixture is stirred
for 30 minutes at r.t. then 2-(4-morpholine)ethyl bromide ( 1 .64 g, 8.45 mmol) is added
and the resulting mixture is stirred at r.t. overnight. The mixture is diluted with water
(100 ml_) and ethyl acetate (50 ml_). The organic is separated and the aqueous phase
is extracted again with ethyl acetate (50 mL). The organic phase is washed with brine
then separated and dried over MgSO . The organic phase is concentrated in vacuo
and the crude residue is flash chromatographed over S1O2 using 50% EtOAc
/heptane as the eluent to afford the title compound ( 1 .60 g, 85%) as an orange oil.
1H NMR (300 MHz, CDCI3) 7.45 (d, 1H), 7.04 (d, 1H), 7.00-6.90 (m, 2H), 6.45 (d,
H), 4.44 (t, 2H), 3.69 (m, 4H), 2.72-2.67 (m, 5H), 2.45 (m, 4H).
G. 2,2,2-Trifluoro-1 -[7-meth -1-(2-morpholin-4-yl-ethyl)-1 H-indol-3-yl]-ethanone
To a solution of 7-methyl-1 -(2-morpholin-4-yl-ethyl)-1 H-indole ( 1 .60 g, 6.55
mmol) in ,-dimethylformamide at 0 °C is added trifluoroacetic anhydride ( 1 .1 mL,
7.91 mmol). The resulting mixture is stirred at 0 °C for one hour. The mixture is
diluted with 150 mL of water and the aqueous phase is extracted with ethyl acetate
(x3). The organic phase is washed with water and brine then separated and dried
(MgSO4) . The organic phase is concentrated in vacuo and the crude residue is flash
chromatographed over S1O2 using heptane:EtOAc (35:65) as the eluent to afford the
title compound (2.20 g, 99%) as a yellow solid.
1H NMR (300 MHz, CDCI3) 8.27 (d, 1H), 8.00 (m, 1H), 7.25 (m, 1H), 7.1 1 (m, 1H),
4.88 (t, 2H), 3.93 (m, 4H), 3.29 (t, 2H), 3.09 (br s, 4H), 2.71 (s, 3H).
H. 7-Methyl-1 -(2-morpholin-4-yl-ethyl)-1 H-indole-3-carboxylic acid
To a solution of 2,2,2-trifluoro-1-[7-methyl-1-(2-morpholin-4-yl-ethyl)-1 H-indol-
3-yl]-ethanone (2.20 g, 6.46 mmol) in water ( 10 mL) is added a solution of 10 N
sodium hydroxide ( 16 mL, 160 mmol) and the resulting mixture is refluxed until
completion. The mixture is cooled to r.t. and acidified with a solution of 6 N HCI to
reach a pH -2-3. The aqueous phase is washed with EtOAc (2X), flash freezed, and
lyophilized. The resulting solid is triturated with methanol:dichloromethane ( 1 :9). The
solid is filtered off, and the filtrate is evaporated in vacuo to afford the title compound
( 1 .80 g, 96%) as a white solid.
1H NMR (300 MHz, CD3OD) 8.06 (s, 1H), 8.00 (d, 1H), 7.14-7.02 (m, 2H), 4.98 (t,
2H), 4.04-3.94 (br m, 4H), 3.65-3.54 (m, 4H), 3.34 (m, 2H), 2.79 (s, 3H).
I . (3-{1 -[7-Methyl-1 -(2-morpholin-4-yl-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-
benzyl)-carbamic acid tert-butyl ester
To a solution of 7-methyl-1 -(2-morpholin-4-yl-ethyl)-1 H-indole-3-carboxylic acid
(464 mg, 1.61 mmol), (3-piperidin-4-yl-benzyl)-carbamic acid tert-butyl ester
hydrochloride (530 mg, 1.82 mmol) and 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (426 mg, 2.22 mmol) in dichloromethane is added
triethylamine (0.77 mL, 5.50 mmol). The resulting mixture is stirred at r.t. overnight.
The mixture is diluted with sat. ammonium chloride (50 mL). The aqueous phase is
extracted with ethyl acetate (3x45 mL). The combined organic layers are washed with
brine then separated and dried over MgSO4. The organic phase is concentrated in
vacuo and the crude residue is flash chromatographed over SiO2 using
MeOH/CH2CI2 (3:97) as the eluent to afford the title compound (450 mg, 44%) as a
white solid.
1H NMR (300 MHz, CD3OD) 7.58 (s, 1H), 7.53 (d, 1H), 7.28-6.96 (m, 6H), 4.56 (m,
4H), 4.20 (bs, 2H), 3.64 (m, 4H), 3.1 9-3.07 (m, 3H), 2.87 (m, 1H), 2.74 (m, 5H), 2.47
(m, 4H), 1.89 (m, 2H), 1.80-1 .66 (m, 2H), 1.45 (s, 9H).
J. [4-(3-Aminomethyl-phenyl)-piperidin-1 -yl]-[7-methyl-1 -(2-morpholin-4-yl-ethyl)-1 Hindol-
3-yl]-methanone hydrochloride
A solution of (3-{1 -[7-methyl-1-(2-morpholin-4-yl-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-carbamic acid te -butyl ester (432 mg, 0.77 mmol) in
HCI/dioxane (4 M, 8 ml_, 32.0 mmol) is added and stirred for 25 min at r.t. The
mixture is vacuum dried and the residue is suspended ether overnight. The
suspension is filtered and the cake is rinsed with ether twice. The solid is dried under
vacuum to afford the title compound (375 mg, 98%) as a white solid.
1H NMR (300 MHz, DMSO) 8.34 (br s, 3H), 7.80 (s, 1H), 7.55 (d, 1H), 7.46 (s, 1H),
7.38-7.28 (m, 3H), 7.08-6.98 (m, 2H), 4.91 (m, 2H), 4.40 (m, 2H), 4.04-3.96 (m, 1H),
3.89-3.68 (m, 6H), 3.57-3.42 (m, 3H), 3.21 -3.02 (m, 4H), 2.86 (m, H), 2.74 (s, 3H),
1.83 (m, 2H), 1.71 - 1 .59 (m, 2H).
EXAMPLE 3
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-methyl-1-(2-morpholin-4-ylethyl)-
1 H-indol-3-yl]-methanone hydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[7-methyl-1 -(2-morpholin-4-yl-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 7-methyl-1-(2-morpholin-4-yl-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting
materials.
1H NMR (300 MHz, CD3OD) 7.58 (s, 1H), 7.53 (d, 1H), 7.28 (m, 1H), 7.1 8 (m, 1H),
7.07-6.96 (m, 3H), 4.56 (m, 4H), 4.41 (s, 2H), 3.64 (m, 4H), 3.1 7 (m, 3H), 2.73 (m,
6H), 2.47 (m, 4H), 1.90-1 .72 (m, 4H).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-methyl-1 -(2-morpholin-4-ylethyl)-
1 H-indol-3-yl]-methanone hydrochloride
To a solution of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[7-methyl-1 -(2-morpholin-4-ylethyl)-
1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (558 mg, 0.97 mmol) in
methanol water (2:1 ) is added potassium carbonate ( 1 .33 g, 9.62 mmol). The
resulting mixture is stirred at r.t. overnight. The solvent is removed in vacuo and the
aqueous residue is partitioned between ethyl acetate and water. The organic layer is
separated and the aqueous phase is extracted twice with ethyl acetate. The
combined organic layers are washed with brine, dried over MgSO4, filtered and
concentrated in vacuo to yield a solid.
To the solid, HCI in dioxane (4 M, 8 ml_, 32.0 mmol) is added and stirred for 25
min. The mixture is vacuum dried and the residue is triturated with ether overnight.
The suspension is filtered and the cake is rinsed with ether twice. The solid is dried
under vacuum to afford the title compound (490 mg, 98%) as a white solid.
1H NMR (300 MHz, DMSO-c/6) 8.29 (br s, 2H), 7.80 (s, H), 7.61 -7.54 (m, 2H), 7.37-
7.34 (m, 1H), 7.25-7.19 (m, 1H), 7.08-6.98 (m, 2H), 4.90 (m, 2H), 4.40 (m, 1H), 4.02-
3.97 (m, 4H), 3.86-3.45 (m, 12H), 2.74 (s, 3H), 1.82-1 .62 (m, 4H);
MS m/z [M+H]+= 461 .
EXAMPLE 4
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-methyl-1 -(3-phenyl-propyl)-1 Hindol-
3-yl]-methanone hydrochloride
A. 7-Methyl-1 -(3-phenyl-propyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 7-methylindole and 1-bromo-3 phenylpropane as the starting materials.
1H NMR (300 MHz, CDCI3) 7.5 (d, 1H), 7.3 (m, 1H), 7.2 (m, 4H), 7.1 -6.9 (m, 3H),
6.5 (d, H), 4.3 (t, 2H), 2.7 (t, 2H), 2.6 (s, 3H), 2.1 5 (m, 2H);
MS m/z [M+H]+=250.
-Trifluoro-1-[7-methyl-1 -(3-phenyl-propyl)-1 H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
1F, using 7-methyl-1 -(3-phenyl-propyl)-1 H-indole as the starting material.
1H NMR (300 MHz, CDCI3) 8.3 (d, 1H), 7.8 (s, 1H), 7.3 (m, 3H), 7.2 (m, 3H), 7.1 5
(d, H), 4.4 (t, 2H), 2.7(t, 2H), 2.6 (s, 3H), 2.2 (m, 2H);
MS m/z: [M+H]+=346.
C. 7-Methyl-1-(3-phenyl-propyl)-1 H-indole-3-carboxylic acid
2,2,2-Trifluoro-1 -[7-methyl-1 -(3-phenyl-propyl)-1 H-indol-3-yl]-ethanone (6 g,
17.4 mmol) and 6 N NaOH (75 ml_) are heated to reflux overnight. The reaction
mixture is cooled to room temperature and acidified to pH = 2 with concentrated HCI.
The resulting precipitate is collected as the title compound.
1H NMR (300 MHz, DMSO-c/6) 12.0 (s, 1H), 8.1 (s, 1H), 7.9 (d, 1H), 7.3 (m, 5H),
7.1 (m, 1H), 6.9 (m, 1H), 4.4 (t, 2H), 3.3 (s, 3H), 2.6 (t, 2H), 2.0 (t, 2H);
MS m/z [M+H]+=294.
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[7-methyl-1 -(3-phenyl-propyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 7-methyl-1 -(3-phenyl-propyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-
(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting materials.
1H NMR (300 MHz, CDCI3) 7.6 (d, H), 7.4 (s, H), 7.35-7.0 (m, 10H), 6.6 (bs, H),
4.6 (m, 2H), 4.5 (m, 2H), 4.35 (t, 2H), 3.1 (m, 3H), 2.7 (t, 2H), 2.5 (s, 3H), 2.2 (m, 2H),
1.9 (m, 2H), 1.75 (m, 2H);
MS m/z [M+H]+=580.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-methyl-1 -(3-phenyl-propyl)-
1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K, using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[7-methyl-1 -(3-phenyl-propyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.3 (bs, 2H), 7.7 (s, H), 7.55 (m, 2H), 7.4-7.2 (m,
7H), 7.0 (m, 1H), 6.9 (m, 1H), 4.4 (m, 4H), 4.0 (t, 2H), 3.1 (m, 3H), 2.7 (t, 2H), 2.6 (s,
3H), 2.1 (m, 2H), 1.8 (m, 2H), 1.75 (m, 2H);
MS m/z: [M+H]+=484.
EXAMPLE 5
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-(7-methyl-1 -phenethyl-1 H-indol-3-
yl)-methanone hydrochloride
A. 2,2,2-Trichloro-1 - 7-methyl-1H-indol-3-yl)-ethanone
To a solution of 7-methylindole ( 10g, 76.3 mmol) in THF (200 mL) at 0 °C is
added pyridine (8 mL, 99.2 mmol) followed by dropwise addition of trichloroacetyl
chloride ( 1 1 mL, 99.2 mmol). The reaction mixture is allowed to warm to r.t. and stir
overnight. The reaction mixture is poured into EtOAc and washed with 1N HCI (2X).
The organic layers are washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo to give the crude product. Purification by flash chromatography
on S1O2 eluting with 20% ethyl acetate/heptane gives the title compound (19 g, 90%
yield).
1H NMR (300 MHz, DMSO-c/6) 12.6 (bs, 1H), 8.5 (s, 1H), 8.0 (d, 1H), 7.2 (m, 1H),
7.1 5 (m, 1H), 3.2 (s, 3H);
MS m/z [M+H]+=276, 278.
B. 7-Methyl-1 H-indole-3-carboxylic acid methyl ester
A mixture of 2,2,2-trichloro-1 -(7-methyl-1 H-indol-3-yl)-ethanone ( 18.5g, 66.8
mmol) and 1 N KOH / MeOH (700 mL) is stirred overnight at r.t. The reaction mixture
is concentrated in vacuo and the crude product is purified by flash chromatography
on S1O2 eluting with 15% ethyl acetate / heptane to give the titled compound (6 g,
48% yield).
1H NMR (300 MHz, CDCI3) 8.5 (bs, 1H), 8.1 (d, 1H), 7.9 (d, 1H), 7.2 (m, 1H), 7.1
(m, 1H), 3.9 (s, 3H), 2.5 (s, 3H);
MS m/z [M+H]+= 190.
C. 7-Methyl-1 -pheneth l-1H-indole-3-carboxylic acid methyl ester
The title compound is prepared in a similar manner as described in Example
2F, using 7-methyl-1 H-indole-3-carboxylic acid methyl ester and 2-
bromoethylbenzene in DMF as the starting materials.
1H NMR (300 MHz, CDCI3) 8.1 (d, 1H), 7.6 (s, 1H), 7.3 (m, 2H), 7.2-7.0 (m, 5H), 4.6
(t, 2H), 3.9 (s, 3H), 3.1 (t, 2H), 2.8 (s, 3H);
MS m/z: [M+H]+=294.
D. 7-Methyl-1 -phenethyl-1 H-indole-3-carboxylic acid
To a solution of 7-methyl-1 -phenethyl-1 H-indole-3-carboxylic acid methyl ester
(0.46 g, 1.57 mmol) in MeOH (20 ml_) is added 6 N NaOH (2 ml_). The solution is
heated to 45 °C for 2 h and then stirred at r.t. overnight. The reaction mixture is
acidified to pH = 2 with concentrated HCI and the resulting precipitate is collected as
the titled compound (0.335 g, 76% yield).
1H NMR (300 MHz, DMSO-c/6) 11.9 (bs, 1H), 7.9 (m, 2H), 7.35-7.2 (m, 5H), 7.1 (m,
H), 7.0 (m, H), 4.6 (t, 2H), 3.1 (t, 2H), 2.75 (s, 3H);
MS m/z [M+H]+=280.
E. 2,2,2-Trifluoro-N-{4-fluoro-3-[1 -(7-methyl-1 -phenethyl-1 H-indole-3-carbonyl)-
piperidin-4-yl]-benzyl}-acetamide
O
The title compound is prepared in a similar manner as described in Example
21, using 7-methyl-1 -phenethyl-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-(4-
fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting materials.
1H NMR (300 MHz, CDCI3) 7.6 (d, H), 7.3 (m, 3H), 7.2-7.0 (m, 8H), 6.6 (bs, H), 4.6
(t, 2H), 4.5 (m, 2H), 4.4 (bs, 1H), 3.1 5 (m, 3H), 3.0 (m, 2H), 2.8 (s, 3H), 1.85 (m, 2H),
1.7 (m, 2H);
MS m/z [M+H]+=566.
F. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-(7-methyl-1 -phenethyl-1 H-indol-
3-yl)-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-{4-fluoro-3-[1 -(7-methyl-1 -phenethyl-1 H-indole-3-carbonyl)-
piperidin-4-yl]-benzyl}-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.2 (bs, 2H), 7.55 (m, 2H), 7.45 (s, 1H), 7.35 (m,
1H), 7.3-7.1 (m, 6H), 7.0 (m, 2H), 4.6 (t, 2H), 4.3 (bs, 2H), 4.0 (t, 2H), 3.0 (m, 5H), 2.8
(s, 3H), 1.8 (m, 2H), 1.6 (m, 2H);
MS m/z: [M+H]+= 470.
EXAMPLE 6
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-cyclopropyl-1 -(2-methoxy-ethyl)-
1H-indol-3-yl]-methanone hydrochloride
A. 7-Bromo-1 -(2-methoxy-ethyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E, using 7-bromo-1 H-indole as the starting material.
1H NMR (300 MHz, CD3CN) 7.55 (d, 1H), 7.33 (d, 1H), 7.20 (d, 1H), 6.91 (t, 1H),
6.47 (d, 1H), 4.68 (t, 2H), 3.69 (t, 2H), 3.22 (s, 3H).
B. 7-Cyclopro l-1-(2-methoxy-ethyl)-1 H-indole
The title compound is prepared according to the procedure by Wallace, D. J. et
al. Tetrahedron Letters 2002, 43, 6987-6990 using cyclopropyl boron ic and 7-bromo-
1-(2-methoxy-ethyl)-1 H-indole as the starting materials.
1H NMR (300 MHz, CD3CN) 7.45-7.40 (m, 1H), 7.1 7 (d, 1H), 6.98-6.91 (m, 2H),
6.45 (d, 1H), 4.88 (t, 2H), 3.69 (t, 2H), 3.25 (s, 3H), 2.41 -2.32 (m, 1H), 1.01-0.95 (m,
2H), 0.85-0.80 (m, 2H).
C. 1-[7-Cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone
The title compound is prepared in a similar manner as described in Example
2G, using 7-cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indole as the starting material.
1H NMR (300 MHz, CD3CN) 8.1 9-8.1 7 (m, 2H), 7.24 (t, 1H), 7.1 5 (m, 1H), 4.91 (t,
2H), 3.77 (t, 2H), 3.26 (s, 3H), 2.41 -2.32 (m, 1H), 1.05-0.99 (m, 2H), 0.88-0.83 (m,
2H).
D. 7-Cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
2H, using 1-[7-cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone
as the starting material.
1H NMR (300 MHz, DMSO-c/6) 11.95 (bs, 1H), 8.01-7.91 (m, 2H), 7.06 (t, 1H), 6.96
(m, 1H), 4.84 (t, 2H), 3.72 (t, 2H), 3.23 (s, 3H), 2.43-2.37 (m, 1H), 1.02-0.95 (m, 2H),
0.85-0.79 (m, 2H).
E. N-(3-{1 -[7-Cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-
fluoro-benzyl)-2,2,2-trifluoro-acetamide
To a solution of 7-cyclopropyl-1-(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
(690 mg, 2.66 mmol) in dichloromethane (40 ml_) and N,N-dimethylformamide (2 ml_)
is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (661 mg, 3.45
mmol), 1-hydroxy-benzotriazole (407 mg, 3.01 mmol) and triethylamine ( 1 .15 ml_,
8.22 mmol). The resulting mixture is stirred for 20 minutes at r.t. 2,2,2-Trifluoro-N-(4-
fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride ( 1 .01 g, 2.96 mmol) is added
and heated at 40 °C for 4 hours. The mixture is poured into water and the organic
layer separated. The aqueous phase is extracted with ethyl acetate (3x). The
combined organic phases are washed with brine, dried over MgSO , filtered and
concentrated in vacuo. The crude residue is flash chromatographed over S1O2 using
heptane/EtOAc (15:85) as the eluent to afford the title compound ( 1 .34 g, 92%) as a
white solid.
1H NMR (300 MHz, CD3CN) 8.1 7 (bs, 1H), 7.59-7.56 (m, 1H), 7.45 (s, H), 7.27-
7.24 (m, 1H), 7.1 7-7.1 2 (m, 1H), 7.05-6.97 (m, 3H), 4.81 (t, 2H), 4.47 (br d, 2H), 3.37
(d, 2H), 3.70 (t, 2H), 3.24 (s, 3H), 3.1 9-3.00 (m, 3H), 2.39-2.30 (m, 1H), 1.83-1 .61 (m,
4H), 1.01 -0.93 (m, 2H), 0.84-0.79 (m, 2H).
F. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-cyclopropyl-1 -(2-methoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1 -[7-cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-
4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material
1H NMR (300 MHz, CD3CN) 8.22 (br s, 2H), 7.68-7.65 (m, H), 7.57-7.55 (m, 2H),
7.36-7.32 (m, H), 7.08-6.96 (m, 3H), 4.79 (t, 2H), 4.40 (br d, 2H), 4.03 (m, 2H), 3.70
(t, 2H), 3.23 (s, 3H), 3.20-2.99 (m, 3H), 2.3-2.29 (m, 1H), 1.79-1 .64 (m, 4H), 1.00-
0.94 (m, 2H), 0.83-0.78 (m, 2H);
MS m/z [M+H]+= 450.
EXAMPLE 7
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-methyl-1-(3-morphol
prop l)-1H-indol-3-yl]-methanone hydrochloride
A. 7-Methyl-1 -(3-morpholin-4-yl-propyl)-1 H-indole-3-carboxylic acid methyl ester
The title compound is prepared in a similar manner as described in Example
2F using 7-methyl-1 H-indole-3-carboxylic acid methyl ester and 4-(3-chloro-propyl)-
morpholine in DMF as the starting materials.
1H NMR (300 MHz, CDCI3) 8.1 (d, 1H), 7.8 (s, 1H), 7.2 (m, 1H), 7.0 (m, 1H), 4.45 (t,
2H), 3.9 (m, 3H), 3.7 (m, 4H), 2.8 (s, 3 H), 2.4 (m, 4H), 2.3 (m, 2H), 2.0 (m, 2H);
MS m/z [M+H]+=31 7.
B. 7-Methyl-1 -(3-morpholin-4-yl-propyl)-1 H-indole-3-carboxylic acid
To a solution of 7-methyl-1 -(3-morpholin-4-yl-propyl)-1 H-indole-3-carboxylic
acid methyl ester ( 1 .2g, 3.8 mmol) in MeOH (30 mL) is added 1 N NaOH ( 10 mL).
The solution is heated to reflux for 2 h and then cooled to room temperature. The
reaction mixture is acidified to pH = 2 with cone. HCI then concentrated in vacuo to
remove MeOH. The aqueous phase is lyophilized to dryness and the solid is
triturated with 10% acetonitrile/ water and collected to yield the title compound (0.85
g, 74% yield).
1H NMR (300 MHz, DMSO-c/6) 9.6 (bs, 1H), 8.1 (s, H), 7.9 (d, 1H), 7.1 (m, 1H), 7.0
(t, 1H), 4.5 (t, 2H), 4.0 (m, 2H), 3.6 (m, 2H), 3.1 (m, 5H), 2.75 (s, 3H), 2.2 (m, 3H);
MS m/z [M+H]+=303.
C. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[7-methyl-1 -(3-morpholin-4-yl-propyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example
2I, using 7-methyl-1 -(3-morpholin-4-yl-propyl)-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting
materials.
1H NMR (300 MHz, CDCI3) 7.6 (d, 1H), 7.4 (s, 1H), 7.1 5 (m, 3H), 7.0 (m, 2H), 6.8
(bs, H), 4.5 (m, 6H), 3.9 (m, 4H), 3.45 (bs, H), 3.1 5 (m, 2H), 3.0 (m, 2H), 2.8 (m, 1H),
2.65 (s, 3H), 2.35 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H);
MS m/z: [M+H]+=589.
D. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-methyl-1 -(3-morpholin-4-ylpropyl)-
1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K, using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[7-methyl-1 -(3-morpholin-4-yl-propyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.3 (bs, 2H), 7.8 (s, 1H), 7.55 (m, 2H), 7.4 (m, 1H),
7.2 (m, H), 7.0 (m, 2H), 4.45 (m, 4H), 4.0 (m, 4H), 3.75 (t, 2H), 3.15 (m, 8H), 2.75 (s,
3H), 1.8 (m, 2H), 1.7 (m, 2H);
MS m/z [M+H]+=493.
EXAMPLE 8
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-{7-methyl-1 -[2-(1 -methyl-piperidin-
2-yl)-ethyl]-1 H-indol-3-yl}-methanone hydrochloride
A. 7-Methyl-1 -[2-(1 -methyl-piperidin-2-yl)-ethyl]-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E, using 7-methylindole and 2-(2-chloroethyl)1-methylpiperdine hydrochloride as the
starting materials.
1H NMR (300 MHz, CDCI3) 7.5 (dd, 1H), 7.0 (d, 1H), 6.95 (m, 2H), 6.45 (d, 2H), 4.4
(m, 2H), 2.85 (m, H), 2.7 (s, 3H), 2.3 (s, 3H), 2.2-2.0 (m, 4H), .8-1 .6 (m, 6H);
MS m/z [M+H]+=257.
B. 2,2,2-Trifluoro-1 -{7-methyl-1 -[2-(1 -methyl-piperidin-2-yl)-ethyl]-1 H-indol-3-yl}-
ethanone
The title compound is prepared in a similar manner as described in Example
1F, using 7-methyl-1 -[2-(1-methyl-piperidin-2-yl)-ethyl]-1 H-indole as the starting
material.
1H NMR (300 MHz, CDCI3) 8.3 (d,1 H), 7.95 (dd, 1H), 7.2 (m, 1H), 7.1 5 (m, 1H), 4.7
(m, 1H), 4.5 (m, 1H), 3.8 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 2.7 (m, 7H), 2.5 (m, 1H),
2.35 (m, 1H), 2.0 (m, 2H), 1.9 (m, 3H);
MS m/z: [M+H]+=353
C. 7-Methyl-1 -[2-(1 -methyl-piperidin-2-yl)-ethyl]-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C, using 2,2,2-trifluoro-1 -{7-methyl-1 -[2-(1 -methyl-piperidin-2-yl)-ethyl]-1 H-indol-3-
yl}-ethanone as the starting material.
1H NMR (300 MHz, DMSO-c/6) 12.0 (bs, 1H), 8.2 (s, 1H), 7.95 (d, 1H), 7.0 (m, 2H),
4.5 (m, 2H), 4.1 (m, 1H), 3.2 (s, 3H), 3.1 5 (m, 1H), 2.7 (m, 6H), 2.1 (m, 2H), 1.8 (m,
4H);
MS m/z [M+H]+=301 .
D. 2,2,2-Trifluoro-N-[4-fluoro-3-(1 -{7-methyl-1 -[2-(1 -methyl-piperidin-2-yl)-ethyl]-1 Hindole-
3-carbonyl}-piperidin-4-yl)-benzyl]-acetamide
The title compound is prepared in a similar manner as described in Example
2I, using 7-methyl-1-[2-(1 -methyl-piperidin-2-yl)-ethyl]-1 H-indole-3-carboxylic acid and
2,2,2-trifluoro-N-(4-fluoro-3-pipendin-4-yl-benzyl)-acetamide hydrochloride as
starting materials.
MS m/z [M+H]+=587.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-{7-methyl-1 -[2-(1 -methylpiperidin-
2-yl)-ethyl]-1 H-indol-3-yl}-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-[4-fluoro-3-(1 -{7-methyl-1 -[2-(1 -methyl-piperidin-2-yl)-ethyl]-
1H-indole-3-carbonyl}-piperidin-4-yl)-benzyl]-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 11.2-10.8 (bd, 1H), 8.5 (bs, 2H), 7.8 (d, 1H), 7.65
(m, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 7.0 (m, 2H), 4.4 (m, 4H), 4.0 (m, 2H),
3.4 (m 2H), 3.2 (m, 3H), 2.75 (m, 1H), 2.6 (m, 2H), 2.55 (m, 4H), 2.2-2.0 (m, 2H), 1.8-
1.6 (m, 9H);
MS m/z: [M+H]+=491 .
EXAMPLE 9
[4-(5-Aminomethyl-2-difluoromethyl-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
methyl-1 H-indol-3-yl]-methanone hydrochloride.
A. 4-Azidomethyl-2-bromo-benzaldehyde.
To a solution of 2-bromo-4-bromomethyl-benzaldehyde (US 20031 14703 A 1)
(7.540 g, 27.1 mmol) in DMF (22 mL) is added sodium azide (3.527 g, 54.3 mmol) in
portions. The resulting mixture is stirred at r.t. overnight. The mixture is diluted with
Et2O and washed with water then brine. The organic layer is dried over MgSO4,
filtered and concentrated in vacuo to give the titled product (6.39 g, 98%) as an
orange oil.
1H NMR (300 MHz, CDCI3) 10.35 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 1.2
Hz, 1H), 7.40 (dd, J = 0.9 Hz, 7.8 Hz, 1H), 4.44 (s, 2H).
B. 4-Azidomethyl-2-bromo-1 -difluoromethyl-benzene.
To a solution of 4-azidomethyl-2-bromo-benzaldehyde (6.47 g, 26.9 mmol) in
CH3CN (50 mL) is added 2,2-difluoro-1 ,3-dimethylimidazolidine (5.4 mL, 43.5 mmol)
dropwise. The amber solution is heated at 84 °C overnight. The reaction mixture is
cooled to r.t. and diluted with Et2O. The organic layer is washed with saturated
Na2CO3 solution, brine and then dried over MgSO , filtered and concentrated in
vacuo. The crude material is purified on silica gel using EtOAc/heptane (5-30%) as
the eluent to give the titled product (5.1 1 g, 72%) as a pale yellow oil.
1H NMR (300 MHz, CDCI3) 7.67 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.38 (d, J = 7.8
Hz, 1H), 6.90 (t, J = 54.6 Hz, 1H), 4.40 (s, 2H);
19F NMR (300 MHz, CDCI3) - 1 14.4 (2F);
LC 3.21 min; MS 263 (M+1 , 88%).
C. 3-Bromo-4-difluoromethyl-benzylamine.
To a solution of 4-azidomethyl-2-bromo-1 -difluoromethyl-benzene (4.67 g, 17.8
mmol) in H2O/THF (7 mL/70 mL) is added triphenylphosphine (9.30 g, 35.5 mmol) in
portions. The mixture is stirred at r.t. overnight. The reaction mixture is concentrated
in vacuo to remove THF then 1 N HCI ( 100 mL) is added and the aqueous solution is
washed with CH2CI2. The aqueous layer is cooled to 0 °C and 6.25 N NaOH (ca. 30
mL) is added until pH 10 . The aqueous layer is extracted with CH CI2 (3x100 mL).
The combined organic layers are washed with brine, dried over MgSO4, filtered and
concentrated in vacuo to give the titled product (3.83 g, 9 1%) as an oil.
1H NMR (300 MHz, CDCI3) 7.63-7.60 (m, 2H), 7.35 (d, 1H), 6.90 (t, J = 54.9 Hz,
1H), 3.91 (s, 2H), 1.42 (br s, 2H);
LC 1.23 min; MS 236, 238 (M+1 ) .
D. 4-Difluoromethyl-3-pyridin-4-yl-benzylamine
A solution of 3-bromo-4-difluoromethyl-benzylamine ( 1 .023 g, 4.33 mmol),
pyridine-4-boronic acid (0.651 g, 4.77 mmol) and NaHCO3 (0.364 g, 4.33 mmol) in
H2O/IPA (3.2 mL/6.6 ml_) is degassed with N2 for 20 min. Pd-dppf Cl2 is added to the
mixture, and the resulting mixture is heated at 85 oC for 22 h. The reaction mixture is
cooled to r.t. and 1 N HCI ( 15 ml_) is added. After the resulting mixture is stirred for
20 min, it is washed with CH2CI2 (x3), and the aqueous layer is treated with 50%
NaOH ( 10 ml_) to adjust to pH > 13 . The aqueous layer is extracted with EtOAc (x3)
and the combined organic layers are dried over MgSO , filtered and concentrated in
vacuo to give the titled compound (0.926 g, 9 1%) as a oil.
1H NMR (300 MHz, CDCI3) 8.71 -8.68 (m, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.52 (d, J =
9.9 Hz, 1H), 7.33-7.26 (m, 3H), 6.49 (t, J = 54.9 Hz, 1H), 3.99 (s, 2H), 1.5 (br s, 2H).
E. N-(4-Difluoromethyl-3-pyridin-4-yl-benzyl)-2,2,2-trifluoro-acetamide hydrochloride
To a solution of 4-difluoromethyl-3-pyridin-4-yl-benzylamine (2.350 g, 10.03
mmol) in n-BuOAc (30 ml_) at 0 °C is added trifluoroacetic anhydride dropwise. The
resulting solution is stirred for 4 hr then the reaction mixture is washed with 10%
Na2CO3 ( 100 ml_) and brine. The organic layer is dried over MgSO4, filtered and
concentrated to dryness in vacuo. The residue is taken up in n-BuOAc (5 mL) and
2.0 M HCI in ether is added. The resulting solution is stirred for 20 min then
concentrated in vacuo to provide the titled product (3.277 g, 88%) as a foamy solid.
1H NMR (300 MHz, DMSO-c/6) 10.1 5 (br s, 1H), 8.92 (d, J = 6 Hz, 1H), 7.83-7.66
(m, 3H), 7.59 (d, J = 9 Hz, 1H), 7.42 (s, 1H), 7.1 6 (t, J = 42 Hz, 1H), 4.53 (d, J = 6 Hz,
2H);
19F NMR (300 MHz, DMSO-c/6) -74.75 (s, 3F), - 107.59 (2F).
F. N-(4-Difluoromethyl-3-piperidin-4-yl-benzyl)-2,2,2-trifluoro-acetamide
hydrochloride
A Parr flask is charged with N-(4-difluoromethyl-3-pyridin-4-yl-benzyl)-2,2,2-
trifluoro-acetamide hydrochloride ( 1 .8 g, 4.9 mmol) and MeOH (50 mL) at r.t., then
5% Pt/C (0.53 g, 30 w/w%) is added. The reaction flask is placed in a Parr
hydrogenation system and charged with H2 at 50-60 psi. The mixture is shaken for 24
h while charging H2 until the pressure reached a steady state. When HPLC analysis
shows completion of the reaction, the reaction mixture is filtered through a pad of
Celite. The filtrate is concentrated to dryness in vacuo to give the titled product ( 1 .63
g, 88%) as a white solid.
1H NMR (300 MHz, DMSO-c/6) 10.09 (br m, 1H), 8.5 (br s, 2H), 7.57 (d, J = 7.8 Hz,
1H), 7.31 -7.27 (m, 2H), 7.1 0 (t, 1H), 4.44 (s, 2H), 3.33-3.04 (m, 3H), 3.05-3.00 (m,
2H), 1.83-1 .81 (m, 4H);
19F NMR (300 MHz, DMSO-c/6) -74.01 (s, 3F), - 109.36 (d, 2F);
LC 1.78 min; MS 337 (M+1 , 97%).
G. 1-(2-Methoxy-ethyl)-7-methyl-1 H-indole.
The title product (7.18 g, 99%) is obtained in a similar manner as described in
Example 1E using 7-methyl-1 H-indole (5 g, 38.2 mmol) as the starting material.
1H NMR (300 MHz, CDCI3) 7.45 (d, 1H), 7.09 (d, 1H), 7.00-6.90 (m, 2H), 6.45 (d,
1H), 4.50 (t, 2H), 3.71 (t, 2H), 3.30 (s, 3H), 2.70 (s, 3H).
H. 2,2,2-Trifluoro-1 -[1-(2-methoxy-ethyl)-7-methyl-1 H-indol-3-yl]-ethanone.
The title product (9 g, 84%) is obtained in a similar manner as described in
Example 1F using 1-(2-methoxy-ethyl)-7-methyl-1 H-indole (7.1 g, 37.6 mmol) as the
starting material. The crude material is purified on silica gel with EtOAc/heptane
(15%) as eluent.
1H NMR (300 MHz, CDCI3) 8.30 (d, 1H), 7.98 (s, 1H), 7.24 (m, 1H), 7.1 0 (d, 1H),
4.60 (t, 2H), 3.78 (t, 2H), 3.30 (s, 3H), 2.70 (s, 3H).
I . 1-(2-Methoxy-ethyl)-7-methyl-1 H-indole-3-carboxylic acid.
The title product (7.3 g, 100%) is obtained in a similar manner as described in
Example 1G using 2,2,2-trifluoro-1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indol-3-yl]-
ethanone (9 g, 3 1.6 mmol) as the starting material and heating to reflux then stirring
at 110 °C overnight.
1H NMR (300 MHz, DMSO-c/6) 1 .90 (s, 1H), 7.95 (s, 1H), 7.90 (d, 1H), 7.05 (t, 1H),
6.95 (d, 1H), 4.60 (t, 2H), 3.65 (t, 2H), 3.22 (s, 3H), 2.65 (s, 3H).
J. N-(4-Difluoromethyl-3-{1-[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-2,2,2-trifluoro-acetamide.
The title product (0.173 g, 68%) is obtained in a similar manner as described in
Example 1J using N-(4-difluoromethyl-3-piperidin-4-yl-benzyl)-2,2,2-trifluoroacetamide
hydrochloride (0.1 72 g, 0.46 mmol) and 1-(2-methoxy-ethyl)-7-methyl-1 Hindole-
3-carboxylic acid (0.1 08 g, 0.46 mmol) as the starting materials.
1H NMR (300 MHz, DMSO-c/6) 7.58 (d, 1H), 7.50 (d, 1H), 7.45 (s, 1H), 7.31 -7.23
(m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.81 (t, J = 5.2 Hz, 1H),
4.60-4.52 (m, 4H), 3.71 (t, J = 5.4 Hz, 2H), 3.50 (br d, 1H), 3.31 (s, 3H), 3.20-3.00 (m,
4H), 2.72 (s, 3H), 1.85-1 .72 (m, 4H);
19F NMR (300 MHz, DMSO-c/6) 5 -75.39 (s, 3F), - 109.00 (d, 2F);
LC 3.29 min; MS 552 (M+1 , 94%).
K. [4-(5-Aminomethyl-2-difluoromethyl-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
methyl-1 H-indol-3-yl]-methanone hydrochloride.
The title product (0.098 g, 64%) is obtained in a similar manner as described in
Example 1K using N-(4-difluoromethyl-3-{1 -[1-(2-methoxy-ethyl)-7-methyl-1 H-indole-
3-carbonyl]-piperidin-4-yl}-benzyl)-2,2,2-trifluoro-acetamide (0.173 g, 0.31 mmol) as
the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.21 (br s, 2H), 7.70-7.51 (m, 4H), 7.41 (d, 1H), 7.39
(t, 1H), 7.05-6.90 (m, 2H), 4.58 (t, 2H), 4.45 (br d, 1H), 4.08 (s, 2H), 3.67 (t, 2H), 3.32
(s, 3H), 3.20-3.00 (br , 4H), 2.68 (s, 3H), 1.72 (m, 4H);
19F NMR (300 MHz, DMSO-c/6) -109.65 (d, J = 58.5 Hz, 2F);
LC 2.36 min; MS 456 (M+1 , 95%).
EXAMPLE 10
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-methyl-1 -(3-pyridin-3-yl-propyl)-
1H-indol-3-yl]-methanone dihydrochloride
A. 7-Methyl-1 -(3-pyridin-3-yl-propyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 3-(3-bromo-propyl)-pyridine and 7-methylindole as the starting materials.
1H NMR (300 MHz, CD3CN) 8.37 (m, 2H), 7.49 (m, H), 7.36 (m, H), 7.20-7.1 6
(m, 1H), 7.09 (m, 1H), 6.90-6.82 (m, 2H), 6.39 (d, 1H), 4.31 (t, 2H), 2.64-2.50 (m,
5H), 2.07-1 .97 (s, 2H).
B. 2,2,2-Trifluoro-1 -[7-m -1H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
2G with 7-methyl-1 -(3-pyridin-3-yl-propyl)-1 H-indole as the starting material.
1H NMR (300 MHz, CD3CN) 8.57 (br s, 2H), 8.1 9-8.09 (m, 3 H), 7.69-7.65 (m, 1H),
7.25-7.20 (m, 1H), 7.14-7.1 2 (m, 1H), 4.51 (t, 2H), 2.86 (t, 2H), 2.69 (s, 3H), 2.29-
2.1 8 (m, 2H).
C. 7-Methyl-1 -(3-pyridin-3-yl-propyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
2H with 2,2,2-trifluoro-1 -[7-methyl-1 -(3-pyridin-3-yl-propyl)-1 H-indol-3-yl]-ethanone as
the starting material.
1H NMR (300 MHz, DMSO-c/6) 11.94 (br s, 1H), 8.46-8.40 (m, 2H), 8.03 (s, 1H),
7.91 (d, 1H), 7.66 (m, 1H), 7.32-7.28 (m, 1H), 7.04 (t, 1H), 6.95 (m, 1H), 4.44 (t, 2H),
2.67 (t, 2H), 2.58 (s, 3H), 2.14-2.04 (m, 2H).
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[7-methyl-1 -(3-pyridin-3-yl-propyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example
6E with 7-methyl-1 -(3-pyridin-3-yl-propyl)-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting
materials.
1H NMR (300 MHz, CD3CN) 8.42-8.37 (m, 2H), 8.07 (br s, H), 7.57 (d, 2H), 7.43
(s, H), 7.29-7.21 (m, 2H), 7.1 9-7.1 2 (m, 1H), 7.07-6.99 (m, 2H), 6.95-6.93 (m, 1H),
4.49-4.38 (m, 6H), 3.1 9-3.01 (m, 3H), 2.69-2.62 (m, 5H), 2.1 2-2.08 (m, 2H), 1.80-1 .63
(m, 4H).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-methyl-1 -(3-pyridin-3-ylpropyl)-
1 H-indol-3-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as described in Example
3B with 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[7-methyl-1 -(3-pyridin-3-yl-propyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.79 (br s, 1H), 8.70 (d, 1H), 8.32 (br s, 3H), 7.87-
7.82 (m, 1H), 7.70 (s, 1H), 7.58 (m, 1H), 7.51 (d, 1H), 7.38-7.35 (m, 1H), 7.25-7.1 9
(m, 1H), 7.03-6.98 (m, 1H), 6.95-6.93 (m, 1H), 4.48-4.38 (m, 4H), 4.00 (m, 2H), 3.19-
3.05 (m, 4H), 2.88-2.83 (m, 2H), 2.65 (s, 3H), 2.1 9-2.14 (m, 2H), 1.1 8-1 .61 (m, 4H);
MS m/z [M+H]+=485.
EXAMPLE 11
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl^
trifluoromethyl-1 H-indol-3-yl]-methanone hydrochloride
A. 7-Trifluoromethyl-1 H-indole-3-carboxylic acid methyl ester
N-(2-Trifluoromethyl-phenyl)-hydroxylamine is prepared according to the
procedure by Oxley, P. W. et al. Org. Syn. 1989, 67, 187-1 90 using 2-
nitrobenzotrifluoride as the starting material. The crude mixture is used for the next
step without any purification.
The title compound is prepared according to the procedure by Jih Ru Hwn et
al. J. Org. Chem. 1994, 59, 1577-1 582 using N-(2-trifluoromethyl-phenyl)-
hydroxylamine as the starting material.
1H NMR (300 MHz, CD3CN) 8.37 (d, 1H), 8.02 (m, H), 7.57 (d, H), 7.36 (t, H),
3.86 (s, 3H).
B. 1-(2-Methoxy-ethyl)-7-trifluoromethyl-1 H-indole-3-carboxylic acid methyl ester
The title compound is prepared in a similar manner as described in Example
2F using 7-trifluoromethyl-1 H-indole-3-carboxylic acid methyl ester and 2-
methoxyethyl bromide as the starting materials.
1H NMR (300 MHz, CD3CN) 8.47 (d, 1H), 8.00 (s, 1H), 7.67 (d, 1H), 7.34 (t, 1H),
4.48 (t, 2H), 3.85 (s, 3H), 3.67 (t, 2H), 3.27 (s, 3H).
C. 1-(2-Methoxy-ethyl)-7-trifluoromethyl-1 H-indole-3-carboxylic acid
To a solution of 1-(2-methoxy-ethyl)-7-trifluoromethyl-1 H-indole-3-carboxylic
acid methyl ester (763 mg, 2.53 mmol) in THF:MeOH:H 2O ( 1 :1 :1 ) ( 15 mL) is added
lithium hydroxide hydrate (533 mg, 12.70 mmol) and the mixture is stirred at r.t.
overnight. The solvents are removed in vacuo and the aqueous residue is flash
frozen and lyophilized. The solid is titrated with EtOAc/DCM/MeOH (8:1 :1 ) . The
resulting suspension is filtered, and the filtrate is evaporated in vacuo and vacuum
dried to give the title compound as a white solid.
1H NMR (300 MHz, DMSO-c/6) 8.73 (d, H), 7.66 (s, H), 7.48 (d, H), 7.1 6 (t, 1H),
4.38 (m, 2H), 3.62 (m, 2H), 3.24 (s, 3H).
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example
6E using 1-(2-methoxy-ethyl)-7-trifluoromethyl-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting
materials.
1H NMR (300 MHz, CD3CN) 8.07 (d, 1H), 7.92 (br s, 1H), 7.65-7.60 (m, 2H), 7.29-
7.24 (m, 2H), 7.1 9-7.14 (m, 1H), 7.07-7.01 (m, 1H), 4.48-4.38 (m, 6H), 3.66 (t, 2H),
3.26 (s, 3H), 3.32-3.04 (m, 3H), 1.87-1 .65 (m, 4H).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
trifluoromethyl-1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethyl-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.34 (br s, 3 H), 8.08 (d, H), 7.82 (s, H), 7.66 (d,
H), 7.59 (d, H), 7.40-7.30 (m, 2H), 7.25-7.1 9 (m, 1H), 4.49-4.59 (m, 4H), 4.00 (m,
2H), 3.65 (m, 2 H), 3.24 (s, 3H), 3.1 7-3.14 (m, 3 H), 1.83-1 .63 (m, 4H).
EXAMPLE 12
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-difluoromethyl-1-(2-
eth l)-1H-indol-3-yl]-methanone hydrochloride
A. 1-(2-Methoxy-ethyl)-1 H-indole-7-carbaldehyde
The title compound is prepared in a similar manner as described in Example
1E using 1H-indole-7-carbaldehyde as the starting material.
1H NMR (300 MHz, CDCI3) 10.0 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.2 (m, 2H), 6.6 (d,
H), 4.8 (t, 2H), 3.7 (t, 2H), 3.2 (s, 3H);
MS m/ z [M+H]+=204
B. 7-Difluoromethyl-1 -(2-methoxy-ethyl)-1 H-indole
-65-
The title compound is prepared according to the procedure by Wong et al
Bioorganic & Medicinal Chemistry, 2006, 14, pp 8386-95 using 1-(2-methoxy-ethyl)-
1H-indole-7-carbaldehyde as the starting material.
1H NMR (300 MHz, CDCI3) 7.75 (d, 1H), 7.35 (d, 1H), 7.3 (m, 1H), 7.1 (m, 1H), 7.0
(s, 1H), 6.6 (d, 1H), 4.5 (t, 2H), 3.7 (t, 2H), 3.3 (s, 3H).
MS m/z [M+H]+=226.
C. 1-[7-Difluoromethyl-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone
The title compound is prepared in a similar manner as described in Example
1F using 7-difluoromethyl-1 -(2-methoxy-ethyl)-1 H-indole as the starting material.
1H NMR (300 MHz, CD3CN) 8.5 (d, 1H), 8.3 (s, 1H), 7.6 (m, 1H), 7.4 (m, 1H), 7.2
(s, 1H), 4.6 (t, 2H), 3.7 (t, 2H), 3.2 (s, 3H).
MS m/z: [M+H]+=322.
D. 7-Difluoromethyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using 1-[7-difluoromethyl-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoroethanone
as the starting material.
1H NMR (300 MHz, CD3CN) 8.5 (d, 1H), 8.3 (s, H), 7.6 (m, H), 7.4 (m , H), 7.2
(s, H), 4.6 (t, 2H), 3.7 (t, 2H), 3.2 (s, 3H).
MS m/z [M+H]+=270.
E. N-(3-{1 -[7-Difluoromethyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-
4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 7-difluoromethyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting
materials.
1H NMR (300 MHz, CDCI3) 8.0 (d, H), 7.5 (s, 1H), 7.4 (d, 1H), 7.2 (m, 3H), 7.0
(m, 2H), 6.6 (bs, H), 4.5 (m, 6H), 3.7 (t, 2H), 3.3 (s, 3H), 3.1 (m, 3H), 1.9 (m, 2H),
1.75 (m, 2H).
MS m/z [M+H]+=556.
F. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-difluoromethyl-1 -(2-methoxyeth
l)-1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described Example 1K
using N-(3-{1 -[7-difluoromethyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-
yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.3 (bs, 2H), 7.9 (d, 1H), 7.8 (s, 1H), 7.5 (m, 2H), 7.3
(m, 1H), 7.2 (m, 2H), 4.6 (t, 2H), 4.5 (m, 2H), 4.0 (t, 2H), 3.7 (m, 2H), 3.6 (m, 2H), 3.3
(s, 3H), 3.2 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H);
LCMS m/z: [M+H]+=460.
EXAMPLE 13
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-methyl-1 -(2-pyrrolidin-1 -yl-ethyl)-
1H-indol-3-yl]-methanone dihydrochloride
A. 7-Methyl-1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 7-methylindole and 1-(2-chloro-ethyl)-pyrrolidine hydrochloride as the
starting materials.
1H NMR (300 MHz, CDCI3) 7.45 (d, 1H), 7.1 5 (d, 1H), 6.95 (m, 2H), 6.50 (d, 1H),
4.50 (m, 2H), 3.85 (m, 2H), 3.70 (s, 3H), 2.55 (m, 4H), 1.80 (m, 4H).
MS m/z [M+H]+=229.
B. 2,2,2-Trifluoro-1 -[7-methyl-1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
1F using 7-methyl-1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indole as the starting material.
1H NMR (300 MHz, CDCI3) 8.3 (d, H), 8.1 (d, 1H), 7.3 (m, 1H), 7.1 (m, 1H), 5.0 (t,
2H), 3.5 (t, 2H), 2.7 (s, 3H), 1.6 (m, 8H).
MS m/z [M+H]+=229.
C. 7-Methyl-1 -(2-pyrroli dole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using 2,2,2-trifluoro-1 -[7-methyl-1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indol-3-yl]-ethanone
as the starting material.
1H NMR (300 MHz, DMSO-c/6) 12.1 (bs, 1H), 8.2 (d, 1H), 7.95 (d, 1H), 7.2 (m, 1H),
7.0 (m, 1H), 4.8 (t, 2H), 3.5 (m, 4H), 3.0 (t, 2H), 2.7 (s, 3H), 1.9 (m, 4H).
MS m/z: [M+H]+=273.
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[7-methyl-1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 7-methyl-1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting
materials.
1H NMR (300 MHz, CDCI3) 7.6 (m, 2H), 7.2-7.0 (m, 5H), 4.9 (t, 2H), 4.6 (bs, 1H),
4.5 (m, 2H), 3.7 (bs, 2H), 3.4 (m, 2H), 3.3-3.0 (m, 5H), 2.8 (s, 3H), 2.6 (bs, 2H), 2.2
(m, 4H), 1.9 (m, 2H), 1.8 (m, 2H);
MS m/z [M+H]+=559.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-methyl-1 -(2-pyrrolidin-1 -ylethyl)-
1 H-indol-3-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as described in Example
K using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[7-methyl-1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indole-
-carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) .4 (bs, H), 8.4 (bs, 2H), 7.8 (s, H), 7.6 (m, H),
.5 (m, H), 7.4 (m, H), 7.2 (m, H), 7.0 (m, 2H), 4.8 (t, 2H), 4.4 (m, 2H), 4.0 (t, 2H),
.6 (m, 4H), 3.2-3.0 (m, 5H), 2.8 (s, 3H), 2.0-1 .8 (m, 8H);
S m/z [M+H]+=463.
EXAMPLE 14
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-difluoromethoxy-1 -(2-methoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
A. 7-Difluoromethoxy-1 H-indole-3-carboxylic acid methyl ester
N-(2-Difluoromethoxy-phenyl)-hydroxylamine is prepared according to the
procedure by Evans, D. A. et al., Org. Lett, 2006, vol. 8, pp. 3351 -3354 using 1-
(difluoromethoxy)-2-nitrobenzene as the starting material. The crude product is used
for the next step without any purification.
The title compound is prepared in a similar manner as described in Example
11A using N-(2-difluoromethoxy-phenyl)-hydroxylamine as the starting material. The
crude mixture is used for the next step without any purification.
B. 7-Difluoromethoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid methyl ester
The title compound is prepared in a similar manner as described in Example
2F using 7-difluoromethoxy-1 H-indole-3-carboxylic acid methyl ester and 2-
methoxyehtyl bromide as the starting materials.
1H NMR (300 MHz, CD3CN) 7.96 (d, 1H), 7.84 (s, 1H), 7.1 6 (q, 1H), 6.99 (m, 1H),
6.88 (t, 1H), 4.53 (t, 1H), 3.83 (s, 3H), 3.69 (t, 2H), 3.23 (s, 3H).
C. 7-Difluoromethoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
C with 7-difluoromethoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid methyl
ester as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.1 7 (d, 1H), 7.58 (s, 1H), 7.30 (t, 1H), 6.99 (t, 1H),
6.86-6.84 (m, 1H), 4.45 (t, 2H), 3.64 (t, 2H), 3.22 (s, 3H).
D. N-(3-{1 -[7-Difluoromethoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-
yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example
6E with 7-difluoromethoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting
materials.
1H NMR (300 MHz, CD3CN) 8.22 (br s, 1H), 7.61 -7.59 (m, 1H), 7.48 (s, 1H), 7.28-
7.25 (m, 1H), 7.1 7-6.95 (m, 4H), 6.89 (t, 1H), 4.54-4.44 (m, 4H), 4.37 (d, 2H), 3.69 (t,
2H), 3.23 (s, 3H), 3.18-3.01 (m, 3H), 1.84-1 .62 (m, 4H).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-difluoromethoxy-1 -(2-
methoxy-ethyl)-1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B with N-(3-{1 -[7-difluoromethoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.1 7 (br s, 2H), 7.7 (m, 1H), 7.59-7.53 (m, 2H), 7.35
(m, 2H), 7.26-7.20 (m, 1H), 7.1 6-7.1 0 (m, 1H), 6.99 (m, 1H), 4.54-4.51 (m, 2H), 4.44-
4.40 (m, 2H), 4.01 (m, 2H), 3.68 (m, 2H), 3.22 (s, 3H), 3.1 7-3.1 3 (m, 3H), 1.83-1 .60
(m, 4H).
EXAMPLE 15
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-(1 -phenethyl-1 H-indol-3-yl)-
methanone hydrochloride
A. 2,2,2-Trifluoro-N-{4-fluoro-3-[1 -(1 -phenethyl-1 H-indole-3-carbonyl)-piperidin-4-yl]-
benzylj-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 1-phenethyl-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-(4-fluoro-3-
piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting materials.
1H NMR (300 MHz, CDCI3) 7.8 (d, 1H), 7.4 (d, 1H), 7.3-7.0 (m, 11H), 6.9 (bs, 1H),
4.5 (t, 2H), 4.4 (m, 4H), 3.2 (t, 2H), 3.0 (m, 3H), 1.9 (m, 2H), 1.75 (m, 2H);
MS m/z [M+H]+=552.
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-(1 -phenethyl-1 H-indol-3-yl)-
methanone h drochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-{4-fluoro-3-[1 -(1 -phenethyl-1 H-indole-3-carbonyl)-piperidin-
4-yl]-benzyl}-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.2 (bs, 2H), 7.7 (d, 1H), 7.6 (d, 1H), 7.6 (m, 2H),
7.4 (m, 1H), 7.2 (m, 8H), 4.5 (t, 2H), 4.3 (m, 2H), 4.0 (t, 2H), 3.1 (m, 5H), 1.8 (m, 2H),
1.6 (m, 2H);
MS m/z [M+H]+=456.
EXAMPLE 16
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(3-fluoro-propyl)-7-methyl-1 Hindol-
3-yl]-methanone hydrochloride
A. 1-(3-Fluoro-propyl)-7-methyl-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 7-methylindole and 1-bromo-3-fluoro-propane as the starting materials.
H NMR (300 MHz, CDCI3) 7.5 (d, 1H), 7.1-6.9 (m, 3H), 6.5 (d, 1H), 4.3 (t, 2H), 2.7
(s, 3H), 2.2 (m, H), 2.1 (m, 1H);
MS m/z: [M+H]+= 192.
B. 2,2,2-Trifluorc-l -[1 -(3-fluoro-propyl)-7-methyl-1 H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
1F using 1-(3-fluoro-propyl)-7-methyl-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 8.3 (d, H), 7.9 (d, H), 7.3 (m, H), 7.1 (m, 1H), 4.6 (m,
3H), 4.4 (t, 1H), 2.7 (s, 3H), 2.3 (m, 1H), 2.2 (m, 1H).
MS m/z [M+H]+=288.
C-1 . 1-(3-Fluoro-propyl)-7-methyl-1 H-indole-3-carboxylic acid and C-2. 1-(3-Hydroxypropyl)-
7-methyl-1 H-indole-3-carboxylic acid
The title compounds are prepared in a similar manner as described in Example
4C using 2,2,2-trifluoro-1 -[1-(3-fluoro-propyl)-7-methyl-1 H-indol-3-yl]-ethanone as the
starting material.
MS m/z: [M+H]+=234, 236 The crude 1:1 mixture is used in the next step.
D-1 . 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(3-fluoro-propyl)-7-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide and D-2. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -
[1-(3-hydroxy-propyl)-7-methyl-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-
acetamide
The title compounds are prepared in a similar manner as described in Example
2 I using a mixture of 1-(3-fluoro-propyl)-7-methyl-1 H-indole-3-carboxylic acid and 1-
(3-hydroxy-propyl)-7-methyl-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-(4-
fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting materials.
D- H NMR (300 MHz, CDCI3) 7.6 (d, 1H), 7.4 (s, 1H), 7.2-7.0 (m, 5H), 6.8 (bs,
1H), 4.5 (m, 7H), 4.4 (t, 1H), 3.1 (m, 3H), 2.7 (s, 3H), 2.3 (m, 1H), 2.2 (m, 1H), 1.9 (m,
2H), 1.8 (m, 2H). MS m/z [M+H]+=522.
D-2 H NMR (300 MHz, CDCI3) 7.6 (d, 1H), 7.5 (s, 1H), 7.2-7.0 (m, 5H), 6.9 (bs,
1H), 4.5 (m, 6H), 3.6 (t, 2H), 3.1 (m, 3H), 2.7 (s, 3H), 2.0 (m, 3H), 1.9 (m, 2H), 1.8 (m,
2H). LCMS m/z: [M+H]+=520.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(3-fluoro-propyl)-7-methyl-1 Hindol-
3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
K using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(3-fluoro-propyl)-7-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.3 (bs, 2H), 7.7 (s, 1H), 7.6 (m, 2H), 7.4 (m, 1H),
7.2 (m, H), 7.0 (m, 2H), 4.6 (m, 4H), 4.4 (m, 2H), 4.0 (t, 2H), 3.1 (m, 3H), 2.7 (s, 3H),
2.2 (m, 1H), 2.1 (m, 1H), 1.8 (m, 2H), 1.75 (m, 2H);
MS m/ z [M+H]+= 426.
EXAMPLE 17
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-(1 -phenethyl-1 H-indol-3-yl)-
methanone hydrochloride
The title compound is prepared in a similar manner as described Example K
using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(3-hydroxy-propyl)-7-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.2 (bs, 2H), 7.6 (s, 1H), 7.6 (m, 2H), 7.4 (m, 1H),
7.2 (m, H), 7.0 (m, 2H), 4.4 (m, 4H), 4.0 (t, 2H), 3.4 (m, 3H), 3.2 (m, 3H), 2.7 (s, 3H),
1.9-1 .6 (m, 6H);
MS m/ z [M+H]+=424.
EXAMPLE 18
3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 Hindole-
7-carbonitrile
The title compound is prepared according to the procedure of WO2005/040133
(pp. 152) using 7-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid (example
6A) and copper cyanide (I) as the starting materials. The crude mixture is used for
the next step without any purification.
B. N-(3-{1 -[7-Cyano-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-
fluoro-benzyl)-2,2,2-trifluoro-acetamide
N
The title compound is prepared in a similar manner as described in Example
6E using 7-cyano-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-
N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting materials.
1H NMR (300 MHz, CD3CN) 8.32 (br s, H), 8.06 (d, H), 7.62-7.59 (m, 2H), 7.27-
7.23 (m, 2H), 7.1 6-7.12 (m, 1H), 7.05-6.98 (m, 1H), 4.66 (t, 2H), 4.46 (br d, 2H), 4.37
(m, 2H), 3.76 (t, 2H), 3.24 (s, 3H), 3.1 8-2.98 (m, 3H), 1.84-1 .62 (m, 4H).
C. 3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-
1H-indole-7-carbonitrile hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1 -[7-cyano-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-
4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.32 (br s, 3H), 8.09 (d, H), 7.90 (s, H), 7.73 (d,
1H), 7.58 (m, 1H), 7.40-7.19 (m, 3H), 4.70 (t, 2H), 4.41 (br d, 2H), 4.00 (m, 2H), 3.76
(t, 2H), 3.23 (s, 3H), 3.1 7-3.01 (m, 4H), 1.81-1 .63 (m, 4H).
EXAMPLE 19
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-cyclobutyl-1 -(2-methoxy-e^
1H-indol-3-yl]-methanone hydrochloride
A. 7-Cyclobutyl-1-(2-methoxy-ethyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
6B using cyclobutylboronic acid as the starting material.
1H NMR (300 MHz, CD3CN) 7.41 -7.38 (m, 1H), 7.1 8-7.1 2 (m, 2H), 7.01 (t, 1H),
6.42 (m, 1H), 4.45 (t, 2H), 4.1 5-4.01 (m, 1H), 3.62 (t, 2H), 3.22 (s, 3H), 2.41 -2.20 (m,
4H), 2.08-1 .95 (m, 2H).
B. 1-[7-Cyclobutyl-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone
The title compound is prepared in a similar manner as described in Example
2G using 7-cyclobutyl-1 -(2-methoxy-ethyl)-1 H-indole as the starting material.
1H NMR (300 MHz, CD3CN) 8.1 9 (d, 1H), 8.1 3 (m, 1H), 7.41 (m, 1H), 7.35-7.30 (m,
1H), 4.58 (t, 2H), 4.1 0 (quin, 1H), 3.71 (t, 2H), 3.24 (s, 3H), 2.42-2.21 (m, 4H), 2.1 2-
1.96 (m, 1H), 1.94-1 .82 (m, 1H).
C. 7-Cyclobutyl-1-(2- ole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
2H using 1-[7-cyclobutyl-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone
as the starting material.
1H NMR (300 MHz, DMSO-c/6) 11.95 (br s, 1H), 7.96-7.93 (m, 2H), 7.24 (m, 1H),
7.1 6 (m, 1H), 4.53 (t, 2H), 4.07 (quin, 1H), 3.66 (t, 2H), 3.22 (s, 3H), 2.38-2.29 (m,
2H), 2.26-2.1 7 (m, 2H), 2.08-1 .96 (m, 1H), 1.89-1 .80 (m, 1H).
D. N-(3-{1 -[7-Cyclobutyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-
fluoro-benzyl)-2,2,2-trifluoro-acetamide

The title compound is prepared in a similar manner as described in Example
6E using 7-cyclobutyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting
materials.
1H NMR (300 MHz, CD3CN) 7.96 (br s, 1H), 7.58 (d, H), 7.41 (m, 1H), 7.28-7.23
(m, 2H), 7.18-7.1 0 (m, 2H), 7.06-7.00 (m, 1H), 4.50-4.40 (m, 4H), 4.38 (m, 2 H), 4.08
(quin, 1H), 3.65 (m, 2H), 3.22 (s, 3H), 3.1 8-3.00 (m, 3H), 2.40-2.20 (m, 4H), 2.08-1 .99
(m, 1H), 1.84-1 .62 (m, 5H).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-cyclobutyl-1 -(2-methoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1 -[7-cyclobutyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-
yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.31 (br s, 2H), 7.62 (s, 1H), 7.57 (d, 2H), 7.40-7.35
(m, 1H), 7.25-7.1 9 (m, 2H), 7.1 5-7.1 0 (m, 1H), 4.51 (t, 2H), 4.42 (br d, 2H), 4.1 3-3.98
(m, 3H), 3.65 (t, 2H), 3.21 (s, 3H), 3.1 5-2.98 (m, 3H), 2.39-2.30 (m, 2H), 2.27-2.1 7
(m, 2H), 2.09-1 .97 (m, 1H), 1.90-1 .61 (m, 5H).
EXAMPLE 20
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-hydroxy-ethyl)-7-methyl-1 Hindol-
3-yl]-methanone hydrochloride
A-1 . 2-(7-methyl-indol-1 -yl)-ethanol and A-2. 2-[2-(7-methyl-indol-1 -yl)-ethoxy]-
ethanol
The title compounds are prepared in a similar manner as described in Example
1E using 7-methylindole and 2-bromoethanol as the starting materials.
A-1 1H NMR (300 MHz, CDCI3) 7.5 (d, 1H), 7.2 (d, 1H), 7.0 (m, 2H), 6.5 (d, 1H), 4.5
(t, 2H), 3.9 (t, 2H), 2.7 (s, 3H). MS m/z [M+H] += 176.
A-2 1H NMR (300 MHz, CDCI3) 7.5 (d, 1H), 7.2 (d, 1H), 7.0 (m, 2H), 6.5 (d, 1H), 4.5
(t, 2H), 3.8 (t, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 2.7 (s, 3H). MS m/z: [M+H] +=220.
B. Trifluoro-acetic acid 2-[7-methyl-3-(2,2,2-trifluoro-acetyl)-indol-1 -yl]-ethyl ester
The title compound is prepared in a similar manner as described in Example
1F using 2-(7-methyl-indol-1-yl)-ethanol as the starting material.
1H NMR (300 MHz, CDCI3) 8.3 (d, H), 8.0 (s, H), 7.3 (m, 1H), 7.1 (m, 1H), 4.6 (t,
2H), 4.0 (t, 2H), 2.7 (s, 3H);
MS m/z [M+H]+=367.
C. 1-(2-Hydroxy-ethyl)-7-methyl-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using trifluoro-acetic acid 2-[7-methyl-3-(2,2,2-trifluoro-acetyl)-indol-1 -yl]-ethyl
ester as the starting material.
1H NMR (300 MHz, DMSO-c/6) 11.9 (s, 1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.1 (m, 1H), 6.9
(m, 1H), 5.0 (t, 1H), 4.5 (t, 2H), 3.7 (t, 2H), 2.7 (s, 3H).
MS m/z: [M+H]+=220.
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-hydroxy-ethyl)-7-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 1-(2-hydroxy-ethyl)-7-methyl-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-
(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting materials.
1H NMR (300 MHz, DMSO-c/6) 10.0 (s, 1H), 7.6 (s, 1H), 7.5 (d, 1H), 7.2 (d, 2H), 7.0
(m, 2H), 5.0 (t, 1H), 4.4 (m, 6H), 3.7 (m, 2H), 3.1 (m, 3H), 2.7 (s, 3H), 1.8 (m, 2H),
1.65 (m, 2H).
MS m/z [M+H]+=506.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-hydroxy-ethyl)-7-methyl-
1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-hydroxy-ethyl)-7-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.2 (bs, 2H), 7.6 (s, H), 7.6 (m, 2H), 7.4 (m, H), 7.2
(m, H), 7.0 (m, 2H), 4.4 (m, 5H), 4.0 (m, 2H), 3.7 (m, 2H), 3.1 (m, 3H), 2.7 (s, 3H), 1.8
(m, 2H), 1.7 (m, 2H).
MS m/z [M+H]+=41 0.
EXAMPLE 2 1
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-{1 -[2-(2-hydroxy-ethoxy)-ethyl]-7-
meth l-1H-indol-3-yl}-methanone hydrochloride
A. Trifluoro-acetic acid 2-{2-[7-methyl-3-(2,2,2-trifluoro-acetyl)-indol-1 -yl]-ethoxy}-ethyl
ester
The title compound is prepared in a similar manner as described in Example
1F using 2-[2-(7-methyl-indol-1 -yl)-ethoxy]-ethanol as the starting material.
1H NMR (300 MHz, CDCI3) 8.3 (d, 1H), 7.9 (s, H), 7.3 (m, H), 7.1 (m, 1H), 4.6 (t,
2H), 4.4 (t, 2H), 3.9 (t, 2H), 3.7 (t, 2H), 2.7 (s, 3H).
MS m/z [M+H]+=41 2.
B. 1-[2-(2-Hydroxy-ethoxy)-ethyl]-7-methyl-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using trifluoro-acetic acid 2-{2-[7-methyl-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-
ethoxy}-ethyl ester as the starting material.
1H NMR (300 MHz, DMSO-c/6) 11.9 (s, 1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.1 (m, 1H), 6.9
(m, 1H), 4.6 (m, 3H), 3.8 (m, 2H), 3.4 (m, 4H), 2.7 (s, 3H).
MS m/z: [M+H]+=264.
C. 2,2,2-Trifluoro-N-[4-fluoro-3-(1 -{1 -[2-(2-hydroxy-ethoxy)-ethyl]-7-methyl-1 H-indole-
3-carbonyl}-piperidin-4-yl)-benzyl]-acetamide
The title compound is prepared in a similar manner as described in Example 2 1
using 1-[2-(2-hydroxy-ethoxy)-ethyl]-7-methyl-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting
materials.
1H NMR (300 MHz, CDCI3) 7.6 (m, 2H), 7.2- 7.0 (m, 5H), 6.8 (bs, H), 4.6 (m, 4H),
4.5 (d, 2H) 3.8 (t, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 3.1 (m, 3H), 2.7 (s, 3H), 2.4 (m, H),
1.9 (m, 2H), 1.8 (m, 2H).
MS m/z [M+H]+=550.
D. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-{1 -[2-(2-hydroxy-ethoxy)-ethyl]-
7-meth l-1H-indol-3-yl}-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-[4-fluoro-3-(1 -{1 -[2-(2-hydroxy-ethoxy)-ethyl]-7-methyl-1 Hindole-
3-carbonyl}-piperidin-4-yl)-benzyl]-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.5 (bs, 2H), 7.7 (s,1 H), 7.6 (m, 2H), 7.4 (m, 1H),
7.2 (m, H), 7.0 (m, 2H), 4.6 (m, 2H), 4.4 (d, 2H), 4.0 (m, 2H), 3.7 (m, 3H), 3.1 (m,
3H), 2.7 (s, 3H), 1.8-1 .6 (m, 4H).
MS m/ z [M+H]+=454.
EXAMPLE 22
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-hydroxy-ethyl)-7-
trifluoromethoxy-1 H-indol-3-yl]-methanone hydrochloride
The title compounds are prepared in a similar manner as described in Example
1E using 7-trifluoromethoxy-1 H-indole and 2-bromoethanol as the starting materials.
A-1 1H NMR (300 MHz, CDCI3) 7.5 (d, H), 7.2 (d, H), 7.1 (m, 2H), 6.55 (d, 1H),
4.5 (t, 2H), 4.0 (m, 2H).
A-2 1H NMR (300 MHz, CDCI3) 7.5 (d, 1H), 7.2 (d,1 H), 7.1 (m, 2H), 6.55 (d, 1H),
4.5 (t, 2H), 3.8 (t, 2H), 3.6 (m, 2H), 3.4 (m, 2H).
B. 2,2,2-Trifluoro-1 -[1 -(2-hydroxy-ethyl)-7-trifluoromethoxy-1 H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
1F using 2-(7-trifluoromethoxy-indol-1-yl)-ethanol as the starting material.
1H NMR (300 MHz, CDCI3) 8.4 (d, 1H), 8.0 (d, 1H), 7.4 (m, 2H), 4.6 (t, 2H), 4.0 (
2H).
C. 1-(2-Hydroxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using 2,2,2-trifluoro-1 -[1 -(2-hydroxy-ethyl)-7-trifluoromethoxy-1 H-indol-3-yl]-
ethanone as the starting material.
1H NMR (300 MHz, DMSO-c/6) 12.2 (s, 1H), 8.1 (m, 2H), 7.2 (m, 2H), 5.0 (m, H)
4.4 (t, 2H), 3.7 (t, 2H).
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-hydroxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-
The title compound is prepared in a similar manner as described Example 2 I
using 1-(2-hydroxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting
materials.
1H NMR (300 MHz, DMSO-c/6) 10.0 (bs, 1H), 7.8 (s, 1H), 7.7 (m, 1H), 7.3 (m, 1H),
7.1 (m, 4H), 5.0 (t, 1H), 4.4 (m, 6H), 3.7 (m, 2H), 3.1 (m, 3H), 1.8 (m, 2H), 1.7 (m,
2H).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[1-(2-hydroxy-ethyl)-7-
trifluoromethoxy-1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
K using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-hydroxy-ethyl)-7-trifluoromethoxy-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 7.8 (s, 1H), 7.7 (m, 1H), 7.6 (m, 1H), 7.4 (m, 1H),
7.2 (m, 3H), 4.4 (m, 4H), 4.0 (m, 2H), 3.75 (m, 3H), 3.1 (m, 3H), 1.8-1 .7 (m, 4H).
MS m/z [M+H]+=480.
EXAMPLE 23
(4-Aminomethyl-2-{1-[1-(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-piperidin-4-
yl}-phenoxy)-acetic acid methyl ester hydrochloride
A. 4-Aminomethyl-2-bromo-phenol hydrobromide
To a mixture of 4-hydroxybenzylamine (6.0 g, 48.7 mmol) in acetic acid (30
mL) is added HBr in acetic acid (33% wt, 24 mL) dropwise. After the addition is
completed, bromine (25 mL, 48.7 mmol) in acetic acid (25 mL) is added dropwise.
The resulting mixture is stirred at room temperature overnight. The precipitate is
collected by suction filtration, washed with acetic acid and Et2O, dried in vacuo to
yield the product (8.05 g, 58%) as a white powder.
1H NMR (300 MHz, DMSO-c/6) 8.00 (br s, 3H), 7.65 (s, H), 7.30-7.20 (m, H),
7.05-6.85 (m, H), 4.05-3.75 (m, 2H).
B (3-Bromo-4-hydroxy-benzyl)-carbamic acid tert-butyl ester
A mixture of 4-aminomethyl-2-bromo-phenol hydrobromide (5.0 g, 17.6 mmol),
DIEA (6.1 mL, 35.3 mmol), and di-t-butyl dicarbonate (4.34 g, 19.4 mmol) in CH2CI2
(50 mL) is stirred at r.t. overnight. The solution is washed with sat. NaHCO3, 10%
aqueous citric acid, H2O, and brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The crude material is purified on silica gel with CH2CI2/MeOH ( 100/0 to 96/4)
as eluent to give the product (3.54 g, 66%) as a brown oil.
1H NMR (300 MHz, CDCI3) 7.40 (s, 1H), 7.20-7.05 (m, 1H), 7.00-6.85 (m, 1H), 6.55
(s, 1H), 4.80 (br s, 1H), 4.30-4.05 (m, 2H);
LC Rt 0.85 min; MS 248 (M-54, 100%).
C. [2-Bromo-4-(tert-butoxycarbonylamino-methyl)-phenoxy]-acetic acid methyl ester
A mixture of (3-bromo-4-hydroxy-benzyl)-carbamic acid tert-butyl ester (2.46 g,
8.14 mmol), methyl bromoacetate (3.85 mL, 40.7 mmol), and Cs2CO3 (6.6 g, 20.35
mmol) in THF (20 mL) is stirred at r.t. overnight. The reaction mixture is filtered, and
the filtrate is concentrated in vacuo. The crude material is purified on silica gel with
heptanes/EtOAc (95/5 to 75/25) as eluent to give the crude product (3.54 g) as a
white solid. This crude material is used in the next step without further purification.
D. [4-(tert-Butoxycarbonylamino-methyl)-2-pyridin-4-yl-phenoxy]-acetic acid methyl
ester
A mixture of [2-bromo-4-(tert-butoxycarbonylamino-methyl)-phenoxy]-acetic
acid methyl ester (2.0 g, 5.34 mmol), pyridine-4-boronic acid (0.78 g, 6.41 mmol),
Cs2CO3 (3.48 g, 10.68 mol), Pd(dppf)CI 2.CH2CI2 (0.29 g, 10% mol) in dioxane/H 2O
(29 ml_, 10 / 1) is heated at 80 °C for 4 h. The reaction mixture is cooled to r.t., and
then concentrated in vacuo. The residue is partitioned between CH CI2 and H O.
The two layers are separated, and the the organic layer is washed with H O, and
brine, dried over Na SO , filtered, and concentrated in vacuo. The crude material is
purified on silica gel with CH CI2/MeOH ( 100/0 to 96/4) as eluent to give the product
( 1 .17 g, 58%) as a light brown foam.
1H NMR (300 MHz, CDCI3) 8.64 (d, J = 6.0 Hz, 2H), 7.52 (d, J = 6 Hz, 2H), 7.26 (m,
2H), 6.84 (d, J = 8.6 Hz), 4.86 (br s, 1H), 4.65 (s, 1H), 4.30 (d, J = 5.7 Hz, 1H), 3.78
(s, 3H), 1.46 (s, 9H);
LC Rt 0.74 min; MS 373 (M+H, 100%).
E. [4-(tert-Butoxycarbonylamino-methyl)-2-piperidin-4-yl-phenoxy]-acetic acid methyl
ester
A mixture of [4-(tert-butoxycarbonylamino-methyl)-2-pyridin-4-yl-phenoxy]-
acetic acid methyl ester and PtO2 (30 mg) in MeOH ( 10 mL) and acetic acid ( 1 mL) is
hydrogenated at 50-60 psi at r.t. for 3 h. The reaction mixture is filtered through
Celite, and the filtrate is concentrated in vacuo. The residue is partitioned between
CH2CI2 and sat'd NaHCO3. The two layers are separated and the organic layer is
washed with H2O and brine, dried over Na2SO , filtered, and concentrated in vacuo
to give the crude material (299 mg) as a yellow foam. This crude material is used in
the next step without further purification.
LC Rt 0.67 min; MS 379 (M+H, 100%).
F. (4-(tert-Butoxycarbonylamino-methyl)-2-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 Hindole-
3-carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid methyl ester
A mixture of 1-(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carboxylic acid (90 mg,
0.387 mmol), DIEA ( 134 _, 0.77 mmol), [4-(tert-butoxycarbonylamino-methyl)-2-
piperidin-4-yl-phenoxy]-acetic acid methyl ester (146 mg, 0.38 mmol), and EDCI (88
mg, 0.46 mmol) in CH2CI2 (5 mL) is stirred at r.t. overnight. The mixture is partitioned
between H2O and CH CI2. The two layers are separated, and the organic layer is
washed with 10% citric acid, sat. NaHCO3, and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The crude material is purified on silica gel with CH CI2/MeOH
(100/0 to 96/4) as eluent to give the product ( 199 mg, 87%) as a light yellow foam.
1H NMR (300 MHz, CDCI3) 7.65-7.50 (m, 1H), 7.40 (s, 1H), 7.20-6.85 (m, 5H), 6.75-
6.65 (m, 1H), 4.80 (br s, 1H), 4.75-4.35 (m, 6H), 4.30-4.1 0 (m, 2H), 3.75 (s, 3H),
3.70-3.60 (m, 2H), 3.40-3.20 (m, 4H), 3.1 5-2.85 (m, 2H), 2.70 (s, 3H), 2.00-1 .50 ( i
4H), 1.40 (s, 9H);
LC Rt 1.02 min; MS 594 (M+H, 100%).
G. (4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-nnethyl-1 H-indole-3-carbonyl]-
piperidin-4-yl}-phenoxy)-acetic acid methyl ester hydrochloride
A mixture of (4-(tert-butoxycarbonylamino-methyl)-2-{1-[1 -(2-methoxy-ethyl)-7-
methyl-1 H-indole-3-carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid methyl ester ( 190
mg, 0.2 mmol) in 4 M HCI in dioxane (3 ml_) is stirred at r.t. for 1 h. The mixture is
concentrated in vacuo, and the residue is triturated with Et2O (4x) to give the product
(160 mg, 94%) as a beige powder.
1H NMR (300 MHz, DMSO-c/6) 8.1 3 (br s, 3H), 7.61 (s, 1H), 7.55 (d, J = 7.5 Hz,
1H), 7.45-7.35 (m, 1H), 7.30-7.20 (m, 1H), 7.1 0-6.85 (m, 3H), 4.89 (s, 2H), 4.65-4.30
(m, 4H), 4.00-3.85 (m, 2H), 3.69 (s, 2H), 3.57 (s, 3H), 3.22 (s, 3H), 3.1 5-2.90 (m, 1H),
2.51 (s, 3H), 2.60-2.30 (m, 2H), 1.90-1 .50 (m, 4H);
LC 0.72 min; MS 494 (M+H, 100%).
EXAMPLE 24
(4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carbonyl]-
piperidin-4-yl}-phenoxy)-acetic acid methyl ester hydrochloride
A. (4-(tert-Butoxycarbonylamino-nnethyl)-2-{1 -[1 -(2-methoxy-ethyl)-7-
trifluoromethoxy-1 H-indole-3-carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid methyl
ester
A mixture of 1-(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carboxylic
acid ( 117 mg, 0.387 mmol), DIEA ( 134 _, 0.77 mmol), [4-(terf-butoxycarbonylaminomethyl)-
2-piperidin-4-yl-phenoxy]-acetic acid methyl ester (146 mg, 0.38 mmol), and
EDCI (88 mg, 0.46 mmol) in CH2CI2 (5 ml_) is stirred at r.t. for 4 h. The mixture is
partitioned between H2O and CH2CI2. The two layers are separated, and the organic
layer is washed with 10% citric acid, sat. NaHCO3, and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The crude material is purified on silica gel with
CH2CI2/MeOH ( 100/0 to 96/4) as eluent to give the product (140 mg, 54%) as a light
yellow foam.
1H NMR (300 MHz, CDCI3) 7.75-7.65 (m, 1H), 7.47 (s, 1H), 7.20-7.00 (m, 4H), 6.68
(d, J = 8.2 Hz, 1H), 4.90-4.30 (m, 4H), 4.24 (d, J = 5.5 Hz, 1H), 3.79 (s, 3H), 3.75-
3.65 (m, 3H), 3.30 (s, 3H), 3.20-2.85 (m, 2H), 2.00-1 .60 (m, 4H), 1.46 (s, 9H); LC Rt
1.09 min; MS 664 (M+H, 100%).
B. (4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-
carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid methyl ester hydrochloride
A mixture (4-(tert-butoxycarbonylamino-methyl)-2-{1 -[1 -(2-methoxy-ethyl)-7-
trifluoromethoxy-1 H-indole-3-carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid methyl
ester (140 mg, 0.21 mmol) in 4 M HCI in dioxane (3 ml_) is stirred at r.t. for 1 h. The
mixture is concentrated in vacuo, and the residue is triturated with Et2O (4x) to give
the product ( 1 14 mg, 90%) as a slightly yellow powder.
1H NMR (300 MHz, DMSO-c/6) 8.1 3 (br s, 3H), 7.79 (s, 1H), 7.75-7.65 (m, 1H), 7.41
(s, 1H), 7.30-7.1 0 (m, 3H), 7.00-6.90 (m, 1H), 4.90 (s, 2H), 4.60-4.30 (m, 3H), 4.05-
3.85 (m, 2H), 3.69 (s, 2H), 3.60 (m, 1H), 3.22 (s, 3H), 3.20-2.95 (m, 2H), 2.00-1 .50
(m, 4H);
LC 0.80 min; MS 564 (M+H, 100%).
EXAMPLE 25
2-(4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-nnethyl-1 H-indole-3-carbonyl]-piperidin-
4-yl}-phenoxy)-N,N-dimethyl-acetannide hydrochloride
A.. [4-(tert-Butoxycarbonylannino-nnethyl)-2-pyridin-4-yl-phenoxy]-acetic acid
A mixture of [2-bromo-4-(tert-butoxycarbonylamino-methyl)-phenoxy]-acetic
acid methyl ester (0.5 g, 1.34 mmol) in MeOH (5 mL) and 1.0 M NaOH (5 mL) is
stirred at r.t. for 1 h. The reaction is concentrated in vacuo, and then partitioned
between H2O and Et2O. The two layers are separated, and the aqueous is acidified
to pH~4 with 10% citric acid. The acidified aqueous layer is extracted with EtOAc
(3x). The combined organic layers are washed with brine, dried ouver Na2SO4,
filtered, and concentrated in vacuo to yield the product (420 mg, 87%) as a beige
solid. This material is used in the next step without further purification.
LC 0.60 min; MS 359 (M+H, 100%).
B. (4-Dimethylcarbamoylmethoxy-3-pyridin-4-yl-benzyl)-carbamic acid tert-butyl ester
A mixture of [4-(ie/t-butoxycarbonylamino-methyl)-2-pyridin-4-yl-phenoxy]-
acetic acid (420 mg, 1.17 mmol), DIEA (449 _, 2.58 mmol), dimethylamine (2.0M in
THF 649 _, 1.29 mmol), and EDCI (270 mg, 1.40 mmol) in CH2CI2 ( 10 mL) is stirred
at r.t. overnight. The mixture is partitioned between sat. NaHCO3 and CH2CI2. The
two layers are separated, and the organic layer is washed with H2O, and brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The crude material is purified on
silica gel with CH2CI2/MeOH (99/1 to 95/5) as eluent to give the product (140 mg,
30%) as a light yellow foam.
1H NMR (300 MHz, CDCI3) 8.60 (s, 2H), 7.60-7.40 (m, 3H), 7.05-6.90 (m, 2H), 4.90
(br s, 1H), 4.70 (s, 2H), 4.60-4.40 (m, 2H), 2.90 (s, 6H), 1.40 (s, 9H); LC Rt 0.62 min;
MS 386 (M+H, 100%).
C. (4-Dimethylcarbamoylmethoxy-3-piperidin-4-yl-benzyl)-carbamic acid tert-butyl
ester
A mixture of (4-dimethylcarbamoylmethoxy-3-pyridin-4-yl-benzyl)-carbamic
acid tert-butyl ester (135 mg, 0.35 mmol) and PtO2 (50 mg) in MeOH (5 mL) and
acetic acid ( 1 mL) is hydrogenated at 50-60 psi at r.t. for 3 h. The reaction mixture is
filtered through Celite, and the filtrate is concentrated in vacuo. The residue is
partitioned between CH2CI2 and sat NaHCO3. The two layers are separated, and the
organic layer is washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated in vacuo to give the crude material (54 mg) as a white foam. This crude
material is used in the next step without further purification.
D. (4-Dimethylcarbamoylmethoxy-3-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-carbamic acid tert-butyl ester
A mixture of 1-(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carboxylic acid (32 mg,
0.13 mmol), DIEA (48 _, 0.27 mmol), (4-dimethylcarbamoylmethoxy-3-piperidin-4-ylbenzyl)-
carbamic acid tert-butyl ester (54 mg, 0.1 3 mmol), and EDCI (32 mg, 0.1 6
mmol) in CH2CI2 (5 mL) is stirred at r.t. overnight. The mixture is partitioned between
H2O and CH2CI2. The two layers are separated, and the organic layer is washed with
10% citric acid, sat. NaHCO3, and brine, dried over Na2SO4, filtered, and
concentrated in vacuo to give a white foam. This crude material is used in the next
step without further purification.
LC Rt 0.96 min; MS 607 (M+H, 100%).
E. 2-(4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
piperidin-4-yl}-phenoxy)-N,N-dimethyl-acetamide hydrochloride
A mixture (4-dimethylcarbamoylmethoxy-3-{1 -[1 -(2-methoxy-ethyl)-7-methyl-
1H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-carbamic acid tert-butyl ester (from the
previous step) in 4 M HCI in dioxane (3 ml_) is stirred at r.t. for 1 h. The mixture is
concentrated in vacuo, and crude material is purified by RP-HPLC to yield the product
(13 mg) as a slightly white powder.
1H NMR (300 MHz, DMSO-c/6) 8.02 (br s, 3H), 7.60 (s, 1H), 7.75 (d, J = 6.6 Hz,
1H), 7.35 (d, J = 1.8 Hz, 1H), 7.30-7.1 5 (m, 1H), 7.1 0-6.85 (m, 3H), 4.91 (s, 2H), 4.57
(t, J = 7.0 Hz, 1H), 4.44 (br d, J = 12.1 Hz, 1H), 3.94 (s, 2H), 3.67 (t, J = 5.4 Hz, 2H),
3.1 5 (s, 3H), 3.05-2.90 (m, 4H), 2.83 (s, 3H), 2.67 (s, 3H), 2.60-2.40 (m, 1H), 1.95-
1.50 (m, 4H);
LC 2.1 1 min; MS 507 (M+H, 100%).
EXAMPLE 26
2-(4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-piperidin-
4-yl}-phenoxy)-N-methyl-acetamide hydrochloride
A. (4-(tert-Butoxycarbonylamino-nnethyl)-2-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 Hindole-
3-carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid
A mixture of (4-(fe/t-butoxycarbonylamino-methyl)-2-{1-[1 -(2-methoxy-ethyl)-7-
methyl-1 H-indole-3-carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid methyl ester (250
mg, 0.42 mmol, Example 23F) in MeOH (2.5 mL) and 1.0 M NaOH (2.5 mL) is stirred
at r.t. for 30 min. The reactiom mixture is concentrated in vacuo, and the residue is
partitioned between H2O and Et2O. The two layers are separated, and the aqueous
is acidified to pH~4 with 10% citric acid. The acidified aqueous layers is extracted
with CH2CI2 (3x), and the combined organic extracts are washed with H2O and brine,
dried over Na2SO4, filtered, and concentrated in vacuo to yield the product (257 mg,
100%) as a yellow foam.
1H NMR (300 MHz, CDCI3) 7.75-7.55 (m, 1H), 7.45 (s, 1H), 7.20-6.85 (m, 4H), 6.80-
6.60 (m, H), 5.00-4.30 (m, 5H), 4.35-4.1 0 (m, 2H), 4.00-3.50 (m, 3H), 3.40-2.80 (m,
6H), 2.70 (s, 3H), 2.00-1 .65 (m, 4H), 1.45 (s, 9H);
LC Rt 0.94 min; MS 580 (M+H, 100%).
B. (3-{1 -[1 -(2-Methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-
methylcarbannoylnnethoxy-benzyl)-carbannic acid tert-butyl ester
A mixture of (4-(tert-butoxycarbonylamino-methyl)-2-{1-[1 -(2-methoxy-ethyl)-7-
methyl-1 H-indole-3-carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid (257 mg, 0.44
mmol), DIEA ( 102 _, 0.53 mmol), methylamine (2.0 M in THF, 4 ml_), and EDCI
(270 mg, 1.40 mmol) in CH2CI2 (5 ml_) is stirred at r.t. for 6 h. The two layers are
separated, and the organic layer is washed with 10% citric acid, sat. NaHCO3, and
brine, dried over Na2SO , filtered, and concentrated in vacuo. The crude material is
purified on silica gel with CH2Cl2/MeOH ( 100/0 to 94/6) as eluent to give the product
(58 mg, 22%) as a light yellow foam.
1H NMR (300 MHz, CDCI3) 7.65-7.55 (m, 1H), 7.45 (s, 1H), 7.20-6.90 (m, 4H), 6.80-
6.65 (m, 1H), 4.80 (br s, 1H), 4.60-4.35 (m, 6H), 4.30-4.1 0 (m, 2H), 3.80-3.60 (t, 2H),
3.30 (s, 3H), 3.30-2.95 (m, 3H), 2.90 (s, 3H), 2.70 (s, 3H), 1.95-1 .60 (m, 4H), 1.45 (s,
9H);
LC Rt 0.93 min; MS 593 (M+H, 100%).
2-(4-Aminonnethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
piperidin-4-yl}-phenoxy)-N-methyl-acetannide hydrochloride
A mixture (3-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-piperidin-
4-yl}-4-methylcarbamoylmethoxy-benzyl)-carbamic acid te -butyl ester (58 mg, 0.098
mmol) in 4 M HCI in dioxane (2 ml_) is stirred at r.t. for 1 h. The mixture is
concentrated in vacuo, and the residue is washed with Et2O several times to give the
product (40 mg, 77%) as a white powder.
1H NMR (300 MHz, DMSO-c/6) 8.1 (br s, 3H), 8.00-7.85 (m, 1H), 7.61 (s, 1H), 7.54
(d, J = 7.1 Hz, 1H), 7.39 (s, 1H), 7.30-7.20 (m, 1H), 7.10-6.80 (m, 3H), 4.65-4.30 (m,
5H), 4.05-3.80 (m, 2H), 3.80-3.20 (m, 4H), 3.22 (s, 3H), 3.20-2.80 (m, 2H), 2.67 (s,
3H), 2.40 (s, 3H), 1.90-1 .40 (m, 4H);
LC 0.65 min; MS 493 (M+H, 100%).
EXAMPLE 27
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-{1 -[2-(2-hydroxy-ethoxy)-ethyl]-7-
trifluoromethoxy-1 H-indol-3-yl}-methanone hydrochloride
- 1 . 2,2,2-Trifluoro-1 -{1 -[2-(2-hydroxy-ethoxy)-ethyl]-7-trifluoromethoxy-1 H-indol-3-
yl}-ethanone and A-2. Trifluoro-acetic acid 2-{2-[3-(2,2,2-trifluoro-acetyl)-7-
trifluoromethoxy-indol-1 -yl]-ethoxy}-ethyl ester
The title compounds are prepared in a similar manner as described in Example
1F using 2-[2-(7-trifluoromethoxy-indol-1 -yl)-ethoxy]-ethanol as the starting material.
The purified 1:1 mixtures of products are used in the next step.
B. 1-[2-(2-Hydroxy-ethoxy)-ethyl]-7-trifluoromethoxy-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using the 1:1 mixture of 2,2,2-trifluoro-1-{1 -[2-(2-hydroxy-ethoxy)-ethyl]-7-
trifluoromethoxy-1 H-indol-3-yl}-ethanone and trifluoro-acetic acid 2-{2-[3-(2,2,2-
trifluoro-acetyl)-7-thfluoromethoxy-indol-1-yl]-ethoxy}-ethyl ester as the starting
material.
1H NMR (300 MHz, DMSO-c/6) 12.2 (bs, 1H), 8.2 (s, 1H), 8.1 (m, 1H), 7.2 (m, 2H),
4.5 (m, 4H), 3.8 (m, 3H), 3.4 (t, 2H).
C. 2,2,2-Trifluoro-N-[4-fluoro-3-(1 -{1 -[2-(2-hydroxy-ethoxy)-ethyl]-7-trifluoromethoxy-
1H-indole-3-carbonyl}-piperidin-4-yl)-benzyl]-acetamide
The title compound is prepared in a similar manner as described Example 2 1
1-[2-(2-hydroxy-ethoxy)-ethyl]-7-trifluoromethoxy-1 H-indole-3-carboxylic acid
and 2,2,2-trifluoro-N-(4-fluoro-3-pipendin-4-yl-phenyl)-acetamide hydrochloride as the
starting materials.
1H NMR (300 MHz, CDCI3) 7.7 (d, H), 7.6 (s, 1H), 7.2 (m, 5H), 7.1 (m, 1H), 6.8
(bs, 1H), 4.6 (m, 6H), 3.8 (m, 2H), 3.6 (m, 2H), 3.5 (m, 2H), 3.1 (m, 2H), 1.9 (m, 2H),
1.8 (m, 2H).
LCMS m/z [M+H]+=620.
D. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-{1 -[2-(2-hydroxy-ethoxy)-ethyl]-
7-trifluoromethoxy-1 H-indol-3-yl}-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-[4-fluoro-3-(1 -{1 -[2-(2-hydroxy-ethoxy)-ethyl]-7-
trifluoromethoxy-1 H-indole-3-carbonyl}-piperidin-4-yl)-benzyl]-acetamide as the
starting material.
1H NMR (300 MHz, DMSO-c/6) 8.4 (bs, 2H), 7.8 (s, 1H), 7.7 (m, 1H), 7.6 (m, 1H),
7.4 (m, 1H), 7.2 (m, 3H), 4.4 (m, 4H), 4.0 (m, 2H), 3.8 (m, 3H), 3.4 (m, 4H), 3.1 (m,
3H), 1.8-1 .7 (m, 4H).
LCMS m/z: [M+H]+=524.
EXAMPLE 28
2-(4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carbonyl]-
piperidin-4-yl}-phenoxy)-N-methyl-acetamide hydrochloride
A. (4-(tert-Butoxycarbonylamino-methyl)-2-{1 -[1 -(2-methoxy-ethyl)-7-
trifluoromethoxy-1 H-indole-3-carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid
A mixture of (4-(tert-butoxycarbonylamino-methyl)-2-{1 -[1 -(2-methoxy-ethyl)-7-
trifluoromethoxy-1 H-indole-3-carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid methyl
ester ( 100 mg, 0.1 5 mmol, Example 24A) in MeOH (2.0 mL) and 1.0 M NaOH (2.0
mL) is stirred at r.t. for 30 min. The reaction mixture is concentrated in vacuo, and
the residue is partitioned between H2O and Et2O. The two layers are separated, and
the aqueous is acidified to pH~4 with 10% citric acid. The acidified aqueous layers
are extracted with CH2CI2 (3x), and the combined organic extracts are washed with
H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield the
product (98 mg, 100%) as a yellow foam.
1H NMR (300 MHz, CDCI3) 7.75-7.65 (m, H), 7.55-7.45 (m, H), 7.20-6.95 (m, 5H),
6.80-6.60 (m, H), 4.70-4.35 (m, 7H), 4.30-4.1 0 (m, 2H), 3.80-3.60 (m, 2H), 3.30 (s,
3H), 3.30-2.80 (m, 3H), 2.10-1 .65 (m, 4H), 1.45 (s, 9H);
LC Rt 1.01 min; MS 650 (M+H, 100%).
B. (3-{1 -[1 -(2-Methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carbonyl]-piperidin-4-yl}-
4-methylcarbamoylmethoxy-benzyl)-carbamic acid tert-butyl ester
To a mixture of (4-(tert-butoxycarbonylamino-methyl)-2-{1 -[1-(2-methoxyethyl)-
7-trifluoromethoxy-1 H-indole-3-carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid
(196 mg, 0.30 mmol) in acetone (3 mL) at 0 °C is added TEA (42 L, 0.30 mmol)
dropwise. After 30 min, iso-butyl chloroformate (39 L, 0.30 mmol) is added. After
30 min, the reaction mixture is filtered, and the filtrate is concentrated in vacuo. The
residue is redissolved in acetone (5 mL), and methylamine (4 mL, 40% in H2O) is
added. After this mixture is stirred at r.t. for 30 min, it is concentrated in vacuo. The
residue is partitioned between CH CI2and 10% citric acid. The two layers are
separated, and the organic layer is washed with sat. NaHCO3, H2O, and brine, dried
over Na2SO , filtered, and concentrated in vacuo. The crude material is purified on
silica gel using CH2CI2/MeOH ( 100/0 to 96/4) as eluent to give the product (45 mg,
22%) as a white solid.
1H NMR (300 MHz, CDCI3) 7.75-7.65 (m, 1H), 7.50 (s, 1H), 7.25-7.00 (m, 4H), 6.85-
6.75 (m, 1H), 6.30 (br s, 1H), 4.90-4.40 (m, 7H), 4.35-4.1 5 (m, 2H), 3.80-3.60 (t, 2H),
3.35 (s, 3H), 3.30-2.95 (m, 3H), 2.90 (s, 3H), 2.70 (s, 3H), 2.00-1 .60 (m, 4H), 1.40 (s,
9H);
LC Rt 1.01 min; MS 663 (M+H, 100%).
C. 2-(4-Aminomethyl-2-{1 -[1-(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-
carbonyl]-piperidin-4-yl}-phenoxy)-N-methyl-acetamide hydrochloride
A mixture of (3-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-
carbonyl]-piperidin-4-yl}-4-methylcarbamoylmethoxy-benzyl)-carbamic acid te -butyl
ester (40 mg, 0.06 mmol) in 4 M HCI in dioxane (2 ml_) is stirred at r.t. for 30 min.
The mixture is concentrated in vacuo, and the residue is washed with Et2O several
times to give the product (28 mg, 73%) as a slighty pink powder.
1H NMR (300 MHz, DMSO-c/6) 8.1 1 (br s, 3H), 8.00-7.85 (m, 1H), 7.79 (s, 1H),
7.75-7.65 (m, 1H), 7.39 (s, 1H), 7.35-7.15 (m, 2H), 6.90 (d, J = 8.5 Hz, 1H), 4.65-4.30
(m, 6H), 4.05-3.90 (m, 2H), 3.68 (t, J = 5.3 Hz, 3H), 3.21 (s, 3H), 3.20-3.30 (m, 3H),
2.67 (d, J = 4.6 Hz, 3H), 1.90-1 .50 (m, 4H);
LC 0.73 min; MS 563 (M+H, 100%).
EXAMPLE 29
2-(4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carbonyl]-
piperidin-4-yl}-phenoxy)-N,N-dimethyl-acetamide hydrochloride
A (4-Dimethylcarbamoylmethoxy-3-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-carbamic acid tert-butyl ester
To a mixture of (4-(te/t-butoxycarbonylamino-methyl)-2-{1 -[1 -(2-methoxyethyl)-
7-trifluoromethoxy-1 H-indole-3-carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid
(160 mg, 0.24 mmol, example 24A) in acetone ( 1 mL) at 0 °C is added TEA (41 pL,
0.27 mmol) dropwise. After 30 min, iso-butyl chloroformate (35 L, 0.27 mmol) in
acetone ( 1 mL) is added. After 30 min, the reaction mixture is filtered, and the filtrate
is concentrated in vacuo. The rsidue is redissolved in THF (3 mL), and methylamine
(4 mL, 2.0 M in THF) is added. After this mixture is stirred at r.t. for 30 min, it is
concentrated in vacuo. The residue is partitioned between CH2CI2 and 10% citric
acid. The two layers are separated, and the organic layer is washed with sat.
NaHCO 3, H2O, and brine, dried over Na2SO , filtered, and concentrated in vacuo.
The crude material is purified on silica gel with C C /MeOH ( 100/0 to 96/4) as
eluent to give the product ( 1 10 mg, 67%) as a white solid.
1H NMR (300 MHz, CDCI3) 7.75-7.60 (m, 1H), 7.45 (s, 1H), 7.25-7.00 (m, 4H), 6.85-
6.65 (m, 1H), 4.80-4.40 (m, 7H), 4.30-4.10 (m, 2H), 3.80-3.60 (m, 2H), 3.30 (s, 3H),
3.30-2.70 (m, 9H), 2.00-1 .60 (m, 4H), 1.40 (s, 9H);
LC Rt 1.04 min; MS 677 (M+H, 100%).
B. 2-(4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-
carbonyl]-piperidin-4-yl}-phenoxy)-N,N-dimethyl-acetamide hydrochloride
A mixture of (4-dimethylcarbamoylmethoxy-3-{1 -[1 -(2-methoxy-ethyl)-7-
trifluoromethoxy-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-carbamic acid tert-butyl
ester ( 108 mg, 0.1 6 mmol) in 4 M HCI in dioxane (2 ml_) is stirred at r.t. for 30 min.
The mixture is concentrated in vacuo, and the residue is washed with Et2O several
times to give the product (82 mg, 83%) as a white powder.
1H NMR (300 MHz, DMSO-c/6) 8.1 1 (br s, 3H), 7.79 (s, 1H), 7.75-7.70 (m, 1H), 7.37
(d, J = 2 Hz, 1H), 7.30-7.1 0 (m, 3H), 6.91 (d, J = 8.6 Hz, 1H), 4.91 (s, 2H), 4.60-4.30
(m, 3H), 4.05-3.85 (m, 2H), 3.68 (t, J = 5.3 Hz, 3H), 3.25 (m, 1H), 3.21 (s, 3H), 3.1 5
(m, 2H), 3.01 (s, 3H), 2.83 (s, 3H), 1.95-1 .50 (m, 4H);
LC 0.75 min; MS 577 (M+H, 100%).
, ,
- 116-
EXAMPLE 30
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-{1 -[2-(1 -methyl-piperidin-2-yl)-
eth l]-1H-indol-3-yl}-methanone dihydrochloride
A. 1-[2-(1 -Methyl-piperidin-2- -ethyl]-1H-indole-3-carboxylic acid methyl ester
The title compound is prepared in a similar manner as described in Example
2F using 1H-indole-3-carboxylic acid methyl ester and 2-(2-chloroethyl)1 -
methylpiperdine hydrochloride in DMF as the starting materials.
1H NMR (300 MHz, CDCI3) 8.2 (m, H), 7.8 (s, H), 7.4 (m, H), 7.3 (m, 2H), 4.2
(m, 2H), 3.9 (s, 3H), 3.6 (m, H), 2.3 (s, 3H), 2.2-2.0 (m, 4H), .8-1 .6 (m, 6H).
B. 1-[2-(1 -Methyl-piperidin-2-yl)-ethyl]-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
D using 1-[2-(1 -methyl-piperidin-2-yl)-ethyl]-1 H-indole-3-carboxylic acid methyl ester
s the starting material.
H NMR (300 MHz, DMSO-c/6) 12.4 (bs, 1H), 8.2 (s, 1H), 8.0 (d, 1H), 7.6 (d, 1H),
.2 (m, 2H), 4.4 (m, 2H), 3.1 (m,2H), 2.8 (m, 2H), 2.6 (m, 1H), 2.5 (s, 3H), 2.1 (m,
H), 1.8 (m, 4H).
C. 2,2,2-Trifluoro-N-[4-fluoro-3-(1 -{1 -[2-(1 -methyl-piperidin-2-yl)-ethyl]-1 H-indole-3-
carbonyl}-piperidin-4-yl)-benzyl]-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
1-[2-(1 -methyl-piperidin-2-yl)-ethyl]-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting
materials.
1H NMR (300 MHz, CDCI3) 7.7 (d, H), 7.5 (s, H), 7.4 (d, H), 7.3-7.1 (m, 4H), 7.0
(m, 1H), 6.7 (bs, 1H), 4.6 (m, 2H), 4.45 (m, 2H), 4.2 (m, 2H), 3.1 (m, 3H), 2.9 (m, 1H),
2.3 (s, 3H), 2.1 (m, 4H), 1.8-1 .5 (m, 10H).
LCMS m/z [M+H]+=573
D. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-{1 -[2-(1 -methyl-piperidin-2-yl)-
eth l]-1H-indol-3-yl}-methanone dihydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-[4-fluoro-3-(1 -{1 -[2-(1 -methyl-piperidin-2-yl)-ethyl]-1 Hindole-
3-carbonyl}-piperidin-4-yl)-benzyl]-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 11.0 (bd, 1H), 8.5 (bs, 2H), 7.9 (s, 1H), 7.7 (m, 1H),
7.6 (m, 1H), 7.4 (m, 1H), 7.2 (m, 4H), 4.4 (m, 4H), 4.0 (m, 2H), 3.4 (m, 2H), 3.1 (m,
4H), 2.3 (s, 3H), 2.0 (m, 2H), 1.8-1 .7 (m, 10H).
MS m/z: [M+H]+=477.
EXAMPLE 3 1
2-(4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-piperidin-
4-yl}-phenoxy)-acetamide hydrochloride
A. (4-Carbamoylmethoxy-3-{1 -[1 -(2-methoxy-ethyl)-7-nnethyl-1 H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-carbannic acid tert-butyl ester
A mixture of 1-(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carboxylic acid (165
mg, 0.70 mmol), DIEA (245 _, 1.40 mmol), (4-carbamoylmethoxy-3-piperidin-4-ylbenzyl)-
carbamic acid tert-butyl ester (249 mg, 0.68 mmol, Example 32C), HOBT
( 1 14 mg, 0.84 mmol), and EDCI ( 162 mg, 0.84 mmol) in CH2CI2 ( 10 mL) is stirred at
r.t. for 6 h. The mixture is partitioned between H2O and CH2CI2. The two layers are
separated, and the organic layer is washed with 10% citric acid, sat. NaHCO3, and
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is
purified on silica gel with CH2CI2/MeOH ( 100/0 to 96/4) as eluent to give the product
(97 mg, 24%) as a beige foam.
1H NMR (300 MHz, CDCI3) 7.70-7.50 (m, H), 7.45 (s, H), 7.20-7.00 (m, 3H), 7.00-
6.90 (m, H), 6.85-6.70 (m, H), 6.35 (br s, H), 5.65 (br s, H), 4.80 (br s, H), 4.70-
4.40 (m, 6H), 4.35-4.15 (m, 2H), 3.80-3.60 (m, 2H), 3.30 (s, 3H), 3.20-2.95 (m, 3H),
2.00-1 .60 (, 4) , 1.45 (s, 9H);
LC Rt 0.90 min; MS 579 (M+H, 100%).
B. 2-(4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
piperidin-4-yl}-phenoxy)-acetamide hydrochloride
A mixture of (4-carbamoylmethoxy-3-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-carbannic acid tert-butyl ester (95 mg, 0.1 6
mmol) in 4 M HCI in dioxane (3 ml_) is stirred at r.t. for 1 h. The mixture is
concentrated in vacuo, and the residue is triturated with Et2O (4X). The solid is
dissolved in H2O, and the resulting solution is lyophilized to give the product (66 mg,
80%) as a white fluffy powder.
1H NMR (300 MHz, DMSO-c/6) 8.1 0 (br s, 3H), 7.61 (s, 1H), 7.60-7.50 (m, 1H),
7.50-7.05 (m, 3H), 7.50-6.80 (m, 4H), 4.60-4.30 (m, 6H), 4.00-3.80 (m, 2H), 3.75-3.60
(m, 2H), 3.22 (s, 3H), 3.20-2.90 (m, 2H), 2.67 (s, 3H), 1.90-1 .45 (m, 4H);
LC 0.60 min; MS 479 (M+H, 100%).
EXAMPLE 32
2-(4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carbonyl]-
piperidin-4-yl}-phenoxy)-acetamide hydrochloride
A. (3-Bromo-4-carbannoylnnethoxy-benzyl)-carbannic acid tert-butyl ester
A mixture of (3-bromo-4-hydroxy-benzyl)-carbamicacid tert-butyl ester ( 1 .30 g,
4.30 mmol), 2-bromoacetamide (0.59 g, 4.3 mmol), and Cs2CO3 (3.50 g, 10.8 mmol)
in THF ( 15 ml_) is stirred at 60 °C for 1 h. The reaction mixture is filtered, and the
filtrate is concentrated in vacuo. The crude material is crystallized from EtOAc give
the product ( 1 .15 g, 74%) as a white power.
1H NMR (300 MHz, CDCI3) 7.50 (s, 1H), 7.35-7.1 0 (m, 1H), 7.00-6.70 (m, 3H), 5.75
(br s, 1H), 4.85 (m, 1H), 4.50 (s, 2H), 4.35-4.1 0 (m, 2H), 1.40 (s, 9H);
LC Rt 0.79 min.
B. (4-Carbamoylmethoxy-3-pyridin-4-yl-benzyl)-carbamic acid tert-butyl ester
A mixture of (3-bromo-4-carbamoylmethoxy-benzyl)-carbamic acid tert-butyl
ester ( 1 .00 g, 2.78 mmol), pyridine-4-boronic acid (0.41 g, 3.34 mmol), Cs2CO3 ( 1 .81
g, 5.56 mol), Pd(dppf)CI 2.CH2CI2 (0.20, 10% mol) in dioxane/H 2O ( 16 mL, 10/1 ) is
heated at 80 °C for 2 h and then at r.t. overnight. The reaction mixture is cooled to
r. , and then concentrated in vacuo. The residue is partitioned between EtOAc and
H O. The two layers are separated, and the the organic layer is washed with H O,
and brine, dried over Na SO , filtered, and concentrated in vacuo. The crude
material is purified on silica gel with CH CI2/MeOH ( 100/0 to 95/5) as eluent to give
the product (0.44 g, 44%) as a brown foam.
1H NMR (300 MHz, CDCI3) 8.80-8.60 (m, 2H), 7.55-7.1 0 (m, 4H), 7.00-6.80 (m,
2H), 4.86 (br s, 1H), 6.10 (br s, 1H), 5.60 (br s, 1H), 4.90 (br s, 1H), 4.70 (s, 2), 4.40-
4.20 (m, 2H), 1.45 (s, 9H);
LC Rt 0.56 min; MS 359 (M+H, 100%).
C. (4-Carbamoylmethoxy-3-piperidin-4-yl-benzyl)-carbamic acid tert-butyl ester
A mixture of (4-carbamoylmethoxy-3-pyridin-4-yl-benzyl)-carbamic acid tertbutyl
ester (440 mg, 1.23 mmol) and PtO (50 mg) in MeOH (15 mL) and acetic acid
( 1 mL) is hydrogenated at 50-60 psi at r.t. for 4 h. The reaction mixture is filtered
through Celite, and the filtrate is concentrated in vacuo. The residue is partitioned
between CH2CI2 and sat NaHCO3. The two layers are separated and the organic
layer is washed with H2O and brine, dried over Na2SO , filtered, and concentrated in
vacuo to give the crude material (501 mg) as a white foam. This crude material is
used in the next step without further purification.
1H NMR (300 MHz, CDCI3) 7.20-7.05 (m, 2H), 6.85-6.70 (m, 1H), 6.50 (br s, 1H),
5.60 (br s, 1H), 4.75 (br s, 1H), 4.50 (s, 4H), 4.40-4.1 0 (m, 3H), 3.30-3.10 (m, 1H),
3.1 0-2.90 (m, 1H), 2.90- 2.65 (m, 1H), 2.30 (s, 1H), 2.20-1 .50 (m, 4H) 1.40 (s, 9H);
LC Rt 0.56 min; MS 364 (M+H, 100%).
D. (4-Carbamoylmethoxy-3-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-carbamic acid tert-butyl ester
A mixture of 1-(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carboxylic
acid (21 9 mg, 0.73 mmol), DIEA (251 _, 1.44 mmol), (4-carbamoylmethoxy-3-
piperidin-4-yl-benzyl)-carbamic acid tert-butyl ester (256 mg, 0.72 mmol), HOBT ( 117
mg, 0.86 mmol), and EDCI ( 166 mg, 0.86 mmol) in CH2CI2 ( 10 mL) is stirred at r.t. for
6 h. The mixture is partitioned between H2O and CH2CI2. The two layers are
separated, and the organic layer is washed with 10% citric acid, sat. NaHCO3, and
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is
purified on silica gel with CH2CI2/MeOH ( 100/0 to 90/1 0) as eluent to give the product
(141 mg, 3 1%) as a light yellow foam.
1H NMR (300 MHz, CDCI3) 7.80-7.60 (m, 1H), 7.45 (s, 1H), 7.20-7.00 (m, 4H), 6.85-
6.70 (m, 1H), 6.35 (br s, 1H), 5.70 (br s, 1H), 4.80 (br s, 1H), 4.70-4.35 (m, 6H), 4.30-
4.1 0 (m, 2H), 3.80-3.60 (m, 2H), 3.30 (s, 3H), 3.25-3.00 (m, 3H), 2.00-1 .50 (m, 4H),
1.40 (s, 9H);
LC Rt 0.99 min; MS 649 (M+H, 100%).
E. 2-(4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-
carbonyl]-piperidin-4-yl}-phenoxy)-acetamide hydrochloride
A mixture of (4-carbamoylmethoxy-3-{1 -[1 -(2-methoxy-ethyl)-7-
trifluoromethoxy-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-carbamic acid tert-butyl
ester ( 130 mg, 0.2 mmol) in 4 M HCI in dioxane (3 ml_) is stirred at r.t. for 1 h. The
mixture is concentrated in vacuo, and the residue is triturated with Et2O (4x) to give
the product (96 mg, 82%) as a beige powder.
1H NMR (300 MHz, DMSO-c/6) 8.1 9 (br s, 3H), 7.79 (s, 1H), 7.75-7.65 (m, 1H), 7.40
(s, 1H), 7.30-7.1 0 (m, 2H), 6.95-6.85 (m, 1H), 4.60-4.25 (m, 4H), 4.00-3.85 (m, 2H),
3.80-3.60 (m, 2H), 3.40-3.25 (m, 2H), 3.21 (s, 3H), 3.20-3.00 (m, 2H), 2.51 (s, 3H),
1.95-1 .50 (m, 4H);
LC 0.70 min; MS 549 (M+H, 100%).
EXAMPLE 33
(4-Aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-piperidin-4-
yl}-phenoxy)-acetic acid hydrochloride
A mixture of (4-aminomethyl-2-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-phenoxy)-acetic acid methyl ester hydrochloride ( 136 mg,
0.25 mmol, example 23G) in MeOH ( 1 .35 mL) and 1 M NaOH ( 1 .35 mL) is stirred at
r.t. for 15 min. The reaction is concentrated in vacuo. The residue is acidified to pH
~3 with 1M HCI. The mixture is puridied by RP-HPLC to give the product (63 mg,
48%) as a white solid.
1H NMR (300 MHz, DMSO-c/6) 13.0 (br s, 1H), 8.1 0 (br s, 3H), 7.61 (s, 1H), 7.54 (d,
J = 7.7 Hz, 1H), 7.45-7.35 (m, 1H), 7.30-7.1 5 (m, 1H), 7.1 0-6.85 (m, 3H), 4.76 (s,
2H), 4.65-4.30 (m, 4H), 3.94 (s, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.22 (s, 3H), 3.1 5-2.90
(m, 2H), 2.67 (s, 3H), 1.90-1 .45 (m, 4H);
LC 0.65 min; MS 480 (M+H, 100%).
EXAMPLE 34
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(3-fluoro-propyl)-7-
trifluoromethoxy-1 H-indol-3-yl]-methanone hydrochloride
A. 1-(3-Fluoro-propyl)-7-trifluoronnethoxy-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 7-trifluoromethoxy-1 H-indole and 1-bromo-3-fluoro-propane as the starting
materials.
1H NMR (300 MHz, CDCI3) 7.5 (d, H), 7.1 (m, 3H), 6.5 (m, 1H), 4.5 (m, 3H), 4.3
(m, H), 2.3 (m, H), 2,2 (m, H).
MS m/z [M+H]+=262.
B. 2,2,2-Trifluoro-l -[1 -(3-fluoro-propyl)-7-trifluoromethoxy-1 H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
1F using 1-(3-fluoro-propyl)-7-trifluoromethoxy-1 H-indole as the starting material.
1H NMR (300 MHz, CDCI3) 8.4 (d, 1H), 7.9 (s, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 4.6 (m,
3H), 4.4 (m, H), 2.4 (m, H), 2.3 (m, H).
MS m/z [M+H]+=358.
C. 1-(3-Fluoro-propyl)-7-trifluoromethoxy-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using 2,2,2-trifluoro-1 -[1 -(3-fluoro-propyl)-7-trifluoromethoxy-1 H-indol-3-yl]-
ethanone as the starting material.
1H NMR (300 MHz, DMSO-c/6) 12.3 (bs, 1H), 8.2 (s, 1H), 8.1 (m, 1H), 7.2 (m, 2H),
4.6-4.3 (m, 4H), 2.2 (m, 2H).
MS m/z: [M+H]+=306.
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(3-fluoro-propyl)-7-trifluoromethoxy-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
1
The title compound is prepared in a similar manner as described in Example 2 I
using 1-(3-fluoro-propyl)-7-trifluoromethoxy-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting
materials.
1H NMR (300 MHz, DMSO-c/6) 10.0 (m, 1H), 7.8 (s, 1H), 7.7 (d, 1H), 7.3 (d, 1H),
7.2 (m, 4H), 4.6 (t, 1H), 4.4 (m, 7H), 3.1 (m, 3H), 2.2 (m, 2H), 1.8 (m, 2H), 1.7 (m,
2H).
MS m/z [M+H]+=592.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(3-fluoro-propyl)-7-
trifluoromethoxy-1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(3-fluoro-propyl)-7-trifluoromethoxy-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.4 (bs, 2H), 7.9 (s, 1H), 7.8 (m, 1H), 7.6 (m, 1H),
7.4 (m, H), 7.2 (m, 3H), 4.6-4.35 (m, 6H), 4.0 (m, 2H), 3.1 (m, 3H), 2.2 (m, 2H), 1.9-
1.6 (m, 4H).
LCMS m/z [M+H]+=496.
EXAMPLE 35
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-pyridin-4-yl-ethyl)-1 H-indol-3-
yl]-methanone dihydrochloride
A. 1-(2-Pyridin-4-yl-ethyl)-1 H-indole
The title compound is prepared according to the procedure by Gill, A. L. et al.
J. Med. Chem., 2005, vol. 48, pp. 414-426 using 4-vinylpyridine and indole as the
starting materials.
1H NMR (300 MHz, CDCI3) 5 8.49-8.47 (m, 2H), 7.66-7.63 (m, 1H), 7.33-7.30 (m, 1H),
7.25-7.1 9 (m, 1H), 7.15-7.10 (m, 1H), 6.97-6.95 (m, 2H), 6.87 (d , 1H), 6.45-6.43 (m,
1H), 4.38 (t, 2H), 3.1 1 (t, 2H).
B. 2,2,2-Trifluoro-1 -[1 -(2-py rid in-4-yl-ethy I)- H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
2G using 1-(2-pyridin-4-yl-ethyl)-1 H-indole as the starting material.
1H NMR (300 MHz, CDCI3) 8.53-8.51 (m, 2H), 8.44-8.40 (m, 1H), 7.64 (m, 1H),
7.41-7.39 (m, 3H), 6.97-6.95 (m, 2H), 4.49 (t, 2H), 3.1 9 (t, 2H).
C. 1-(2-Pyridin-4-yl-ethyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
2H using 2,2,2-trifluoro-1 -[1 -(2-pyridin-4-yl-ethyl)-1 H-indol-3-yl]-ethanone as the
starting material.
1H NMR (300 MHz, DMSO-c/6) 8.78-8.76 (m, 2H), 8.04 (s, 1H), 8.01 -7.98 (m, 1H),
7.87-7.85 (m, 2H), 7.65-7.63 (m, 1H), 7.26-7.1 6 (m, 2H), 4.64 (t, 2H), 3.42 (t, 2H).
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-pyridin-4-yl-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example
6E using 1-(2-pyridin-4-yl-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-(4-
fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting materials.
1H NMR (300 MHz, CDCI3) 8.58 (br d, 2H), 7.72-7.69 (m, H), 7.61 (br s, 1H), 7.34-
7.28 (m, 5H), 7.1 7-7.07 (m, 3H), 7.04-6.98 (m, 1H), 4.54 (t, 2H), 4.49-4.47 (m, 4H),
3.38 (t, 2H), 3.1 9-3.04 (m, 3H), 1.88-1 .84 (m, 2H), 1.68-1 .56 (m, 2H).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-pyridin-4-yl-ethyl)-1 H-indol-
3-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as described in Example
3B using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-py rid in-4-y I-ethyl )- H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.81 (br d, 2H), 8.52 (br s, 3H), 7.92 (d, 2H), 7.70 (s,
1H), 7.68-7.63 (m, 3H), 7.42-7.36 (m, 1H), 7.24-7.13 (m, 3H), 4.66 (t, 2H), 4.31 (br d,
2H), 4.03-3.98 (m, 2H), 3.46 (t, 2H), 3.1 8-3.02 (m, 3H), 1.81 - 1 .77 (m, 2H), 1.72-1 .61
(m, 2H).
EXAMPLE 36
[4-(5-Aminomethyl-2-chloro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
trifluoromethoxy-1 H-indol-2-yl]-methanone hydrochloride
A. (3-Bromo-4-chloro-phenyl)-methanol
To a mixture of 3-bromo-4-chloro-benzoic acid ( 10.0 g, 42.5 mmol) in THF (50
mL) under nitrogen at 0 °C is added 1.0 M solution of borane.THF (55.3 mL, 55.3
mmol). After stirring at ambient temperature overnight the reaction is poured into a
mixture of NaHCO3/H2O/ice and extracted with EtOAc. The organic layer is washed
with saturated aqueous NaCI, dried over MgSO4, filtered and concentrated in vacuo
to provide the desired product (9.4 g, 100%) as a clear, colorless oil.
H NMR (300 MHz, CDCI3) 7.61 (s, 1H), 7.41 (d, J = 5.1 Hz, 1H), 7.21 (d, J = 5.1
Hz, 1H), 4.63 (s, 2H), 2.1 2 (br s, 1H).
B. Methanesulfonic acid 3-bromo-4-chloro-benzyl ester
OI
I
^ll O
O I
To a mixture of 3-bromo-4-chloro-phenyl)-methanol (6.0 g, 27.1 mmol) in THF
(50 mL ) under nitrogen at Oo C is added triethyl amine (3.6 g, 35.3 mmol) followed by
methanesulfonyl chloride (4.0 g, 35.3 mmol). After stirring at ambient temperature for
1h the reaction is poured into a mixture of NaHCO3/H2O/ice and extracted with
EtOAc. The organic layer is washed with saturated aqueous NaCI, dried over
MgSO4, filtered and concentrated in vacuo to provide the desired product (8.0 g,
99%) as a white solid.
H NMR (300 MHz, CDCI3) 7.49 (m, 1H), 7.49 (m, 1H), 7.28 (m, 1H), 5.1 7 (s, 2H),
3.00 (s, 3H).
C. 2-(3-Bromo-4-chloro-benzyl)-isoindole-1 ,3-dione
To a mixture of methanesulfonic acid 3-bromo-4-chloro-benzyl ester (7.5 g,
25.1 mmol) in DMF (60 mL) under nitrogen is added potassium phthalimide (5.6 g,
30.1 mmol). After heating on a steam bath for 2h the reaction is poured into a mixture
of H2O/ice. The white solid is dried in vacuo and recrystallized from CH2Cl2/heptanes
to deliver the desired product (6.1 g, 69%) as a white powder.
H NMR (300 MHz, CDCI3) 7.88 (m, 2H), 7.73 (m, 2H), 7.68 (m, 1H), 7.39 (m, 1H),
7.31 (m, 1H), 4.79 (s, 2H).
D. 4-[2-Chloro-5-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-phenyl]-piperidine-1 -
carboxylic acid tert-butyl ester
The compound is prepared utilizing the procedure described in J. Org. Chem.
2004, 69, 5 120. From 2-(3-bromo-4-chloro-benzyl)-isoindole-1 ,3-dione (3.5 g, 10.0
mmol) is obtained the titled compound (2.9 g, 64%) as an off white foam. 1.1g (31 %)
of the starting material was recovered.
H NMR (300 MHz, CDCI3) 7.95 (m, 2H), 7.72 (m, 2H), 7.24 (m, 3H), 4.79 (s, 2H),
4.23 (m, 2H), 3.1 0 (m, 1H), 2.85 (m, 2H), 1.83 (m, 2H), 1.49 (s, 9H).
MS m/z [M+H]+=455.
E. 2-(4-Chloro-3-piperidin-4-yl-benzyl)-isoindole-1 ,3-dione; hydrochloride
4-[2-Chloro-5-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-phenyl]-piperidine-1 -
carboxylic acid tert-butyl ester ( 1 .00 g, 2.20 mmol) is stirred in methanolic HCI (20
ml_) at 50 °C for 1h. The reaction is cooled to 0 °C. The resulting precipitate is
filtered off and dried to deliver the titled compound (0.77 g, 89.5%) as a white solid
(mp 285-287 °C).
H NMR (300 MHz, DMSO-c/6) 8.75 (m, 1H), 8.44 (m, 1H), 7.91 (m, 4H), 7.43 (m,
1H), 7.29 (m, 1H), 7.20 (m, 1H), 4.77 (s, 2H), 3.40-2.90 (m, 5H), 1.97-1 .72 (m, 4H).
LCMS m/z [M+H]+=355.
F. 2-(4-Chloro-3-{1 -[1 -(2-methoxy-ethyl)-7-trifluoronnethoxy-1 H-indole-2-carbonyl]-
piperidin-4-yl}-benzyl)-isoindole-1 ,3-dione
To a mixture of 1-(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-2-carboxylic
acid (0.25 g, 0.82 mmol) in THF (5 ml_) under nitrogen is added 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.1 7 g, 0.91 mmol)
followed by triethylamine (0.32 g, 3.2 mmol) and DMF (3 ml_). After stirring h at
ambient temperature, 2-(4-chloro-3-piperidin-4-yl-benzyl)-isoindole-1 ,3-dione
hydrochloride (0.35 g, 0.91 mmol) is added and the reaction is stirred overnight. The
reaction is quenched with aqueous 10% HCI solution and extracted with EtOAc. The
combined organic layers are washed with aqueous saturated NaHCO3 solution, dried
over MgSO4, filtered and concentrated in vacuo. The crude material is purified on
silica gel with 50% EtOAc /heptanes as eluent to deliver the titled compound (0.2 g,
34%) as a white foam.
H NMR (300 MHz, CDCI3) 7.86 (m, 2H), 7.73 (m, 2 H), 7.25 (m, 7H), 4.80 (s, 2H),
4.57 (m, 2H), 4.45 (m, 2H), 3.75 (m, 2H), 3.32 (s, 3H), 3.25 (m, 1H), 3.05 (m, 2H),
1.93 (m, 2H), 1.68 (m, 2H).
MS m/z: [M+H]+=641 .
G. [4-(5-Aminomethyl-2-chloro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
trifluoromethoxy-1 H-indol-2-yl]-methanone hydrochloride
To a solution of 2-(4-chloro-3-{1 -[1 -(2-methoxy-ethyl)-7-trifluoronnethoxy-1 Hindole-
2-carbonyl]-piperidin-4-yl}-benzyl)-isoindole-1 ,3-dione (0.46g, 0.72 mmol) in
THF (8 ml_) is added hydrazine (0.51 g, 15.9 mmol) and the reaction heated to reflux.
After 2h the reaction was concentrated in vacuo to deliver a slurry which was
triturated with EtOAc. The organic layer is treated with methanolic HCI and
concentrated in vacuo. Recrystallization from EtOAc/MeOH delivers the titled
compound (0.35 g, 89%) as an off-white solid.
H NMR (300 MHz, DMSO-c/6) 8.21 (br s, 3H), 7.80 (m, 1H), 7.74 (m, 1H), 7.59 (m,
1H), 7.49 (m, 1H), 7.31 (m, 1H), 7.21 (m, 1H), 4.49 (m, 4H), 4.03 (m, 2H), 3.68 (m,
2H), 3.40-3.30 (m, 6H), 2.0-1 .6 (m, 4H).
MS m/z [M+H]+=51 0.
EXAMPLE 37
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-diethylamino-ethyl)-1 H-indol-
3-yl]-methanone dihydrochloride
A. Diethyl-(2-indol-1 -yl-ethyl)-amine
The title compound is prepared in a similar manner as described in Example
1E using 1H-indole and (2-bromo-ethyl)-diethyl-amine hydrobromide as the starting
materials.
H NMR (300 MHz, CDCI3) 7.6 (d, 1H), 7.4 (d, 1H), 7.3-7.0 (m, 3H), 6.5 (d, 1H), 4.2
(t, 2H), 2.8 (t, 2H), 2.6 (m, 4H), 1.0 (m, 6H).
MS m/z [M+H]+=21 7.
B. 1-[1 -(2-Diethylamino-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone
The title compound is prepared in a similar manner as described in Example
1F using diethyl-(2-indol-1 -yl-ethyl)-amine as the starting material.
H NMR (300 MHz, CDCI3) 8.4 (d, H), 8.1 (s, 1H), 7.5 (m, 3H), 4.8 (t, 2H), 3 . 5 (t,
2H), 3.2 (m, 4H), 1.5 (m, 6H).
MS m/z [M+H]+=313.
C. 1-(2-Diethylamino-ethy -1H-indole-3-carboxylic acid hydrochloride
The title compound is prepared in a similar manner as described in Example
2H using 1-[1 -(2-diethylamino-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone as the
starting material.
H NMR (300 MHz, DMSO-c/6) 12.0 (s, 1H), 10.6 (bs, 1H), 8.2 (s, 1H), 8.0 (d, 1H),
7.75 (d, 1H), 7.3 (m, 2H), 4.7 (t, 2H), 3.5 (t, 2H), 3.2 (m, 4H), 1.2 (m, 6H).
MS m/z: [M+H]+=261 .
D. N-(3-{1 -[1 -(2-Diethylamino-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-fluorobenzyl
)-2 ,2,2-trif Iuoro-aceta mide trif Iuorocetate
The title compound is prepared in a similar manner as described in Example 2 1
using 1-(2-diethylamino-ethyl)-1 H-indole-3-carboxylic acid hydrochloride and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting
materials and is purified by RP-HPLC.
H NMR (300 MHz, CDCI3) 7.8 (d, 1H), 7.7 (s, 1H), 7.4 (m, 2H), 7.2 (m, 2H), 7.0 (m,
3H), 4.8 (t, 2H), 4.6 (m, 2H), 4.5 (m, 2H), 3.4 (t, 2H), 3.1 (m, 7H), 1.9-1 .8 (m, 4H), 1.3
(m, 6H).
LCMS m/z [M+H]+=547.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-diethylamino-ethyl)-1 Hindol-
3-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as described in Example
1K using N-(3-{1 -[1 -(2-diethylamino-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-
fluoro-benzyl)-2,2,2-trifluoro-acetamide trifluorocetate as the starting material.
H NMR (300 MHz, DMSO-c/6) 10.5 (bs, 1H), 8.3 (bs, 2H), 8.0 (s, 1H), 7.7 (m, 2H),
7.6 (d, 1H), 7.4-7.1 (m, 4H), 4.7 (t, 2H), 4.4 (m, 2H), 4.0 (m, 2H), 3.5 (m, 2H), 3.2 (m,
7H), 1.9-1 .6 (m, 4H), 1.2 (m, 6H).
MS m/z [M+H]+=451 .
EXAMPLE 38
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indol-
3-yl]-methanone dihydrochloride
A. 1-(2-Pyrrolidin-1 -yl-ethyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 1H-indole and 1-(2-Chloro-ethyl)-pyrrolidine hydrochloride as the starting
materials.
H NMR (300 MHz, CD3OD) 7.7 (d, 1H), 7.4 (d, 1H), 7.3-7.1 (m, 3H), 6.5 (d, 1H),
4.3 (t, 2H), 2.9 (t, 2H), 2.6 (m, 4H), 1.8 (m, 4H).
MS m/z [M+H]+=21 5.
B. 2,2,2-Trifluoro-1 -[1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
1F using 1-(2-pyrrolidin-1 -yl-ethyl)-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 8.4 (d, 1H), 8.1 (s, 1H), 7.4 (m, 3H), 4.8 (t, 2H), 3.8 (bs,
H), 3.5 (t, 2H), 2.7 (bs, 1H), 2.1 (bs, 4H), 1.6 (bs, 2H).
MS m/z: [M+H]+=31 1.
-Pyrrolidin-1 -yl-ethyl)-1 H-indole-3-carboxylic acid hydrochloride
The title compound is prepared in a similar manner as described in Example
2H using 2,2,2-trifluoro-1 -[1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indol-3-yl]-ethanone as the
starting material.
H NMR (300 MHz, DMSO-c/6) 12.1 (s, 1H), 10.8 (bs, 1H), 8.2 (s, 1H), 8.1 (d, 1H),
7.75 (d, 1H), 7.3 (m, 2H), 4.7 (t, 2H), 3.6 (t, 2H), 3.5 (m, 2H), 3.0 (m, 2H), 1.9 (m, 2H),
1.8 (m, 2H).
MS m/z [M+H]+=259.
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-acetamide trifluorocetate
The title compound is prepared in a similar manner as described in Example 2 I
using 1-(2-pyrrolidin-1-yl-ethyl)-1 H-indole-3-carboxylic acid hydrochloride and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting
materials and is purified by RP-HPLC.
H NMR (300 MHz, CDCI3) 7.8 (d, 1H), 7.6 (s, 1H), 7.4-7.1 (m, 6H), 7.0 (m, 1H), 4.8
(t, 2H), 4.6 (m, 2H), 4.4 (m, 2H), 3.7 (m, 2 H), 3.6 (m, 2H), 3.2 (m, 3H), 2.6 (m, 3H),
2.4 (m, 3h), 1.9 (m, 2H), 1.8 (m, 2H).
MS m/z: [M+H]+=545.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-pyrrolidin-1 -yl-ethyl)-1 Hindol-
3-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-(4-fluoro-3-{1-[1 -(2-pyrrolidin-1 -yl-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide trifluorocetate as the starting material.
H NMR (300 MHz, DMSO-c/6) 11.0 (bs, 1H), 8.4 (bs, 2H), 7.9 (s, H), 7.8 (m, 2H),
7.6 (d, 1H), 7.4-7.2 (m, 4H), 4.7 (t, 2H), 4.5 (d, 2H), 4.0 (t, 2H), 3.6 (t, 2H), 3.2 (m,
3H), 2.9 (m, 3H), 2.0-1 .6 (m, 9H).
MS m/z [M+H]+=449.
EXAMPLE 39
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-fluoro-1 -(2-methoxy-ethyl)-1 Hindol-
3-yl]-methanone hydrochloride.
A. 7-Fluoro-1 -(2-methoxy-ethyl)-1 H-indole
The title product ( 1 .43 g, 100%) is obtained in a similar manner as described in
Example 1E using 7-fluoro-1 H-indole ( 1 .00 g, 7.4 mmol) as the starting material. H
NMR (300 MHz, CDCI3) 7.36 (d, J = 8.1 Hz, 1H), 7.1 1 (d, J = 3 Hz, 1H), 7.00-6.95
(m, 1H), 6.86 (dd, 1H), 6.48 (m, 1H), 4.45 (t, J = 5.7 Hz, 2H), 3.73 (t, J = 5.7 Hz, 2H),
3.30 (s, 3H);
9F NMR (300 MHz, CDCI3) - 135.93 (d, 3F).
B. 2,2,2-Trifluoro-1 -[7-fluoro-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-ethanone
The title product ( 1 .76 g, 82%) is obtained in a similar manner as described in
Example 1F using 7-fluoro-1-(2-methoxy-ethyl)-1 H-indole ( 1 .43 g, 7.4 mmol) as the
starting material.
H NMR (300 MHz, CDCI3) 8.00 (d, 1H), 7.96 (s, 1H), 7.30-7.25 (m, 1H), 7.05 (dd,
1H), 4.53 (t, J = 5.1 Hz, 2H), 3.77 (t, J = 5.1 Hz, 2H), 3.32 (s, 3H);
9F NMR (300 MHz, CDCI3) -72.25 (s, 3F), - 134.23 (s, 1F).
C. 7-Fluoro-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid.
The title product ( 1 .44 g, 100%) is obtained in a similar manner as described in
Example 1G using 2,2,2-trifluoro-1 -[7-fluoro-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-
ethanone ( 1 .76 g, 6.1 mmol) as the starting material.
H NMR (300 MHz, DMSO-c/6) 12.1 7 (s, 1H), 8.04 (s, 1H), 7.83 (d, J = 7.5 Hz, 1H),
7.1 8-7.1 1 (m, 1H), 7.08-7.01 (m, 1H), 4.50 (t, J = 5.1 Hz, 2H), 3.69 (t, J = 5.1 Hz, 2H),
3.22 (s, 3H);
9F NMR (300 MHz, DMSO-c/6) - 134.07 (d, 1F).
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[7-fluoro-1 -(2-methoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide.
The title product ( 1 .51 g, 85%) is obtained in a similar manner as described in
Example 1J using 7-fluoro-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid (0.81 g,
3.4 mmol) as the starting material.
H NMR (300 MHz, CDCI3) 7.57 (d, 1H), 7.45 (s, 1H), 7.20-7.00 (m, 4H), 6.98-6.8
(dd, 1H), 6.70 (br s, 1H), 4.6 (br d, 1H), 4.50-4.60 (m, 4H), 3.74 (t, 2H), 3.31 (s, 3H),
3.20-3.00 (m, 4H), 1.95-1 .90 (m, 2H), 1.80-1 .70 (m, 2H);
9F NMR (300 MHz, CDCI3) -74.57 (s, 3F), - 1 19.1 1 (s, 1F), - 135.1 0 (s, 1F).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-fluoro-1 -(2-methoxy-ethyl)-
1H-indol-3-yl]-methanone hydrochloride.
The title product (0.81 g, 60%) is obtained in a similar manner as described in
Example 1K using 2,2,2-trifluoro-N-(4-fluoro-3-{1-[7-fluoro-1 -(2-methoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide ( 1 .51 g, 2.9 mmol) as the starting
material.
H NMR (300 MHz, DMSO-c/6) 8.27 (br s, 2H), 7.75 (s, 1H), 7.57-55 (m, 1H), 7.52
(d, J = 7.5 Hz, 1H), 7.36 (m, 1H), 7.23 (dd, J = 8.7, 10.5 Hz, 1H), 7.1 1-7.01 (m, 2H),
4.50 (m, 2H), 4.40 (br d, 1H), 4.00 (t, 2H), 3.70 (t, 2H), 3.22 (s, 3H), 3.1 7-3.09 (m,
4H), 1.82-1 .79 (m, 2H), 1.70-1 .60 (m, 2H);
9F NMR (300 MHz, DMSO-c/6) - 119.89 (s, 1F), - 134.37 (s, 1F)
LC 2.34 min; MS 428 (M+1 , 100%).
EXAMPLE 40
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-pyridin-2-yl-ethyl)-1 H-indol-3-
yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as described in Example
1E using 1H-lndole and 2-(2-bromo-ethyl)-pyridine hydrobromide as the starting
materials.
H NMR (300 MHz, CDCI3) 8.6 (d, H), 7.6 (d, H), 7.5 (m, H), 7.4 (d, H), 7.2 (m,
3H), 7.0 (d, H), 6.9 (d, H), 6.4 (d, H), 4.6 (t, 2H), 3.3 (t, 2H).
MS m/z [M+H]+=223.
B. 2,2,2-Trifluoro-1 -[1 -(2-pyridin-2-yl-ethyl)-1 H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
1F using 1-(2-pyridin-2-yl-ethyl)-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 8.8 (bs, H), 8.4 (d, 1H), 7.9 (m, H), 7.7 (s, H), 7.6-
7.2 (m, 4H), 7.0 (m, H), 4.8 (t, 2H), 3.6 (t, 2H).
MS m/z [M+H]+=31 9.
C. 1-(2-Pyridin-2-yl-ethyl)-1 H-indole-3-carboxylic acid hydrochloride
The title compound is prepared in a similar manner as described in Example
4C using 2,2,2-trifluoro-1 -[1 -(2-pyridin-2-yl-ethyl)-1 H-indol-3-yl]-ethanone as the
starting material.
H NMR (300 MHz, DMSO-c/6) 8.6 (d, H), 8.0 (m, 3H), 7.6 (d, 4H), 7.5 (m, 2H), 4.7
(t, 2H), 3.4 (t, 2H).
MS m/z: [M+H]+=267.
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-pyrid in-2-yI-ethyl )- H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as in Example 2 1 using 1-
(2-pyridin-2-yl-ethyl)-1 H-indole-3-carboxylic acid hydrochloride and 2,2,2-trifluoro-N-
(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting materials.
H NMR (300 MHz, CDCI3) 8.6 (d, H), 7.8 (d, H), 7.5 (m, H), 7.4 (d, H), 7.2 (m,
6H), 7.0 (m, 1H), 6.9 (d, 1H), 6.6 (bs, H), 4.6 (t, 2H), 4.5 (m, 4H), 3.3 (t, 2H), 3.1 (m,
3H), 1.9 (m, 2H), 1.8 (m, 2H).
MS m/z [M+H]+=553.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-pyridin-2-yl-ethyl)-1 H-indol-
3-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-pyridin-2-yl-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.7 (d, 1H), 8.4 (bs, 2H), 8.2 (m, 1H), 7.6 (m, 1H),
7.4 (m, H), 7.2 (m, 3H), 4.7 (t, 2H), 4.4 (m, 2H), 4.0 (m, 2H), 3.4 (t, 2H), 3.1 (m, 3H),
1.8 (m, 2H), 1.6 (m, 2H).
MS m/ z [M+H]+=449.
EXAMPLE 4 1
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-piperidin-1 -yl-ethyl)-1 H-indol-
3-yl]-methanone dihydrochloride
A. 1-(2-Piperidin-1 -yl-ethyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 1H-indole and 1-(2-chloro-ethyl)-piperidine hydrochloride as the starting
materials.
H NMR (300 MHz, CDCI3) 7.6 (d, H), 7.4 (d, H), 7.2 (m, 4H), 6.5 (d, H), 4.3 (t,
2H), 2.7 (t, 2H), 2.4 (m, 4H), .6 (m, 3H), .4 (m, 2H).
MS m/z [M+H]+=229.
B. 2,2,2-Trifluoro-1 -[1 -(2-pi indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
1F using 1-(2-piperidin-l -yl-ethyl)-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 8.4 (d, H), 8.0 (m, H), 7.4 (m, 3H), 4.8 (t, 2H), 3.6 (m,
2H), 3.4 (t, 2H), 2.6 (m, 2H), .9 (m, 6H).
MS m/z: [M+H]+=325.
C. 1-(2-Piperidin-1 -yl-ethyl)-1 H-indole-3-carboxylic acid hydrochloride
The title compound is prepared in a similar manner as described in Example
2H using 2,2,2-trifluoro-1 -[1 -(2-piperidin-1 -yl-ethyl)-1 H-indol-3-yl]-ethanone as the
starting material.
H NMR (300 MHz, DMSO-c/6) 2.0 (bs, H), 1 .0 (bs, 1H), 8.2 (s, 1H), 8.0 (d, 1H),
7.8 (d, 1H), 7.3 (m, 2H), 4.8 (t, 2H), 3.5 (m, 4H), 3.0 (m, 2H), 1.7 (m, 5H), 1.4 (m,
1H).
LCMS m/z [M+H]+=273.
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-piperidin-1 -yl-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-acetamide trifluorocetate
The title compound is prepared in a similar manner as described in Example 2 I
using 1-(2-piperidin-1 -yl-ethyl)-1 H-indole-3-carboxylic acid hydrochloride and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting
materials and is purified by RP-HPLC.
H NMR (300 MHz, CDCI3) 7.8 (d, 1H), 7.6 (s, 1H), 7.4-7.1 (m, 5H), 7.0 -6.8 (m,
2H), 4.8 (t, 2H), 4.6 (m, 2H), 4.4 (d, 2H), 3.5 (m, 2 H), 3.4 (t, 2H), 3.1 (m, 3H), 2.6 (m,
2H), 2.0-1 .6 (m, 9H), 1.4 (m, 1H).
MS m/z: [M+H]+=559.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-piperidin-1 -yl-ethyl)-1 Hindol-
3-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as described Example 1K
using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-piperidin-1 -yl-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-acetamide trifluorocetate as the starting material.
H NMR (300 MHz, DMSO-c/6) 11.0 (bs, 1H), 8.4 (bs, 2H), 7.9 (s, 1H), 7.8 (d, 2H),
7.6 (d, 1H), 7.4 (m, 1H), 7.2 (m, 3H), 4.8 (t, 2H), 4.5 (m, 2H), 4.0 (m, 4H), 3.4 (m, 3H),
3.2 (m, 3H), 2.9 (m, 2H), 2.0-1 .6 (m, 8H) 1.4 (m, H).
MS m/z [M+H]+=463.
EXAMPLE 42
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-chloro-1-(2-methoxy-ethyl)-
H-indol-3-yl]-methanone
A. 4-Chloro-1 -(2-methoxy-ethyl)-1 H-indole
To a 0 °C solution of 4-chloroindole (2.0 g, 13.2 mmol) in DMF (40 mL) under
nitrogen is added sodium hydride (0.5 g, 19.8 mmol, 60% suspension in oil). After
stirring for 10 min at 0 °C, 1-bromo-2-methoxy-ethane (2.7 g, 19.8 mmol) is added
followed by a catalytic amount of Nal. After stirring an additional 2h at 0 °C the
reaction is quenched with aqueous sat NaHCO3 solution and extracted with EtOAc.
The combined organic layers are dried over MgSO4, filtered and concentrated in
vacuo. The crude material is purified on silica gel with 30% EtOAc /heptane as eluent
to deliver the titled compound (2.8 g, 100%) as an orange oil.
H NMR (300 MHz, CDCI3) 7.25 (m, 2H), 7.1 1 (m, 2H), 6.63 (m, 1H), 4.29 (t, J = 5.3
Hz, 2H), 3.70 (t, J = 5.3 Hz, 2H), 3.32 (s, 3H).
B. 1-[4-Chloro-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone
To a 0 °C solution of 4-chloro-1 -(2-methoxy-ethyl)-1 H-indole (2.8 g, 13.2
mmol) in DMF (20 mL) under nitrogen is added trifluoracetic anhydride ( 1 1.1 g, 52.8
mmol). The reaction is allowed to warm to r.t. over 9 h. At 0 °C the reaction is
quenched with aqueous sat NaHCO3 solution and extracted with EtOAc. The
combined organic layers are dried over MgSO4, filtered and concentrated in vacuo to
deliver the titled compound (3.2 g, 79%) as white needles (recrystallized from
EtOAc/heptane). mp 57-59 °C.
H NMR (300 MHz, CDCI3) 8.06 (m, H), 7.30 (m, 3H), 4.36 (t, J = 4.9 Hz, 2H), 3.74
(t, J = 4.9 Hz, 2H), 3.33 (s, 3H);
MS 306 (M+1 ) .
C. 4-Chloro-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
To a solution of 1-[4-chloro-1-(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoroethanone
(2.0 g, 6.54 mmol) in EtOH/H2O (40 mL/20 mL) is added KOH (3.7 g, 65.4
mmol) and the reaction is heated on a steam bath for 30 min. The resulting clear
solution is concentrated in vacuo, cooled to 0 °C, acidified with 10% aqueous HCI and
extracted with EtOAc. The organic layer is dried over MgSO4, filtered and
concentrated in vacuo. The resulting solid is recrystallized from CH2Cl2/heptane to
deliver the desired product ( 1 .51 g, 9 1%) as a light orange solid: mp 142-145 °C.
H NMR (300 MHz, CDCI3) 8.06 (m, 1H), 7.30 (m, 3H), 4.31 (t, J = 4.9 Hz, 2H), 3.73
(t, J = 4.9 Hz, 2H), 3.32 (s, 3H);
MS 254 (M+1 ) .
D. N-(3-{1 -[4-Chloro-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-
fluoro-benzyl)-2,2,2-trifluoro-acetamide
To a mixture of 4-chloro-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid (0.25
g, 1.0 mmol) in THF (6 mL) under nitrogen is added carbonyl diimidazole (0.1 9 g, 1.2
mmol). After heating to boil and then stirring 1h at ambient temperature 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide (0.33 g, 1.1 mmol) is added
and the reaction is heated to reflux overnight. The reaction is quenched with 10%
aqueous HCI and extracted with EtOAc. The combined organic layers are washed
with aqueous saturated NaHCO3 solution, dried over MgSO4, filtered and
concentrated in vacuo to deliver the titled compound (0.41 g, 76%) as a white foam.
H NMR (300 MHz, CDCI3) 7.2-7.0 (m, 7H), 6.6 (br s, 1H), 5.0 (m, 1H), 4.5 (m, 2H),
4.3 (t, J = 5.3 Hz, 2H), 3.8 (m, 1H), 3.7 (t, J = 5.3 Hz, 2H) 3.3 (s, 3H), 3.1 (m, 2H), 2.9
(m, 1H), 1.9-1 .6 (m, 4H);
MS 540 (M+1 ) .
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-chloro-1 -(2-methoxy-ethyl)-
1H-indol-3-yl]-methanone
To a solution of N-(3-{1 -[4-chloro-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (0.40 g, 0.74 mmol) in MeOH
(6 ml_) and H2O (2 ml_) is added aqueous 50% NaOH solution ( 1 .0 ml_). After stirring
at ambient temperature overnight the mixture is concentrated in vacuo. To the
resulting material is added aqueous sat NaHCO 3 solution and the mixture extracted
with EtOAc. The combined organic layers are dried over MgSO4, filtered and
concentrated in vacuo diluted with MeOH and adsorbed onto silica gel. This material
is purified on silica gel using 5% MeOH/ CH2CI2 as the eluent. Concentration of
appropriate fractions delivers the titled compound (0.19 g, 58%) as a white foam.
H NMR (300 MHz, CDCI3) 7.34 (m, 2H), 7.1 9 (m, 5H), 6.98 (m, 1H), 5.01 (m, 1H),
4.28 (t, J = 5.3 Hz, 2H), 3.84 (m, 2H), 3.71 (t, J = 5.3 Hz, 2H), 3.32 (s, 3H), 3.1 1 (m,
3H), 2.90 (m, 1H), 1.94-1 .52 (m, 5H);
MS 444 (M+1 ) .
EXAMPLE 43
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-(1 -butyl-7-trifluoromethoxy-1 Hindol-
3-yl)-methanone hydrochloride
A. 1-Butyl-7-trifluoromethoxy-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 7-trifluoromethoxyindole and 1-bromobutane as the starting materials.
H NMR (300 MHz, CDCI3) 7.53-7.50 (dd, 1 H), 7.1 0-7.00 (m, 3 H), 6.50 (d, 1H),
4.28 (t, 2H), 1.80 (quin, 2H), 1.35 (sext, 2H), 0.95 (t, 3H).
B. 1-(1 -Butyl-7-trifluoromethoxy-1 H-indol-3-yl)-2,2,2-trifluoro-ethanone
The title compound is prepared in a similar manner as described in Example
2G using 1-butyl-7-trifluoromethoxy-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 8.35 (d, H), 7.90 (m, H), 7.36-7.31 (m, 1H), 7.24 (br s,
1H), 4.37 (t, 2H), 1.89 (quin, 2H), 1.40 (sext, 2H), 0.98 (t, 3H).
C. 1-Butyl-7-trifluoromethoxy-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
2H using 1-(1 -butyl-7-trifluoromethoxy-1 H-indol-3-yl)-2,2,2-trifluoro-ethanone as the
starting material.
H NMR (300 MHz, DMSO-c/6) 8.22-8.1 8 (m, 1H), 7.94 (s, 1H), 7.1 8-7.1 1 (m, 2H),
4.28 (t, 2H), 1.72 (quin, 2H), 1.25 (sext, 2H), 0.87 (t, 3H).
D. N-{3-[1 -(1 -Butyl-7-tnfluoromethoxy-l H-indole-3-carbonyl)-piperidin-4-yl]-4-fluorobenzyl}-
2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example
6E using 1-butyl-7-trifluoromethoxy-1 H-indole-3-carboxylic acid and 2,2,2-tnfluoro-N(
4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting materials.
H NMR (300 MHz, CD3OD) 7.69-7.65 (m, 2H), 7.30-7.27 (m, 1H), 7.20-7.1 5 (m,
3H), 7.07-7.01 (m, 1H), 4.52 (br s, 2H), 4.41 -4.34 (m, 4H), 3.20 (br s, 4H), 1.91 - 1 .72
(m, 6H), 1.35 (sext, 2H), 0.95 (t, 3H).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-(1 -butyl-7-trifluoromethoxy-1 Hindol-
3-yl)-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-{3-[1 -(1 -butyl-7-trifluoromethoxy-1 H-indole-3-carbonyl)-piperidin-4-yl]-4-
fluoro-benzyl}-2,2,2-trifluoro-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.57 (br s, 3H), 7.91 (s, 1H), 7.76-7.70 (m, 1H),
7.67-7.64 (m, 1H), 7.43-7.38 (m, 1H), 7.24-7.1 7 (m, 3H), 4.41 (br d, 2H), 4.33 (t, 2H),
4.02-3.96 (m, 2H), 3.20-3.07 (m, 3H), 1.83-1 .66 (m, 6H), 1.28 (sext, 2H), 0.90 (t, 3H).
EXAMPLE 44
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-methyl-1 Hindol-
3-yl]-methanone hydrochloride
A. 1-(2-Methoxy-ethyl)-4-methyl-1 H-indole
The title compound is prepared in a similar manner as described in Example
E using 4-methylindole as the starting material.
H NMR (300 MHz, CDCI3) 7.2 (m, 3H), 6.9 (m, H), 6.5 (d, H), 4.3 (t, 2H), 3.7 (t,
H), 3.3 (s, 3H), 2.6 (s, 3H).
S m/z [M+H]+= 90.
B. 2,2,2-Trifluoro-1 -[1 -(2-methoxy-ethyl)-4-methyl-1 H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
F using 1-(2-methoxy-ethyl)-4-methyl-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 8.0 (s, H), 7.3 (m, 2H), 7.1 (m, 1H), 4.4 (t, 2H), 3.8 (t,
H), 3.4 (s, 3H), 2.8 (s, 3H).
S m/z: [M+H]+=234.
C. 1-(2-Methoxy-ethyl)-4-methyl-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using 2,2,2-trifluoro-1-[1 -(2-methoxy-ethyl)-4-methyl-1 H-indol-3-yl]-ethanone as
the starting material.
H NMR (300 MHz, DMSO-c/6) 11.7 (bs, 1H), 8.0 (s, 1H), 7.4 (d, 1H), 7.2 (m, 1H),
6.9 (m, 1H), 4.4 (t, 2H), 3.8 (t, 2H), 3.2 (s, 3H), 2.8 (s, 3H).
MS m/z [M+H]+=234.
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 1-(2-methoxy-ethyl)-4-methyl-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-
(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting materials.
H NMR (300 MHz, CDCI3) 7.3-7.1 (m, 5H), 7.0 (m, 2H), 6.8 (bs, 1H), 4.5 (m, 2H),
4.3 (m, 2H), 3.7 (m, 2H), 3.3 (s, 3H), 2.6 (s, 3H), 1.9-1 .6 (m, 6H).
MS m/z: [M+H]+=520.
E [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-methyl-
1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.4 (bs, 2H), 7.5 (m, 2H), 7.4 (m, 2H), 7.2 (m, 1H),
7.1 (m, 1H), 6.9 (m, 1H), 4.4 (t, 2H), 4.0 (m, 2H), 3.7 (t, 2H), 3.6 (m, 2H), 3.2 (s, 3H),
3.1 (m, 3H), 2.4 (s, 3H), 1.8 (m, 2H), 1.6 (m, 2H).
MS m/z [M+H]+=424.
EXAMPLE 45
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2,2-difluoro-2-phenyl-ethyl)-1 Hindol-
3-yl]-methanone hydrochloride
A. 1-(2-Oxo-2-phenyl-ethyl)-1 H-indole-3-carboxylic acid methyl ester
A mixture of 1H-indole-3-carboxylic acid methyl ester (2.00 g, 11.43 mmol), 2-
bromo-1 -phenyl-ethanone (2.27 g, 11.43mmol) and K2CO3 (3.1 5 g, 22.86 mmol) in
acetonitrile (70 mL) is heated to reflux overnight. The reaction mixture is poured into
ice/water and the resulting precipitate is collected. The crude product is triterated
with CH2CI2 to yield the titled compound ( 1 .25 g, 37%).
H NMR (300 MHz, CDCI3) 8.2 (m, 1H), 8.0 (m, 2H), 7.8 (m, 1H), 7.7 (m, 1H), 7.5
(m, 2H), 7.2 (m, 3H), 5.6 (s, 2H), 3.9 (s, 3H).
MS m/z [M+H]+=294.
B. 1-(2,2-Difluoro-2-phenyl- arboxylic acid methyl ester
A solution of 1-(2-oxo-2-phenyl-ethyl)-1 H-indole-3-carboxylic acid methyl ester
(0.7 g, 2.4 mmol) and diethylaminosulfur trifluoride (0.8 g, 4.8 mmol) in benzene ( 15
mL) is heated at 65 °C overnight. The reaction mixture is poured into EtOAc and the
organic layer washed with H2O (2x) and brine, dried with MgSO4, filtered and
concentrated in vacuo to give the crude product. Purification by flash
chromatography on S1O2 eluting with 10% ethyl acetate/heptane gives 0.2 g, (26%) of
the title compound.
H NMR (300 MHz, CDCI3) 8.2 (m, 1H), 7.7 (m, 1H), 7.4-7.25 (m, 8H), 4.7 (m, 2H),
3.9 (s, 3H).
MS m/z [M+H]+=31 6.
C. 1-(2,2-Difluoro-2-phenyl-ethyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
5D using 1-(2,2-difluoro-2-phenyl-ethyl)-1 H-indole-3-carboxylic acid methyl ester as
the starting material.
H NMR (300 MHz, DMSO-c/6) 12.1 (bs, 1H), 8.0 (m, 2H), 7.5 (m, 6H), 7.2 (m, 2H),
5.1 (t, 2H).
MS m/z: [M+H]+=302.
D. N-(3-{1 -[1 -(2,2-Difluoro-2-phenyl-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-
fluoro-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example 2 1
using 1-(2,2-difluoro-2-phenyl-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-
(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting materials.
H NMR (300 MHz, CDCI3) 7.7 (m, 1H), 7.4-7.2 (m, H), 7.1 (m, 1H), 6.6 (bs, H),
4.6 (m, 2H), 4.5 (m, 4H), 3.1 (m, 3H), 1.9 (m, 2H), 1.7 (m, 2H).
MS m/z [M+H]+=588.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2,2-difluoro-2-phenyl-ethyl)-
1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described Example 1K
using N-(3-{1 -[1 -(2,2-difluoro-2-phenyl-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-
fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.5 (bs, 2H), 7.8- 7.0 (m, 13H), 5.2 (m, 2H), 4.4 (m,
2H), 4.0 (m, 2H), 3.2 (m, 3H), 1.9-1 .6 (m, 4H).
LCMS m/z: [M+H]+=492.
EXAMPLE 46
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-(1 -butyl-4-methoxy-1 H-indol-3-yl)-
methanone hydrochloride
Butyl-4-methoxy-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 4-methoxyindole and 1-bromo-butane as the starting materials.
1H NMR (300 MHz, CDCI3) 7.1 (m, 1H), 7.0 (m, 2H), 6.6 (d, H), 6.5 (d, 1H), 4.1 (t,
2H), 4.0 (s, 3H), 1.8 (m, 2H), 1.5 (m, 2H), 0.9 (m, 3H).
MS m/z [M+H]+=204.
B. 1-(1 -Butyl-4-methoxy-1 H-indol-3-yl)-2,2,2-trifluoro-ethanone
The title compound is prepared in a similar manner as described in Example
1F using 1-butyl-4-methoxy-1 H-indole as the starting material.
1H NMR (300 MHz, CDCI3) 7.8 (d, H), 7.3 (m, H), 7.0 (d, H), 6.8 (d, H), 4.2 (t,
2H), 4.0 (s, 3H), .9 (m, 2H), .4 (m, 2H), .0 (m, 3H).
MS m/z [M+H]+=300.
C. 1-Butyl-4-methoxy-1 H-indole-3-carboxylic acid
1-(1 -Butyl-4-methoxy-1 H-indol-3-yl)-2,2,2-trifluoro-ethanone (2.6 g, 8.7 mmol)
in 6 N NaOH (35 mL) is heated to reflux until no starting material is present. The
reaction mixture is cooled to room temperature, diluted with H2O (100 mL) and
acidified to pH = 2 with concentrated HCI. The reaction mixture is extracted with
EtOAc (2x) and the organic layers are combined and dried over Na2SO4, filtered and
concentrated in vacuo to yield the title compound (2.0 g, 93%).
1H NMR (300 MHz, DMSO-c/6) 11.6 (s, 1H), 8.0 (s, 1H), 7.2 (d, 1H), 6.8 (m, 1H), 4.2
(t, 2H), 4.0 (s, 3H), 1.8 (m, 2H), 1.3 (m, 2H), 0.8 (m, 3H).
LCMS m/z: [M+H]+=248.
D. N-{3-[1 -(1 -Butyl-4-methoxy-1 H-indole-3-carbonyl)-piperidin-4-yl]-4-fluoro-benzyl}-
2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example 2 1
using 1-butyl-4-methoxy-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-(4-fluoro-3-
piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting materials.
1H NMR (300 MHz, CDCI3) 7.2 (m, 4H), 7.0 (m, 2H), 6.7 (bs, 1H), 6.5 (d, 1H), 4.5
(m, 2H), 4.2 (m, 4H), 3.9 (s, 3H), 3.1-2.8 (m, 3H), 1.9-1 .8 (m, 6H), 1.4 (m, 2H), 0.9
(m, 3H).
MS m/z [M+H]*=534.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-(1 -butyl-4-methoxy-1 H-indol-3-
l)-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using N-{3-[1 -(1 -butyl-4-methoxy-1 H-indole-3-carbonyl)-piperidin-4-yl]-4-fluorobenzyl}-
2,2,2-trifluoro-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.4 (bs, 2H), 7.6 (m, 1H), 7.4 (m, 2H), 7.2 (m, 1H),
7.1 (m, 2H), 6.6 (m, 1H), 4.2 (m, 2H), 4.0 (m, 2H), 3.8 (s, 3H), 3.5 (m, 2H), 3.1 -2.8
(m, 3H), 1.9-1 .6 (m, 6H), 1.2 (m, 2H), 0.9 (m, 3H).
MS m/z: [M+H]+=438.
EXAMPLE 47
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[4-methoxy-1 -(2-methoxy-ethyl)-
1H-indol-3-yl]-methanone hydrochloride
A. 4-Methoxy-1 -(2-methoxy-ethyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 4-methoxyindole as the starting material.
1H NMR (300 MHz, CDCI3) 7.2-7.1 (m, 2H), 7.0 (d, 1H), 6.6 (d, 1H), 6.5 (d, 1H), 4.3
(t, 2H), 4.0 (s, 3H), 3.7 (t, 2H), 3.3 (s, 3H).
MS m/z [M+H]+=206.
B. 2,2,2-Trifluoro-1 -[4-methoxy-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
1F using 4-methoxy-1 -(2-methoxy-ethyl)-1 H-indole as the starting material.
1H NMR (300 MHz, CDCI3) 8.0 (m, H), 7.3 (m, H), 7.0 (d, H), 6.8 (d, H), 4.4 (t,
2H), 4.0 (s, 3H), 3.8 (t, 2H), 3.3 (s, 3H).
MS m/z [M+H]+=302.
C. 4-Methoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using 2,2,2-trifluoro-1 -[4-methoxy-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-ethanone as
the starting material.
1H NMR (300 MHz, DMSO-c/6) .6 (s, H), 8.0 (s, H), 7.2 (m, 2H), 6.8 (d, H), 4.4
(t, 2H), 3.9 (s, 3H), 3.6 (t, 2H), 3.2 (s, 3H).
MS m/z: [M+H]+=250.
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-methoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example 2 1
using 4-methoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-
N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting materials.
1H NMR (300 MHz, CDCI3) 7.2 (m, 3H), 7.0 (m, 2H), 6.8 (bs, H), 6.6 (d, H), 5.0
(bs, H), 4.5 (m, 2H), 4.3 (t, 2H), 3.9 (s, 3H), 3.7 (t, 2H), 3.3 (s, 3H), 3.1 (m, 3H), 1.9-
1.6 (m, 6H).
MS m/z [M+H]+=535.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-methoxy-1 -(2-methoxy-ethyl)-
1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-(4-fluoro-3-{1-[4-methoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
1H NMR (300 MHz, DMSO-c/6) 8.3 (bs, 2H), 7.5 (m, 1H), 7.4 (m, 2H), 7.2 (m, 3H),
6.6 (m, 1H), 4.4 (m, 2H), 4.0 (m, 2H), 3.9 (s, 3H), 3.8-3.5 (m, 5H), 3.3 (s, 3H), 3.1 (m,
2H), 1.8 (m, 2H), 1.6 (m, 2H).
MS m/z: [M+H]+=440.
EXAMPLE 48
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-bromo-1 -(2-methoxy-ethyl)-1 Hindol-
3-yl]-methanone hydrochloride
A 4-Bromo-1 -(2-methoxy-ethyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 2-bromoethylmethylether as the starting material.
1H NMR (300 MHz, CDCI3) 7.32-7.28 (m, 2 H), 7.22 (d, H), 7.1 0-7.04 (m, 1H), 6.56
(m, 1H), 4.28 (t, 2H), 3.70 (t, 2H), 3.31 (s, 3H).
B 1-[4-Bromo-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone
The title compound is prepared in a similar manner as described in Example
2G using 4-bromo-1 -(2-methoxy-ethyl)-1 H-indole as the starting material.
1H NMR (300 MHz, CDCI3) 7.99 (m, 1H), 7.49 (m, 1H), 7.32-7.29 (m, 1H), 7.1 3 (t,
1H), 4.28 (t, 2H), 3.67 (t, 2H), 3.25 (s, 3H).
C 4-Bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
2H using 1-[4-bromo-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone as
the starting material.
1H NMR (300 MHz, CD3OD) 8.00 (s, 1H), 7.51 -7.48 (m, 1H), 7.42-7.40 (m, 1H),
7.1 0 (t, 1H), 4.36 (t, 2H), 3.70 (t, 2H), 3.26 (s, 3H).
D N-(3-{1 -[4-Bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-
fluoro-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example
6E using 4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-
N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting materials.
1H NMR (300 MHz, CD3OD) 7.53-7.50 (m, 2H), 7.33-7.30 (m, 1H), 7.27-7.24 (m,
1H), 7.1 9-7.1 0 (m, 2H), 7.06-6.99 (m, 1H), 4.85 (s, 3H), 4.41 -4.36 (m, 4H), 3.71 (t,
2H), 3.28 (s, 3H), 3.24-3.1 2 (m, 2H), 3.01 -2.92 (m, 1H), 1.92 (br s, 2H), 1.68 (br s,
2H).
E [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-bromo-1 -(2-methoxy-ethyl)-
1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1-[4-bromo-1-(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-
4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material.
1H NMR (300 MHz, CD3OD) 7.55-7.52 (m, 2H), 7.44-7.42 (m, 1H), 7.36-7.31 (m,
2H), 7.17-7.1 1 (m, 2H), 4.93-4.88 (m, 2H), 4.40 (t, 2H), 4.10 (s, 2H), 3.72 (t, 2H), 3.28
(s, 3H), 3.26-3.18 (m, 2H), 3.07-2.98 (m, 1H), 1.96 (br s, 2H), 1.74 (br s, 2H). MS
m/ z [M+H]+=488, 490.
EXAMPLE 49
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-(2,3-dihydro-pyrrolo[1 ,2,3-de]-1 ,4-
benzoxazin-6-yl)-methanone hydrochloride
A. 7-(2-Chloro-ethoxy)-1 H-indole
To a solution of 7-hydroxyindole ( 1 .5 g, 11 mmol) in THF (60 ml_) is added
triphenylphosphine (5.8 g, 22 mmol), diisopropyl azodicarboxylate (4.4 g, 22 mmol)
and 2-chloro-ethanol ( 1 .47 ml_, 22 mmol). The reaction mixture is stirred at room
temperature overnight. The reaction mixture is concentrated in vacuo and purified by
flash chromatography on SiO2 eluting with 10% ethyl acetate/heptane to give the
titled compound ( 1 .4 g, 65%).
H NMR (300 MHz, CDCI3) 8.4 (bs, 1H), 7.3 (m, 1H), 7.2 (m, 1H), 7.0 (m, 1H), 6.6
(d, 1H), 6.5 (m, 1H), 4.4 (t, 2H), 3.9 (t, 2H).
MS m/z [M+H]+= 196.
B. 2,3-Dihydro-pyrrolo[1 ,2,3-de]-1 ,4-benzoxazine
To a solution of 7-(2-chloro-ethoxy)-1 H-indole ( 1 .20 g, 6.1 2 mmol) in N, i
dimethylformamide (15 ml_) under N2 at 0 °C is added NaH (0.49 g, 12.24 mmol).
The reaction mixture is stirred at room temperature for 2h then quenched with 1N
HCI. The reaction mixture is poured into EtOAc and washed with H2O, brine , dried
with MgSO4, filtered and concentrated in vacuo to yield the titled compound (0.89 g,
90%).
H NMR (300 MHz, CDCI3) 7.3 (m, 1H), 7.1 (m, 1H), 7.0 (m, 1H), 6.7 (m, 1H), 6.5
(m, 1H), 4.6 (t, 2H), 4.3 (t, 2H).
MS m/z: [M+H]+= 160.
C. 1-(2,3-Dihydro-pyrrolo[1 ,2,3-de]-1 ,4-benzoxazin-6-yl)-2,2,2-trifluoro-ethanone
The title compound is prepared in a similar manner as described in Example
1F using 2,3-dihydro-pyrrolo[1 ,2,3-de]-1 ,4-benzoxazine as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.5 (s, H), 7.6 (d, H), 7.2 (m, H), 6.8 (d, H), 4.5
(m, 4H).
MS m/z [M+H]+=256.
D. 2,3-Dihydro-pyrrolo[1 -de]-1,4-benzoxazine-6-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using 1-(2,3-dihydro-pyrrolo[1 ,2,3-de]-1 ,4-benzoxazin-6-yl)-2,2,2-trifluoroethanone
as the starting material.
H NMR (300 MHz, DMSO-c/6) 12.0 (s, 1H), 8.0 (s, 1H), 7.4 (d, 1H), 7.0 (m, 1H), 6.6
(d, 1H), 4.5 (t, 2H), 4.4 (t, 2H).
MS m/z: [M+H]+=204.
E. N-{3-[1 -(2,3-Dihydro-pyrrolo[1 ,2,3-de]-1 ,4-benzoxazine-6-carbonyl)-piperidin-4-yl]-
4-fluoro-benzyl}-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example 2 1
using 2,3-dihydro-pyrrolo[1 ,2,3-de]-1 ,4-benzoxazine-6-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting
materials.
H NMR (300 MHz, CDCI3) 7.5 (s, H), 7.3-7.0 (m, 5H), 6.7 (d, 1H), 6.6 (bs, H),
4.6 (m, 2H), 4.5 (m, 4H), 4.3 (m, 2H), 3.1 (m, 3H), 1.9-1 .7 (m, 4H).
MS m/z [M+H]+=490.
F. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-(2,3-dihydro-pyrrolo[1 ,2,3-de]-
1,4-benzoxazin-6-yl)-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using N-{3-[1 -(2,3-dihydro-pyrrolo[1 ,2,3-de]-1 ,4-benzoxazine-6-carbonyl)-
piperidin-4-yl]-4-fluoro-benzyl}-2,2,2-trifluoro-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.6 (bs, 2H), 7.8 (s, 1H), 7.6 (m, 1H), 7.4 (m, 1H),
7.2 (m, 2H), 7.0 (m, 1H), 6.6 (m, 1H), 4.4 (m, 4H), 4.0 (m, 2H), 3.7 (m, 2H), 3.1 (m,
3H), 1.8-1 .6 (m, 4H).
MS m/z: [M+H]+=394.
EXAMPLE 50
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(3-hydroxy-3-methyl-butyl)-1 Hindol-
3-yl]-methanone hydrochloride
A. 3-lndol-1-yl-propionic acid methyl ester
The title compound is prepared in a similar manner as describedin Example 1E
using 1H-indole and 3-bromo-propionic acid methyl ester as the starting materials. H
NMR (300 MHz, CDCI3) 7.6 (d, H), 7.4 (m, H), 7.2 (m, H), 7.1 (m, 2H), 6.4 (m,
1H), 4.5 (t, 2H), 3.6 (s, 3H), 2.8 (t, 2H).
MS m/z [M+H]+=204.
B. 4-lndol-1 -yl-2-methyl-butan-2-ol
To a solution of 3-indol-1 -yl-propionic acid methyl ester (3.0 g, 14.78 mmol) in
THF (50 mL) at 0 °C is added 3.0 M methylmagnesium iodide solution in diethyl ether
(9.81 mL, 29.56 mmol). The reaction mixture is allowed to slowly warm to room
temperature and stir overnight. The reaction mixture is quenched with saturated
NH CI, poured into EtOAc and washed with H2O, brine, dried with MgSO4, filtered
and concentrated in vacuo. The crude product is purified by flash chromatography on
S1O2 eluting with 20% ethyl acetate / heptane to give the titled compound (2.6 g,
87%).
H NMR (300 MHz, CDCI3) 7.6 (d, 1H), 7.4 (d, 1H), 7.2 (m, 1H), 7.1 (m, 2H), 6.5 (m,
1H), 4.3 (m, 2H), 2.0 (m, 2H), 1.3 (s, 6H).
MS m/z [M+H]+=204.
C. Trifluoro-acetic acid 1,1 -dimet -acetyl)-indol-1-yl]-propyl ester
The title compound is prepared in a similar manner as described in Example
1F using 4-indol-1 -yl-2-methyl-butan-2-ol as the starting material.
H NMR (300 MHz, CDCI3) 8.4 (m, H), 7.9 (s, H), 7.4 (m, 3H), 4.4 (m, 2H), 2.4
(m, 2H), 1.7 (s, 6H).
MS m/z [M+H]+=396.
D. 1-(3-Hydroxy-3-methyl-butyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using trifluoro-acetic acid , 1 -dimethyl-3-[3-(2,2,2-trifluoro-acetyl)-indol-1 -yl]-
propyl ester as the starting material.
H NMR (300 MHz, DMSO-c/6) .9 (s, 1H), 8.0 (m, 2H), 7.5 (d, 1H), 7.2 (m, 2H),
4.5 (s, H), 4.3 (m, 2H), 1.8 (m, 2H), 1.2 (s, 6H).
MS m/z: [M+H]+=248.
E. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(3-hydroxy-3-methyl-butyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 1-(3-hydroxy-3-methyl-butyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-
(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the starting materials.
H NMR (300 MHz, CDCI3) 7.7 (d, 1H), 7.5 (s, 1H), 7.4 (m, 1H), 7.2 (m, 4H), 7.0
(m, H), 6.7 (bs, H), 4.6 (m, 2H), 4.5 (m, 2H), 4.3 (m, 2H), 3.1 (m, 3H), 2.0 (m, 3H),
1.9-1 .6 (m, 4H), 1.3 (s, 6H).
MS m/z [M+H]+=534.
F. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(3-hydroxy-3-methyl-butyl)-
1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(3-hydroxy-3-methyl-butyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.3 (bs, 2H), 7.8 (s, 1H), 7.7 (d, 1H), 7.5 (m, 2H), 7.4
(m, 1H), 7.2 (m, 3H), 4.5 (m, 2H), 4.3 (m, 2H), 4.1 (m, 2H), 3.1 (m, 3H), 1.9-1 .6 (m,
6H), 1.2 (s, 6H).
MS m/z: [M+H]+=438.
EXAMPLE 5 1
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-fluoro-1 -(2-methoxy-ethyl)-1 Hindol-
3-yl]-methanone hydrochloride
A. 4-Fluoro-1 -(2-methoxy-ethyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 4-fluroindole as the starting material.
H NMR (300 MHz, CDCI3) 7.2 (m, 3H), 6.8 (m, H), 6.6 (m, 1H), 4.3 (t, 2H), 3.7 (t,
2H), 3.35 (s, 3H).
LCMS m/z [M+H]+= 94.
B. 2,2,2-Trifluoro-1 -[4-fluo -1-(2-methoxy-ethyl)-1 H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
1F using 4-fluoro-1 -(2-methoxy-ethyl)-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 8.1 (s, 1H), 7.4 (m, 2H), 7.2 (m, 1H), 7.1 (m, 1H), 4.4 (t,
2H), 3.8 (t, 2H), 3.3 (s, 3H).
MS m/z [M+H]+=290.
-Fluoro-1 -(2-met ole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using 2,2,2-trifluoro-1 -[4-fluoro-1-(2-methoxy-ethyl)-1 H-indol-3-yl]-ethanone as the
starting material.
H NMR (300 MHz, DMSO-c/6) 11.7 (bs, 1H), 8.0 (s, 1H), 7.4 (d, 1H), 7.2 (m, 1H),
6.9 (m, 1H), 4.4 (t, 2H), 3.7 (t, 2H), 3.2 (s, 3H).
MS m/z: [M+H]+=238.
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-fluoro-1 -(2-methoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example 2 1
using 4-fluoro-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-
(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting materials.
H NMR (300 MHz, CDCI3) 5 7.5 (s, 1H), 7.2 (m, 4H), 7.1 (m, 1H), 6.9 (m, 1H), 6.6
(bs, H), 4.5 (m, 2H), 4.3 (m, 2H), 3.8 (m, 2H), 3.4 (s, 3H), 3.1 (m, 4H), 1.9-1 .65 (m,
4H).
MS m/z [M+H]+=524.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-fluoro-1 -(2-methoxy-ethyl)-
1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[4-fluoro-1 -(2-methoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.2 (bs, 2H), 7.6 (s, 1H), 7.5 (m, 1H), 7.4 (m, 1H),
7.3 (m, 1H), 7.2 (m, 2H), 6.9 (m, 1H), 4.4 (m, 2H), 4.0 (m, 2H), 3.7 (m, 2H), 3.2 (s,
3H), 3.1 (m, 4H), 1.8 (m, 2H), 1.6 (m, 2H).
MS m/z: [M+H]+=428.
EXAMPLE 52
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-cyclopropyl-1 -(2-methoxy-ethyl)-
1H-indol-3-yl]-methanone hydrochloride
A. 4-Cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
6B using 4-bromo-1 -(2-methoxy-ethyl)-1 H-indole and cyclopropylboronic acid as the
starting materials.
H NMR (300 MHz, CDCI3) 7.20-7.1 2 (m, 3H), 6.73-6.71 (d, 1H), 6.69-6.68 (m, 1H),
4.29 (t, 2H), 3.72 (t, 2H), 3.33 (s, 3H), 2.30-2.21 (m, 1H), 1.04-0.98 (m, 2H), 0.88-
0.82 (m, 2H).
B. 1-[4-Cyclopropyl-1 -(2- ol-3-yl]-2,2,2-trifluoro-ethanone
The title compound is prepared in a similar manner as described in Example
2G using 4-cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 8.1 0-8.08 (m, 1H), 7.30-7.1 9 (m, 2H), 6.94-6.92 (m, 1H),
4.34 (t, 2H), 3.75 (t, 2H), 3.33 (s, 3H), 2.24-2.1 5 (m, 1H), 1.05-0.98 (m, 2H), 0.74-
0.69 (m, 2H).
C. 4-Cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
2H using 1-[4-cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone
as the starting material.
H NMR (300 MHz, DMSO-c/6) .75 (s, 1H), 7.37-7.34 (m, 1H), 7.1 2 (t, 1H), 6.66
(d, 1H), 6.58-6.56 (m, 1H), 4.38 (t, 2H), 3.66 (t, 2H), 3.52-3.43 (m, 1H), 3.21 (s, 3H),
0.93-0.87 (m, 2H), 0.68-0.62 (m, 2H).
D. N-(3-{1 -[4-Cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-
4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example
6E using 4-cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting
materials.
H NMR (300 MHz, CDCI3) 7.1 8 (m, 2H), 7.14-7.08 (m, 2H), 7.02-6.96 (m, 2H),
6.81-6.78 (m, 1H), 4.45 (d, 2H), 4.27 (t, 2H), 3.70 (t, 2H), 3.31 (s, 3H), 3.20-3.04 (m,
2H), 2.36 (br s, 1H), 1.94-1 .73 (m, 4H), 0.92-0.90 (m, 2H), 0.74 (br s, 2H).
E- [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-cyclopropyl-1 -(2-methoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1 -[4-cyclopropyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-
4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material .
H NMR (300 MHz, DMSO-c/6) 8.53 (br s, 3H), 7.57 (m, 1H), 7.51 (s, 1H), 7.40 (m,
1H), 7.36-7.33 (m , 1H), 7.26-7.17 (m, 1H), 7.1 1-7.06 (m, 1H), 6.68 (d, 1H), 4.35 (t,
2H), 3.99 (br d, 3H), 3.66 (t, 2H), 3.22 (s, 3H), 3.1 5-3.00 (m, 4H), 2.30 (m, 1H), 1.80-
1.63 (m, 4H), 0.89-0.86 (m, 2H), 0.66 (br s, 2H).
MS m/z [M+H]+=450.
EXAMPLE 53
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-e
trifluoromethyl-1 H-indol-3-yl]-methanone hydrochloride
A. 1-(2-Methoxy-ethyl)-4-trifluoromethyl-1 H-indole
A mixture of 4-trifluoromethyl-1 H-indole ( 105 mg, 0.57 mmol), powder KOH
(159 mg, 2.83 mmol) in DMSO (6 mL) is stirred at r.t. for 5 min. 2-Methoxyethyl
bromide (80 _, 0.85 mmol) is added. After the reaction mixture is stirred at r.t.
overnight, it is partitioned between H2O and Et2O. The two layers are separated, and
the aqueous layer is extracted with Et2O (3x). The combined organic extracts are
washed with H2O and brine, dried over MgSO , filtered, and concentrated in vacuo.
The crude material is purified on silica gel with heptane/EtOAc ( 100/0 to 70/30) as
eluent to yield the product ( 100 mg, 72%) as a clear colorless liquid.
H NMR (300 MHz, CDCI3) 7.53 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.35-
7.20 (m, 2H), 6.69 (s, 1 H), 4.32 (t, J = 5.4 Hz, 2H), 3.71 (t, J = 5.4 Hz, 2H), 3.31 (s,
3H);
9F NMR (300 MHz, CDCI3) -60.99 (s, 3F);
LC Rt: 3.21 min; MS 244 (M+H, 100%).
B. 2,2,2-Trifluoro-1 -[1 -(2-methoxy-ethyl)-4-trifluoromethyl-1 H-indol-3-yl]-ethanone
A mixture of 1-(2-methoxy-ethyl)-4-trifluoromethyl-1 H-indole (95 mg, 0.39
mmol) and TFAA (0.1 6 mL, 1.17 mmol) in DMF ( 10 mL) is heated at 45 °C overnight.
The mixture is then partitioned between H2O and Et O. The two layers are
separated, and the organic layer is washed with H2O and brine, dried over MgSO4,
filtered, and concentrated in vacuo. The crude material is purified on silica gel with
hepatane/EtOAc (95/5 to 50/50) as eluent to yield the product (92 mg, 69%) as a
yellow waxy solid.
H NMR (300 MHz, CDCI3) 8.1 6 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.47
(d, J = 8.1 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 4.42 (t, J = 5.1 Hz, 2H), 3.76 (t, J = 5.1
Hz, 2H), 3.33 (s, 3H);
9F NMR (300 MHz, CDCI3) -58.25 (s, 3F), -70.91 (s, 3F);
LC Rt: 3.28 min; MS 340 (M+H, 100%).
C. 1-(2-Methoxy-ethyl)-4-trifluoromethyl-1 H-indole-3-carboxylic acid
A mixture of 2,2,2-trifluoro-1 -[1 -(2-methoxy-ethyl)-4-trifluoromethyl-1 H-indol-3-
yl]-ethanone (90 mg, 0.27 mmol) in MeOH ( 10 mL) and NaOH (5 M, 5 mL) is heated
at 80 °C overnight. This mixture is concentrated in vacuo to remove the methanol.
The residue is diluted with H2O, and then washed with Et2O once. The aqueous layer
is acidified to pH 2 with HCI (6 M). The acidified mixture is extracted with EtOAc (2X).
The combined organic extracts are washed with H2O and brine, dried over MgSO4,
filtered, and concentrated in vacuo. The residue is coevaportated with CH2CI2 and
heptane to yield the product (56 mg, 73%) as a beige powder.
H NMR (300 MHz, CDCI3) 8.14 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.2
Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 4.36 (t, J = 5.2 Hz, 2H), 3.74 (t, J = 5.3 Hz, 2H), 3.32
(s, 3H);
19 F NMR (300 MHz, CDCI3) -58.39 (s, 3F);
LC Rt: 2.52 min; MS 288 (M+H, 100%).
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-trifluoromethyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of 1-(2-methoxy-ethyl)-4-trifluoromethyl-1 H-indole-3-carboxylic acid
(50 mg, 0.1 7 mmol), Et3N (73 _, 0.55 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-
yl-benzyl)-acetamide hydrochloride (77 mg, 0.23 mmol), and EDCI (50 mg, 0.26
mmol) in CH2CI2 ( 10 ml_) is stirred at r.t. overnight. The mixture is partitioned
between H2O and CH2CI2. The two layers are separated, and the organic layer is
washed with brine, dried over MgSO , filtered, and concentrated in vacuo. The crude
material is purified on silica gel with heptane/EtOAc (50/50 to 0/1 00) as eluent to give
the product (52 mg, 52%) as a white powder.
H NMR (300 MHz, CDCI3) 7.65-7.45 (m, 2H), 7.35-7.25 (m, 2H), 7.20-7.1 0 (m, 1H),
7.1 0-6.95 (m, 1H), 6.69 (br s, 1H), 5.1 0-4.90 (br m, 1H), 4.55-4.40 (m, 2H), 4.40-4.25
(m, 2H), 4.40-3.75 (br m, 1H), 3.71 (t, J = 5.1 Hz, 2H), 3.95-3.60 (m, 3H), 3.31 (s,
3H), 3.25-3.00 (m, 2H), 3.00-2.85 (m, 1H), 2.05-1 .50(m, 4H);
9F NMR (300 MHz, CDCI3) -58.47 (br m, 3F), -75.36 (s, 3F), - 1 18.84 (br m, 1F); LC
Rt 3.32 min; MS 574 (M+H, 100%).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-
trifluoromethyl-1 H-indol-3-yl]-methanone hydrochloride
A mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-
trifluoromethyl-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (45 mg, 0.078
mmol) in MeOH (5 mL) is added aqueous K2CO3 ( 130 mg, 0.94 mmol, dissolved in
1.5 mL H2O). This mixture is stirred at r.t. overnight. LC/MS indicates the reaction is
completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and EtOAc. The two layers are
separated, and the organic layer is washed with H2O and brine, dried over MgSO4,
filtered, and concentrated in vacuo. The residue is dissolved in Et2O, and HCI in Et O
( 1 .0 M, 3 mL) is added. The resulting suspension is concentrated in vacuo, and then
dried in vacuo to yield the product (35 mg, 87%) as a beige solid.
H NMR (300 MHz, DMSO-c/6) 8.35 (br,s 3H), 7.93 (d, J = 8.2 Hz, 1H), 7.80-7.65
(m, 1H), 7.60-7.45 (m, 2H), 7.25-7.1 0 (m, 2H), 7.21 (t, J = 10.2 Hz, 1H), 4.85-4.65 (br
m, 1H), 4.55-4.45 (m, 2H), 4.1 0-3.90 (m, 2H), 3.90-3.60 (m, 3H), 3.22 (s, 3H), 3.20-
3.00 (m, 1H), 3.00-2.85 (br m, 1H), 2.00-1 .40 (m, 4H);
9F NMR (300 MHz, DMSO-c/6) -57.72 (s, 3F), - 1 19.29 (s, 1F);
LC 2.65 min; MS 478 (M+H, 100%).
EXAMPLE 54
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-
trifluoromethoxy-1 H-indol-3-yl]-methanone hydrochloride
A. 1-(2-Methoxy-ethyl)-4-trifluoromethoxy-1 H-indole-3-carboxylic acid
A mixture of 7-chloro-1 -(2-methoxy-ethyl)-4-trifluoromethoxy-1 H-indole-3-
carboxylic acid ( 100 mg, 0.30 mmol) and Pd/C ( 10%, 75 mg) in MeOH is
hydrogenated at 50 psi at r.t. for 4 h. The reaction is filtered through Celite, and the
filtrate is concentrated in vacuo. The residue is redissolved in EtOAc. MgSO and a
small amount of activated charcoal are added. This mixture is then filtered, and the
filtrate is concentrated in vacuo to yield the product (50 mg, 55%) as a white powder.
H NMR (300 MHz, CDCI3) 8.08 (s, 1H), 7.45-7.1 5 (m, 3H), 4.33 (t, J = 5.1 Hz, 2H),
3.75 (t, J = 5.2 Hz, 2H), 3.34 (s, 3H);
9F NMR (300 MHz, CDCI3) -57.28 (s, 3F);
LC Rt: 2.59 min; MS 304 (M+H, 100%).
B. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-trifluoromethoxy-1 H-indole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of 1-(2-methoxy-ethyl)-4-trifluoromethyl-1 H-indole-3-carboxylic acid
(50 mg, 0.1 7 mmol), Et3N (73 _, 0.55 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-
4-yl-benzyl)-acetamide hydrochloride (77 mg, 0.23 mmol), and EDCI (50 mg, 0.26
mmol) in CH2CI2 ( 10 ml_) is stirred at r.t. overnight. The mixture is partitioned
between H2O and CH2CI2. The two layers are separated, and the organic layer is
washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude
material is purified on silica gel with heptane/EtOAc (50/50 to 0/1 00) as eluent to give
the product (52 mg, 52%) as a white powder.
H NMR (300 MHz, CDCI3) 7.45 (s, 1H), 7.40-7.20 (m, 2H), 7.20-6.90 (m, 4H), 6.68
(br s, 1H), 5.10-4.90 (br m, 1H), 4 ..48 (d, J = 5.7 Hz, 2H), 4.29 (t, J = 5.3 Hz, 2H),
4.40-3.80 (br m, 1H), 3.74 (t, J = 5.4 Hz, 2H), 3.34 (s, 3H), 3.25-2.70 (m, 3H), 2.05-
1.50 (m, 4H);
9F NMR (300 MHz, CDCI3) -57.12 (s, 3F), -75.38 (s, 3F), - 1 19.1 3 (s, 1F);
LC Rt 3.36 min; MS 590 (M+H, 100%).
C. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-
trifluoromethoxy-1 H-indol-3-yl]-methanone hydrochloride
A mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-
trifluoromethoxy-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (45 mg,
0.076 mmol) in MeOH (3 mL) is added aqueous K2CO3 (84 mg, 0.61 mmol, dissolved
in 1.5 mL H2O). This mixture is stirred at r.t. overnight. LC/MS indicates the reaction
is completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and EtOAc. The two layers are
separated, and the organic layer is washed with H2O and brine, dried over MgSO4,
filtered, and concentrated in vacuo. The residue is dissolved in Et2O and HCI in Et O
( 1 .0 M, 3 mL) is added. The resulting suspension is concentrated in vacuo, and then
dried in vacuo to yield the product (40 mg, 100%) as a beige solid.
H NMR (300 MHz, DMSO-c/6) 8.30 (br,s 3H), 7.80-7.65 (m, 3H), 7.55-7.05 (m, 4H),
4.90-4.30 (m, 3H), 4.20-3.90 (m, 2H), 3.90-3.60 (m, 3H), 3.23 (s, 3H), 3.20-2.80 ( m,
3H), 1.90-1 .40 (m, 4H);
9F NMR (300 MHz, DMSO-c/6) -56.20 (s, 3F), - 1 19.1 8 (s, 1F);
LC 2.53 min; MS 494 (M+H, 100%).
EXAMPLE 55
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(3-hydroxy-3-methyl-butyl)-1 -(2-
methoxy-ethyl)-1 H-indol-3-yl]-methanone hydrochloride
A. (E)-3-(1 H-lndol-4-yl)-acrylic acid methyl ester
The title compound is prepared according to the procedure in Heterocycles,
1983, vol. 20(1 0), pp. 1983-5.
H NMR (300 MHz, CDCI3) 8.4 (bs, 1H), 8.1 (d, H), 7.6-7.2 (m, 4H), 6.8 (m, 1H), 6.6
(d, 1H), 3.8 (s, 3H).
MS m/z [M+H]+=202.
B. 3-(1 H-lndol-4-yl)-propionic acid methyl ester
A solution of (E)-3-(1 H-lndol-4-yl)-acrylic acid methyl ester (6.9g, 34.33 mmol)
dissolved in EtOAc (50 mL) is hydrogenated via a hydrogen paar shaker for 4 h at 50
psi with 10%Pd/C ( 1 .0 g) as a catalyst. The reaction is filtered through celite and is
concentrated in vacuo. The crude product is purified by flash chromatography on
S1O2 eluting with 20% ethyl acetate / heptane to give the titled compound (5.6 g,
80%).
H NMR (300 MHz, CDCI3) 8.2 (bs, 1H), 7.3-7.1 (m, 3H), 6.9 (m, 1H), 6.6 (m, 1H),
3.7 (s, 3H), 3.3 (t, 2H), 2.8 (t, 2H).
MS m/z [M+H]+=204.
C. 3-[1 -(2-Methoxy-et ionic acid methyl ester
The title compound is prepared in a similar manner as described in Example
2F using 3-(1 H-indol-4-yl)-propionic acid methyl ester and 2-methoxyethyl bromide in
DMF as the starting materials.
H NMR (300 MHz, CDCI3) 7.3-7.1 (m, 3H), 6.9 (d, 1H), 6.55 (m, 1H), 4.3 (t, 2H),
3.7 (t, 2H), 3.65 (s, 3H), 3.3 (s, 3H), 3.2 (m, 2H), 2.8 (m, 2H).
LCMS m/z: [M+H]+=262
D. 4-[1 -(2-Methoxy-ethyl)-1 H-indol-4-yl]-2-methyl-butan-2-ol
The title compound is prepared in a similar manner as described in Example
50B using 3-[1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-propionic acid methyl ester as the
starting material.
H NMR (300 MHz, CDCI3) 7.3-7.1 (m, 3H), 6.9 (m, 1H), 6.5 (m, 1H), 4.3 (t, 2H), 3.7
(t, 2H), 3.3 (s, 3H), 3.0 (m, 2H), 1.9 (m, 2H), 1.6 (bs, 1H), 1.3 (s, 6H).
MS m/z [M+H]+=262.
E. Trifluoro-acetic acid 3-[1 -(2-methoxy-ethyl)-3-(2,2,2-trifluoro-acetyl)-1 H-indol-4-yl]-
1,1 -dimethyl-propyl ester
The title compound is prepared in a similar manner as described in Example
1F using 4-[1-(2-methoxy-ethyl)-1 H-indol-4-yl]-2-methyl-butan-2-ol as the starting
material.
H NMR (300 MHz, CDCI3) 7.2 (m, 3H), 6.9 (m, 1H), 6.5 (m, 1H), 4.3 (t, 2H), 3.7 (t,
2H), 3.3 (s, 3H), 3.0 (m, 2H), 1.9 (m, 2H), 1.3 (s, 6H).
MS m/z [M+H]+=262.
F. 4-(3-Hydroxy-3-methyl-butyl)-1-(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using trifluoro-acetic acid 3-[1-(2-methoxy-ethyl)-3-(2,2,2-trifluoro-acetyl)-1 H-indol-
4-yl]-1 , 1 -dimethyl-propyl ester as the starting material.
H NMR (300 MHz, DMSO-c/6) 1 .8 (s, H), 8.0 (s, 1H), 7.4 (d, 1H), 7.2 (m, 1H), 6.9
(d, 1H), 4.4 (t, 2H), 4.1 (s, 1H), 3.6 (t, 2H), 3.2 (m, 5H), 1.6 (m, 2H), 1.2 (s, 6H). MS
m/z: [M+H]+=306.
G. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-(3-hydroxy-3-methyl-butyl)-1 -(2-methoxy-ethyl)-
1H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 4-(3-hydroxy-3-methyl-butyl)-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
and 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the
starting materials and purified by RP-HPLC.
H NMR (300 MHz, CDCI3) 7.3 (m, 4H), 7.1 (m, 1H), 7.0 (m, 2H), 6.9 (bs, 1H), 4.5
(m, 2H), 4.3 (t, 2H), 4.1 (m, 1H), 3.7 (t, 2 H), 3.3 (s, 3H), 3.2-2.9 (m, 6H), 1.9-1 .7 (m,
6H), 1.2 (m, 7H).
MS m/z [M+H]+=592.
H. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(3-hydroxy-3-methyl-butyl)-1 -
(2-methoxy-ethyl)-1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[4-(3-hydroxy-3-methyl-butyl)-1-(2-methoxyethyl)-
1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.3 (bs, 2H), 7.5 (m, 2H), 7.4 (m, 2H), 7.2 (m, 1H),
7.1 (m, 1H), 6.9 (m, 1H), 4.4 (m, 2H), 4.0 (m, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 3.2 (s,
3H), 3.1 -2.8 (m, 5H), 1.9-1 .6 (m, 7H), 1.2 (s, 6H).
MS m/z: [M+H]+=496.
EXAMPLE 56
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-pyrid
1H-indol-3-yl]-methanone
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-pyridin-4-yl-1 H-indole-3-
e
To a mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (0.30 g, 0.51 mmol) in
dioxane (9 mL) and H2O ( 1 mL) under nitrogen is added pyridine-4-boronic acid (0.1 2
g, 1.02 mmol) followed by of cesium fluoride (0.1 5 g, 1.02 mmol) and a catalytic
amount of [ 1 ,1 '-Bis(diphenylphosphino)-ferrocene]dichloropalladium(ll). After stirring
6h at reflux the reaction is quenched with H2O solution and extracted with CH2CI2.
The combined organic layers are washed with aqueous saturated NaHCO3 solution,
dried over MgSO4, filtered and concentrated in vacuo. The crude material is purified
on silica gel with EtOAc as eluent to deliver the titled compound (0.21 g, 7 1%) as a
beige solid mp 152-1 55 °C.
H NMR (300 MHz, CDCI3) 8.61 (m, 1H), 7.61 (m, 2H), 7.50 (m, 2H), 7.39 (m, 2H),
7.1 8 (m, 2H), 6.94 (m, 2H), 4.65 (m, 2H), 4.48 (m, 2H), 4.35 (t, J = 5.1 Hz, 2H), 3.78
(t, J = 5.1 Hz, 2H), 3.35 (s, 3H), 3.30 (m, 2H), 2.96 (m, 1H), 2.83 (m, 1H), 1.66 (m,
2H), 1.35 (m, 1H);
MS 583 (M+1 ) .
B [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-pyridin-4-
-1H-indol-3-yl]-methanone
To a solution of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-pyndin-4-
yl-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (0.1 7 g 0.29 mmol) in
MeOH ( 10 mL) and H2O (5 mL) is added aqueous 50% NaOH solution ( 1 mL). After
stirring at ambient temperature for 1h the mixture is concentrated in vacuo, diluted
with H2O and extracted with EtOAc as well as CH2CI2. The combined organic layers
are dried over MgSO4, filtered and concentrated in vacuo diluted with MeOH and
adsorbed onto silica gel. This material is purified on silica gel (5% 7N
NH3/MeOH:95% CH2CI2 as eluent). Concentration of appropriate fractions delivers
the titled compound (0.1 2 g, 85%) as a foam.
H NMR (300 MHz, CDCI3) 8.69 (br s, 2H), 7.52 (m, 2H), 7.39 (m, 2H), 7.1 9 (m,
2H), 7.09 (m, 1H), 4.56 (m, 1H), 4.35 (t, J = 4.5 Hz, 2H), 3.80 (t, J = 4.5 Hz, 2H), 3.76
(m, 2H), 3.35 (s, 3H), 3.36 (m, 1H), 2.80 (m, 1H), 1.8-1 .2 (m, 4H);
MS 487 (M+1 ) .
EXAMPLE 57
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-ethoxy-1 -(2-methoxy-ethyl)-1 Hindol-
3-yl]-methanone hydrochloride
A. 4-Ethox -1H-indole
The title compound is prepared in a similar manner as described in Example
49A using 4-hydroxyindole and anhydrous ethanol as the starting materials.
H NMR (300 MHz, CDCI3) 8.14 (br s, 1H), 7.14-7.09 (m, 2H), 7.02-7.00 (m, 1H),
6.70-6.68 (m, 1H), 6.55-6.53 (m, 1H), 4.21 (q, 2H), 1.51 (t, 3H).
B. 4-Ethox -1-(2-methoxy-ethyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 4-ethoxy-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 7.14-7.09 (m, 1H), 6.98-6.95 (m, 1H), 6.63-6.61 (m, 1H),
6.52 (d, 1H), 4.27 (t, 2H), 4.20 (q, 2H), 3.70 (t, 2H), 3.31 (s, 3H), 1.50 (t, 3H).
C. 1-[4-Ethoxy-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone
The title compound is prepared in a similar manner as described in Example
2G using 4-ethoxy-1-(2-methoxy-ethyl)-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 7.89-7.88 (m, H), 7.24-7.1 8 (m, 1H), 6.93-6.90 (m, 1H),
6.69 (d, 1H), 4.25 (t, 2H), 4.22 (q, 2H), 3.67 (t, 2H), 3.24 (s, 3H), 1.50 (t, 3H).
D, 4-Ethoxy-1 -(2- -3-carboxylic acid
The title compound is prepared in a similar manner as describedin Example
2H using 1-[4-ethoxy-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone as
the starting material.
H NMR (300 MHz, DMSO-c/6) 11.69 (s, 1H), 8.00 (s, 1H), 7.27-7.1 6 (m, 2H), 6.79
(d, 1H), 4.38 (t, 2H), 4.26 (q, 2H), 3.66 (t, 2H), 3.21 (s, 3H), 1.42 (t, 3H).
E. N-(3-{1 -[4-Ethoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-
fluoro-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example 2 1
using 4-ethoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-
(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting materials.
H NMR (300 MHz, CDCI3) 7.1 8-7.08 (m, 4H), 7.02-6.95 (m, 2H), 6.55 (d, 1H), 4.97
(br s, 1H), 4.44 (d, 2H), 4.24 (t, 2H), 4.1 6-4.08 (m, 3H), 3.90 (br s, 1H), 3.71 (t, 2H),
3.1 8-3.03 (m, 2H), 2.04 (s, 1H), 1.90-1 .56 (m, 4H), 1.46 (t, 3H), 1.26 (t, 2H).
F. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-ethoxy-1 -(2-methoxy-ethyl)-
1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1 -[4-ethoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-
4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material .
H NMR (300 MHz, DMSO-c/6) 8.64 (br s, 3H), 7.54 (br s, 1H), 7.40 (m, 2H), 7.21 -
7.1 5 (m , 1H), 7.1 2-7.5 (m, 2H), 6.59-6.57 (m, 1H), 4.31 (t, 2H), 4.1 2-4.06 (m, 2H),
3.95 (br s, 2H), 3.67-3.64 (m, 3H), 3.22 (s, 3H), 3.1 6-2.99 (m, 3H), 2.82 (br s, 1H),
1.90-1 .59 (m, 4H), 1.38 (t, 3H).
EXAMPLE 58
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-cyclopropoxy-1-(2-methoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
Carbonic acid tert-but l ester 1H-indol-4-yl ester
The title compound is prepared according to the procedure by Somei, M. et al.,
Chem. Pharm. Bull., 2002, vol. 50, pp. 92-99 using 4-hydroxy-1 H-indole and di-tertbutyldicarbonate
as the starting materials.
H NMR (300 MHz, CDCI3) 8.26 (br s, 1H), 7.02 (m, 1H), 7.21 -7.21 (m, 1H), 7.1 7-
7.1 1 (m, 2H), 6.95-6.93 (m, 1H), 6.50-6.48 (m, 1H), 1.60 (s, 9H).
B. Carbonic acid tert-butyl ester 1-(2-methoxy-ethyl)-1 H-indol-4-yl ester
The title compound is prepared in a similar manner as described in Example
1E using carbonic acid tert-butyl ester 1H-indol-4-yl ester as the starting material.
H NMR (300 MHz, CDCI3) 7.77 (d, H), 7.49 (d, H), 7.21 (t, 1H), 6.73 (m, 1 H),
6.67 (d, 1H), 4.26 (t, 2H), 3.83 (t, 2H), 3.49 (s, 3H), 1.67 (s, 9H).
C. 1-(2-Methoxy-ethyl)-1 H-indol-4-ol
To a mixture of carbonic acid tert-butyl ester 1-(2-methoxy-ethyl)-1 H-indol-4-yl
ester (5.81 g, 19.94 mmol) in 1,4-dioxane (90 mL) is added a solution of 2 N HCI in
water (50 mL). The resulting mixture is refluxed for ~ 1 hour. The solvent is removed
in vacuo and the residue is partitioned between water and EtOAc. The mixture is
basified with 10 N NaOH and the organic layer is separated. The aqueous phase is
extracted with EtOAc (x2). The organic phases are combined, washed with water and
brine then separated and dried over MgSO4. The organic phase is concentrated in
vacuo and the crude residue is flash chromatographed over S1O2 using
Heptane:EtOAc (70:30) to afford the titled compound (900 mg, 24%) as an orange oil.
H NMR (300 MHz, CDCI3) 8.1 5 (br s, 1H), 7.1 3-7.02 (m, 3H), 6.71 -6.69 (m, 1H),
6.55-6.53 (m, 1H), 4.30 (t, 2H), 3.86 (t, 2H), 3.50 (s, 3H).
D. 4-Cyclopropoxy-1 -(2-methoxy-ethyl)-1 H-indole
The title compound is prepared according to the procedure by Chiu, G. et al.,
Bioorg. Med. Chem. Lett., 2007, vol. 17, pp. 3930-3934 using 1-(2-methoxy-ethyl)-
1H-indol-4-ol and cyclopropyl bromide in ,-dimethyl-acetamide as the starting
materials.
H NMR (300 MHz, CDCI3) 7.21 -7.09 (m, 2H), 7.02 (m, 1H), 6.56-6.53 (m, 2H), 4.28
(t, 2H), 3.83 (t, 2H), 3.48 (s, 3H), 3.36-3.29 (m, 1H), 1.05-1 .00 (m, 4H).
E. 1-[4-Cyclopropoxy-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoro-ethanone
The title compound is prepared in a similar manner as described in Example
2G using 4-cyclopropoxy-1 -(2-methoxy-ethyl)-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 7.86 (m, 1H), 7.22-7.24 (m, 2H), 6.81 (m, 1H), 4.26 (t,
2H), 3.94 (t, 2H), 3.50 (s, 3H), 3.44 (sept, 1H), 1.26-1 .05 (m, 4H).
F. 4-Cyclopropoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
2H using 1-[4-cyclopropoxy-1-(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoroethanone
as the starting material.
H NMR (300 MHz, CD3OD) 8.00 (s, 1H), 7.41 -7.39 (m, 1H), 7.28 (t, 1H), 6.88 (d,
1H), 4.43-4.40 (m, 2H), 3.85-3.82 (m, 2H), 3.49 (sept, 1H), 3.44 (s, 3H), 1.21 - 1 .14 (m,
2H), 1.06-1 .01 (m, 2H).
N-(3-{1 -[4-Cyclopropoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-
yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example
6E using 4-cyclopropoxy-1-(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting
materials.
H NMR (300 MHz, CDCI3) 7.24-7.1 0 (m, 5H), 7.03-6.97 (m, 2H), 6.59-6.57 (m, 1H),
4.46 (d, 2H), 4.22 (br s, 2H), 3.80 (br s, 3H), 3.46-3.30 (m, 5H), 3.1 5-3.03 (m, 1H),
2.96 (s, 3H), 1.97-1 .71 (m, 3H), 1.08-1 .02 (m, 4H).
H. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-cyclopropoxy-1 -(2-methoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1 -[4-cyclopropoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material .
H NMR (300 MHz, DMSO-c/6) 8.40 (br s, 3H), 7.52-7.50 (m, H), 7.39-7.35 (m,
2H), 7.23-7.1 1 (m , 3H), 6.65-6.62 (m, 1H), 4.72 (br s, 1H), 4.43 (br s, 4H), 4.1 6 (br s,
2H), 3.98 (m, 2H), 3.72 (br s, 2H), 3.62 (br s, 1H), 3.48-3.42 (m, 1H), 3.36 (s, 3H),
3.1 0-3.02 (m, 1H), 2.84 (br s, 1H), 1.82-1 .56 (m, 4H), 0.98 (m, 1H).
EXAMPLE 59
[3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 Hindol-
4-yl]-morpholin-4-yl-methanone hydrochloride
A. ( 1 H-lndol-4-yl)-morpholin-4-yl-methanone
To a mixture of 1H-indole-4-carboxylic acid ( 1 .0 g, 6.2 mmol) in THF ( 10 ml_)
under nitrogen is added carbonyl diimidazole ( 1 .1 g, 6.8 mmol). After stirring 0.5 h at
ambient temperature, morpholine (0.7 g, 8.1 mmol) is added. After stirring for 2h, the
reaction is quenched with 5% aqueous HCI and extracted with EtOAc. The combined
organic layers are washed with aqueous saturated NaHCO3 solution, dried over
MgSO4, filtered and concentrated in vacuo. The resulting solid is recrystallized from
EtOAc/heptane to yield the titled compound ( 1 .3 g, 92%) as a beige solid (mp 127-
129 °C).
H NMR (300 MHz, CDCI3) 8.36 (s, 1H), 7.45 (m, 1H), 7.24 (m, 4H), 3.43 (m, 8H);
MS 231 (M+1 ) .
B. [ 1 -(2-Methoxy-ethyl)-1 H-indol-4-yl]-morpholin-4-yl-methanone
To a solution of ( 1 H-indol-4-yl)-morpholin-4-yl-methanone ( 1 .00 g, 4.3 mmol) in
DMSO ( 10 ml_) under nitrogen is added KOH (0.73 g, 13.0 mmol). After stirring for
10 minutes, 1-bromo-2-methoxy-ethane (0.72 g, 5.2 mmol) is added followed by a
catalytic amount of Kl. After stirring an additional 4h the reaction is quenched with
aqueous saturated NaCI solution and extracted with EtOAc. The combined organic
layers are dried over MgSO4, filtered and concentrated in vacuo to yield the titled
compound ( 1 .20 g, 96%) as a clear light yellow oil.
H NMR (300 MHz, CDCI3) 7.42 (m, 1H), 7.25 (m, 2H), 7.1 2 (m, 1H), 6.49 (m, 1H),
4.28 (t, J = 6.5 Hz, 2H), 3.65 (t, J = 6.5 Hz, 2H), 3.59 (m, 8H), 3.31 (s, 3H);
MS 289 (M+1 ) .
C. 1-(2-Methoxy-ethyl)-4-(morpholine-4-carbonyl)-1 H-indole-3-carbaldehyde
To DMF (5ml_) at 0 °C under nitrogen is added POCI3 (0.34g, 0.21 mmol).
After stirring 5 minutes, [1-(2-methoxy-ethyl)-1 H-indol-4-yl]-morpholin-4-yl-methanone
(0.50 g, 0.1 7 mmol) in DMF (3 mL) is added dropwise. After stirring at ambient
temperature for 1 h the mixture is diluted with aqueous 1 N KOH (5 mL) solution and
stirred an additional 1.5 h. The reaction is acidified with aqueous 10% HCI and
extracted with EtOAc as well as CH2CI2. The combined organic layers are dried over
MgSO4, filtered and concentrated in vacuo to yield the titled compound (0.50 g, 9 1%)
as a yellow oil.
H NMR (300 MHz, CDCI3) 9.95 (s, 1H), 7.92 (m, 1H), 7.39 (m, 2H), 7.22 (m, 1H),
4.38 (m, 2H), 3.98 (m, 3H), 3.75 (m, 3H), 3.54 (m, 2H), 3.34 (s, 3H), 3.21 (m, 2H);
MS 3 17 (M+1 ) .
D. 1-(2-Methoxy-ethyl)-4-(morpholine-4-carbonyl)-1 H-indole-3-carboxylic acid
This compound is prepared via the Pinnick Oxidation method described in
Tetrahedron 1981 , 37, 2091 . From 1-(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-
1H-indole-3-carbaldehyde (0.20 g, 0.63 mmol) is obtained the titled compound (0.1 0
g, 48%) as solid mp 201 -203 °C (from CH2CI2/heptane).
H NMR (300 MHz, CDCI3) 8.04 (s, 1H), 7.42 (m, 1H), 7.30 (m, 2H), 7.1 9 (m, 1H),
4.35 (m, 2H), 4.01 (m, 2H), 3.76 (m, 4H), 3.63 (m, 1H), 3.51 (m, 1H), 3.34 (s, 3H),
3.22 (m, 2H);
MS 333 (M+1 ) .
E. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 1-(2-methoxy-ethyl)-4-(morpholine-4-carbonyl)-1 H-indole-3-carboxylic acid and
2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-yl-phenyl)-acetamide hydrochloride as the
starting materials.
H NMR (300 MHz, CDCI3) 7.42 (m, 2H), 7.08 (m, 3H), 6.99 (m, 2H), 4.47 (m, 2H),
4.29 (m, 2H), 3.79 (m, 2H), 3.70 (m, 4H), 3.32 (s, 3H), 3.1 0 (m, 1H), 2.00-1 .60 (m,
8H);
MS 6 19 (M+1 ) .
F. [3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-
1H-indol-4-yl]-morpholin-4-yl-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(morpholine-4-
carbonyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (mp 142-147 o C)
as the starting material.
H NMR (300 MHz, CDCI3) 8.1 2 (br s, 3H), 7.64 (m, 2H), 7.54 (m, 1H), 7.35 (m,
1H), 7.24 (m, 1H), 7.01 (m, 1H), 4.41 (m, 3H), 4.38 (m, 2H), 4.00 (m, 6H), 3.67 (m,
2H), 3.50-3.00 (m, 11H), 1.80-1 .60 (m, 2H);
MS 523 (M+1 ) .
EXAMPLE 60
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-phenyl-1 Hindol-
3-yl]-methanone hydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-phenyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (200 mg, 0.34 mmol),
phenylboronic acid (50 mg, 0.41 mmol), cesium carbonate (223 mg, 0.68 mmol), and
Pd(dppf)CI 2.CH2CI2 (28 mg, 10% mol) in dioxane/H 2O ( 10 mL/1 mL) is heated at 80
°C overnight. The reaction mixture is cooled to r.t., and then partitioned between
EtOAc and 10% citric acid. The two layers are separated, and the aqueous layer is
extracted with EtOAc once. The combined organic layers are washed with sat
NaHCO 3, H O, and brine, dried over Na SO , filtered, and concentrated in vacuo.
The crude material is purified on silica gel with CH CI2/MeOH ( 100/0 to 99/1 ) as
eluent to give the product (175 mg, 88%) as a beige foam.
H NMR (300 MHz, CDCI3) 7.75-7.1 5 (m, 8H), 7.1 5-6.90 (m, 4H), 6.50 (br s, 1H),
4.65-4.40 (m, 3H), 4.34 (t, J = 5.3 Hz, 2H), 3.78 (t, J = 5.5 Hz, 2H), 3.45 (m, 1H), 3.36
(s, 3H), 2.80-2.60 (m, 1H), 2.20-1 .75 (m, 2H), 1.75-1 .05 (m, 4H);
LC Rt 1.06 min; MS 582 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-phenyl-
1H-indol-3-yl]-methanone hydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-phenyl-
1H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide ( 120 mg, 0.29 mmol) in
MeOH (5 ml_) is added aqueous K2CO3 (323 mg, 2.33 mmol, dissolved in 1.0 ml_
H2O). This mixture is heated at 45 °C for 2 h. LC/MS indicates the reaction is
completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and EtOAc. The two layers are
separated, and the organic layer is washed with H2O and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting
suspension is concentrated in vacuo, and then dried in vacuo to yield the product
(156 mg, 100%) as a slightly pink solid.
H NMR (300 MHz, DMSO-c/6) 8.1 6 (br,s 3H), 7.70-7.50 (m, 2H), 7.55-7.40 (m, 5H),
7.40-7.20 (m, 3H), 7.20-7.00 (m, 2H), 4.55-4.20 (m, 3H), 4.1 0-3.90 (m, 2H), 3.80-3.60
(m, 3H), 3.30 (m, 1H), 3.25 (s, 3H), 2.80-2.60 (m, 1H), 2.40-1 .80 (m, 2H), 1.70-1 .00
(m, 4H);
LC 0.77 min; MS 486 (M+H, 100%).
EXAMPLE 6 1
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-pyrimidin-5-
yl-1 H-indol-3-yl]-methanone dihydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-pyrimidin-5-yl-1 H-indole-3-
e
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (200 mg, 0.34 mmol), 5-
pyrimidineboronic acid (51 mg, 0.21 mmol), cesium carbonate (223 mg, 0.68 mmol),
and Pd(dppf)CI 2.CH2CI2 (28 mg, 10% mol) in dioxane/H 2O ( 10mL/1 mL) is heated at
80 °C overnight. The reaction mixture is evaporated to dryness. The residue is
dissolved in EtOAc and the resulting solution is washed with H O and brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The crude material is used in the
next step without further purification.
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy
pyrimidin-5-yl-1 H-indol-3-yl]-methanone dihydrochloride
A mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-pyrimidin-5-
yl-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (from entry 6 1A) in MeOH
(5 mL) is added aqueous K2CO3 (323 mg, 2.33 mmol, dissolved in 1.0 mL H2O). This
mixture is heated at 45 °C for 2 h. LC/MS indicates the reaction is completed. The
reaction mixture is concentrated in vacuo to remove most of the methanol. The
residue is partitioned between H2O and EtOAc. The two layers are separated, and
the organic layer is washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. 4.0 M HCI in dioxane is added. The crude material is purified
by RP-HPLC to yield 45 mg of the product as a beige solid.
H NMR (300 MHz, DMSO-c/6) 9.22 (s, 1H), 8.84 (s, 1H), 8.08 (br s 4H), 7.95-7.70
(m, 2H), 7.0-7.30 (m, 3H), 7.30-7.1 0 (m, 3H), 4.50-4.40 (m, 2H), 4.1 5-3.95 (m, 3H),
3.80-3.65 (m, 3H), 3.30 (m, 1H), 3.24 (s, 3H), 3.05-2.85 (m, 1H), 2.60-2.40 (m, 2H),
1.75-1 .05 (m, 4H);
LC 0.63 min; MS 488 (M+H, 100%).
EXAMPLE 62
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-imidazol-1 -yl-ethyl)-7-methyl-
1H-indol-3-yl]-methanone dihydrochloride
A. 2-(7-Methyl-indol-1 -yl)-ethanol
A mixture of 7-methyl-1 H-indole (500 mg, 3.81 mmol) and powdered KOH (853
mg, 15.24 mmol) in DMSO (5 mL) is stirred at r.t. for 30 min then (2-bromo-ethoxy)-
tert-butyl-dimethyl-silane ( 1 .27 g, 5.72 mmol) is added. After the reaction mixture is
stirred at r.t. for 2 h, it is partitioned between H2O and Et2O. The two layers are
separated, and the aqueous layer is extracted with Et2O (3x). The combined organic
extracts are washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The crude material is purified on silica gel with
heptane/EtOAc (95/5 to 60/40) as eluent to yield the titled product (232 mg, 34%) as
a yellow liquid.
H NMR (300 MHz, CDCI3) 7.48 (d, J = 7.7 Hz, 1H), 7.1 1 (d, J = 3.1 Hz, 1H), 7.10-
6.90 (m, 2H), 6.51 (d, J = 3.3 Hz, 1H), 4.51 (t, J = 6.2 Hz, 2H), 3.93 (q, J = 5.3 Hz,
2H), 2.71 (s, 3H), 1.42 (t, J = 5.9 Hz, 1H);
LC Rt: 0.84 min; MS 176 (M+H, 100%).
B. Methanesulfonic acid 2-(7-methyl-indol-1 -yl)-ethyl ester
To a mixture of 2-(7-methyl-indol-1 -yl)-ethanol ( 1 .00 g, 5.71 mmol) and DIEA
( 1 .49 mL, 8.56 mmol) in CH2CI2 ( 10 mL) at 0 °C is added methansulfonyl chloride
(0.53 mL, 6.85 mmol) dropwise. After the addition is completed, the cooling bath is
removed. The reaction mixture is stirred at r.t. for 2 h. The mixture is then partitioned
between sat 10% citric acid and CH2CI2. The two layers are separated and the
organic acid is washed with sat. NaHCO3, and brine, dried over Na2SO4, filtered, and
concentrated in vacuo to yield the crude titled product ( 1 .55 g, >100%) as a yellow
solid. This solid is used in the next step without further purification.
H NMR (300 MHz, CDCI3) 7.47 (d, J = 7.1 Hz, 1H), 7.15-6.85 (m, 3H), 6.52 (d, J =
3.3 Hz, 1H), 4.69 (t, J = 5.5 Hz, 2H), 4.46 (t, J = 5.5 Hz, 2H), 2.70 (s, 3H), 2.58 (s,
3H);
LC Rt: 1.01 min; MS 254 (M+H, 100%).
C. 1-(2-lmidazol-1 -yl-ethyl)-7-methyl-1 H-indole
To a mixture of methanesulfonic acid 2-(7-methyl-indol-1 -yl)-ethyl ester ( 1 .55
g, 6.1 2 mmol) in DMF ( 12 mL) is added sodium imidazole (0.86 g, 9.1 8 mmol). After
the reaction mixture is stirred at r.t. for 3 h, the reaction mixture is concentrated in
vacuo, and the crude material is purified on silica gel with CH2Cl2/MeOH ( 100/0 to
86/14) as eluent to yield the titled product ( 1 .38 g, 100%) as a light yellow oil.
H NMR (300 MHz, CDCI3) 7.48 (d, J = 7.7 Hz, 1H), 7.1 3 (s, 1H), 7.1 0-6.85 (m, 3H),
6.65-6.50 (m, 2H), 6.44 (d, J = 3.3 Hz, 1H), 4.64 (t, J = 5.7 Hz, 2H), 4.27 (t, J = 6.0
Hz, 2H), 2.66 (s, 3H);
LC Rt: 0.67 min; MS 226 (M+H, 100%).
D. 2,2,2-Trifluoro-1 -[1 -(2-imidazol-1 -yl-ethyl)-7-methyl-1 H-indol-3-yl]-ethanone
A mixture of 1-(2-imidazol-1 -yl-ethyl)-7-methyl-1 H-indole (460 mg, 2.04 mmol)
and TFAA (0.77 ml_, 5.55 mmol) in DMF (5 ml_) is heated at 40 °C for 3 h. The
reaction is cooled to r.t. and then partitioned between H2O and Et2O. The two layers
are separated and the aqueous layer is extracted with Et2O (2x). The combined
organic layers are washed with sat. NaHCO3 and brine, dried over Na2SO , and
concentrated in vacuo. The crude material is purified on silica gel with CH CI2/MeOH
(100/0 to 98/2) as eluent to yield the titled product (51 2 mg, 78%) as a light brown
solid.
H NMR (300 MHz, CDCI3) 8.55-8.30 (m, 1H), 7.50-6.90 (m, 5H), 6.60 (bs, 1H)),
4.90-4.60 (m, 2H), 4.50-4.30 (m, 2H), 2.75 (s, 3H);
LC Rt: 0.66 min; MS 322 (M+H, 100%).
E. 1-(2-lmidazol-1 -yl-ethyl)-7-methyl-1 H-indole-3-carboxylic acid
A mixture of 2,2,2-trifluoro-1 -[1-(2-imidazol-1 -yl-ethyl)-7-methyl-1 H-indol-3-yl]-
ethanone (51 0 mg, 1.58 mmol) in MeOH (3 mL) and 5.0 M NaOH (3 mL) is heated at
70 °C overnight. This mixture is concentrated in vacuo to remove the methanol. The
residue is evaporated to dryness with a high vacuum pump. 3.0 M HCI is added to
the residue until pH is ~6. The resulting solution is concentrated to dryness in vacuo.
The crude material is used in the next step without further purification.
LC Rt: 0.50 min; MS 270 (M+H, 100%).
F. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-imidazol-1 -yl-ethyl)-7-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of crude 1-(2-imidazol-1 -yl-ethyl)-7-methyl-1 H-indole-3-carboxylic
acid ( 1 .58 mmol), DIEA (0.69 mL, 3.97 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-
4-yl-benzyl)-acetamide hydrochloride (0.54 g, 1.58 mmol), and EDCI (0.46 g, 2.38
mmol) in CH2CI2 ( 10 mL) is stirred at r.t. for 2 h. The mixture is partitioned between
H2O and CH2CI2. The two layers are separated, and the organic layer is washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is
purified on silica gel with CH2CI2/MeOH ( 100/0 to 95/5) as eluent to give the titled
product (450 mg, 5 1%) as a white powder.
H NMR (300 MHz, CDCI3) 8.65 (bs, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.40-6.90 (m,
7H), 6.69 (s, 1H), 6.62 (s, 1H), 4.72 9t, J = 5.0 Hz, 2H), 4.60-4.25 (m, 6H), 3.35-2.85
(m, 3H), 2.73 (s, 3H), 1.90-1 .40 (m, 4H);
LC Rt 0.75 min; MS 556 (M+H, 100%).
G. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-imidazol-1 -yl-ethyl)-7-
methyl-1 H-indol-3-yl]-methanone dihydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-imidazol-1 -yl-ethyl)-7-
methyl-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (445 mg, 0.80 mmol)
in MeOH ( 10 mL) is added aqueous K2CO3 (885 mg, 6.40 mmol dissolved in 2.0 mL
H2O). This mixture is heated at 45 °C for 4 h. LC/MS indicates the reaction is
completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and CH2CI2. The two layers are
separated and the aqueous layer is extracted with CH2CI2. The combined organic
layers are washed with H2O and brine, dried over Na2SO , filtered, and concentrated
in vacuo. 1.0 M HCI in Et2O is added to the residue, and the resulting suspension is
concentrated to dryness in vacuo. After the resulting solid is washed with Et2O and
heptane, it is dissolved in H2O. The solution is lyophilized to dryness to give the titled
product (274 mg, 64%) as a white powder.
H NMR (300 MHz, DMSO-c/6) 8.55 (bs, 4H), 7.80-6.90 (m, 0H), 5.00-4.80 (m,
2H), 4.70-4.50 (m, 2H), 4.40-4.1 0 (m, 2H), 4.1 0-3.90 (m, 2H), 3.30-2.90 (m, 3H), 2.70
(s, 3H), 1.95-1 .50 (m, 4H);
LC 0.49 min; MS 460 (M+H, 100%).
EXAMPLE 63
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(3-fluoro-phenyl)-1 -(2-
methoxy chloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-(3-fluoro-phenyl)-1 -(2-methoxy-ethyl)-1 H-indole-
3- e
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (200 mg, 0.34 mmol), 3-
fluorophenylboronic acid (57 mg, 0.41 mmol), cesium carbonate (223 mg, 0.68
mmol), and Pd(dppf)CI 2.CH2CI2 (28 mg, 10% mol) in dioxane/H 2O ( 10 mL/1 mL) is
heated at 80 °C overnight. The reaction mixture is cooled to r. , and then filtered
through Celite. The filtrate is partitioned between EtOAc and 10% citric acid. The
two layers are separated, and the aqueous layer is extracted with EtOAc once. The
combined organic layers are washed with H2O, and brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The crude material is purified on silica gel with
CH2CI2/MeOH ( 100/0 to 98/2) as eluent to give the product (140 mg, 68%) as a beige
foam.
H NMR (300 MHz, CDCI3) 7.60-6.95 (m, 11H), 6.55 (br s, 1H), 4.70-4.40 (m, 3H),
4.34 (t, J = 5.4 Hz, 2H), 3.77 (t, J = 5.3 Hz, 2H), 3.70-3.40 (m, 1H), 3.35 (s, 3H), 2.90-
2.70 (m, 1H), 2.60-1 .80 (m, 2H), 1.80-1 .00 (m, 4H);
LC Rt 1.07 min; MS 600 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(3-fluoro-phenyl)-1 -(2-
methoxye chloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1-[4-(3-fluoro-phenyl)-1 -(2-
methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (140 mg, 0.23
mmol) in MeOH (5 ml_) is added aqueous K2CO3 (258 mg, 1.87 mmol, dissolved in
1.0 ml_ H2O). This mixture is heated at 45 °C for 2 h. LC/MS indicates the reaction is
completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and EtOAc. The two layers are
separated, and the organic layer is washed with H2O and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting
suspension is concentrated in vacuo, and then dried in vacuo. The residue is
redissolved in H O, and the resulting solution is lyophilized to yield the product ( 1 14
mg, 9 1%) as a slightly purple fluffy solid.
H NMR (300 MHz, DMSO-c/6) 8.37 (br s, 3H), 7.80-7.05 (m, H), 4.55-4.30 (m,
3H), 4.1 0-3.90 (m, 2H), 3.80-3.60 (m, 2H), 3.30 (m, 1H), 3.25 (s, 3H), 2.90-2.65 (m,
1H), 2.50-1 .95 (m, 2H), 1.80-1 .05 (m, 4H);
LC 0.77 min; MS 486 (M+H, 100%).
EXAMPLE 64
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4
yl-1 H-indol-3-yl]-methanone hydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-thiophen-2-yl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (200 mg, 0.34 mmol), 2-
thiophenelboronic acid (53 mg, 0.41 mmol), cesium carbonate (223 mg, 0.68 mmol),
and Pd(dppf)CI 2.CH2Cl2 (28 mg, 10% mol) in dioxane/H 2O ( 10ml_/1 ml_) is heated at
80 °C overnight. The reaction mixture is cooled to r.t., and then filtered through
Celite. The filtrate is partitioned between EtOAc and 10% citric acid. The two layers
are separated, and the aqueous layer is extracted with EtOAc once. The combined
organic layers are washed with H2O, and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The crude material is purified on silica gel with CH2Cl2/MeOH
(100/0 to 98/2) as eluent to give the product (140 mg, 70%) as a beige foam.
H NMR (300 MHz, CDCI3) 7.65-6.90 (m, 10H), 6.54 (br s, 1H), 4.80-4.65 (m, 1H),
4.55-4.45 (m, 2H), 4.40-4.20 (m, 2H), 3.85-3.70 (m, 2H), 3.60-3.40 (m, 1H), 3.35 (s,
3H), 2.95-2.75 (m, 1H), 2.40-2.00 (m, 2H), 2.00-1 .00 (m, 4H);
LC Rt 1.06 min; MS 588 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-
thiophen-2-yl-1 H-indol-3-yl]-methanone hydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-thiophen-
2-yl-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide ( 138 mg, 0.23 mmol) in
MeOH (5 ml_) is added aqueous K2CO3 (260 mg, 1.88 mmol, dissolved in 1.0 ml_
H2O). This mixture is heated at 45 °C for 2 h. LC/MS indicates the reaction is
completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and EtOAc. The two layers are
separated, and the organic layer is washed with H2O and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting
suspension is concentrated in vacuo, and then dried in vacuo. The crude material is
purified by RP-HPLC to yield the product (78 mg, 64%) as a white fluffy solid.
LC 0.75 min; MS 492 (M+H, 100%).
EXAMPLE 65
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(5-chloro-pyridin
methoxy-ethyl)-1 H-indol-3-yl]-methanone dihydrochloride
A. N-(3-{1 -[4-(5-Chloro-pyridin-3-yl)-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (200 mg, 0.34 mmol), 3-
chloropyridinelboronic acid (64 mg, 0.41 mmol), cesium carbonate (223 mg, 0.68
mmol), and Pd(dppf)CI 2.CH2CI2 (28 mg, 10% mol) in dioxane/H 2O (10mL/1 ml_) is
heated at 80 °C overnight. The reaction mixture is cooled to r. , and then filtered
through Celite. The filtrate is partitioned between EtOAc and 10% citric acid. The
two layers are separated, and the aqueous layer is extracted with EtOAc once. The
combined organic layers are washed with H O, and brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The crude material is purified on silica gel with
CH2CI2/MeOH ( 100/0 to 98/2) as eluent to give the product ( 176 mg, 83%) as a
yellow foam.
H NMR (300 MHz, CDCI3) 8.75 (s, 1H), 8.55 (s, 1H), 8.05 (br s, 1H), 7.60-7.30 (m,
3H), 7.20-6.85 (m, 5H), 4.85-4.35 (m, 3H), 4.40-4.25 (m, 2H), 3.80-3.70 (m, 2H),
3.60-3.40 (m, 1H), 3.35 (s, 3H), 3.00-2.80 (m, 1H), 2.80-2.20 (m, 2H), 1.85-0.60 (m,
4H);
LC Rt 1.02 min; MS 6 17 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(5-chloro-pyridin-3-yl)-1 -(2-
metho -ethyl)-1H-indol-3-yl]-methanone dihydrochloride
To a mixture of N-(3-{1-[4-(5-chloro-pyridin-3-yl)-1 -(2-methoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide ( 176 mg,
0.29 mmol) in MeOH (5 ml_) is added aqueous K2CO3 (31 5 mg, 2.29 mmol, dissolved
in 1.0 ml_ H2O). This mixture is heated at 45 °C for 2 h. LC/MS indicates the reaction
is completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H O and EtOAc. The two layers are
separated, and the organic layer is washed with H O and brine, dried over Na SO ,
filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting
suspension is concentrated in vacuo, and then dried in vacuo. The crude material is
purified by RP-HPLC to yield the product (88 mg, 5 1%) as a pale green solid.
H NMR (300 MHz, DMSO-c/6) 8.75-8.55 (m, 2H), 8.22 (br s, 3H), 7.89 (s, 1H),
7.75-7.65 (m, 2H), 7.45-7.25 (m, 3H), 7.25-7.05 (m, 2H), 4.80-4.1 0 (m, 4H), 4.1 0-3.85
(m, 2H), 3.80-3.30 (m, 3H), 3.24 (s, 3H), 3.00-2.80 (m, 1H), 2.80-2.00 (m, 2H), 1.85-
1.00 (m, 4H);
LC 0.71 min; MS 521 (M+H, 100%).
EXAMPLE 66
4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(3,5-dichloro-phenyl^
metho -ethyl)-1H-indol-3-yl]-methanone hydrochloride
A. N-(3-{1 -[4-(3,5-Dichloro-phenyl)-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (200 mg, 0.34 mmol), 3,5-
dichlorophenyllboronic acid (78 mg, 0.41 mmol), cesium carbonate (223 mg, 0.68
mmol), and Pd(dppf)CI 2.CH2CI2 (28 mg, 10% mol) in dioxane/H 2O (10mL/1 ml_) is
heated at 80 °C overnight. The reaction mixture is cooled to r. , and then filtered
through Celite. The filtrate is partitioned between EtOAc and 10% citric acid. The
two layers are separated, and the aqueous layer is extracted with EtOAc once. The
combined organic layers are washed with H O, and brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The crude material is purified on silica gel with
CH2CI2/MeOH ( 100/0 to 98/2) as eluent to give the product ( 190 mg, 85%) as a beige
foam.
H NMR (300 MHz, CDCI3) 7.60-6.90 (m, 10H), 6.53 (br s, 1H), 4.80-4.60 (m, 1H),
4.55-4.45 (m, 2H), 4.40-4.30 (m, 2H), 3.80-3.70 (m, 2H), 3.70-3.35 (m, 1H), 3.34 (s,
3H), 3.00-2.75 (m, 1H), 2.75-2.05 (m, 2H), 1.95-1 .00 (m, 4H);
LC Rt 1.17 min; MS 650 (M+H, 100%).
B. 4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(3,5-dichloro-phenyl)-1 -(2-
meth loride
To a mixture of N-(3-{1 -[4-(3,5-dichloro-phenyl)-1 -(2-methoxy-ethyl)-1 H-indole-
3-carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (185 mg, 0.28
mmol) in MeOH (5 ml_) is added aqueous K2CO3 (314 mg, 2.27 mmol, dissolved in
1.0 ml_ H2O). This mixture is heated at 45 °C for 2 h. LC/MS indicates the reaction is
completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and EtOAc. The two layers are
separated, and the organic layer is washed with H2O and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting
suspension is concentrated in vacuo, and then dried in vacuo. The crude material is
purified by RP-HPLC to yield the product (82 mg, 52%) as a white fluffy solid.
H NMR (300 MHz, DMSO-c/6) 8.22 (br,s 3H), 7.75-7.60 (m, 2H), 7.55-7.1 0 (m, 8H),
4.60-4.20 (m, 3H), 4.1 0-3.90 (m, 2H), 3.75-3.65 (m, 2H), 3.40-3.30 (m, 1H), 3.24 (s,
3H), 2.90-2.80 (m, 1H), 2.80-2.10 (m, 2H), 1.85-1 .05 (m, 4H);
LC 0.86 min; MS 554 (M+H, 100%).
EXAMPLE 67
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(1 -propyl-
1H-pyrazol-4-yl)-1 H-indol-3-yl]-methanone hydrochloride
.-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(1 -propyl-1 H-pyrazol-4-yl)-
1H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (200 mg, 0.34 mmol), 1-
propylpyrazoyl-3-boronic acid (68 mg, 0.44 mmol), cesium carbonate (223 mg, 0.68
mmol), and Pd(dppf)CI2.CH2CI2 (28 mg, 10% mol) in dioxane/H 2O (10mL/1 ml_) is
heated at 80 °C overnight. The reaction mixture is cooled to r. , and then filtered
through Celite. The filtrate is partitioned between EtOAc and 10% citric acid. The
two layers are separated, and the aqueous layer is extracted with EtOAc once. The
combined organic layers are washed with H O, and brine, dried over Na SO , filtered,
and concentrated in vacuo. The crude material is purified on silica gel with
CH2CI2/MeOH ( 100/0 to 98/2) as eluent to give the product ( 187 mg, 89%) as a
yellow foam.
H NMR (300 MHz, CDCI3) 9.20 (br s, 1H), 8.00-7.90 (m, 1H), 8.80-8.60 (m, 2H),
7.80-6.85 (m, 6H), 4.90-4.70 (m, 1H), 4.65-4.40 (m, 2H), 4.35-4.20 (m, 2H), 4.20-4.00
(m, 2H), 3.80-3.60 (m, 2H), 3.55-3.40 (m, 1H), 3.35 (s, 3H), 3.05-2.55 (m, 3H), 2.1 0-
0.75 (m, 9H);
LC Rt OO min; MS 614 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(1 -
propyl-1 H-pyrazol-4-yl)-1 H-indol-3-yl]-methanone hydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(1 -propyl-
1H-pyrazol-4-yl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide ( 185 mg,
0.30 mmol) in MeOH (5 mL) is added aqueous K2CO3 (333 mg, 2.32 mmol, dissolved
in 1.0 mL H2O). This mixture is heated at 45 °C for 2 h. LC/MS indicates the reaction
is completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and EtOAc. The two layers are
separated, and the organic layer is washed with H2O and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting
suspension is concentrated in vacuo, and then dried in vacuo. The crude material is
purified by RP-HPLC to yield the product ( 132 mg, 78%) as a pale green solid.
H NMR (300 MHz, DMSO-c/6) 8.1 0 (br s, 3H), 7.80 (s 1H), 7.70-7.40 (m, 3H),
7..40-7.00 (m, 5H), 4.70-4.50 (m, 1H), 4.45-4.30 (m, 2H), 4.20-3.90 (m, 4H), 3.80-
3.60 (m, 2H), 3.40 (m, 1H), 3.20 (s, 3H), 2.90-2.70 (m, 1H), 2.60-2.00 (m, 2H), 2.00-
0.80 (m, 9H);
LC 0.69 min; MS 518 (M+H, 100%).
EXAMPLE 68
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-isopropoxy-1 -(2-methoxy^
1H-indol-3-yl]-methanone hydrochloride
A. 4-lsopropoxy-1 H-indole
The title compound is prepared in a similar manner as described in Example
49A using 4-hydroxyindole and 2-propanol as the starting materials.
H NMR (300 MHz, CDCI3) 8.1 1 (br s, 1 H), 7.1 2-7.07 (m, 2 H), 7.02-6.99 (m, 1 H),
6.67-6.65 (m, 1 H), 6.56 (d, 1 H), 4.72 (sept, 1 H), 1.43 (s, 3 H), 1.41 (s, 3H).
B. 4-lsopropoxy-1 -(2-methoxy-ethyl)-1 H-indole
The title compound is prepared in a similar manner as described in Example
1E using 4-isopropoxy-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 7.1 3-7.05 (m, 2 H), 6.96-6.93 (m, 1H), 6.59 (d, 1H), 6.54
(d, 1H), 4.70 (sept, 1H), 4.26 (t, 2H), 3.70 (t, 2H), 3.31 ( s, 3H), 1.42 (s, 3H), 1.40 (s,
3H).
C. 2,2,2-Trifluoro-1 -[4-isopropoxy-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-ethanone
The title compound is prepared in a similar manner as described in Example
2G using 4-isopropoxy-1 -(2-methoxy-ethyl)-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 7.94 (q, 1H), 7.27 (t, 1H), 6.98-6.95 (m, 1H), 6.79 (d,
1H), 4.69 (sept, 1H), 4.31 (t, 2H), 3.74 (t, 2H), 3.32 (s, 3H), 1.46 (s, 3H), 1.44 (s, 3H).
D. 4-lsopropoxy-1-(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
2H using 2,2,2-trifluoro-1 -[4-isopropoxy-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-ethanone
as the starting material.
H NMR (300 MHz, DMSO-c/6) .84 (br s, 1H), 8.02 (s, 1H), 7.28-7.1 8 (m, 2H),
6.88-6.85 (m, 1H), 4.92 (sept, 1H), 4.39 (t, 2H), 3.66 (t, 2H), 3.22 (s, 3H), 1.38 (s,
3H), 1.36 (s, 3H).
E. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-isopropoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 4-isopropoxy-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-
trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting
materials.
H NMR (300 MHz, CDCI3) 7.2 (m, 3H), 6.9 (m, 2H), 6.6 (m, 2H), 5.0 (bs, 1H), 4.7
(m, 1H), 4.5 (m, 2H), 4.3 (m, 2H), 4.1 (m, 1H), 3.9 (bs, 1H), 3.7 (t, 2H), 3.35 (s, 3H),
3.2 (m, 2H), 2.9 (m, 1H), 1.9-1 .7 (m, 4H), 1.5 (s, 6H).
MS m/ z [M+H]+ = 564.
F. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-isopropoxy-1 -(2-methoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
K using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[4-isopropoxy-1-(2-methoxy-ethyl)-1 H-indole-
-carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.4 (bs, 2H), 7.5 (m, 1H), 7.35 (m, 2H), 7.2 (m, 1H),
.1 (m, 2H), 6.8 (m, 1H), 4.8 (bs, 1H), 4.7 (m, 1H), 4.3 (m, 2H), 4.0 (m, 2H), 3.6 (m,
H), 3.3 (s, 3H), 3.1 (m, 2H), 2.8 (m, 1H), 1.8 (m, 2H), 1.6 (m, 2H), 1.3 (s, 6H).
S m/z [M+H]+ = 468.
EXAMPLE 69
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(4-
trifluorometh rochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(4-trifluoromethoxy-phenyl)-
1H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (200 mg, 0.34 mmol), 4-
trifluorormethoxyphenylboronic acid (85 mg, 0.41 mmol), cesium carbonate (223 mg,
0.68 mmol), and Pd(dppf)CI 2.CH2CI2 (28 mg, 10% mol) in dioxane/H 2O ( 10ml_/1 ml_) is
heated at 80 °C overnight. The reaction mixture is cooled to r. , and then filtered
through Celite. The filtrate is partitioned between EtOAc and 10% citric acid. The
two layers are separated, and the aqueous layer is extracted with EtOAc once. The
combined organic layers are washed with H O, and brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The crude material is purified on silica gel with
CH2CI2/MeOH ( 100/0 to 98/2) as eluent to give the product ( 186 mg, 82%) as a
yellow foam.
H NMR (300 MHz, CDCI3) 7.80-6.90 (m, 11H), 6.80 (br s, 1H), 4.60-4.25 (m, 5H),
4.65-4.40 (m, 2H), 3.80-3.70 (m, 2H), 3.55-3.40 (m, 1H), 3.35 (s, 3H), 2.80-2.60 (m,
1H), 2.40-1 .80 (m, 2H), 1.70-1 .00 (m, 4H);
LC Rt 1.14 min; MS 666 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(4-
trifluoromethoxy-phenyl)-1 H-indol-3-yl]-methanone hydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1-[1 -(2-methoxy-ethyl)-4-(4-
trifluoromethoxy-phenyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide ( 184
mg, 0.27 mmol) in MeOH (5 ml_) is added aqueous K2CO3 (305 mg, 2.21 mmol,
dissolved in 1.0 ml_ H2O). This mixture is heated at 45 °C for 2 h. LC/MS indicates
the reaction is completed. The reaction mixture is concentrated in vacuo to remove
most of the methanol. The residue is partitioned between H2O and EtOAc. The two
layers are separated, and the organic layer is washed with H2O and brine, dried over
Na2SO4, filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The
resulting suspension is concentrated in vacuo, and then dried in vacuo. The crude
material is purified by RP-HPLC to yield the product ( 130 mg, 79%) as a pale green
solid.
H NMR (300 MHz, DMSO-c/6) 8.1 9 (br s, 3H), 7.70-7.05 (m 11H), 4.50-4.1 0 (m,
3H), 4.05-3.85 (m, 2H), 3.80-3.60 (m, 2H), 3.80-3.60 (m, 2H), 3.40 (m, 1H), 3.25 (s,
3H), 2.80-2.60 (m, 1H), 2.60-1 .80 (m, 2H), 1.75-1 .10 (m, 4H);
LC 0.85 min; MS 570 (M+H, 100%).
EXAMPLE 70
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(4-methoxyyl)-
1 H-indol-3-yl]-methanone hydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(4-methoxy-phenyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (200 mg, 0.34 mmol), 4-
methoxyphenylboronic acid (64 mg, 0.41 mmol), cesium carbonate (223 mg, 0.68
mmol), and Pd(dppf)CI 2.CH2CI2 (28 mg, 10% mol) in dioxane/H 2O (4.5ml_/0.5ml_) is
heated at 80 °C overnight. The reaction mixture is concentrated in vacuo to remove
the solvent. The crude material is purified on silica gel with CH CI2/MeOH (100/0 to
98/2) as eluent to give the product (180 mg, 86%).
H NMR (300 MHz, CDCI3) 7.70-6.40 (m, 12H), 4.75-4.10 (m, 5H), 3.95-3.60 (m,
5H), 3.50-3.1 0 (m, 4H), 2.90-2.60 (m, 1H), 2.40-1 .20 (m, 6H);
LC Rt 1.05 min; MS 6 12 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(4-
methoxy-phenyl)-1 H-indol-3-yl]-methanone hydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(4-
methoxy-phenyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (168 mg,
0.27 mmol) in MeOH (5 mL) is added aqueous K2CO3 (303 mg, 2.1 9 mmol, dissolved
in 1.0 mL H2O). This mixture is heated at 45 °C for 2 h. LC/MS indicates the reaction
is completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and EtOAc. The two layers are
separated, and the organic layer is washed with H2O and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting
suspension is concentrated in vacuo, and then dried in vacuo. The crude material is
triturated with Et2O, and the beige solid ( 126 mg, 85%) is collected by vacuum
filtration.
H NMR (300 MHz, DMSO-c/6) 8.25 (br s, 3H), 7.70-6.90 (m 11H), 4.50-4.30 (m,
3H), 4.1 0-3.85 (m, 2H), 3.81 (s, 3H), 3.75-3.60 (m, 2H), 3.50-3.1 0 (m, 4H), 2.80-2.60
(m, 1H), 2.40-1 .10 (m, 6H);
LC 0.76 min; MS 516 (M+H, 100%).
EXAMPLE 7 1
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(4-fluoro-phenyl)-1 -(2-methoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-(4-fluoro-phenyl)-1 -(2-methoxy-ethyl)-1 H-indole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (200 mg, 0.34 mmol), 4-
fluorophenylboronic acid (57 mg, 0.41 mmol), cesium carbonate (223 mg, 0.68
mmol), and Pd(dppf)CI 2.CH2CI2 (28 mg, 10% mol) in dioxane/H 2O (4.5ml_/0.5ml_) is
heated at 80 °C overnight. The reaction mixture is concentrated in vacuo to remove
the solvent. The crude material is purified on silica gel with CH CI2/MeOH (100/0 to
98/2) as eluent to give the product (187 mg, 9 1%).
H NMR (300 MHz, CDCI3) 7.80-6.90 (m, 11H), 6.70-6.50 (bs, 1H), 4.75-4.20 (m,
5H), 3.90-3.70 (m, 2H), 3.50-3.30 (m, 4H), 2.90-2.60 (m, 1H), 2.1 0-1 .20 (m, 6H);
LC Rt 1.07 min; MS 600 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(4-fluoro-phenyl)-1 -(2-
methoxy-ethyl)-1 H-indol-3-yl]-methanone hydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1-[4-(4-fluoro-phenyl)-1 -(2-
methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide ( 185 mg, 0.31
mmol) in MeOH (5 mL) is added aqueous K2CO3 (341 mg, 2.4 mmol, dissolved in 1.0
mL H2O). This mixture is heated at 45 °C for 2 h. LC/MS indicates the reaction is
completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and EtOAc. The two layers are
separated, and the organic layer is washed with H2O and brine, dried over Na SO ,
filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting
suspension is concentrated in vacuo, and then dried in vacuo. The crude material is
triturated with Et O and the beige solid ( 128 mg, 76%) is collected by vacuum
filtration.
H NMR (300 MHz, DMSO-c/6) 8.25 (br s, 3H), 7.80-7.00 (m 11H), 4.50-4.1 0 (m,
3H), 4.1 0-3.85 (m, 2H), 3.80-3.60 (m, 2H), 3.40-3.1 0 (m, 4H), 2.90-2.65 (m, 1H),
2.40-1 .00 (m, 6H);
LC 0.75 min; MS 504 (M+H, 100%).
EXAMPLE 72
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(3-hydroxy-phenyl)-1 -(2-
methoxy-ethyl)-1 H-indol-3-yl]-methanone hydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-(3-hydroxy-phenyl)-1 -(2-methoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (200 mg, 0.34 mmol), 3-
hydroxyphenylboronic acid (57 mg, 0.41 mmol), cesium carbonate (223 mg, 0.68
mmol), and Pd(dppf)CI 2.CH2CI2 (28 mg, 10% mol) in dioxane/H 20 (4.5ml_/0.5ml_) is
heated at 80 °C overnight. The reaction mixture is concentrated in vacuo to remove
the solvent. The crude material is purified on silica gel with CH CI2/MeOH (100/0 to
98/2) as eluent to give the product ( 158 mg, 77%) as a beige foam. This material is
used in the next step without further purification.
LC Rt 0.99 min; MS 598 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(3-hydroxy-phenyl)-1 -(2-
methoxy-ethyl)-1 H-indol-3-yl]-methanone hydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[4-(3-hydroxy-phenyl)-1 -(2-
methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide ( 156 mg, 0.26
mmol) in MeOH (5 mL) is added aqueous K2CO3 (288 mg, 2.1 mmol, dissolved in 1.0
mL H2O). This mixture is heated at 45 °C for 2 h. LC/MS indicates the reaction is
completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and CH2CI2. The two layers are
separated, and the aqueous layer is extracted with CH2CI2 (3x). The crude material is
purified by RP-HPLC to give the product (74 mg, 52%) as a white fluffy solid.
H NMR (300 MHz, DMSO-c/6) 9.43 (s, 1H), 8.07 (br s, 3H), 7.65-6.70 (m 11H),
4.60-4.25 (m, 3H), 4.10-3.90 (m, 2H), 3.80-3.60 (m, 2H), 3.40-3.1 0 (m, 4H), 2.85-2.65
(m, 1H), 2.40-1 .00 (m, 6H);
LC 0.70 min; MS 502 (M+H, 100%).
EXAMPLE 73
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-pyridin-3-yl-
1H-indol-3-yl]-methanone dihydrochloride
A. 2,2,2-Trifluoro-1 -[1 -(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-
yl)-1 H-indol-3-yl]-ethanone
A mixture of 1-[4-bromo-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-2,2,2-trifluoroethanone
(entry 48B) (700 mg, 2 mmol), bis-(pinacolate) diboron (776 mg, 3 mol),
potassium acetate (784 mg, 8 mmol), Pd(dppf)Cl 2.CH2Cl2 ( 1 14 mg, 0.14 mmol) in
anhydrous DMSO (15 ml_) is heated at 70 °C for 5 h. The mixture is cooled to r.t.,
and is partitioned between water and EtOAc. The two layers are separated, and the
organic layer is washed with water and brine, and concentrated in vacuo. The crude
material is purified on silica gel with heptane/EtOAc (75/25 to 55/45) as eluent to give
the product as a whilte solid (507 mg, 63%).
H NMR (300 MHz, CDCI3) 8.01 (d, J = 1.5 Hz, 1H), 7.60-7.25 (m, 3H), 4.35 (t, J =
5.1 Hz, 2H), 3.70 (t, J = 5.4 Hz, 2H), 3.28 (s, 3H), 1.48 (s, 12H);
LC Rt 1.09 min; MS 398 (M+H, 100%).
B. 2,2,2-Trifluoro-1 -[1 -(2-methoxy-ethyl)-4-pyridin-3-yl-1 H-indol-3-yl]-ethanone
A mixture of 2,2,2-trifluoro-1 -[1 -(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-
[ 1 ,3,2]dioxaborolan-2-yl)-1 H-indol-3-yl]-ethanone (370 mg, 0.93 mmol), 3-
bromopyridine (0.1 mL, 1.1 1 mmol), Cs2CO3 (606 mg, 1.86 mmol), and
Pd(dppf)CI 2.CH2CI2 (76 mg, 10% mmol) in dioxane (4.5 ml_)/water (0.5 mL) is heated
at 75 °C overnight. The solvent is removed in vacuo, and the crude material is
purified on silica gel with heptane/EtOAC (70/30 to 50/50) as eluent to give the
product (275 mg, 84%) as a light brown oil.
H NMR (300 MHz, CDCI3) 8.70-8.50 (m, 2H), 8.20-8.1 0 (m, 1H), 7.70-7.55 (m,
1H), 7.50-7.40 (m, 2H), 7.40-7.20 (m, 2H), 4.44 (t, J = 4.9 Hz, 2H), 3.81 (t, J = 5.3
Hz, 2H), 3.36 (s, 3H);
LC Rt 0.67 min; MS 349 (M+H, 100%).
C. 1-(2-Methoxy-ethyl)-4-pyridin-3-yl-1 H-indole-3-carboxylic acid hydrochloride
A mixture of 2,2,2-trifluoro-1 -[1 -(2-methoxy-ethyl)-4-pyridin-3-yl-1 H-indol-3-yl]-
ethanone (270 mg, 0.77 mmol) in MeOH ( 1 .6 mL) and 5 M NaOH ( 1 .6 mL) is heated
at 70 °C overnight. The solvent is removed in vacuo, and the residue is dissolved in
water. The pH of the solution is adjusted to ~3 with 3 M HCI. The solution is
concentrated to dryness in vacuo. The residue is used in the next step without further
purification.
LC Rt 0.53 min; MS 297 (M+H, 00%).
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-pyridin-3-yl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of 1-(2-methoxy-ethyl)-4-pyridin-3-yl-1 H-indole-3-carboxylic acid
hydrochloride (0.77 mmol), DIEA (0.47 ml_, 2.7 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-
piperidin-4-yl-benzyl)-acetamide hydrochloride (31 7 mg, 0.93 mmol), and EDCI (193
mg, 1.0 mmol) in CH2CI2 (20 ml_) is stirred at r.t. for 5 h. The mixture is partitioned
between H2O and CH2CI2. The two layers are separated, and the organic layer is
washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
crude material is purified on silica gel with CH2Cl2/MeOH ( 100/0 to 98/2) as eluent to
give the product ( 166 mg, 36% from entry 73B) as a white foam.
H NMR (300 MHz, CDCI3) 8.85-8.75 (m, 1H), 8.60-8.50 (m, 1H), 8.09 (bs, 1H),
7.60-6.80 (m, 9H), 4.80-4.30 (m, 5H), 3.80-3.70 (m, 2H), 3.50-3.25 (m, 4H), 3.00-2.20
(m, 3H), 1.70-0.80 (m, 4H);
LC Rt 0.85 min; MS 583 (M+H, 100%).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-pyridin-3-
yl-1 H-indol-3-yl]-methanone dihydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-pyndin-3-
yl-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (160 mg, 0.27 mmol) in
MeOH (5 mL) is added aqueous K2CO3 (303 mg, 2.2 mmol, dissolved in 1.0 mL H2O).
This mixture is heated at 45 °C for 4 h. LC/MS indicates the reaction is completed.
The reaction mixture is concentrated in vacuo to remove most of the methanol. The
residue is partitioned between H2O and CH2CI2. The two layers are separated, and
the organic layer is washed with water and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue is suspended in 1M HCI in Et2O. The solid is
triturated with Et2O. The slightly yellow solid (170 mg, quantitative) is collected by
suction filteration.
H NMR (300 MHz, DMSO-c/6) 8.80-8.20 (m, 4H), 8.1 0-7.00 (m, 11H), 4.60-3.60
(m, 7H), 3.30-3.20 (m, 4H), 2.90-2.60 (m, 1H), 2.40-1 .00 (m, 6H);
LC 0.58 min; MS 487 (M+H, 100%).
EXAMPLE 74
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-pyridin-2-yl-
1H-indol-3-yl]-methanone dihydrochloride
A. 2,2,2-Trifluoro-1 -[1 -(2-methoxy-ethyl)-4-pyridin-2-yl-1 H-indol-3-yl]-ethanone
A mixture of 2,2,2-trifluoro-1 -[1 -(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-
[ 1 ,3,2]dioxaborolan-2-yl)-1 H-indol-3-yl]-ethanone (entry 73A) (220 mg, 0.55 mmol), 2-
bromopyridine (59 _, 0.61 mmol), CS2CO3 (360 mg, 1.1 mmol), and
Pd(dppf)CI 2.CH2CI2 (45 mg, 10% mmol) in dioxane (4.5 ml_)/water (0.5 mL) is heated
at 80 °C for 4 h. The solvent is removed in vacuo, and the crude material is purified
on silica gel with heptane/EtOAC (70/30 to 50/50) as eluent to give the product (87
mg, 46%) as a light yellow oil.
H NMR (300 MHz, CDCI3) 8.61 (d, J = 4.7 Hz, 1H), 8.80 (d, J = 1.6 Hz, 1H), 7.90-
7.80 (m, 1H), 7.60-7.40 (m, 3H), 7.40-7.1 0 (m, 2H), 4.42 (t, J = 5.2 Hz, 2H), 3.77 (t, J
= 5.1 Hz, 2H), 3.34 (s, 3H);
LC Rt 0.67 min; MS 349 (M+H, 100%). LC Rt 0.66 min; MS 349 (M+H, 100%).
B. 1-(2-Methoxy-ethyl)-4-pyridin-2-yl-1 H-indole-3-carboxylic acid hydrochloride
A mixture of 2,2,2-trifluoro-1 -[1 -(2-methoxy-ethyl)-4-pyridin-2-yl-1 H-indol-3-yl]-
ethanone (85 mg, 0.24 mmol) in MeOH (0.49 mL) and 5 M NaOH (0.49 mL) is heated
at 70 °C overnight. The solvent is removed in vacuo, and the residue is dissolved in
water. The pH of the solution is adjusted to ~3 with 3 M HCI. The solution is
concentrated to dryness in vacuo. The residue is used in the next step without further
purification.
LC Rt 0.50 min; MS 297 (M+H, 00%).
C. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-pyridin-2-yl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of 1-(2-methoxy-ethyl)-4-pyridin-2-yl-1 H-indole-3-carboxylic acid
hydrochloride (0.24 mmol), DIEA (0.15 mL, 0.85 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-
piperidin-4-yl-benzyl)-acetamide hydrochloride (100 mg, 0.29 mmol), and EDCI (60
mg, 0.32 mmol) in CH2CI2 ( 10 mL) is stirred at r.t. overnight. The mixture is
partitioned between H2O and CH2CI2. The two layers are separated, and the organic
layer is washed with brine, dried over Na2SO , filtered, and concentrated in vacuo.
The crude material is purified on silica gel with CH2CI2/MeOH ( 100/0 to 98/2) as
eluent to give the product ( 110 mg, 77% from entry 74A) as a white foam.
H NMR (300 MHz, CDCI3) 8.80-8.65 (m, 1H), 7.80-6.85 (m, 10H), 6.64 (bs, 1H),
4.80-4.20 (m, 5H), 3.80-3.70 (m, 2H), 3.70-3.45 (m, 1H), 3.34 (s, 3H), 2.90-2.60 (m,
1H), 2.50-1 .1 0 (m, 6H);
LC Rt 0.84 min; MS 583 (M+H, 100%).
D. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-pyridin-2-
yl-1 H-indol-3-yl]-methanone dihydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-pyridin-2-
yl-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (105 mg, 0.1 8 mmol) in
MeOH (5 mL) is added aqueous K2CO3 ( 199 mg, 1.4 mmol, dissolved in 1.0 mL H2O).
This mixture is heated at 45 °C for 2 h. LC/MS indicates the reaction is completed.
The reaction mixture is concentrated in vacuo to remove most of the methanol. The
residue is partitioned between H2O and CH2CI2. The two layers are separated, and
the organic layer is washed with water and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue is suspended in 1M HCI in Et2O. The solid is
triturated with Et2O. The yellowish green solid (74 mg, 73%) is collected by suction
Alteration.
H NMR (300 MHz, DMSO-c/6) 8.90-8.10 (m, 4H), 7.90-7.1 0 (m, 11H), 4.60-3.60
(m, 7H), 3.30-3.10 (m, 4H), 3.00-2.80 (m, 1H), 2.40-1 .00 (m, 6H);
LC 0.58 min; MS 487 (M+H, 100%).
EXAMPLE 75
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-amino-1 -(2-methoxy-ethyl)-1 Hindol-
3-yl]-methanone hydrochloride
A. 1-(2-methoxy-ethyl)-4-nitro-1 H-indole
The title compound is prepared in a similar manner as described in Example
E using 4-nitro-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 8.2 (d, H), 7.47(d, 2H), 7.5 (m, H), 7.3 (m, 2H), 4.4 (t,
H), 3.8 (t, 2H), 3.3 (s, 3H).
S m/z [M+H]+=221 .
B. 2,2,2-Trifluoro-1 -[1 -(2-methoxy-ethyl)-4-nitro-1 H-indol-3-yl]ethanone
The title compound is prepared in a similar manner as described in Example
G using 1-(2-methoxy-ethyl)-4-nitro-1 H-indole as the starting material.
H NMR (300 MHz, CDCI3) 8.2 (d, H), 7.8 (m, 2H), 7.5 (m, 1H), 4.5 (t, 2H), 3.8 (t,
2H), 3.4 (s, 3H).
MS m/z [M+H]+=31 7.
C. 1-(2-Methoxy-ethyl)- 4-nitro-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as describedin Example
2H using 2,2,2-trifluoro-1 -[1 -(2-methoxy-ethyl)-4-nitro-1 H-indol-3-yl]ethanone as the
starting material.
H NMR (300 MHz, DMSO-c/6) 12.2 (bs, H), 8.2 (s, H), 8.0 (d, H), 7.6 (d, H),
7.4 (m, H), 4.5 (t, 2H), 3.7 (t, 2H), 3.2 (s, 3H).
MS m/z: [M+H]+=265.
D. 2,2,2-Trifluoro- N-(4-fluoro-3-{1 -[1-(2-methoxy-ethyl)-4-nitro-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example
6E using 1-(2-methoxy-ethyl)- 4-nitro-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-
N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting materials.
H NMR (300 MHz, CDCI3) 8.1 (d, 1H), 7.8 (d, 1H), 7.6 (s, 1H), 7.4 (m, 1H), 7.2 (m,
1H), 7.1 5 (m, 1H), 7.0 (m, 1H), 6.7 (bs, 1H), 5.0 (m, 1H), 4.5 (m, 2H), 4.35 (m, 2H),
3.8 (m, 1H), 3.7 (m, 2H), 3.3 (s, 3H), 3.20 (m, 2H), 3.0 (m, 1H), 1.9 (m, 2H), 1.6 (m,
2H).
MS m/z [M+H]+=551 .
E. N-(3-{1 -[4-Amino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-
fluoro-benzyl)-2,2,2-trifluoro-acetamide
A solution of 2,2-trifluoro- N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-nitro-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (2.8 g, 5.1 mmol) and 10% Pd/C
( 1 .0 g) in methanol (35 ml_) is hydrogentated at 50 psi for 3 hours. The mixture is
then filtered over a cake of celite and the cake is washed with excess methanol. The
filtrate is then concentrated in vacuo to give 2.0 g of the title compound.
H NMR (300 MHz, CDCI3) 7.3 (s, 1H), 7.2-7.0 (m, 4H), 6.8 (d, 1H), 6.7 (bs, 1H),
6.4 (d, 1H), 4.7 (m, 2H), 4.5 (m, 2H), 4.2 (m, 2H), 3.7 (m, 2H), 3.3 (s, 3H), 3.1 5 (m,
3H), 1.9 (m, 2H), 1.8 (m, 2H), 1.6 (bs, 2H).
MS m/z: [M+H]+=521 .
F- [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-amino-1 -(2-methoxy-ethyl)-
1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1 -[4-amino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-
4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material .
H NMR (300 MHz, DMSO-c/6) 8.3 (bs, 2H), 7.9 (m, 1H), 7.7 (m, 1H), 7.4 (m, 2H),
7.2 (m, 2H), 6.9 (bs, H), 4.6 (m, 2H), 4.4 (m, 2H), 4.0 (m, 2H), 3.6 (m, 2H), 3.3 (m,
3H), 3.2 (s, 3H), 2.6 (m, 2H), .9-1 .7 (m, 4H).
MS m/ z [M+H]+=425.
EXAMPLE 76
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-methylamino-1-(2-methoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
A-1 . [N-(3-{1 -[4-methylamino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide and A-2. N-(3-{1 -[4-
dimethylamino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-fluorobenzyl)-
2,2,2-trifluoro-acetamide
To a solution of N-(3-{1 -[4-amino-1-(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide ( 1 .5 g, 2.88 mmol) in 20 mL
MeOH is added 1 mL of 37% formaldehyde. The reaction mixture is stirred for 5 min.
A solution of zinc chloride (20 mg, 0.14 mmol) and sodium cyanoborohydride (0.1 8 g,
2.88 mmol) in MeOH (5 mL) is added. The mixture is stirred for 18 h at r.t. The
mixture is diluted with 100 mL of water and 250 mL of ethyl acetate. The organic
phase is separated and is washed with brine, dried with Na2SO 4 , filtered and is
concentrated in vacuo. The crude residue is flash chromatographed over S1O2 eluting
with 100% EtOAc to afford 0.34 g of [N-(3-{1 -[4-methylamino-1 -(2-methoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
H NMR (300 MHz, CDCI3) 7.3 (m, 3H), 7.2 (m, 1H), 7.1 (m, 1H), 6.7 (d, 1H), 6.6
(bs, 1H), 6.4 (m, 1H), 6.3 (d, 1H), 4.7 (m, 2H), 4.5 (m, 2H), 4.2 (m, 2H), 3.7 (m, 2H),
3.3 (s, 3H), 3.2 (m, 3H), 2.9 (d, 3H), 1.9 (m, 2H), 1.8 (m, 2H). MS m/z [M+H]+=535.
and 0.51 g of [N-(3-{1 -[4-dimethylamino-1-(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide. H NMR (300 MHz, CDCI3) 
7.4 (m, 1H), 7.2 (m, 3H), 7.0 (m, 2H), 6.7 (m, 2H), 5.0 (bs, 1H), 4.5 (m, 2H), 4.3 (m,
3H), 3.8 (m, 3H), 3.3 (s, 3H), 3.2 (m, 2H), 2.8 (s, 6H), 1.9 (m, 2H), 1.8 (m, 2H). MS
m/z [M+H]+=549.
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-methylamino-1 -(2-methoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1 -[4-methylamino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-
4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material .
H NMR (300 MHz, DMSO-c/6) 8.4 (bs, 2H), 7.8 (m, 1H), 7.6 (m, 1H), 7.4 (m, 1H),
7.2 (m, 3H), 6.7 (bs, 1H), 4.6 (m, 2H), 4.4 (m, 2H), 4.0 (m, 4H), 3.7 (m, 2H), 3.3 (m,
3H), 3.2 (s, 3H), 2.8 (m, 3H), 1.9-1 .7 (m, 4H).
MS m/z: [M+H]+=439.
EXAMPLE 77
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[4-dimethylamino-1 -(2-methoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1 -[4-dimethylamino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material .
H NMR (300 MHz, DMSO-c/6) 8.4 (bs, 2H), 8.2 (m, 1H), 7.8 (m, 2H), 7.6 (m, 1H),
7.5 (m, H), 7.4 (m, H), 7.2 (m, H), 4.6 (bs, H), 4.5 (m, 2H), 4.0(m, 2H), 3.7 (m,
2H), 3.5 (m, 4H), 3.3 (m, 3H), 3.2 (s, 6H), .9-1 .7 (m, 4H).
MS m/z [M+H]+=453.
EXAMPLE 78
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-pyridin-4-yl-1
trifluoromethoxy-ethyl)-1 H-indol-3-yl]-methanone dihydrochloride
A. 1-(4-B thanone
A mixture of 4-bromoindole (5.0 g, 25.5 mmol) and TFAA ( 10.6 ml_, 76.5
mmol) in DMF (20 ml_) is heated at 40 °C overnight. The reaction mixture is
partitioned between water and Et2O. The two layers are separated, and the organic
layer is washed with saturated Na2CO3, water, and brine, dried over MgSO4, filtered,
and concentrated in vacuo to yield the product (5.64 g, 75%) as a brown powder.
H NMR (300 MHz, DMSO-c/6) 5 12.91 (bs, 1H), 8.55 (s, 1H), 7.62 (d, J = 8.0 Hz,
1H), 7.53 (d, J = 7.5 Hz, 1H), 7.40-7.10 (m, 1H);
9F NMR (300 MHz, DMSO-c/6) 5 -70.1 2;
LC Rt 0.91 min; MS 293 (M+H, 100%).
B. 1-[4-Bromo-1 -(2-trifluoromet ol-3-yl]-2,2,2-trifluoro-ethanone
A mixture of 1-(4-bromo-1 H-indol-3-yl)-2,2,2-trifluoro-ethanone (4.50 g, 22.0
mmol) and NaH (0.97 mg, 60% oil dispersion, 24.1 mmol) in THF (40 mL) is stirred at
0 °C for 5 min. Trifluoro-methanesulfonic acid 2-trifluoromethoxy-ethyl ester (J. Org.
Chem 2001 , 66, 1061-1 062) (6.30 g, 24.1 mmol) is added. This mixture is stirred at 0
°C for 10 min and then at r.t. for 1 h. The mixture is partitioned between water and
EtOAc. The two layers are separated, and the organic layer is washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo. The crude material is purified
on silica gel with heptane/EtOAc ( 100/0 to 50/50) as eluent to give the product (5.21
g, 80%).
H NMR (300 MHz, CDCI3) 8.00 (d, J = 1.7 Hz, 1H), 7.65-7.55 (m, 1 H), 7.40-7.1 5
(m, 2H), 4.52 (t, J = 5.1 Hz, 2H), 4.33 (t, J = 5.3 Hz, 2H);
9F NMR (300 MHz, CDCI3) -61 .82 (s, 3F), -72.1 7 (s, 3F);
LC Rt: 1.18 min; MS 405 (M+1 ) .
C. 4-Bromo-1 -(2-trifluorom H-indole-3-carboxylic acid
A mixture of 1-[4-bromo-1 -(2-trifluoromethoxy-ethyl)-1 H-indol-3-yl]-2,2,2-
trifluoro-ethanone (5.0 g, 12.4 mmol) in MeOH ( 100 mL) and aqueous NaOH (5.0 M,
50 ml_) is stirred at 80 °C for 1 h and then at 60 °C for 1.5 h. The mixture is
concentrated in vacuo to remove the organic solvent. The residue is partitioned
between water and Et2O. The two layers are separated, and the aqueous layer is
acidified to pH ~2 with cone. HCI at 0 °C. The acidified aqueous layer is extracted
with EtOAc. The organic extract is washed with water and brine, dried over MgSO4,
filtered, and concentrated in vacuo to give the crude product (3.77 g, 86%) which is
used in the next step without further purification.
H NMR (300 MHz, DMSO-c/6) 12.1 0 (bs, 1H), 8.1 6 (s,1 H), 7.68 (d, J = 7.7 Hz, 1H),
7.42 (d, J = 7.1 Hz, 1 H), 7.1 6 (t, J = 8.1 Hz, 1H), 4.62 (t, J = 4.7 Hz, 2H), 4.44 (t, J =
5.2 Hz, 2H);
9F NMR (300 MHz, CDCI3) -59.63;
LC Rt: 0.95 min; MS 353 (M+1 ) .
N-(3-{1 -[4-Bromo-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-
yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
A mixture of 4-bromo-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic acid
( 1 .0 g, 2.84 mmol), Et3N ( 1 .18 ml_, 8.52 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-
4-yl-benzyl)-acetamide hydrochloride ( 1 .26 g, 3.69 mmol), and EDCI (81 7 mg, 4.26
mmol) in CH2CI2 (20 ml_) is stirred at r.t. for 3.5 h. The mixture is partitioned between
H2O and EtOAc. The two layers are separated, and the organic layer is washed with
brine, dried over MgSO , filtered, and concentrated in vacuo. The crude material is
purified on silica gel with heptane/EtOAc (30/70 to 0/1 00) as eluent to give the
product ( 1 .04 g, 57%).
H NMR (300 MHz, CDCI3) 7.25-6.90 (m, 7H), 6.75 (br s, 1H), 5.1 5-4.90 (br m, 1H),
4.60-4.30 (m, 4H), 4.30-4.10 (m, 2H), 4.00-3.45 (m, 1H), 3.30-3.00 (m, 2H), 3.00-2.80
(m, 1H), 2.1 0-1 .50 (m, 4H);
9F NMR (300 MHz, CDCI3) -60.66 (s, 3F), -75.31 (s, 3F), - 120.03 (s, 1F), - 1 18.88
(m, 1F);
LC Rt 1.05 min; MS 638 (M+1 , 100%).
E. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-pyridin-4-yl-1 -(2-trifluoromethoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (200 mg, 0.34
mmol), 4-pyridineboronic acid (46 mg, 0.37 mmol), cesium carbonate (204 mg, 0.62
mmol), and Pd(dppf)CI 2.CH2CI2 (26 mg, 10% mol) in dioxane/H 2O (9 mL/1 ml_) is
heated at 80 °C for 5 h. The reaction mixture is concentrated in vacuo to remove the
solvent. The crude material is purified on silica gel with CH CI2/MeOH (100/0 to 97/3)
as eluent to give the product ( 187 mg, 94%) as a white solid.
H NMR (300 MHz, CDCI3) 8.75-8.55 (m, 1H), 7.70-6.80 (m, 11H), 4.80-4.20 (m,
6H), 3.40-3.20 (m, 1H), 3.00-2.00 (m, 3H), 1.80-1 .00 (m, 4H);
LC Rt 0.86 min; MS 637 (M+H, 100%).
F. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-pyridin-4-yl-1 -(2-
trifluoromethoxy-ethyl)-1 H-indol-3-yl]-methanone dihydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[4-pyridin-4-yl-1 -(2-
trifluoromethoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}benzyl)-acetamide ( 185
mg, 0.29 mmol) in MeOH (5 ml_) is added aqueous K2CO3 (321 mg, 2.3 mmol,
dissolved in 1.0 ml_ H2O). This mixture is heated at 45 °C for 4 h. LC/MS indicates
the reaction is completed. The reaction mixture is concentrated in vacuo to remove
most of the methanol. The residue is partitioned between H2O and CH2CI2. The two
layers are separated, and the organic layer is washed with H2O and brine, dried over
Na2SO4, filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The
resulting suspension is concentrated in vacuo, and then dried in vacuo. The crude
material is triturated with Et2O, and the yellowish green solid ( 108 mg, 60%) is
collected by vacuum filtration.
H NMR (300 MHz, DMSO-c/6) 9.0-8.80 (m, 1H), 8.60-8.30 (bs, 4H), 8.00-7.80 (m,
2H), 7.70-7.1 0 (m, 8H), 4.90-4.60 (m, 2H), 4.60-3.80 (m, 6H), 3.00-2.85 (m, 1H),
2.40-2.00 (m, 2H), 1.80-1 .30 (m, 4H);
LC 0.61 min; MS 541 (M+H, 100%).
EXAMPLE 79
4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-bromo-1 -(2-trifluoromethoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
A mixture of N-(3-{1 -[4-bromo-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (entry 78D) (50 mg,
0.078 mmol) in MeOH ( 1 .8 ml_) is added aqueous K2CO3 (86 mg, 0.62 mmol,
dissolved in 0.2 ml_ H2O). This mixture is heated at 45 °C for 4 h. LC/MS indicates
the reaction is completed. The reaction mixture is concentrated in vacuo to remove
most of the methanol. The residue is partitioned between H2O and CH2CI2. The two
layers are separated, and the organic layer is washed with H2O and brine, dried over
Na2SO4, filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The
resulting suspension is concentrated in vacuo, and then dried in vacuo. The crude is
triturated with Et2O, and the beige solid is collected by vacuum filtration to yield the
title product (25 mg, 55%).
H NMR (300 MHz, DMSO-c/6) 7.80-7.00 (m, 7H), 5.1 0 (bs, 3H), 4.90-4.30 (m, 5H),
4.00-3.50 (m, 3H), 3.20-2.70 (m, 3H), 2.40-2.00 (m, 2H), 2.00-1 .40 (m, 4H);
LC 0.75 min; MS 543 (M+H, 100%).
EXAMPLE 80
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-phenyl-1 -(2-trifluoromethoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-phenyl-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (entry 78D) (200
mg, 0.34 mmol), phenylboronic acid (46 mg, 0.37 mmol), cesium carbonate (204 mg,
0.62 mmol), and Pd(dppf)CI 2.CH2CI2 (26 mg, 10% mol) in dioxane/H 2O (9 mL/1 mL) is
heated at 80 °C for 5 h. The reaction mixture is concentrated in vacuo to remove the
solvent. The crude material is purified on silica gel with CH CI2/MeOH (100/0 to 97/3)
as eluent to give the product ( 196 mg, 96%) as a white foam.
H NMR (300 MHz, CDCI3) 7.80-6.80 (m, 12H), 6.50 (bs, 1H), 4.65-4.20 (m, 5H),
3.50-3.20 (m, 1H), 2.80-2.60 (m, 1H), 2.20-1 .00 (m, 6H);
LC Rt 1.1 1 min; MS 636 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-phenyl-1 -(2-trifluoromethoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[4-phenyl-1 -(2-trifluoromethoxyethyl)-
1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (195 mg, 0.31 mmol) in
MeOH (5 mL) is added aqueous K2CO3 (339 mg, 2.4 mmol, dissolved in 1.0 mL H2O).
This mixture is heated at 45 °C for 4 h. LC/MS indicates the reaction is completed.
The reaction mixture is concentrated in vacuo to remove most of the methanol. The
residue is partitioned between H2O and CH2CI2. The two layers are separated, and
the organic layer is washed with H O and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting suspension is
concentrated in vacuo, and then dried in vacuo. The crude material is triturated with
Et O, and the yellowish green solid ( 122 mg, 44%) is collected by vacuum filtration.
H NMR (300 MHz, DMSO-c/6) 8.20 (bs, 3H), 7.80-7.00 (m, 12H), 4.80-4.10 (m,
5H), 4.05-3.85 (m, 2H), 3.20-3.00 (m, 1H), 2.80-2.60 (m, 1H), 2.40-0.08 (m, 6H);
LC 0.82 min; MS 540 (M+H, 100%).
EXAMPLE 8 1
4-([5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-trifluoromethoxy-ethyl)-1 Hindol-
3-yl]-methanone hydrochloride
A. 2,2,2-Trifl yl)-ethanone
To a solution of 1H-indole (0.38 g, 3.2 mmol) in DMF ( 15 mL) at r.t. is added
TFAA (0.44 mL, 16.2 mmol). After 2h at 40 °C the reaction mixture is poured into 400
mL 10% sodium bicarbonate solution and the precipitate is filtered, and washed with
water (100 mL). The solid is dissolved in EtOAc (200 mL), dried over Na2S0 ,
filtered, and concentrated in vacuo to yield the title product (0.40 g).
H NMR (300 MHz, CDCI3) 8.35 (d, 1H), 8.0 (s, 1H), 7.4 (m, 1H), 7.2 (m, 2H); MS
m/z [M+H]+=214.
A solution of 2,2,2-trifluoro-(1 H-indol-3-yl)-ethanone (0.32 g) in 5 N NaOH (20
heated at 140 oC for 1.5 hour. The solution is diluted with water ( 100 mL),
extracted with ether(1 00 mL) and brought to a pH=1 with cone. HCI (10 mL). The
solution is extracted with EtOAC (2x1 00 mL). The organic solution is washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title product
(0.27 g).
H NMR (300 MHz, CD3OD) 8.0 (d, 1H ) , 7.9 (s, 1H), 7.2 (d, 2H), 7.1 (m, 1H); MS
m/z [M+H] += 16 1.
C. 1H-lndole-3-carboxylic acid methyl ester
A solution of 1H-indole-3-carboxylic acid (0.49 g) in saturated HCI in MeOH
(50 mL) is stirred at r.t. for one hour. The solution is evaporated in vacuo, treated
with 10% sodium bicarbonate ( 100 mL) and extracted with EtOAc (200 mL). The
organic solution is washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo to give the title product (0.50 g).
H NMR (300 MHz, CD3OD) 8.1 (d, 2H ) , 7.9 (s, 1H), 7.5 (m, 1H), 7.2 (m, 2H), 3.9
(s, 3H);
MS m/z: [M+H] += 176.
D. 1-(2-Trifluoromethoxy-et carboxylic acid methyl ester
1H-lndole-3-carboxylic acid methyl ester (0.32 g, 1.8 mmol) is dissolved in
THF (50 mL) and NaH (0.1 1 g, 2.7 mmol) is added under N2 at r.t. in one portion.
The suspension is stirred at r. t . for 15 minutes. Trifluoromethanesulfonic acid 2-
trifluoromethoxy-ethyl ester (0.51 g, 1.8 mmol) is added in one portion to the reaction
mixture. The solution is stirred at r.t. for 15 minutes. The suspension is diluted with
N HCI ( 100 mL) and extracted with EtOAc ( 100 mL). The organic solution is washed
with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title
product (0.36 g).
H NMR (300 MHz, CD3OD) 8.1 (d, 1H), 8.0 (s, 1H), 7.5 (m, 1H), 7.3-7.2 (m, 2H),
4.6 (t,2H), 4.4 (t, 2H) 3.9 (s, 3H);
MS m/z [M+H]+ =288.
E. 1-(2-Trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic acid
1-(2-Trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic acid methyl ester (0.30 g)
in 2 N NaOH /MeOH /THF (25 mL/25 mL/25 mL) is stirred at r.t.. After 16 hours, the
solution is evaporated in vacuo, treated with water ( 100 mL) and extracted with ether
(200 mL). The aqueous solution is brought to pH= 1-2 and extracted with EtOAc ( 100
mL). The organic solution is washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo to give the title product (0.27 g).
H NMR (300 MHz, CD3OD) 8.1 (d, 1H), 8.0 (s, 1H), 7.5 (m, 1H), 72-7.3 (m, 2H),
4.6 (t,2H), 4.4 (t, 2H);
MS m/z: [M+H]+=274.
F. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-acetamide
To a suspension of 1-(2-trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic acid
(0.30 g, 1.13 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-pipendin-4-yl-benzyl)-
acetamide hydrochloride (0.41 g, 1.1 7 mmol), and EDCI (0.33 g, 1.7 mmol) in CH2CI2
(50 ml_) is added Et3N (0.49 ml_, 3.5 mmol). The reaction is stirred at room
temperature overnight. The reaction mixture is poured into EtOAc and the organic
layer washed with sat. NH CI, water and brine. The organic layer is dried over
MgSO4, filtered and concentrated in vacuo to give the crude product. Purification by
flash chromatography on S1O2 eluting with 50% ethyl acetate/ heptane gives 0.32 g,
(49 %) of the desired product (0.32 g, 49%).
H NMR (300 MHz, CD3OD) 7.8 (d, 1H), 7.7 (s, 1H), 7.5 (d, 1H), 7.2-7.4 (m, 4H),
7.0 (m, 1H) , 4.6 (t, 2H), 4.4 (t, 2H), 3.1 -3.3 (m, 3H), 1.7-1 .9 (m, 3H), 1.3 (m, 2H), 0.8
(m, 1H);
LCMS m/z [M+H] +=560.
G. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-trifluoromethoxy-ethyl)-
1H-indol-3-yl]-methanone hydrochloride
A solution of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1-(2-trifluoromethoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (0.20 g, 0.36 mmol) in MeOH
(100 ml_) is prepared. To this solution, aqueous K2CO3 (0.40 g, 2.8 mmol dissolved
in 20 ml_ water) is added dropwise and the solution is stirred at r.t. overnight. The
solution is diluted with water (400 ml_) and extracted with EtOAc (2 x 100 ml_). The
organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue is dissolved in Et2O (30 ml_) and 1 N HCI solution (0.40 ml_) is
added. The precipitate is filtered, washed with ether and dried under vacuum to give
the title product (0.22 g, 80%)
H NMR (300 MHz, CD3OD) 7.7 (d, 1H), 7.6 (s, 2H), 7.5-7.4 (m, 2H), 7.0-7.3 (m,
3H), 4.6 (t, 2H), 4.45 (t, 2H), 3.2 (m, 3H), 1.9-1 .7 (m, 4H) 1.3 (m, 1H), 0.8 (m,1 H);
MS m/z [M+H]+=464.
EXAMPLE 82
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(5-
pyridin-3-yl)-1 H-indol-3-yl]-methanone dihydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(5-methyl-pyridin-3-yl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (entry 48D) (200 mg, 0.34
mmol), 5-methylpyridine-3-boronic acid (56 mg, 0.41 mmol), cesium carbonate (223
mg, 0.68 mmol), and Pd(dppf)CI 2.CH2CI2 (28 mg, 10% mol) in dioxane/H2O
(4.5mL/0.5ml_) is heated at 80 °C overnight. The reaction mixture is concentrated in
vacuo to remove the solvent. The crude material is purified on silica gel with
CH2CI2/MeOH ( 100/0 to 98/2) as eluent to give the product ( 17 1 mg, 84%).
H NMR (300 MHz, CDCI3) 8.64 (s, 1H), 8.37 (s, 1H), 7.97 (bs, 1H), 7.60-6.80 (m,
8H), 4.80-4.30 (m, 5H), 3.85-3.70 (m, 2H), 3.55-3.30 (m, 4H), 3.00-2.45 (m, 3H), 2.41
(s, 3H), 1.80-0.80 (m, 4H);
LC Rt 0.87 min; MS 597 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(5-
methyl-pyridin-3-yl)-1 H-indol-3-yl]-methanone dihydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(5-
methyl-pyridin-3-yl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (168 mg,
0.28 mmol) in MeOH (5 mL) is added aqueous K2CO3 (31 1 mg, 2.25 mmol, dissolved
in 1.0 mL H2O). This mixture is heated at 45 °C for 3 h. LC/MS indicates the reaction
is completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and CH2CI2. The two layers are
separated, and the organic layer is washed with H2O and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting
suspension is concentrated in vacuo, and then dried in vacuo. The crude material is
triturated with Et2O, and the beige solid (88 mg, 54%) is collected by vacuum
filtration.
H NMR (300 MHz, DMSO-c/6) 8.60-8.40 (m, 2H), 8.20-7.80 (br s, 4H), 7.70-6.90
(m, 8H), 4.50-4.20 (m, 3H), 4.05-3.85 (m, 2H), 3.80-3.60 (m, 2H), 3.50-3.10 (m, 4H),
2.80-2.60 (m, 1H), 2.40-2.00 (m, 5H), 1.80-1 .1 0 (m, 4H);
LC 0.62 min; MS 501 (M+H, 100%).
EXAMPLE 83
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(2-
pyrid in-4-y I)- H-indol-3-yl]-methanone dihydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(2-methyl-pyridin-4-yl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (entry 48D) (200 mg, 0.34
mmol), 2-picoline-4-boronic acid (56 mg, 0.41 mmol), cesium carbonate (223 mg,
0.68 mmol), and Pd(dppf)CI 2.CH2Cl2 (28 mg, 10% mol) in dioxane/H 2O
(4.5mL/0.5ml_) is heated at 80 °C overnight. The reaction mixture is concentrated in
vacuo to remove the solvent. The crude material is purified on silica gel with
CH2CI2/MeOH ( 100/0 to 97/3) as eluent to give the product ( 180 mg, 88%).
H NMR (300 MHz, CDCI3) 8.60-8.40 (m, 1H), 7.60-6.80 (m, 10H), 4.80-4.20 (m,
5H), 3.85-3.65 (m, 2H), 3.55-3.30 (m, 4H), 2.90-2.70 (m, 1H), 2.70-2.20 (m, 5H),
1.80-1 .10 (m, 4H);
LC Rt 0.78 min; MS 597 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(2-
methyl-pyridin-4-yl)-1 H-indol-3-yl]-methanone dihydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(2-
methyl-pyridin-4-yl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (175 mg,
0.29 mmol) in MeOH (5 mL) is added aqueous K2CO3 (324 mg, 2.34 mmol, dissolved
in 1.0 mL H2O). This mixture is heated at 45 °C for 3 h. LC/MS indicates the reaction
is completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and CH2CI2. The two layers are
separated, and the organic layer is washed with H O and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting
suspension is concentrated in vacuo, and then dried in vacuo. The crude material is
triturated with Et O, and the slightly yellow solid ( 105 mg, 63%) is collected by
vacuum filtration.
H NMR (300 MHz, DMSO-c/6) 8.80-8.70 (m, 1H), 8.41 (br s, 4H), 8.00-7.00 (m,
9H), 4.60-4.1 0 (m, 3H), 4.05-3.90 (m, 2H), 3.80-3.60 (m, 2H), 3.50-3.10 (m, 4H),
3.05-2.85 (m, 1H), 2.73 (s, 3H), 2.40-2.10 (m, 2H), 1.80-1 .20 (m, 4H);
LC 0.56 min; MS 501 (M+H, 100%).
EXAMPLE 84
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(5-fluoro-pyridin-3-yl)-1 -(2-
methoxy- chloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-(5-fluoro-pyridin-3-yl)-1 -(2-methoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (entry 48D) (200 mg, 0.34
mmol), 5-fluoropyridine-3-boronic acid (58 mg, 0.41 mmol), cesium carbonate (223
mg, 0.68 mmol), and Pd(dppf)CI 2.CH2Cl2 (28 mg, 10% mol) in dioxane/H 2O
(4.5mL/0.5ml_) is heated at 80 °C overnight. The reaction mixture is concentrated in
vacuo to remove the solvent. The crude material is purified on silica gel with
CH2CI2/MeOH ( 100/0 to 97/3) as eluent to give the product (142 mg, 69%).
H NMR (300 MHz, CDCI3) 8.65-8.60 (m, 1H), 8.50-8.40 (m, 1H), 7.90-7.70 (m, 1H),
7.60-6.80 (m, 8H), 4.75-4.25 (m, 5H), 3.80-3.70 (m, 2H), 3.70-3.55 (m, 1H), 3.35 (s,
3H), 3.00-2.80 (m, 1H), 2.80-2.20 (m, 2H), 1.90-0.80 (m, 4H);
LC Rt 1.00 min; MS 601 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(5-fluoro-pyridin
methoxy-ethyl)-1 H-indol-3-yl]-methanone dihydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[4-(5-fluoro-pyridin-3-yl)-1 -(2-
methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (140 mg, 0.23
mmol) in MeOH (5 ml_) is added aqueous K CO3 (324 mg, 2.34 mmol, dissolved in
1.0 ml_ H2O). This mixture is heated at 45 °C for 2 h. LC/MS indicates the reaction is
completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and CH2CI2. The two layers are
separated, and the organic layer is washed with H2O and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting
suspension is concentrated in vacuo, and then dried in vacuo. The crude material is
triturated with Et2O, and the yellow solid ( 135 mg, quantitative) is collected by
vacuum filtration.
H NMR (300 MHz, DMSO-c/6) 8.70-8.20 (m, 6H), 7.90-7.00 (m, 8H), 4.20-4.1 0 (m,
1H), 4.05-3.90 (m, 2H), 4.05-3.90 (m, 2H), 3.60-3.40 (m, 3H), 3.25 (s, 3H), 3.00-2.80
(m, 1H), 2.40-2.1 0 (m, 2H), 1.80-1 .20 (m, 4H);
LC 0.71 min; MS 505 (M+H, 100%).
EXAMPLE 85
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(2-
pyrid in-4- I)- H-indol-3-yl]-methanone dihydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(2-methoxy-pyridin-4-yl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (entry 48D) (200 mg, 0.34
mmol), 2-methoxypyridine-4-boronic acid (63 mg, 0.41 mmol), cesium carbonate (223
mg, 0.68 mmol), and Pd(dppf)CI 2.CH2Cl2 (28 mg, 10% mol) in dioxane/H 2O
(4.5mL/0.5ml_) is heated at 80 °C for 5 h. The reaction mixture is concentrated in
vacuo to remove the solvent. The crude material is purified on silica gel with
CH2CI2/MeOH ( 100/0 to 97/3) as eluent to give the product ( 124 mg, 59%) as a beige
foam.
H NMR (300 MHz, CDCI3) 8.20-8.1 0 (m, 1H), 7.60-6.80 (m, 10H), 4.80-4.40 (m,
3H), 4.35 (d, J = 5.4 Hz, 2H), 3.94 (s, 3H), 3.77 (d, J = 5.5 Hz, 2H), 3.60-3.40 (m,
1H), 3.35 (s, 3H), 3.00-2.80 (m, 1H), 2.80-2.20 (m, 2H), 1.80-1 .20 (m, 4H);
LC Rt 1.04 min; MS 6 13 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(2-
methoxy-pyridin-4-yl)-1 H-indol-3-yl]-methanone dihydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(2-
methoxy-pyridin-4-yl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide ( 12 1
mg, 0.1 9 mmol) in MeOH (5 ml_) is added aqueous K2CO3 (21 8 mg, 1.58 mmol,
dissolved in 1.0 ml_ H2O). This mixture is heated at 45 °C for 3 h. LC/MS indicates
the reaction is completed. The reaction mixture is concentrated in vacuo to remove
most of the methanol. The residue is partitioned between H2O and CH2CI2. The two
layers are separated, and the organic layer is washed with H O and brine, dried over
Na2SO4, filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The
resulting suspension is concentrated in vacuo, and then dried in vacuo. The crude
material is triturated with Et O, and the yellow solid (136 mg) is collected by vacuum
filtration.
H NMR (300 MHz, DMSO-c/6) 8.50-8.1 0 (m, 5H), 7.80-6.80 (m, 9H), 4.60-4.20 (m,
3H), 4.00-3.75 (m, 5H), 3.70-3.60 (m, 2H), 3.60-3.40 (m, 1H), 3.24 (s, 3H), 3.00-2.80
(m, 1H), 2.80-2.1 0 (m, 2H), 1.80-1 .20 (m, 4H);
LC 0.75 min; MS 517 (M+H, 100%).
EXAMPLE 86
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[7-fluoro-1 -(2-trifluoromethoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
A. 2,2,2-Trifluoro-1 -(7-fluoro-1 H-indol-3-yl)-ethanone
To a solution of 7-fluoro-1 H-indole (0.66 g, 4.9 mmol) in DMF (20 mL) at r.t. is
added TFAA (2.0 mL). After 2h at 40 °C the reaction mixture is poured into 10%
sodium bicarbonate solution (400 mL) and the precipitate is filtered and washed with
water ( 100 mL). The solid is dissolved in EtOAc (200 mL), dried over Na2S04, filtered
and concentrated in vacuo to afford the product (0.66 g).
H NMR (300 MHz, DMSO-c/6) 8.45 (m, 2H ) , 7.3 (m, 1H), 7.0-7.1 (m, 1H),
MS m/z [M+H]+ =232.
B. 7-Fluoro- H-indole-3-carboxylic acid
A solution of 2,2,2-trifluoro-1 -(7-fluoro-1 H-indol-3-yl)-ethanone (0.66 g) in 5 N
NaOH (20 mL) is heated at 140 °C for one hour. The solution is diluted with water
(100 mL), extracted with ether ( 100 mL) and brought to pH=1 with cone HCI (10 mL).
The solution is extracted with EtOAc (2x1 00 mL). The organic layer is washed with
brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the product
(0.66 g).
H NMR (300 MHz, CD3OD) 8.0 (s, 1H), 7.8 (d, 1H), 7.1 (m, 1H), 6.9-7.0 (m, 1H);
MS m/z: [M+H]+= 1809.
C. 7-Fluoro-1 H-indole-3-carboxylic acid methyl ester
A solution 7-fluoro-1 H-indole-3-carboxylic acid (0.66 g) in saturated HCI in
MeOH (50 mL) is stirred at r.t. for one hour. The solution is evaporated in vacuo,
treated with 10% sodium bicarbonate solution ( 100 mL) and extracted with EtOAc
(200 mL). The organic layer is washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo to afford the title product (0.65 g).
H NMR (300 MHz, DMSO-c/6) 8.0 (s, 1H ) , 7.8 (d, 1H), 7.1 (m, 1H), 6.9-7.0 (m,
1H), 3.8 (s, 3H);
MS m/z [M+H]+= 194.
D. 7-Fluoro-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic acid methyl ester
To a solution of 7-fluoro-1 H-indole-3-carboxylic acid methyl ester (0.41 g, 2.1
mmol) in THF (50 mL) under N2 is added NaH (0.1 6 g, 4.2 mmol) at r.t. in one
portion. The suspension is stirred at r.t. for 15 min then trifluoromethanesulfonic acid
2-trifluoromethoxy-ethyl ester (0.55 g, 2.1 mmol) is added in one portion. The
reaction mixture is stirred at r.t. for 15 min then the suspension is diluted with 1 N HCI
(100 mL) and extracted with EtOAc (100 mL). The organic layer is washed with
brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the product
(0.42 g).
H NMR (300 MHz, CDCI3) 8.0 (d, H), 7.8 (s, H), 7.0 (m, H), 6.9-7.0 (m,
(t, 2H), 4.3 (t, 2H), 3.9 (s, 3H),
LCMS m/z [M+H]+=306.
E. 7-Fluoro-1-(2-trifluoro indole-3-carboxylic acid
A solution of 7-fluoro-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic acid
methyl ester (0.47 g) in 2 N NaOH/MeOH/THF (25 mL/25 mL/25 mL) is stirred at r.t.
After 16 hours the reaction mixture is evaporated in vacuo, treated with water (100
mL) and extracted with ether (200 mL). The aqueous layer is brought to pH= 1-2 and
extracted with EtOAc ( 100 mL). The organic layer is washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo to afford the product (0.47 g).
H NMR (300 MHz, CD3OD) 8.1 (d, 1H), 7.9 (s, 1H), 7.3 (m, 1H), 7.1 (m, 1H), 4.8 (t,
2H), 4.4 (t, 2H);
MS m/z: [M+H]+=292.
F. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[7-fluoro-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
To a suspension of 7-fluoro-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic
acid (0.47 g, 1.6 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-pipendin-4-yl-benzyl)-acetamide
hydrochloride (0.70 g, 2.1 mmol), and EDCI (0.41 g, 2.1 mmol) in CH2CI2 (50 mL) is
added Et3N (0.68 mL, 4.9 mmol). The reaction is stirred at room temperature
overnight. The reaction mixture is poured into EtOAc and the organic layer washed
with sat. NH CI, water and brine. The organic layer is dried over MgSO4, filtered and
concentrated in vacuo to give the crude product. Purification by flash chromatography
on S1O2 eluting with 50% ethyl acetate/ heptane gives of the desired product (0.55 g,
59%).
H NMR (300 MHz, CD3OD) 7.65 (s, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 7.2-6.9 (m, 4H),
4.6 (t, 2H), 4.4 (m, 4H), 3.2 (m, 2H), 2.0 (m, 2H), 1.7-1 .9 (m,2H), 1.3 (m, 2H), 0.8 (m,
1H);
MS m/z [M+H]+=587.
G. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-fluoro-1 -(2-trifluoromethoxyethyl)-
1 H-indol-3- l -methanone h chlo ide
To a solution of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[7-fluoro-1 -(2-trifluoromethoxyethyl)-
1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (0.40 g, 0.86 mmol) in
MeOH (100 mL) is added aqueous K2CO3 (0.94 g dissolved in 20 mL water). The
solution is stirred at r.t. overnight. The reaction mixture is diluted with water (400 mL)
and extracted with EtOAc (2x1 00 mL). The organic layer is washed with brine, dried
over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in Et2O
(50 mL) and 1N HCI (0.90 mL) is added. The resulting precipitate is filtered, washed
with ether and dried under vacuum to afford the product (0.33 g, 80 %).
H NMR (300 MHz, CD3OD) 7.6 (s, 1H), 7..6-7.5 (m, 2H), 7.4-7.3 (m, 1H), 7.1 -7.2
(m, 2H), 7.1-6.9 (m, 2H), 4.7 (t, 2H), 4.6-4.5 (m, 1H), 4.4 (t, 2H), 4.1 (m, 2H), 3.2 (m,
3H),2.0-1 .7 (m, 3H);
MS m/z [M+H]+=483.
EXAMPLE 87
4-([5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-chloro-1 -(2-trifluoromethoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
A. 2,2,2-Trifluoro-1 -(7-Chloro-1 H-indol-3-yl)-ethanone
To a solution of 7-chloro-1 H-indole (0.1 6 g, 0.71 mmol) in DMF (5 mL) at r.t. is
added TFAA (0.30 mL, 2.14 mmol). After 2h at 40 °C the reaction mixture is poured
into 10% sodium bicarbonate solution (400 mL) and the precipitate is filtered and
washed with water ( 100 mL). The solid is dissolved in EtOAc (200 mL), dried over
Na2SO4, filtered and concentrated in vacuo to afford the product (0.1 6 g).
H NMR (300 MHz, DMSO-c/6) 8.35 (m, 2H), 7.3 (m, 1H), 7.0-7.1 (m, 1H);
MS m/z: [M+H]+=248.
B. 7-Chloro-1 H-indole-3-carboxylic acid
A solution of 2,2,2-trifluoro-1 -(7-chloro-1 H-indol-3-yl)-ethanone (0.32 g) in 5 N
NaOH (20 mL) is heated at 140 °C for 1.5 hour. The reaction mixture is diluted with
water ( 100 mL), extracted with ether ( 100 mL) and the aqueous layer is brought to
pH=1 with cone HCI ( 10 mL). The aqueous layer is extracted with EtOAc (2x100 mL)
and the organic layers are washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo to afford the product (0.27 g).
H NMR (300 MHz, CD3OD) 8.0 (s, 1H), 7.9 (d, 1H), 7.2 (d, 1H), 7.1 (m, 1H);
MS m/z [M+H]+= 196.
C. 7-Chloro-1 H-indole-3-carboxylic acid methyl ester
A solution of 7-chloro-1 H-indole-3-carboxylic acid (0.49 g) in sat HCI in MeOH
(50 mL) is stirred at r.t. for one hour. The reaction mixture is evaporated in vacuo,
treated with 10% sodium bicarbonate solution ( 100 mL) and extracted with EtOAc
(200 mL). The organic layer is washed with brine, dried over Na2SO , filtered and
concentrated in vacuo to afford the product (0.50 g).
H NMR (300 MHz, CD3OD) 8.0 (m, 2H), 7.3 (m, 1H), 7.2 (m, 1H), 3.9 (s, 3H);
MS m/z: [M+H]+= 2 10.
D. 7-Chloro-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic acid methyl ester
To a solution of 7-chloro-1 H-indole-3-carboxylic acid methyl ester (0.30 g, 1.4
mmol) in THF (50 ml_) under N2 is added NaH (0.12 g, 2.9 mmol) at r.t. in one portion.
The suspension is stirred at r.t. for 15 min then trifluoromethanesulfonic acid 2-
trifluoromethoxy-ethyl ester (0.36 g, 1.4 mmol) is added in one portion. The reaction
mixture is stirred at r.t. for another 15 min then the suspension is diluted withi N HCI
(100 ml_) and extracted with EtOAc (100 ml_). The organic layer is washed with
brine, dried over Na2SO , filtered and concentrated in vacuo to afford the product
(0.33 g).
H NMR (300 MHz, CD3OD) 8.1 (d, 1H), 8.0 (s, 1H), 7.5 (m, 1H), 72-7.3 (m, 1H),
4.6 (t, 2H), 4.4 (t, 2H), 3.9 (s, 3H);
MS m/z [M+H]+=322.
E. 7-Chloro-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic acid
A solution of 7-chloro-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic acid
methyl ester (0.29 g) in 2 N NaOH/MeOH /THF (25 mL/25ml_/25ml_) is stirred at r.t..
After 16 hours the reaction mixture is evaporated in vacuo, treated with water (100
ml_) and extracted with ether ( 100 ml_). The aqueous layer is brought to pH= 1-2 with
cone. HCI and extracted with EtOAc ( 100 ml_). The organic layer is washed with
brine, dried over Na2SO 4 , filtered and concentrated in vacuo to afford the product
(0.27 g).
H NMR (300 MHz, CD3OD) 8.1 (d, 1H), 7.9 (s, 1H), 7.3-7.1 (m, 2H), 4.9 (t, 2H),
4.4 (t, 2H);
MS m/z [M+H]+=308.
F. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[7-Chloro-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-
ca de
To a suspension of 7-chloro-1-(2-trifluoromethoxy-ethyl)-1 H-indole-3-
carboxylic acid (0.36g, 1.16 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-
acetamide hydrochloride (0.39 g, 1.1 7 mmol), and EDCI (0.31 g, 1.6 mmol) in CH2CI2
(50 ml_) is added Et3N (0.34 ml_, 2.5 mmol). The reaction is stirred at r.t. overnight
then the reaction mixture is poured into EtOAc and the organic layer washed with sat
NH CI, water and brine. The organic layer is dried over MgSO , filtered and
concentrated in vacuo to give the crude product. Purification by flash chromatography
on S1O2 eluting with 50% ethyl acetate/ heptane gives of the desired product (0.38 g,
49%).
H NMR (300 MHz, CD3OD) 7.7 (d, 1H), 7.6 (s, 1H), 7.3-7.0 (d, 5H), , 4.9 (t, 2H),
4.6-4.4 (m, 2H), 3.3-3.1 (m, 1H), 1.9-1 .7 (m, 4H), 1.3 (m, 1H), 0.8 (m, 1H);
MS m/z: [M+H]+=594.
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-chloro-1 -(2-trifluoromethoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
To a solution of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[7-chloro-1 -(2-tnfluoromethoxyethyl)-
1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (0.30 g, 0.50 mmol) in
MeOH ( 100 mL), aqueous K2CO3 (0.55 g, 4.0 mmol in 20 mL water) is added
dropwise and the reaction mixture is stirred at r.t. overnight. The solution is diluted
with water (400 mL) and extracted with EtOAc (2x100 mL). The organic layers are
washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The
residue is dissolved in Et2O (30 mL) and 1 N HCI (0.60 mL) is added. The precipitate
is filtered, washed with ether and dried under vacuum to afford the titled product (0.1 9
g, 73 %).
H NMR (300 MHz, CD3OD) 7.7 (d, 1H), 7.6 (d, 2H), 7.5-7.2 (m, 3H), 7.1 -7.0 (m,
1H), 4.6 (t, 2H), 4.45 (t, 2H), 3.2 (m, 2H),1 .9-1 .7 (m, 3H) 1.3 (m, 1H), 0.8 (m,1 H); MS
m/z [M+H]+=498.
EXAMPLE 88
4-([5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-methyl-1 -(2-trifluoromethoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
A. 7-Methyl-1 -(2-trifluoromet -carboxylic acid methyl ester
NaH (0.05 g, 2.0 mmol) is added in one portion to a solution of 7-methyl-1 Hindole-
3-carboxylic acid methyl ester (0.20 g, 0.98 mmol) in THF (20 mL) under N2 at
r.t. and stirred for 15 min. Trifluoromethanesulfonic acid 2-trifluoromethoxy-ethyl
ester (0.26 g, 0.98 mmol) is added to the reaction mixture and the solution stirred at
r.t. for an additional 15 min. The suspension is then diluted with 1 N HCI ( 100 mL)
and extracted with EtOAc (100 mL). The organic layer is washed with brine, dried
over Na2SO4, filtered and concentrated in vacuo to yield the titled product (0.26 g).
H NMR (300 MHz, CDCI3) 8.1 (d, 1H), 7.8 (s, 1H), 7.2 (m, 1H), 7.0 (m, 1H), 4.6 (t,
2H), 4.4 (t, 2H) 3.9 (s, 3H), 2.6 (s, 3H);
MS m/z [M+H]+=302.
B. 7-methyl-1 -(2-trifluoro H-indole-3-carboxylic acid
A solution of 7-methyl-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic acid
methyl ester (0.32 g) in 2 N NaOH/MeOH /THF (25 mL/25mL/25mL) is stirred at r.t.
for 16 hours. The reaction mixture is then evaporated in vacuo, treated with water
(100 mL) and extracted with ether (200 mL). The aqueous layer is brought to pH= 1-
2 with conc.HCI and extracted with EtOAc ( 100 mL). The organic layer is washed with
brine, dried over Na2SO4, filtered and concentrated in vacuo to yield the titled product
(0.24 g).
H NMR (300 MHz, CD3OD) 8.0 (d, H), 7.9 (s, H), 7.1 (m, 1H), 6.9 (m, 1H), 4.8 (t,
2H), 4.4 (t, 2H), 2.9 (s, 3H);
MS m/z [M+H]+=288.
C. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[7-methyl-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-
car ide
To a suspension of 7-methyl-1-(2-trifluoromethoxy-ethyl)-1 H-indole-3-
carboxylic acid (0.20 g, 0.69 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-
acetamide hydrochloride (0.35 g, 0.69 mmol) and EDCI (0.33 g, 1.7 mmol) in CH2CI2
(50 ml_) is added Et3N (0.20 ml_, 2.1 mmol). The reaction mixture is stirred at r.t.
overnight then the reaction mixture is poured into EtOAc and the organic layer
washed with sat NH CI, water and brine. The organic layer is dried over MgSO ,
filtered and concentrated in vacuo to give the crude product. Purification by flash
chromatography on S1O2 eluting with 50% ethyl acetate/ heptanes gives the desired
product (0.1 7 g, 43 %).
H NMR (300 MHz, CD3OD) 7.6 (m, 2H), 7.4 (d, 1H), 7.2 (m, 1H), 7.1 -6.9 (m, 2H),
4.8 (t, 2H), 4.6-4.3 (m, 3H), 3.3-3.1 (m, 3H), 2.6 (s, 3H),1 .9-1 .3 (m, 3H), 1.3 (m, 1H),
0.8 (m, 1H);
MS m/z: [M+H]+=574.
D. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[7-methyl-1 -(2-trifluoromethoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
Aqueous K2CO3 (0.38 g, 2.7 mmol dissolved in 20 mL water) is added
dropwise to a solution of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[7-methyl-1 -(2-trifluoromethoxy-
ethyl)-1 H-indole-3-carbonyl]-piperidin-4 -yl}-benzyl)-acetamide (0.22 g, 0.35
mmol) in MeOH ( 100 mL) and stirred at r.t. overnight. The reaction mixture is diluted
with water (400 mL) and extracted with EtOAc (2x100 mL). The organic layers are
washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The
residue is dissolved in Et2O (20 mL) and 1 N HCI solution (0.40 mL) is added. The
precipitate is filtered, washed with ether and dried under vacuum to provide the titled
product (0.1 6 g, 80%)
H NMR (300 MHz, CD3OD) 7.5 (m, 2H), 7.3 (m, 1H), 7.2 (m, 1H), 7.1 -6.9 (m, 3H),
4.8 (t, 2H), 4.5-4.4 (m, 3H), 3.2-3.1 (m, 3H), 2.6 (s, 3H), 1.9-1 .7 (m, 4H), 1.3 (m, 1H),
0.8 (m,1 H);
MS m/z [M+H]+=477.
EXAMPLE 89
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(2-
2H-pyrazol-3-yl)-1 H-indol-3-yl]-methanone dihydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(2-methyl-2H-pyrazol-3-yl)-
1H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (entry 48D) (200 mg, 0.34
mmol), 1-methyl-1 H-pyrazole-5-boronic acid (85 mg, 0.41 mmol), cesium carbonate
(223 mg, 0.68 mmol), and Pd(dppf)CI 2.CH2CI2 (28 mg, 10% mol) in dioxane/H 2O
(4.5mL/0.5ml_) is heated at 80 °C overnight. The reaction mixture is concentrated in
vacuo to remove the solvent. The crude material is purified on silica gel with
CH2CI2/MeOH ( 100/0 to 97/3) as eluent to give the product as a beige foam ( 107 mg,
52%).
H NMR (300 MHz, CDCI3) 7.70-6.85 (m, 9H), 6.56 (bs, 1H), 4.85-4.45 (m, 3H),
4.34 (d, J = 5.3 Hz, 2H), 3.85-3.60 (m, 5H), 3.60-3.40 (m, 1H), 3.36 (s, 3H), 3.00-2.40
(m, 3H), 1.90-1 .20 (m, 4H);
LC Rt 0.98 min; MS 586 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-(2-
methyl-2H-pyrazol-3-yl)-1 H-indol-3-yl]-methanone dihydrochloride
A mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(2-methyl-
2H-pyrazol-3-yl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide ( 105 mg,
0.17 mmol) in MeOH (5 mL) is added aqueous K2CO3 ( 198 mg, 1.43 mmol, dissolved
in 1.0 mL H2O). This mixture is heated at 45 °C for 3 h. LC/MS indicates the reaction
is completed. The reaction mixture is concentrated in vacuo to remove most of the
methanol. The residue is partitioned between H2O and CH2CI2. The two layers are
separated, and the organic layer is washed with H O and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The resulting
suspension is concentrated in vacuo, and then dried in vacuo. The crude material is
triturated with Et O, and the beige solid (66 mg, 69%) is collected by vacuum
filtration.
H NMR (300 MHz, DMSO-c/6) 8.41 (bs, 4H), 7.80-7.00 (m, 8H), 4.60-4.20 (m, 5H),
3.80-3.60 (m, 5H), 3.65-3.30 (m, 1H), 3.25 (s, 3H), 3.00-2.75 (m, 1H), 2.80-2.1 0 (m,
2H), 1.80-1 .10 (m, 4H);
LC 0.68 min; MS 490 (M+H, 100%).
EXAMPLE 90
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-fluoro-(2-trifluoromethoxy-ethyl)-
1H-indol-3-yl]-methanone hydrochloride
To a solution of 4-fluoro-1 H-indole (0.66 g, 4.9 mmol) in DMF (20 mL) is added
TFAA (2.0 mL). After 2h the reaction mixture is poured into 10% sodium bicarbonate
solution (400 mL) and the precipitate is filtered, and washed with water ( 100 mL).
The solid is dissolved in EtOAc (200 mL) and dried over Na2SO , filtered and
concentrated in vacuo to afford the titled product (0.66 g).
H NMR (300 MHz, DMSO-c/6) 8.5 (s, 1H), 7.4 (d, 1H), 7.3 (m, 1H), 7.0-7.1 (m, H);
MS m/z [M+H]+=233.
B. 4-Fluoro- H-indole-3-carboxylic acid
A solution of 2,2,2-trifluoro-1 -(4-fluoro-1 H-indol-3-yl)-ethanone (0.66 g) in 5 N
NaOH (20 mL) is heated at 14 °C for 1 hour. The reaction mixture is allowed to cool,
diluted with water ( 100 mL) and extracted with ether (100 mL). The aqueous layer is
brought to pH=1 using cone HCI ( 10 mL) and extracted with EtOAc (2x1 00 mL). The
organic layers are washed with brine, dried over Na2SO4, filtered and contentrated in
vacuo to provide the titled product (0.63 g).
H NMR (300 MHz, DMSO-c/6) 8.0 (s, 1H), 7.2 (d, 1H), 7.1 (m, 1H), 7.0-7.1 (m, 1H);
MS m/z [M+H] += 180.
C. 4-Fluoro-1 H-indole-3-carboxylic acid methyl ester
A solution of 4-fluoro-1 H-indole-3-carboxylic acid (0.60 g) in sat HCI in MeOH
(50 mL) is stirred at r.t. for 1 hour. The reaction mixture is evaporated in vacuo,
treated with 10% sodium bicarbonate solution ( 100 mL) and extracted with EtOAc
(200 mL). The organic layer is washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo to give the titled product (0.60 g).
H NMR (300 MHz, DMSO-c/6) 8.0 (s, 1H), 7.2 (d, 1H), 7.1 (m, 1H), 7.0-7.1 (m, 1H),
3.8 (s, 3H);
LCMS m/z: [M+H] += 194.
D. 4-Fluoro-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic acid methyl ester
To a solution of 4-fluoro-1 H-indole-3-carboxylic acid methyl ester (0.30 g, 1.3
mmol) in THF (20 mL) under N2 is added NaH (0.10 g, 2.6 mmol) at r.t. in one portion.
The suspension is stirred at r.t. for 15 min then trifluoromethanesulfonic acid 2-
trifluoromethoxy-ethyl ester (0.34 g, 1.3 mmoles) is added in one portion. The
reaction mixture is stirred at r.t. for an additional 15 min then the suspension is diluted
with 1 N HCI ( 100 mL) and extracted with EtOAc ( 100 mL). The organic layer is
washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide
the titled product (0.34 g).
H NMR (300 MHz, CD3OD) 7.8 (s, 1H), 7.1 (d, 1H), 7.0 (m, 1H), 7.0-6.9 (m, 1H),
4.5 (t, 2H), 4.25 (t, 2H) 3.8 (s, 3H);
MS m/z [M+H]+=306.
E. 4-Fluoro-1-(2-trifluoro H-indole-3-carboxylic acid
A solution of 4-fluoro-1-(2-trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic acid
methyl ester (0.1 6 g) in 2 N NaOH/MeOH /THF (25 mL/25 mL/25 mL) is stirred at r.t.
for 16 hours. The reaction mixture is then evaporated in vacuo and the residue is
treated with water (100 mL) and extracted with ether ( 100 mL). The aqueous solution
is acidified to pH= 1-2 with cone HCI and extracted with EtOAc ( 100 mL). The
organic layer is washed with brine, dried over Na2SO4, filtered and concentrated in
vacuo to yield the titled product (0.1 2 g).
H NMR (300 MHz, CD3OD) 8.0 (s, 1H), 7.4 (d, 1H), 7.2 (m, 1H), 6.8 (m, 1H), 4.6 (t,
2H), 4.4 (t, 2H);
MS m/z: [M+H]+=292.
F. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-fluoro-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-
car ide
To a suspension of 4-fluoro-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-carboxylic
acid 0.1 g, 0.34 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-pipendin-4-yl-benzyl)-acetamide
hydrochloride (0.1 5 g, 0.44 mmol), and EDCI (0.097 g, 0.50 mmol) in CH2CI2 (50 ml_)
is added Et3N (0.14 ml_, 1.0 mmol). The reaction mixture is stirred at r.t. overnight.
The reaction mixture is then poured into EtOAc and the organic layer is washed with
sat NH CI, water and brine. The organic layer is dried over MgSO4, filtered and
concentrated in vacuo to give the crude product. Purification by flash chromatography
on S1O2 eluting with 50% ethyl acetate/ heptane affords the desired product (0.097 g,
49%).
H NMR (300 MHz, CD3OD) 8.0 (s, 1H), 7.5 (s, 1H), 7.3 (d, 1H), 7.2-7.1 (m, 3H),
6.95 (t, 1H), 6.8 (t, 1H), 4.6 (t, 2H), 4.4 (m, 4H), 3.2 (m, 2H), 2.0 (m, 2H), 1.8-1 .6 (m,
2H), 1.3 (m, 2H), 0.8 (m, 1H);
MS m/z [M+H]+=578.
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-fluoro-1 -(2-trifluoromethoxyethyl)-
1 H-indol-3-yl]-methanone hydrochloride
Aqueous K2CO3 (0.74 g dissolved in 5 mL water) is added dropwise to a
solution of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[4-fluoro-1 -(2-trifluoromethoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (0.31 g, 0.54 mmol) in MeOH (30
mL). The reaction mixture is stirred at r.t. overnight. The solution is then diluted with
water (200 mL) and extracted with EtOAc (2x1 00 mL). The organic layers are
washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The
residue is dissolved in Et2O (10 mL) and 1N HCI (0.60 mL) is added. The precipitate
is filtered, washed with ether and dried under vacuum to yield the titled product (0.21
g, 80 %).
H NMR (300 MHz, CD3OD) 7.7 (s, 1H), 7.5 (d, 1H), 7.4-7.1 (m, 4H), 7.0-6.9 (m,
1H), 4.7 (t, 2H), 4.6-4.5 (m, 1H), 4.3 (t, 2H), 4.1 (m, 2H), 3.8 (m, 3H), 3.2 (m, 2H),2.1 -
1.8 (m, 3H);
MS m/z [M+H] +=483.
EXAMPLE 9 1
3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 Hindol-
4-carboxylic acid dimethylamide hydrochloride
A. 1-(2-methoxy-ethyl)-1 H-indole-4-carboxylic acid methyl ester
The title compound is prepared in a similar manner as described in Example
1E using 1H-indole-4-carboxylic acid methyl ester as the starting material.
H NMR (300 MHz, CDCI3) 7.9 (d, 1H), 7.6 (d, 1H), 7.2 (m, 2H), 7.1 (m, 1H), 4.4 (t,
2H), 4.0 (s, 3H), 3.7 (t, 2H), 3.3 (s, 3H);
MS m/z [M+H]+=234.
B. 1-(2-Methoxy-ethyl)-3-(2,2,2-trifluoro-acetyl)-1 H-indole-4-carboxylic acid methyl
ester
The title compound is prepared in a similar manner as described in Example
1F using 1-(2-methoxy-ethyl)-1 H-indole-4-carboxylic acid methyl ester as the starting
material.
H NMR (300 MHz, CDCI3) 8.1 (s, 1H), 7.6 (m, 2H), 7.3 (m, 1H), 4.4 (t, 2H), 4.0 (s,
3H), 3.8 (t, 2H), 3.3 (s, 3H);
MS m/z: [M+H]+=330.
C. 1-(2-Methoxy-ethyl)-3-(2,2,2-trifluoro-acetyl)-1 H-indole-4-carboxylic acid
The title compound is prepared in a similar manner as described in Example
5D using 1-(2-methoxy-ethyl)-3-(2,2,2-trifluoro-acetyl)-1 H-indole-4-carboxylic acid
methyl ester as the starting material.
H NMR (300 MHz, DMSO-c/6) 12.8 (s, 1H), 8.5 (s, 1H), 7.9 (d, 1H), 7.5 (m, 2H), 4.6
(t, 2H), 3.7 (t, 2H), 3.2 (s, 3H);
MS m/z [M+H]+=31 6.
D. 1-(2-Methoxy-ethyl)-3-(2,2,2-trifluoro-acetyl)-1 H-indole-4-carboxylic acid
dimethylamide
The title compound is prepared in a similar manner as described in Example
59A using 1-(2-methoxy-ethyl)-3-(2,2,2-trifluoro-acetyl)-1 H-indole-4-carboxylic acid
and dimethylamine as the starting materials.
H NMR (300 MHz, CDCI3) 8.1 (s, 1H), 7.4 (m, 2H), 7.2 (m, 1H), 4.4 (t, 2H), 3.8 (t,
2H), 3.4 (s, 3H), 3.3 (s, 3H), 2.8 (s, 3H).
MS m/z: [M+H]+=343.
E. 4-Dimethylcarbamoyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using 1-(2-methoxy-ethyl)-3-(2,2,2-trifluoro-acetyl)-1 H-indole-4-carboxylic acid
dimethylamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 11.9 (bs, H), 8.0 (s, H), 7.6 (d, H), 7.3 (m, H),
7.0 (d, H), 4.4 (t, 2H), 3.8 (t, 2H), 3.3 (s, 3H), 3.2 (s, 3H), 3.0 (s, 3H).
LCMS m/z [M+H]+=291 .
F. 3-(4-{2-Fluoro-5[(2,2,2-trifluoro-acetylamino)-methyl]-phenyl}-piperidine-1 -
carbonyl)-1 -(2 imethylamide
The title compound is prepared in a similar manner as described in Example 2 I
using 4-dimethylcarbamoyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and
2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the
starting materials.
H NMR (300 MHz, CDCI3) 7.6 (m, H), 7.4 (m, H), 7.2 (m, 2H), 7.0 (m, 2H), 4.5 (m,
2H), 4.3 (t, 2H), 3.7 (t, 2H), 3.3 (s, 3H), 3.2 (m, 3H), 3.1 (s, 3H), 3.0 (m, 2H), 2.9 (s,
3H), 1.9-1 .7 (m, 4H).
LCMS m/z: [M+H]+=577.
G. 3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-
1H-indole-4-carboxylic acid dimethylamide hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 3-(4-{2-fluoro-5[(2,2,2-trifluoro-acetylamino)-methyl]-phenyl}-piperidine-1 -
carbonyl)-1 -(2-methoxy-ethyl)-1 H-indole-4-carboxylic acid dimethylamide as the
starting material.
H NMR (300 MHz, DMSO-c/6) 8.3 (bs, 2H), 7.6 (m, 3H), 7.4 (m, 1H), 7.2 (m, 2H),
7.0 (m, H), 4.4 (m, 2H), 4.2 (bs, H), 4.0 (m, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 3.3 (2,
3H), 3.1 (m, 2H), 3.0 (s, 3H), 2.9 (s, 3H), .8-1 .6 (m, 4H).
MS m/ z [M+H]+=481 .
EXAMPLE 92
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-pyrimidin-5-yl-1 -(2-
trifluoromethoxy-ethyl)-1 H-indol-3-yl]-methanone dihydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-pyrimidin-5-yl-1 -(2-trifluoromethoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (entry 78D) (200
mg, 0.34 mmol), 5-pyrimidylboronic acid (46 mg, 0.37 mmol), cesium carbonate (204
mg, 0.62 mmol), and Pd(dppf)CI 2.CH2CI2 (26 mg, 10% mol) in dioxane/H 2O (9 mL/1
ml_) is heated at 80 °C for 18 h. The reaction mixture is concentrated in vacuo to
remove the solvent. The crude material is purified on silica gel with CH CI /MeOH
(100/0 to 98/2) as eluent to give the product ( 188 mg, 92%) as a white foam.
H NMR (300 MHz, CDCI3) 9.23 (s, 1H), 8.95 (s, 2H), 7.60-6.80 (m, 8H), 4.80-4.20
(m, 7H), 3.70-3.40 (m, 1H), 3.1 0-2.40 (m, 3H), 1.80-0.80 (m, 4H);
LC Rt 0.97 min; MS 638 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-pyrimidin-5-yl-1 -(2-
trifluoromethoxy-ethyl)-1 H-indol-3-yl]-methanone dihydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[4-pyrimidin-5-yl-1 -(2-
trifluoromethoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide ( 185
mg, 0.29 mmol) in MeOH (5 ml_) is added aqueous K2CO3 (320 mg, 2.3 mmol,
dissolved in 1.0 ml_ H2O). This mixture is heated at 45 °C for 4 h. LC/MS indicates
the reaction is completed. The reaction mixture is concentrated in vacuo to remove
most of the methanol. The residue is partitioned between H2O and CH2CI2. The two
layers are separated, and the organic layer is washed with H2O and brine, dried over
Na2SO4, filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The
crude material is purified by RP-HPLC to give a whilte fluffy solid as the titled product
(126 mg, 70%).
H NMR (300 MHz, DMSO-c/6) 9.22 (s, 1H), 8.85 (s, 2H), 8.1 1 (bs, 4H), 7.80-7.60
(m, 2H), 7.40-7.05 (m, 4H), 4.80-3.70 (m, 8H), 3.00-2.00 (m, 3H), 1.80-1 .00 (m, 4H);
LC 0.68 min; MS 542 (M+H, 100%).
EXAMPLE 93
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(1 -propyl-1 H-pyrazol-4-yl)-1 -(2-
trifluoromethoxy-ethyl)-1 H-indol-3-yl]-methanone dihydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-(1 -propyl-1 H-pyrazol-4-yl)-1 -(2-trifluoromethoxyethyl)-
1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of N-(3-{1 -[4-bromo-1 -(2-trifluoromethoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (entry 78D) (200
mg, 0.34 mmol), 1-propyl pyrazol-4-boronic acid (58 mg, 0.37 mmol), cesium
carbonate (204 mg, 0.62 mmol), and Pd(dppf)CI 2.CH2CI2 (26 mg, 10% mol) in
dioxane/H 2O (9 mL/1 ml_) is heated at 80 °C for 5 h. The reaction mixture is
concentrated in vacuo to remove the solvent. The crude material is purified on silica
gel with CH2CI2/MeOH ( 100/0 to 98/2) as eluent to give the product ( 137 mg, 92%) as
a beige foam.
H NMR (300 MHz, CDCI3) 9.20-9.05 (m, 1H), 8.00-6.80 (m, 9H), 4.90-4.00 (m, 9H),
3.50-2.20 (m, 4H), 2.00-0.80 (m, 9H);
LC Rt 1.05 min; MS 667 (M+H, 100%).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[4-(1 -propyl-1 H-pyrazol-4-yl)-1 -
(2-trifluoromethoxy-ethyl)-1 H-indol-3-yl]-methanone dihydrochloride
To a mixture of 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[4-(1 -propyl-1 H-pyrazol-4-yl)-1 -
(2-trifluoromethoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
(135 mg, 0.20 mmol) in MeOH (5 mL) is added aqueous K2CO3 (233 mg, 1.6 mmol,
dissolved in 1.0 mL H2O). This mixture is heated at 45 °C for 4 h. LC/MS indicates
the reaction is completed. The reaction mixture is concentrated in vacuo to remove
most of the methanol. The residue is partitioned between H2O and CH2CI2. The two
layers are separated, and the organic layer is washed with H2O and brine, dried over
Na2SO4, filtered, and concentrated in vacuo. 4.0 M HCI in dioxane is added. The
crude material is purified by RP-HPLC to give a whilte fluffy solid as the titled product
(586 mg, 44%).
H NMR (300 MHz, DMSO-c/6) 8.09 (bs, 4H), 7.90-7.00 (m, 9H), 5.00-4.50 (m, 5H),
4.30-3.75 (m, 4H), 3.20-3.00 (m, 1H), 2.90-2.00 (m, 3H), 2.00-0.80 (m, 9H);
LC 0.75 min; MS 572 (M+H, 100%).
EXAMPLE 94
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -yl]-[1 -(2-methoxy-ethyl)-4-(piperidine-
1-carbonyl)-1 H-indol-3-yl]-methanone hydrochloride
A. 2,2,2-Trifluoro-1 -[1 -(2-methoxy-ethyl)-4-(piperidine-1 -carbonyl)-1 H-indol-3-yl]-
ethanone
The title compound is prepared in a similar manner as described in Example
59A using 1-(2-methoxy-ethyl)-3-(2,2,2-trifluoro-acetyl)-1 H-indole-4-carboxylic acid
(example 9 1C) and piperidine as the starting materials.
H NMR (300 MHz, CDCI3) 8.1 (s, 1H), 7.4 (m, 2H), 7.2 (m, 1H), 4.4 (t, 2H), 4.1 (m,
1H), 3.8 (t, 2H), 3.7 (m, 1H), 3.4 (s, 3H), 3.3 (m, 1H), 3.1 (m, 1H), 1.9 (m, 1H), 1.8-1 .6
(m, 3H), 1.4 (m, 1H).
MS m/ z [M+H]+=383.
B. 1-(2-Methoxy-ethyl)-4-(piperidine-1 -carbonyl)-1 H-indol-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
4C using 2,2,2-trifluoro-1 -[1 -(2-methoxy-ethyl)-4-(piperidine-1 -carbonyl)-1 H-indol-3-
yl]-ethanone as the starting material.
H NMR (300 MHz, DMSO-c/6) 12.0 (bs, 1H), 8.0 (s, 1H), 7.6 (d, 1H), 7.3 (m, 1H),
7.0 (d, 1H), 4.4 (t, 2H), 3.8 (m, 1H), 3.7 (t, 2H), 3.4 (m, 1H), 3.2 (s, 3H), 3.1 (m, 1H),
2.9 (m, 1H), 1.8 (m, 1H), 1.6 (m, 1H), 1.5 (m, 3H), 1.3 (m,1 H).
MS m/z [M+H]+=331 .
C. (2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4(piperidine-1 -carbonyl)-1 Hindole-
3-carbon l - i eridine-4- l -benz l -acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 1-(2-methoxy-ethyl)-4-(piperdine-1 -carbonyl)-1 H-indol-3-carboxylic acid and
2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the
starting materials.
H NMR (300 MHz, CDCI3) 7.4 (m, 1H), 7.3 (m, 1H), 7.2 - 7.0 (m, 5H), 6.7 (bs, 1H),
4.8 (m, 1H), 4.5 (m, 3H), 4.3 (t, 2H), 4.0 (m, 1H), 3.7 (t, 2H), 3.4 (s, 3H), 3.3-3.0 (m,
5H), 2.6 (m, 1H), 2.0-1 .8 (m, 2H), 1.8-1 .5 (m, 8H).
MS m/z [M+H]+=61 7.
D. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -yl]-[1 -(2-methoxy-ethyl)-4-
(piperdine-1 -carbon l)-1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using (2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4(piperdine-1 -carbonyl)-
1H-indole-3-carbonyl]-piperidine-4-yl}-benzyl)-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.4 (bs, 2H), 7.6 (m, 3H), 7.4 (m, 1H), 7.2 (m, 2H),
7.0 (m, H), 4.4 (m, 2H), 4.2-4.0 (m, 5H), 3.7 (t, 2H), 3.6 (m, 2H), 3.3 (s, 3H), 3.2-2.9
(m, 6H), 1.8-1 .4 (m, 10H).
MS m/z: [M+H]+=521 .
EXAMPLE 95
Tetrahydro-pyran-4-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperidineA.
(Tetrahydro-pyran-4-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-
trifluoroacetylamino)methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 Hindol-
4-yl]amide
The title compound is prepared in a similar manner as described in Example
6E using tetrahydropyran-4-carboxylic acid and N-(3-{1 -[4-amino-1 -(2-methoxy-ethyl)-
1H-indole-3-carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
(example 75E) as the starting materials.
H NMR (300 MHz, DMSO-c/6) 0.80 (s, H), 9.95 (t, H), 7.92 (d, H), 7.80 (s, H),
7.33-7.1 5 (m, 5H), 4.60 (d, 2H), 4.40 (t, 2H), 4.35 (d, 2H), 3.92-3.85 (m, 2H), 3.66 (t,
2H), 3.41 -3.33 (m, 3H), 3.25-3.1 3 (m, 6H), 1.89-1 .63 (m, 8H).
B. Tetrahydro-pyran-4-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
The title compound is prepared in a similar manner as described in Example
3B with (tetrahydro-pyran-4-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-
trifluoroacetylamino)methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 Hindol-
4-yl]amide as the starting material.
H NMR (300 MHz, DMSO-c/6) 10.82 (s, 1H), 8.35 (br s, 3H), 7.94 (d, 1H), 7.81 (s,
1H), 7.56-7.51 (m, 1H), 7.42-7.36 (m, 1H), 7.34-7.31 (m, 1H), 7.27-7.1 7 (m, 2H), 4.60
(d, 2H), 4.41 (t, 2H), 4.02-3.95 (m, 2H), 3.92-3.85 (m, 2H), 3.66 (t, 2H), 3.42-3.34 (m,
3H), 3.21 (br s, 6H), 1.89-1 .65 (m, 8H).
MS m/z [M+H] +=537.
EXAMPLE 96
N-[3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxy-e^
H-indol-4-yl]-acetamide hydrochloride
A. N-(3-{1 -[4-Acetylamino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-
fluoro-benzyl)-2,2,2-trifluoro-acetamide
To a solution of acetic acid (29 L, 0.51 mmol), N-(3-{1-[4-amino-1 -(2-
methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoroacetamide
(264 mg, 0.51 mmol) and EDCI ( 1 17 mg, 0.61 mmol) in CH2CI2 (5 mL) is
added triethylamine ( 170 L, 1.2 mmol). The resulting mixtue is stirred under N2 at
r.t. overnight. The reaction mixture was then diluted with CH2CI2 and washed with
brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo.
The crude material is purified on silica gel with 3% MeOH/CH 2Cl2 as eluent to give
the title product as a foamy white solid (240 mg, 84%).
H NMR (300 MHz, CDCI3) 10.50 (s, 1H), 8.02 (d, 1H), 7.37-7.00 (m, 6H), 4.75-4.62
(br d, 2H), 4.46 (d, J= 5.4Hz, 2H), 4.30 (t, J=5.1 Hz, 2H), 3.69 (t, J= 5.1 Hz, 2H), 3.30
(s, 3H), 3.20-3.00 (m, 4H), 2.17 (s, 3H), 1.95-1 .80 (m, 2H), 1.80-1 .63 (m, 2H).
9F NMR (300 MHz, CDCI3) -75.42.
MS m/z [M+H] +=563.
B. N-[3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxyet
e
The title compound is prepared in a similar manner as described in Example
1K using N-(3-{1 -[4-acetylamino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-
4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 1 .04 (s, 1H), 8.51 (br s, 2H), 7.94 (d, 1H), 7.84 (s,
1H), 7.63 (d, 1H), 7.40 (m, 1H), 7.30 (d, 1H), 7.21 (m, 2H), 4.60 (br d, 2H), 4.42 (t,
2H), 3.99 (m, 2H), 3.67 (t, 2H), 3.40 (s, 3H), 3.22 (br m, 3H), 2.07 (s, 3H), 1.89-1 .65
(m, 4H).
9F NMR (300 MHz, DMSO-c/6) - 119.86.
MS m/z: [M+H] += 467.
EXAMPLE 97
1-Methyl-piperidine-4-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
The title compound is prepared in a similar manner as described in Example
6E using N-methylisonipecotic acid and N-(3-{1 -[4-amino-1 -(2-methoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the
starting materials.
H NMR (300 MHz, DMSO-c/6) 0.81 (s, 1H), 9.96 (t, 1H), 7.92 (d, 1H), 7.79 (s, 1H),
7.33-7.30 (m, 1H), 7.27 (d, 1H), 7.22-7.1 5 (m, 3H), 4.60 (d, 2H), 4.40 (t, 2H), 4.35 (d,
2H), 3.66 (t, 2H), 3.32 (br s, 2H), 3.1 8-3.1 6 (m, 4H), 2.89 (br s, 2H), 2.24 (br s, 4H),
2.09 (br s, 2H), 1.90-1 .65 (m, 8H).
B. 1-Methyl-piperidine-4-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
The title compound is prepared in a similar manner as described in Example
3B with 1-methyl-piperidine-4-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoroacetylamino)-
methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-
yl]-amide as the starting material.
H NMR (300 MHz, DMSO-c/6) 0.97 (s, 1H), 8.84 (br s, 3H), 7.93 (d, 1H), 7.84 (s,
1H), 7.64-7.62 (m, 1H), 7.41 -7.33 (m, 2H), 7.26-7.1 8 (m, 2H), 4.61 (d, 2H), 4.42 (t,
2H), 4.01 (s, 2H), 3.66 (t, 2H), 3.35-3.25 (br s, 4H), 3.21 (s, 4H), 2.95 (br t , 2H), 2.66
(s, 3H), 2.55 (br s, 1H), 2.1 2-1 .96 (m, 4H), 1.89-1 .69 (m, 4H).
MS m/z [M+H]+=550.
EXAMPLE 98
Bicyclo[2.2.1]heptane-2-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperidine-1 -c hydrochloride
A. Bicyclo[2.2.1]heptane-2-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoroacetylamino)-
methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-
-amide
The title compound is prepared in a similar manner as described in Example
6E using norbornane-2-carboxylic acid (predominantly endo isomer) and N-(3-{1 -[4-
amino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-
2,2,2-trifluoro-acetamide as the starting materials.
H NMR (300 MHz, DMSO-c/6) 0.67 (s, 1H), 9.96 (br s, 1H), 7.96 (d, 1H), 7.78 (s,
1H), 7.31 -7.25 (m, 2H), 7.21 -7.15 (m, 3H), 4.62 (br s, 2H), 4.40 (t, 2H), 4.35 (d, 2H),
3.66 (t, 2H), 3.22 (s, 3H), 3.21-3.14 (br s, 3H), 2.87-2.81 (m, 1H), 2.70 (br s, 1H),
2.36-2.31 (m, 1H), 2.25-2.20 (m, 1H), 1.85 (br s, 2H), 1.75-1 .55 (m, 4H), 1.48-1 .39
(m, 3H), 1.35-1 .24 (m, 2H).
B. Bicyclo[2.2.1]heptane-2-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperidine-1 -ca hydrochloride
The title compound is prepared in a similar manner as described in Example
3B with bicyclo[2.2.1]heptane-2-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoroacetylamino)-
methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-
yl]-amide as the starting material.
H NMR (300 MHz, DMSO-c/6) 10.71 (s, 1H), 8.42 (br s, 3H), 7.96 (d, 1H), 7.80 (s,
1H), 7.57-7.56 (m, 1H), 7.43-7.39 (m, 2H), 7.28 (t, 1H), 7.23-7.1 6 (m, 1H), 4.62 (d,
2H), 4.41 (t, 2H), 3.98 (br s, 2H), 3.76 (br s, 1H), 3.66 (t, 2H), 3.21 (br s, 6H), 2.86-
2.80 (m, 1H), 2.70 (br s, 1H), 2.24 (br s, 1H), 1.90-1 .71 (m, 5H), 1.48-1 .15 (m, 6H).
MS m/z [M+H] +=547.
EXAMPLE 99
Morpholine -4-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperdine-1 -
carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
A. Morpholine-4-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoro-acetylamino)-
methyl]-phenyl}-piperdine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide
To a solution of N-(3-{1 -[4-amino-1-(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide ( 1 .00 g, 1.92 mmol) and Et3N
(0.64 mL, 4.6 mmol) in CH2CI2 (50 mL) is added morpholine-4-carbonyl chloride (0.66
mL, 5.7 mmol). The reaction mixture is stirred at 40 °C for 12h. The mixture is diluted
with CH2CI2 ( 100 mL) and is washed with water, brine, dried with MgSO4, filtered and
is concentrated in vacuo. The crude residue is flash chromatographed over SiO2
eluted with 70% EtOAc/heptane to afford the titled compound (0.82 g).
H NMR (300 MHz, CDCI3) 9.6 (s, 1H), 7.8 (d, 1H), 7.3 (m, 1H), 7.2-7.0 (m, 5H), 4.7
(m, 2H), 4.4 (m, 2H), 4.3 (m, 2H), 3.8-3.6 (m, 10H), 3.3 (s, 3H), 3.2 (m, 3H), 1.9 (m,
2H), 1.7 (m, 2H), 1.5 (m, 2H).
MS m/z [M+H]+=634.
B- Morpholine -4-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperdine-1-
carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
The title compound is prepared in a similar manner as described in Example
B using N-(3-{1 -[4-methylamino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-
-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material .
H NMR (300 MHz, DMSO-c/6) 10.0 (s, 1H), 8.2 (bs, 2H), 7.8 (m, 2H), 7.6 (m, 1H),
.4 (m, 1H), 7.2 (m, 3H), 4.6 (m, 2H), 4.4 (m, 2H), 4.0 (m, 2H), 3.7 (m, 10H), 3.5 (m,
H), 3.2 (s, 3H), 1.9 (m, 2H), 1.8 (m, 2H).
S m/z [M+H]+=538
EXAMPLE 100
3-[3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperdine-1 -carbonyl]-1 -(2-methoxy-ethyl)-
1H-indol-4-yl]-1 , 1 -dimethyl-urea hydorchloride
A. N-(3-{1 -[4-(3,3-Dimethyl-ureido)-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperdin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example
99A using N-(3-{1 -[4-amino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-
4-fluoro-benzyl)-2,2,2-trifluoro-acetamide and dimethylcarbamyl chloride as the
starting materials.
H NMR (300 MHz, CDCI3) 9.4 (s, H), 7.8 (d, H), 7.3 (m, H), 7.2-7.0 (m, 5H), 4.7
(m, 2H), 4.5 (m, 2H), 4.3 (m, 2H), 3.6 (m, 2H), 3.3 (s, 3H), 3.2 (m, 3H), 3.0 (s, 6H),
1.9 (m, 2H), 1.7 (m, 2H).
MS m/z [M+H]+=592.
B- 3-[3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperdine-1 -carbonyl]-1 -(2-methoxy-ethyl)-
-indol-4-yl]- , 1 -dimethyl-urea hydorchloride
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1-[4-(3,3-dimethyl-ureido)-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperdin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material .
H NMR (300 MHz, DMSO-c/6) 9.7 (s, H), 8.3 (bs, 2H), 7.8 (d, H), 7.8 (m, H), 7.6
(m, 1H), 7.4 (m, H), 7.3-7.0 (m, 3H), 4.6 (m, 2H), 4.4 (m, 2H), 4.0 (m, 6H), 3.6 (m,
2H), 3.2 (s, 3H), 3.0 (s, 6H), .9 (m, 2H), .7 (m, 2H).
MS m/z [M+H] +=496.
EXAMPLE 10 1
1-N-[3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-
H-indol-4-yl]-isonicotinamide hydrochloride
The title compound is prepared in a similar manner as described in Example
6E using isonicotinic acid and N-(3-{1 -[4-amino-1 -(2-methoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting
materials.
H NMR (300 MHz, DMSO-c/6) 11.88 (s, 1H), 9.93 (t, 1H), 8.82-8.80 (m, 2H), 8.1 9
(d, 1H), 8.00-7.98 (m, 2H), 7.88 (s, 1H), 7.46-7.43 (m, 1H), 7.39-7.29 (m, 1H), 7.27-
7.24 (m, 1H), 7.1 5 (d, 2H), 4.64 (br d, 2H), 4.45 (t, 2H), 4.33 (d, 2H), 3.69 (t, 2H), 3.23
(s, 3H), 3.1 7 (br s, 3H), 1.88-1 .84 (m, 2H), 1.76-1 .69 (m, 2H).
B. N-[3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-
et e
The title compound is prepared in a similar manner as described in Example
3B with N-[3-(4-{2-fluoro-5-[(2,2,2-trifluoro-acetylamino)-methyl]-phenyl}-piperidine-1 -
carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-isonicotinamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 12.1 0 (s, 1H), 8.95 (d, 2H), 8.42 (br s, 3H), 8.22-
8.1 8 (m, 3H), 7.93 (s, 1H), 7.58-7.56 (m, 1H), 7.48-7.45 (m, 1H), 7.41 -7.37 (m, 1H),
7.31 (t, 1H), 7.21 (dd, 1H), 4.65 (d, 2H), 4.47 (t, 2H), 3.97-3.95 (m, 2H), 3.70 (t, 2H),
3.23 (br s, 6H), 1.90-1 .70 (m, 4H).
MS m/z [M+H] +=496.
EXAMPLE 102
1-Pyrimidine-5-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperidine-1 -
carbonyl]- -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
A. Pyrimidine-5-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoro-acetylamino)-methyl]-
phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide
The title compound is prepared in a similar manner as described in Example
6E using pyrimidine-5-carboxylic acid and N-(3-{1 -[4-amino-1 -(2-methoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the
starting materials.
H NMR (300 MHz, DMSO-c/6) 10.02 (s, 1H), 9.93 (t, 1H), 9.39 (s, 2H), 9.38 (s, 1H),
8.1 8 (d, 1H), 7.89 (s, 1H), 7.46-7.44 (m, 1H), 7.28 (q, 2H), 7.14 (d, 2H), 4.61 (br d, 2
H), 4.45 (t, 2H), 4.34 (d, 2H), 3.69 (t, 2H), 3.23 (s, 3H), 3.1 9 (br s, 3H), 1.87-1 .62 (m,
4H).
B. Pyrimidine-5-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperidine-1-
carbonyl -1-(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
The title compound is prepared in a similar manner as described in Example
3B with pyrimidine-5-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoro-acetylamino)-
methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide as
the starting material.
H NMR (300 MHz, DMSO-c/6) 12.05 (s, 1H), 9.39 (s, 3H), 8.39 (br s, 3H), 8.1 8 (d,
1H), 7.92 (s, 1H), 7.54 (d, 1H), 7.47-7.44 (m, 1H), 7.41-7.38 (m, 1H), 7.30 (t, 1H),
7.25-7.1 8 (m, 1H), 4.61 (br d, 2H), 4.46 (t, 2H), 3.98-3.96 (m, 2H), 3.70 (t, 2H), 3.23
(s, 6H), 1.88-1 .70 (m, 4H).
MS m/z [M+H] +=530.
EXAMPLE 103
lsoxazole-5-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperidine-1 -
A. lsoxazole-5-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoro-acetylamino)-methyl]-
phenyl}-piperidi -1-carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide
The title compound is prepared in a similar manner as described in Example
96A using isoxazole-5-carboxylic acid and N-(3-{1 -[4-amino-1 -(2-methoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the
starting materials.
H NMR (300 MHz, CDCI3) 11.62 (s, 1H), 8.38 (s, 1H), 8.25 (d, 1H), 7.44 (s, 1H),
7.38 (t, 1H), 7.18 (m, 3H), 7.03 (d, 2H), 4.72 (br d, 2H), 4.44 (m, 2H), 4.32 (t, 2H),
3.71 (t, 2H), 3.31 (s, 3H), 3.20 (m, 1H), 1.90 (m, 2H), 1.70 (m, 1H), 1.53 (m, 4H). MS
m/z [M+H]+=61 6.
B. lsoxazole-5-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperidine-1-
carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using isoxazole-5-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoro-acetylamino)-
methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide as
the starting material.
H NMR (300 MHz, DMSO-c/6) 0.82 (s, 1H), 8.39 (br s, 2H), 7.80 (m, 1H), 7.60 (m,
1H), 7.40-7.21 (m, 4H), 7.20-7.1 0 (m, 3H), 4.70 (br s, 2H), 4.45 (br s, 2H), 4.00 (br m,
2H), 3.70 (br s, 2H), 3.50-3.30 (m, 3H), 3.23 (s, 3H), 1.80 (br m, 2H), 1.50 (br m, 2H).
MS m/z [M+H]+=520.
EXAMPLE 104
Dimethylamino-1 -sulfonic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperdine-1 -
carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide
A. N-(3-{1 -4-(Dimethylamino-1 -sulfonylamino)-1 -(2-methoxy-ethyl)-1 H-indole-3-
carbonyl}-piperdine-4-yl)-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example
99A using N-(3-{1 -[4-amino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-
4-fluoro-benzyl)-2,2,2-trifluoro-acetamide and dimethylsulfamoyl chloride as the
starting materials.
H NMR (300 MHz, CDCI3) 9.7 (s, H), 7.4 (m, 2H), 7.3 (m, H), 7.2 (m, 3H), 7.0
(m, H), 4.7 (m, 2H), 4.4 (m, 2H), 4.3 (m, 2H), 3.7 (m, 2H), 3.3 (s, 3H), 3.2 (m, 3H),
3.0 (s, 6H), 1.8 (m, 4H).
MS m/z [M+H]+=628.
B- Dimethylamino-1 -sulfonic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperdine-1 -
carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1 -4-(dimethylamino-1 -sulfonylamino)-1 -(2-methoxy-ethyl)-1 H-indole-3-
carbonyl}-piperdine-4-yl)-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting
material .
H NMR (300 MHz, DMSO-c/6) 10.5 (s, 1H), 8.4 (bs, 2H), 7.9 (d, 1H), 7.6 (m, 1H),
7.4 (m, 2H), 7.2 (m, 3H), 4.6 (m, 2H), 4.4 (m, 2H), 4.0 (m, 3H), 3.7 (m, 2H), 3.5 (m,
2H), 3.2 (s, 3H), 2.6 (s, 6H), 1.9 (m, 2H), 1.7 (m, 2H).
MS m/z: [M+H]+=532.
EXAMPLE 105
1-Methyl-1 H-imidazole-4-sulfonic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperdine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(1 -methyl-1 H-imidazole-4-
sulfonylamino)-1 H-indole-3-carbonyl]-piperdin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example
99A using N-(3-{1 -[4-amino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-
4-fluoro-benzyl)-2,2,2-trifluoro-acetamide and 1-methyl-1 H-imidazole-4-sulfonyl
chloride as the starting materials.
H NMR (300 MHz, CDCI3) 10.1 (s, 1H), 7.5-7.3 (m, 5H), 7.2 (m, 3H), 7.0 (m, 2H),
4.6 (m, 2H), 4.4 (m, 2H), 4.2 (m, 2H), 3.6 (m, 5H), 3.3 (s, 3H), 3.2 (m, 3H), 1.9 (m,
2H), 1.8 (m, 2H).
MS m/z [M+H]+=665.
B- 1-Methyl-1 H-imidazole-4-sulfonic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperdine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(1 -methyl-1 Himidazole-
4-sulfonylamino)-1 H-indole-3-carbonyl]-piperdin-4-yl}-benzyl)-acetamide as
the starting material.
H NMR (300 MHz, DMSO-c/6) 10.9 (s, 1H), 8.4 (bs, 2H), 7.8 (m, 2H), 7.6 (m, 2H),
7.4 (m, 1H), 7.3-7.0 (m, 3H), 4.6 (m, 4H), 4.4 (m, 2H), 4.0 (m, 2H), 3.5 (m, 4H), 3.2
(m, 6H), 2.0-1 .7 (m, 4H).
MS m/z [M+H]+=567.
EXAMPLE 106
Pyridine-3-sulfonic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperdine-1 -carbonyl]-
1-(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
A. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(pyridine-3-sulfonylamino)-
1H-indole-3-carbonyl]-piperdin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example
99A using N-(3-{1 -[4-amino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-
4-fluoro-benzyl)-2,2,2-trifluoro-acetamide and pyridine-3-sulfonyl chloride as the
starting materials.
H NMR (300 MHz, CDCI3) 10.8 (s, 1H), 9.1 (s, 1H), 8.6 (m, 1H), 8.0 (m, 1H), 7.4-
7.0 (m, 7H), 4.6 (m, 2H), 4.5 (m, 2H), 4.3 (m, 2H), 4.2 (m, 2H), 3.6 (m, 2H), 3.3 (s,
3H), 3.2 (m, 3H), 1.9 (m, 2H), 1.7 (m, 2H).
MS m/z [M+H]+=662.
B. Pyridine-3-sulfonic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperdine-1 -
carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(pyridine-3-
sulfonylamino)-1 H-indole-3-carbonyl]-piperdin-4-yl}-benzyl)-acetamide as the starting
material .
H NMR (300 MHz, DMSO-c/6) 1 .2 (s, H), 8.75 (bs, 2H), 8.4 (m, 1H), 7.9 (m, 1H),
7.8 (m, 1H), 7.7 (m, 1H), 7.5 (m, 1H), 7.4 (m, 2H), 7.0 (m, 2H), 4.4 (m, 5H), 4.0 (m,
2H), 3.6 (m, 2H), 3.3 (m, 3H), 3.2 (s, 3H), 1.8 (m, 2H), 1.7 (m, 2H).
MS m/z [M+H]+=566.
EXAMPLE 107
Butane-1 -sulfonic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperdine-1 -carbonyl]-1 -
(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
A. N-(3-{1 -[4-(Butane-1 -sulfonylamino)-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-
piperdin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example
99A using N-(3-{1 -[4-amino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-
4-fluoro-benzyl)-2,2,2-trifluoro-acetamide and 1-butanesulfonyl chloride as the
starting materials.
H NMR (300 MHz, CDCI3) 9.8 (s, 1H), 7.4 (m, 1H), 7.3 (m, 2H), 7.2-7.0 (m, 4H),
4.7 (m, 2H), 4.5 (m, 2H), 4.3 (m, 2H), 4.1 (m, 2H), 3.7 (m, 2H), 3.3 (s, 3H), 3.2 (m,
2H), 3.1 (m, 3H), 2.0-1 .8 (m, 4H), 1.6 (m, 2H), 1.4 (m, 2H), 0.9 (m, 3H).
MS m/z: [M+H]+=545.
B. Butane-1 -sulfonic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperdine-1 -
carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-(3-{1 -[4-(butane-1 -sulfonylamino)-1 -(2-methoxy-ethyl)-1 H-indole-3-
carbonyl]-piperdin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting
material .
H NMR (300 MHz, DMSO-c/6) 10.6 (s, 1H), 8.3 (bs, 2H), 7.8 (d, 1H), 7.6 (m, 1H),
7.4 (m, 2H), 7.2 (m, 3H), 4.6 (m, 2H), 4.4 (m, 2H), 4.0 (m, 2H), 3.7 (m, 2H), 3.5 (m,
2H), 3.2 (s, 3H), 3.1 (m, 2H), 1.9 (m, 2H), 1.8 (m, 2H), 1.6 (m, 2H), 1.3 (m, 2H), 0.8
(m, 3H).
MS m/z [M+H]+=641 .
EXAMPLE 108
1-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-
(pyrrolidine-1 -carbonyl)-1 H-indol-3-yl]-methanone hydrochloride
A. 1-(2-Methoxy-ethyl)-1 H-indole-4-carboxylic acid
33Q
The title compound is prepared in a similar manner as described in Example
1E using indole-4-carboxylic acid and 2-bromoethylmethylether as the starting
material.
H NMR (300 MHz, CDCI3) 8.03 (d, H), 7.63 (d, H), 7.35-7.34 (m, H), 7.32-7.29
(m, H), 7.24-7.23 (m, H), 4.35 (t, 2H), 3.73 (t, 2H), 3.32 (s, 3H).
B. [ 1 -(2-Methoxy-ethyl)-1 H-indol-4-yl]-pyrrolidin-1 -yl-methanone
The title compound is prepared in a similar manner as described in Example
6E with pyrrolidine and 1-(2-methoxy-ethyl)-1 H-indole-4-carboxylic acid as the
starting materials.
H NMR (300 MHz, CDCI3) 7.40-7.36 (m, H), 7.25-7.1 5 (m, 3H), 6.55-6.53 (m, 1H),
4.30 (t, 2H), 3.76-3.68 (m, 4H), 3.35 (t, 2H), 3.30 (s, 3H), 1.98 (quin, 2H), 1.83 (quin,
2H).
C. 3-Formyl-1 -(2-methoxy-ethyl)-1 H-indole-4-carboxylic acid ethyl-propyl-amide
The title compound is prepared in a similar manner as described in Example
59C with with [1-(2-methoxy-ethyl)-1 H-indol-4-yl]-pyrrolidin-1 -yl-methanone and
phosphorus oxychloride (POCI3) as the starting materials. The material was used in
the next step without any further purification.
MS 301 (M+1 ) .
D. 1-(2-Methoxy-ethyl)-4-(pyrrolidine-1-carbonyl)-1 H-indole-3-carboxylic acid
The title compound is prepared in a similar manner as described in Example
59D with with 3-formyl-1 -(2-methoxy-ethyl)-1 H-indole-4-carboxylic acid ethyl-propylamide
and sodium chlorite (NaCIO2) as the starting materials. The material was used
in the next step without any further purification.
MS 3 17 (M+1 ) .
E. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(pyrrolidine-1 -carbonyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example
6E using 1-(2-methoxy-ethyl)-4-(pyrrolidine-1 -carbonyl)-1 H-indole-3-carboxylic acid
and 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as the
starting materials.
H NMR (300 MHz, DMSO-c/6) 9.95 (t, 1H),7.61 -7.58 (m, 2H), 7.39 (d, 1H), 7.25-
7.20 (m, 1H), 7.1 5-7.1 2 (m, 2H), 7.03-7.01 (m, 1H), 4.40-4.35 (m, 5H), 3.69 (t, 2H),
3.45 (t, 2H), 3.23 (s, 3H), 3.1 7-3.1 2 (m, 3H), 3.09-2.97 (m, 3H), 1.90-1 .83 (m, 2H),
1.81-1 .74 (m, 3H), 1.71 - 1 .65 (m, 3H).
F. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-4-
(pyrrolidine-1-carbonyl)-1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using 2,2,2-trifluoro-N-(4-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-4-(pyrrolidine-1 -
carbonyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting
material.
H NMR (300 MHz, DMSO-c/6) 8.37 (br s, 3H),7.58 (s, 2H), 7.55 (s, 1H), 7.38-7.33
(m, 1H), 7.21 -7.1 3 (m, 2H), 7.00-6.98 (m, 1H), 4.36 (t, 2H), 4.06 ( br s, 2H), 3.95-3.93
(m, 2H), 3.65 (t, 2H), 3.40 (t, 2H), 3.19 (s, 3H), 3.1 3-3.05 (m, 3H), 2.96 (br s, 2H),
1.85-1 .64 (m, 8H).
EXAMPLE 109
3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 Hindole-
4-carboxylic acid trifluoroacetate
A. 1-(2-Methoxy-ethyl)-1 H-indole-4-carbaldehyde
A mixture of 4-formyl-1 H-indole ( 1 .0 g, 6.89 mmol) and powdered KOH ( 1 .16
g, 20.7 mmol) in DMSO ( 10 mL) is stirred at r.t. for 5 min then 2-methoxyethyl
bromide (972 _, 10.3 mmol) is added. After the reaction mixture is stirred at r.t. 15
min, it is partitioned between H2O and Et2O. The two layers are separated, and the
aqueous layer is extracted with Et2O (3X). The combined organic extracts are
washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo.
The crude material is purified on silica gel with heptane/EtOAc (75/25 to 50/50) as
eluent to yield the titled product ( 1 .25 g, 89%) as a yellow liquid.
H NMR (300 MHz, CDCI3) 10.25 (s, 1H), 7.70-7.50 (m, 2H), 7.45-7.20 (m, 3H),
4.35 (t, J = 5.4 Hz, 2H), 3.71 (t, J = 5.4 Hz, 2H), 3.30 (s, 3H);
LC Rt: 0.82 min.
B. 1-(2-Methoxy-ethyl)-3-(2,2,2-trifluoro-acetyl)-1 H-indole-4-carbaldehyde
A mixture of 1-(2-methoxy-ethyl)-1 H-indole-4-carbaldehyde ( 1 .25 g, 6.1 5
mmol) and TFAA (2.57 mL, 18.5 mmol) in DMF ( 15 mL) is heated at r.t. for 3 days.
The mixture is then partitioned between sat. Na2CO3 and Et O. The two layers are
separated and the organic layer is washed with H O and brine, dried over MgSO ,
filtered, and concentrated in vacuo. The crude material is purified on silica gel with
heptane/EtOAc (75/25 to 40/60) as eluent. The residue is recrystallized from CH CI2/
heptane to provide the product ( 1 .42 g, 77%) as a yellow waxy solid.
H NMR (300 MHz, CDCI3) 11.24 (s, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.03 (d, J = 7.5
Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 4.46 (t, J = 5.0 Hz, 2H),
3.78 (t, J = 5.1 Hz, 2H), 3.34 (s, 3H);
9F NMR (300 MHz, CDCI3) -69.88 (s, 3F);
LC Rt: 0.90 min; MS 300 (M+H, 100%).
C. 4-Formyl-1 -(2-meth dole-3-carboxylic acid
A mixture of 1-(2-methoxy-ethyl)-3-(2,2,2-trifluoro-acetyl)-1 H-indole-4-
carbaldehyde ( 1 .40 g, 4.68 mmol) in MeOH ( 10 mL) and NaOH (5 M, 10 mL) is
heated at 80 °C overnight. This mixture is concentrated in vacuo to remove the
methanol. The residue is diluted with H2O, and then washed with EtOAc once. The
aqueous layer at 0 °C is acidified to pH 1 with cone. HCI. The acidified mixture is
extracted with EtOAc (2X). The combined organic extracts are washed with H2O and
brine, dried over MgSO4, filtered, and concentrated in vacuo to yield the product ( 1 .56
g, 100%) as a beige powder. This material is used in the next step without further
purification.
LC Rt: 0.69 min.
D. 2,2,2-Trifluoro-N-(4-fluoro-3-{1 -[4-formyl-1 -(2-methoxy-ethyl)-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
A mixture of 4-formyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid (736
mg, 2.98 mmol), Et3N ( 1 .04 mL, 7.45 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-
yl-benzyl)-acetamide hydrochloride ( 1 .22 g, 3.57 mmol), and EDCI (0.86 g, 4.47
mmol) in CH2CI2 (20 mL) is stirred at r.t. overnight. The mixture is partitioned
between H2O and CH2CI2. The two layers are separated, and the organic layer is
washed with brine, dried over MgSO , filtered, and concentrated in vacuo. The crude
material is purified on silica gel with EtOAc/MeOH ( 100/0 to 80/20) as eluent to give
the product (918 mg, 57%) as a white powder.
H NMR (300 MHz, CDCI3) 10.34 (s, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 8.2
Hz, 1H), 7.48 (s, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.25.7.1 0 (m, 2H), 7.1 0-6.90 (m, 2H),
5.30-4.60 (br m, 1H), 4.60-4.20 (m, 5H), 3.73 (t, J = 5.3 Hz, 2H), 3.32 (s, 3H), 3.25-
2.80 (m, 3H), 2.1 0-1 .50 (m, 4H);
9F NMR (300 MHz, CDCI3) -75.30 (s, 3F), - 1 19.49 (br m, 1F);
LC Rt 0.95 min; MS 534 (M+H, 100%).
E. 3-(4-{2-Fluoro-5-[(2,2,2-trifluoro-acetylamino)-methyl]-phenyl}-piperidine-1 -
carbonyl)-1 -(2-methoxy-ethyl)-1 H-indole-4-carboxylic acid
To a solution of 2,2,2-trifluoro-N-(4-fluoro-3-{1-[4-formyl-1-(2-methoxy-ethyl)-
1H-indole-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (900 mg, 1.69 mmol) and 2-
methyl-2-butene (0.8 mL) in THF ( 10 ml_)/t-BuOH (5 mL) is added a solution of
sodium chlorite (764 mg, 8.45 mmol) and sodium dihydrogen phosphate ( 1 .26 g, 10.1
mol) in water (4 mL). This mixture is stirred at r.t. for 2 h. The mixture is
concentrated in vacuo to remove the organic solvents. The residue is partitioned
between water and EtOAc. The two layers are separated, and the organic layer is
washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude
material is purified on silica gel with EtOAc/MeOH ( 100/0 to 80/20) as eluent to give
the product (780 mg, 84%) as a beige powder.
H NMR (300 MHz, CDCI3) 8.61 (bs, 1H), 7.90-7.70 (m, 1H), 7.70-7.50 (m, 1H),
7.50-7.30 (m, 2H), 7.30-7.1 0 (m, 1H), 7.1 0-6.95 (m, 1H), 6.88 (d, J = 9.9 Hz, 1H),
5.1 0-4.95 (br m, 1H), 4.45-4.30 (m, 2H), 4.1 0-3.80 (m, 2H), 3.70 (t, J = 4.9 Hz, 2H),
3.31 (s, 3H), 3.25-3.00 (m, 2H), 3.00-2.75 (m, 1H), 2.30-1 .50 (m, 4H);
9F NMR (300 MHz, CDCI3) -76.01 (s, 3F), - 122.34 (br s, 1F);
LC Rt 0.90 min; MS 550 (M+H, 100%).
F. 3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-
1H-indole-4-carboxylic acid trifluoroacetate
To a mixture of 3-(4-{2-fluoro-5-[(2,2,2-trifluoro-acetylamino)-methyl]-phenyl}-
piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indole-4-carboxylic acid (30 mg, 0.055
mmol) in MeOH (5 mL) is added aqueous K2CO3 (200 mg dissolved in 2.0 mL H2O).
This mixture is stirred at r.t. overnight. LC/MS indicates the reaction is completed.
The reaction mixture is concentrated in vacuo to remove most of the methanol. The
residue is partitioned between H2O and EtOAc. The residue is diluted with water, and
3 M HCI is added until pH~1 . The suspension is concentrated to dryness in vacuo.
The residue is purified by RP-HPLC to give the product ( 12 mg, 38%) as a white
powder.
H NMR (300 MHz, DMSO-c/6) 8.1 7 (br,s 3H), 7.81 (d, J = 8.1 Hz, 1H), 7.70-7.55
(m, 2H), 7.50-7.40 (m, 1H), 7.40-7.15 (m, 3H), 4.90-4.50 (br m, 1H), 4.50-4.30 (m,
2H), 4.20-3.80 (m, 3H), 3.75-3.65 (m, 2H), 3.22 (s, 3H), 3.1 5-2.65 (m, 3H), 1.95-1 .45
(m, 4H);
9F NMR (300 MHz, DMSO-c/6) -73.37 (s, 3F), - 1 19.49 (s, 1F);
LC 0.63 min; MS 454 (M+H, 100%).
EXAMPLE 110
[4-(5-Aminomethyl-2-trifluoromethyl-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
meth l-1H-indol-3-yl]-methanone hydrochloride
A. 3-Bromo-4-trifluoromethyl-benzoic acid
To a 0 °C solution of copper (II) bromide (7.0 g, 48.6 mmol) in acetonitrile
(150mL) is added t-butyl nitrite (5.6 mL, 46.4 mmol) followed by addition of 3-amino-4-
trifluoromethyl-benzoic acid (5.0 g, 24.4 mmol) over a 5 min period. The reaction
mixture is stirred at 0 °C for 2h and then at r.t. overnight. The reaction mixture is
poured into EtOAc, washed with 1N HCI (2X), brine, dried over MgSO4, filtered, and
concentrated in vacuo to give the titled compound (6.22 g, 95%).
H NMR (300 MHz, DMSO-c/6) 13.8 (bs, H), 8.3 (s, H), 8.1 (m, 2H).
B. (3-Bromo-4 nyl)-methanol
To a 0 °C solution of 3-bromo-4-trifluoromethyl-benzoic acid (6.2 g, 23 mmol)
in THF (50 mL) is added a 1.0M borane/THF solution (39 mL, 39 mmol). The resulting
mixture is allowed to warm to r.t. and stir overnight. To the reaction mixture is added
MeOH (7 mL) and 1 N HCI (7 mL). The resulting mixture is heated to reflux for 1 h
and then cooled to r.t. The reaction mixture is concentrated in vacuo and the residue
is taken up in ethyl acetate, washed with H2O, sat. NaHCO3 , brine, dried over
Na2SO , filtered and concentrated in vacuo. Purification by flash chromatography on
SiO2 eluting with 30% ethyl acetate / heptane yields the titled compound (4.75g,
8 1%).
H NMR (300 MHz, DMSO-c/6) 7.8 (m, 2H), 7.5 (m, 1H), 5.5 (m, 2H).
C. (3-Bromo-4-trifluoromethyl-benzyloxy)-tert-butyl-dimethyl-silane
To a solution of (3-bromo-4-trifluoromethyl-phenyl)-methanol (4.7 g, 18.43
mmol) in CH2CI2 (250 mL) is added tert-butyldimethylsilyl chloride (5.6 g, 36.86 mmol)
and dropwise addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (3.3 mL, 22.1 2 mmol).
The reaction mixture is stirred at r.t. overnight. The reaction mixture is poured into
Et2O, washed with sat NaHCO3, brine, dried over Na2SO4, filtered, and concentrated
in vacuo to give the crude product. Purification by flash chromatography on S1O2
eluting with 1% ethyl acetate / heptane yields the titled compound (6.35 g, 93% yield).
H NMR (300 MHz, CDCI3) 7.8 (m, 2H), 7.5 (s, 1H), 4.8 (s, 2H), 0.9 (s, 9H), 0.5 (s,
6H).
D. 4-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-trifluoromethyl-phenyl]-3,6-dihydro-
-pyridine-1-carboxylic acid benzyl ester
To a -78 °C solution of (3-bromo-4-trifluoromethyl-benzyloxy)-tert-butyldimethyl-
silane (5.0 g, 14.3 mmol) in THF ( 100 mL) is added a 1.7 M tertbutyllithium/
pentane solution (8.6 mL, 14.6 mmol). The resulting mixture is stirred at -
78 °C for 15 min then N-CBZ-piperidin-4-one (3.3 g, 14.3 mmol) as a solution in THF
(25 mL) is added. The reaction is allowed to warm to r.t. and stirred overnight. The
reaction mixture is heated at 40 °C for 2h and is then cooled to r.t. The reaction is
poured into ethyl acetate, washed with sat NH CI, H2O, brine, dried over MgSO ,
filtered and concentrated in vacuo. Purification by flash chromatography on S1O2
eluting with 20% ethyl acetate/heptane yields the titled compound (2.52 g, 36%).
H NMR (300 MHz, DMSO-c/6) 7.8 (d, 1H), 7.6 (s, 1H), 7.4 (m, 6H), 5.1 (s, 2H), 4.8
(s, 2H), 3.9 (m, 2H), 3.3 (m, 2H), 3.2 (bs, 1H), 1.9 (m, 2H), 1.8 (m, 2H), 0.9 (s, 9H),
0.5 (s, 6H).
MS m/z [M+H]+=524.
E. 4-(5-Hydroxymethyl-2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic
acid benzyl ester
To a solution of 4-[5-(tert-butyl-dimethyl-silanyloxymethyl)-2-trifluoromethylphenyl]-
3,6-dihydro-2H-pyridine-1 -carboxylic acid benzyl ester (2.00 g, 3.82 mmol) in
CH2CI2 ( 100 mL) is added a solution of boron trifluoride diethyl etherate (4.84 mL,
38.2 mmol). The resulting mixture is stirred at r.t. overnight. The reaction mixture is
quenched with sat NaHCOs ( 150 mL) and stirred at r.t. for 3 h. The reaction mixture is
extracted with ethyl acetate (3X) and the combined organic extracts are washed with
brine, dried over Na2SO , filtered and concentrated in vacuo. Purification by flash
chromatography on SiO2 eluting with 40% ethyl acetate / heptane yields the titled
compound (0.39 g, 26%).
H NMR (300 MHz, CDCI3) 7.6 (d, 1H), 7.4 (m, 6H), 7.2 (s, 1H), 5.6 (m, 1H), 5.2 (s,
2H), 4.8 (m, 2H), 4.1 (m, 2H), 3.7 (m, 2H), 2.4 (m, 2H), 1.8 (m, 1H).
MS m/z [M+H]+=392.
F. 4-(5-Azidomethyl-2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1 -carboxylic
acid benzyl ester
A solution of 4-(5-hydroxymethyl-2-trifluoromethyl-phenyl)-3,6-dihydro-2Hpyridine-
1 -carboxylic acid benzyl ester (0.5 g, 1.28 mmol), triethylamine (0.34 mL,
2.43 mmol) and diphenylphosphoryl azide (0.55 mL, 2.56 mmol) in THF (5 mL) is
subjected to a microwave apparatus at 80 °C for 1 h. The reaction mixture is
concentrated in vacuo and the residue is diluted with a solution of EtOH (20 mL) and
6 N NaOH (20 mL) and stirred for 30 min. The reaction mixture is poured into EtOAc,
washed with H2O, brine, dried over Na2SO 4 , filtered and concentrated in vacuo.
Purification by flash chromatography on S1O2 eluting with 20% ethyl acetate / heptane
yields the titled compound (0.1 8 g, 34%).
H NMR (300 MHz, CDCI3) 7.7 (d, H), 7.4 (m, 6H), 7.2 (s, H), 5.6 (m, H), 5.2 (s,
2H), 4.4 (m, 2H), 4.1 (m, 2H), 3.7 (m, 2H), 2.4 (m, 2H).
MS m/z [M+H]+=41 7.
G. 4-(5-Aminomethyl-2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1 -carboxylic
acid benzyl ester
The titled compound is prepared according to the procedure by Lin, Wenqing
et al. Synthetic Communications, 2002, 32(21 ) , pp.3279-3284 using 4-(5-
azidomethyl-2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid
benzyl ester as the starting material.
H NMR (300 MHz, CDCI3) 7.6 (d, 1H), 7.4 (m, 6H), 7.2 (s, 1H), 5.6 (m, 1H), 5.2 (s,
2H), 4.2 (m, 2H), 3.9 (m, 2H), 3.7 (m, 2H), 2.4 (m, 2H).
MS m/z: [M+H]+=391 .
H. 4-[5-(tert-Butoxycarbonylamino-methyl)-2-trifluoromethyl-phenyl]-3,6-dihydro-2Hpyridine-
1 -carboxylic acid benzyl ester
To a solution of 4-(5-aminomethyl-2-trifluoromethyl-phenyl)-3,6-dihydro-2Hpyridine-
1 -carboxylic acid benzyl ester ( 1 .10 g, 2.82 mmol) in THF (50 mL) is added
Boc-anhydride ( 1 .23 g, 5.64 mmol) and triethylamine (0.55 mL, 3.95 mmol). The
resulting mixture is stirred at r.t. overnight. The reaction is poured into ethyl acetate,
washed with 0.5 N NaOH, brine, dried over MgSO , filtered and concentrated in
vacuo. Purification by flash chromatography on S1O2 eluting with 20% ethyl acetate /
heptane yields the titled compound ( 1 .0 g, 72%).
H NMR (300 MHz, CDCI3) 7.6 (d, 1H), 7.4 (m, 6H), 7.1 (s, 1H), 5.6 (m, 1H), 5.2 (s,
2H), 4.9 (m, 1H), 4.4 (m, 2H), 4.1 (m, 2H), 3.7 (m, 2H), 2.4 (m, 2H), 1.5 (s, 9H). MS
m/z [M+H]+=491 .
I . [3-(1 ,2,3,6-Tetrahydro-pyridin-4-yl)-4-trifluoromethyl-benzyl]-carbamic acid tertbut
l ester
A solution of 4-[5-(tert-butoxycarbonylamino-methyl)-2-trifluoromethyl-phenyl]-
3,6-dihydro-2H-pyridine-1 -carboxylic acid benzyl ester (0.88 g, 1.78 mmol) and 10%
Pd/C (0.25 g) in THF (5 mL) is subjected to H2 at 50 psi for 6 h. The reaction mixture
is filtered through Celite and concentrated in vacuo to yield the titled compound (0.63
g, 99%).
H NMR (300 MHz, CDCI3) 7.6 (d, 1H), 7.4 (d, 1H), 7.1 (s, 1H), 5.6 (m, 1H), 4.9 (m,
1H), 4.4 (m, 2H), 3.5 (m, 1H), 3.1 (m, 1H), 2.3 (m, 1H), 1.9-1 .7 (m, 4H), 1.5 (s, 9H).
MS m/z: [M+H]+=357.
J. (3-{1-[1 -(2-Methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-1 ,2,3,6-tetrahydropyridin-
4-yl}-4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester
The title compound is prepared in a similar manner as described in Example 2 1
using [3-(1 ,2,3,6-tetrahydro-pyridin-4-yl)-4-trifluoromethyl-benzyl]-carbamic acid tertbutyl
ester and 1-(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carboxylic acid as the
starting materials.
H NMR (300 MHz, CDCI3) 7.6 (m, 2H), 7.4 (s, H), 7.1 (m, 3H), 7.0 (m, 1H), 5.6
(m, 1H), 4.9 (m, 1H), 4.5 (t, 2H), 4.3 (m, 2H), 3.9 (m, 2H), 3.7 (t, 2H), 3.3 (s, 3H), 2.7
(s, 3H), 2.5 (m, 2H), 1.6 (m, 2H), 1.5 (m, 9H).
MS m/z [M+H]+=572.
K. 4-(5-Aminomethyl-2-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridin-1 -yl]-[1 -(2-
methoxy-ethyl)-7-methyl-1 H-indol-3-yl]-methanone hydrochloride
To a 2M HCI/Et2O solution (25 ml_) is added (3-{1 -[1 -(2-methoxy-ethyl)-7-
methyl-1 H-indole-3-carbonyl]-1 ,2,3,6-tetrahydro-pyridin-4-yl}-4-trifluoromethylbenzyl)-
carbamic acid tert-butyl ester (0.65 g, 1.1 mmol). The resulting mixture is
stirred at r.t. overnight. The precipitate is collected to give the titled compound (0.5 g,
93%).
L. 4-(5-Aminomethyl-2-trifluoromethyl-phenyl)-pipendin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
methyl-1 H-indol-3-yl]-methanone hydrochloride
To a solution of 4-(5-aminomethyl-2-trifluoromethyl-phenyl)-3,6-dihydro-2Hpyridin-
1 -yl]-[1 -(2-methoxy-ethyl)-7-methyl-1 H-indol-3-yl]-methanone hydrochloride
(0.50 g, 1.1 mmol) in MeOH (20 mL) is added ammonium formate (0.63 g, 10 mmol)
and 10% Pd/C (0.4 g). The reaction mixture is heated to reflux for 8 h and is
concentrated in vacuo. The residue is treated with 2 M HCI/Et2O ( 10 mL) and the
resulting mixture is stirred at r.t. overnight. The precipitate is collected to yield the
titled compound (0.43 g, 85%).
H NMR (300 MHz, DMSO-c/6) 8.4 (bs, 2H), 7.9 (s, 1H), 7.8 (m, 1H), 7.7 (m, 1H),
7.5 (m, 1H), 7.0 (m, 2H), 4.6 (t, 2H), 4.5 (m, 1H), 4.1 (m, 2H), 3.7 (t, 2H), 3.2 (s, 3H),
3.1 (m, 4H), 2.7 (s, 3H), 1.9-1 .7 (m, 4H).
MS m/z [M+H]+=474.
EXAMPLE 111
[4-(5-Aminomethyl-2,4-difluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-methyl-
1H-indol-3-yl]-methanone hydrochloride
A. 5-Bromo-2,4-difluorobenzoic acid
The title compound is prepared according to the procedure by Tochon-
Danguy, H. J. et al., Nuclear Medicine and Biology, 2004, vol. 3 1, p. 839 with 2,4-
difluorobenzoic acid. The titled compound is obtained as a white solid.
H NMR (300 MHz, CDCI3) 8.29 (t, 1H), 7.01 (dd, 1H).
9F NMR (300 MHz, CDCI3) -93.4 (m), - 103.9 (m).
LCMS m/z [M+H]+=234, 236.
B. 5-Bromo -2,4-difluorobenzoic acid methyl ester
The tiltle compound is prepared according to the procedure by Shioiri, T et al.,
Chem. Pharm. Bull., 1981 , vol. 29, pp. 1475-1478 with 5-bromo-2,4-difluoro-benzoic
acid. The titled compound was obtained as an amber solid.
H NMR (300 MHz, CDCI3) 8.20 (t, 1H), 6.97 (dd, 1H), 3.94 (s, 3 H).
9F NMR (300 MHz, CDCI3) -95.6 (m), - 105.5 (m).
LCMS m/z [M+H]+=249, 251 .
C. (5-Bromo- -difluorophenyl)methanol
To a solution of diisobutylaluminum hydride ( 105 mL, 157.5 mmol)) in toluene
(50 mL) cooled at 0 °C is added a solution of 2,4-difluoro-5-bromomethyl benzoate
(19.20 g, 76.48 mmol) in DCM dropwise over 15 min. The resulting mixture is stirred
at 0 °C for ~2½ hours under nitrogen atmosphere. The mixture is poured into an
Erlenmeyer flask containing a cold saturated solution of Rochelle's salt. The resulting
mixture is stirred until the mixture became clear. The aqueous phase is extracted
ethyl acetate (x3). The combined organic layers are washed with brine then
separated and dried (MgSO4) . The organic phase is concentrated in vacuo without
any further purification to afford the titled compound ( 17.05 g, 99%) as an orange oil.
H NMR (300 MHz, CDCI3) 7.64 (t, 1H), 6.92-6.86 (m, 1H), 4.71 (s, 2H).
9F NMR (300 MHz, CDCI3) - 104.6 (m), - 1 16.9 (m).
D. 1-Bromo-5-bromomethyl-2,4-difluorobenzene
To a solution of phosphorus (V) oxybromide (26.50 g, 92.43 mmol) in
dichloromethane (300 mL) at 0 °C is added N,N-dimethylformamide (150 mL)
dropwise over -20 min. To the resulting white suspension at 0 °C is added a solution
of (5-bromo-2,4-difluorophenyl)methanol (17.05 g, 76.45 mmol) in dichloromethane
dropwise over -15 min. The resulting mixture is stirred at 0 °C for ~ hour under
nitrogen atmosphere. The aqueous phase is extracted ethyl acetate (x3). The
combined organic phases are washed with brine then separated and dried (MgSO4) .
The organic phase is concentrated in vacuo and the crude residue is flash
chromatographed over S1O2 using (heptane:EtOAc (90:1 0) to afford the titled
compound ( 17.43 g, 80%) as a colorless oil.
H NMR (300 MHz, CDCI3) 7.77-7.71 (m, 1H), 7.1 5-7.08 (m, 1H), 4.52 (s, 2H).
9F NMR (300 MHz, CDCI3) - 104.2 (m), - 1 14.9 (m).
MS m/z [M+H]+=283, 285, 287.
E. 1-Azidomethyl-5-bromo-2,4-difluorobenzene
To a solution of 1-bromo-5-bromomethyl-2,4-difluorobenzene (17.1 2 g, 59.88
mmol) in N,N-dimethylformamide (75 ml_) at r.t. is added sodium azide (7.87 g, 12 1.1
mmol) and the mixture is stirred at r.t. over night. The mixture is poured into water
and the aqueous phase is extracted ethyl acetate (x3). The combined organic phases
are washed with brine then separated and dried (MgSO4) . The organic phase is
concentrated in vacuo without any further purification to afford the titled compound
(14.55 g, 98%) as a yellow oil.
H NMR (300 MHz, CDCI3) 7.56 (t, 1H), 6.99-6.93 (m, 1H), 4.38 (s, 2H).
9F NMR (300 MHz, CDCI3) - 102.6 (m), - 1 14.8 (m).
F. 5-Bromo -2,4-difluorobenzylamine
To a solution of 1-azidomethyl-5-bromo-2,4-difluoro-benzene (14.55 g, 58.66
mmol) in THF and water ( 10:1 ) at r.t. is added triphenylphosphine (30.81 g, 117.4
mmol) and the mixture is stirred at r.t. for one hour. THF is removed in vacuo and the
syrup is acidified with 10% HCI. The aqueous phase is extracted ethyl acetate. The
aqueous phase is basified with 50% NaOH and the aqueous phase is extracted with
ethyl acetate (3x) and the combined organic phases are washed with brine then
separated and dried (MgSO4) . The organic phase is concentrated in vacuo and the
crude residue is flash chromatographed over S1O2 using CH2Cl2:MeOH (90:1 0) to
afford the titled compound (4.53 g, 35%) as a pale yellow oil.
H NMR (300 MHz, CDCI3) 7.57 (t, 1H), 6.90-6.84 (m, 1H), 3.86 (s, 2H), 1.54 (br s,
2H).
9F NMR (300 MHz, CDCI3) - 106.1 (m), - 1 17.1 (m).
MS m/z [M+H]+=221 , 223.
G. 2,4-Difluoro-5-pyridin-4-yl-benzylamine
A solution of 5-bromo-2,4-difluoro-benzylamine (2.39 g, 10.76 mmol), 4-
pyridineboronic acid ( 1 .65 g, 13.42 mmol) and sodium bicarbonate (2.84 g, 33.76
mmol) in iso-propanol and water ( 1 :1 ) is degasses with nitrogen. Dichloro[1 , 1 '-
bis(diphenylphosphino)ferrocene]palladium(ll) dichloromethane complex is added
(450 mg. 0.55 mmol) and the mixture is purged again with nitrogen. The mixture is
heated at 90 °C under nitrogen stream over night. The solvent is removed in vacuo
and the residue is acidified with 10% HCI. The aqueous phase is extracted with DCM.
The aqueous phase is basified with 50% NaOH and the aqueous phase is extracted
with ethyl acetate (x3) and the combined organic phases are washed with brine then
separated and dried (MgSO ) . The organic phase is concentrated in vacuo without
any further purification to afford the titled compound (2.30 g, 97%) as a brown solid.
H NMR (300 MHz, CDCI3) 8.68 (d, 2H), 7.56-7.45 (m, 3H), 6.94 (t, 1H), 3.96 (s,
2H), 1.69 (br s, 2H).
9F NMR (300 MHz, CDCI3) - 5.1 (m), - 1 15.8 (m).
MS m/z [M+H]+=221 .
The title compound is prepared in a similar manner as described in Example
1F using 2,4-difluoro-5-pyridin-4-yl-benzylamine as a beige solid.
H NMR (300 MHz, CD3OD) 8.84 (br s, 2H), 8.1 (br s, 2H), 7.81 (t, 1H), 7.29 (t,
1H), 4.57 (s, 2H).
9F NMR (300 MHz, CDCI3) -77.0 (s), - 1 11.9 (m), - 1 14.5 (m).
MS m/z [M+H]+=31 7.
I . N-(2,4-Difluoro-5-piperidin-4-yl-benzyl)-2,2,2-trifluoro-acetamide hydrochloride
N-(2,4-Difluoro-5-pyridin-4-yl-benzyl)-2,2,2-trifluoro-acetamide is treated with
2.0 M HCI in ether ( 10 mL, 20.0 mmol) and stirred for 15 minutes. The mixture is
vacuum dry and the residue is suspended ether overnight. The suspension is filtered
and the cake is rinsed with ether twice. The solid is dried under vacuum.
To a solution of N-(2,4-difluoro-5-pyridin-4-yl-benzyl)-2,2,2-trifluoro-acetamide
hydrochloride ( 1 .71 g, 4.85 mmol) in methanol (50 mL) is added 5% Pt C ( 1 .06 g,
0.27 mmol) and concentrated HCI (5 drops). The resulting mixture is hydrogenated
under 60 psi of hydrogen over night. The mixture is filtered on a bed of Celite and
rinsed with methanol. The solvent is removed in vacuo to afford the titled compound
( 1 .50 g, 86%) as a gum.
H NMR (300 MHz, DMSO-c/6) 10.04 (t, 1H), 8.74 (br s, 2H), 7.30-7.23 (m, 2H),
4.41 (d, 2H), 3.42-3.27 (m, 2H), 3.14-2.80 (m, 3H), 188-1 .76 (m, 4H).
9F NMR (300 MHz, CDCI3) 5 -74.7 (s), - 1 16.2 (m), - 1 17.2 (m).
MS m/z: [M+H]+=323.
J. N-(2,4-Difluoro-5-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-piperidin-
4-yl}-benzyl)-2,2,2-trifluoro-acetamide
By proceeding in a similar manner to the method described in Example 2 I with
7-methyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and N-(2,4-difluoro-5-
piperidin-4-yl-benzyl)-2,2,2-trifluoro-acetamide hydrochloride as the starting material,
the titled compound is prepared as a gum.
H NMR (300 MHz, CDCI3) 7.57 (br d, H), 7.43 (s, H), 7.21 (t, 1H), 7.09 (t, 1H),
6.98 (m, 1H), 6.86-6.79 (m, 2H), 4.60-4.51 (m, 6H), 3.71 (t, 2H), 3.31 (s, 3H), 3.1 1-
3.01 (m, 3H), 2.72 (s, 3H), 1.88-1 .65 (m, 4H).
9F NMR (300 MHz, CDCI3) -76.1 (s), - 1 15.6 (m), - 1 18.0 (m).
MS m/z [M+H] +=538.
K. [4-(5-Aminomethyl-2,4-difluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
methyl-1 H-indol-3-yl]-methanone hydrochloride
By proceeding in a similar manner to the method described in Example 3B with
N-(2,4-difluoro-5-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-piperidin-4-
yl}-benzyl)-2,2,2-trifluoro-acetamide as the starting material, the titled compound is
prepared as an off-white solid.
H NMR (300 MHz, DMSO-c/6) 8.39 (br s, 3H), 7.67 (t, H), 7.61 (s, 1H), 7.51 (d,
1H), 7.29 (t, 1H), 7.01 -6.96 (m, 1H), 6.92-6.90 (m, 1H), 4.55 (t, 2H), 4.39 (br d, 2H),
4.01 (br s, 2H), 3.64 (t, 2H), 3.20 (s, 3H), 3.14-2.96 (m, 3H), 2.65 (s, 3H), 1.80-1 .57
(m, 4H).
9F NMR (300 MHz, DMSO-c/6) - 1 15.3 (m), - 1 16.5 (m).
MS m/ z [M+H] +=442.
EXAMPLE 112
[4-(3-Aminomethyl-4-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-methyl-1 Hindol-
3-yl]-methanone hydrochloride
A. 2-Fluoro-5-pyridin-4-yl-benzylamine
By proceeding in a similar manner to the method described in Example 112G
with 5-bromo-2-fluorobenzylamine hydrochloride and 4-pyridineboronic acid as the
starting material, the titled compound is prepared as a brown oil.
H NMR (300 MHz, CDCI3) 8.63 (d, 2H), 7.66-7.62 (m, 1H), 7.54-7.46 (m, 3H), 7.14
(t, 1H), 3.98 (s, 2H), 1.94 (br s, 2H).
B. 2,2,2-Trifluoro-N-(2-fluoro-5-pyridin-4-yl-benzyl)-acetamide
By proceeding in a similar manner to the method described in Example 1F with
2-fluoro-5-pyridin-4-yl-benzylamine as the starting material, the titled compound is
prepared as a beige solid.
H NMR (300 MHz, CD3OD) 58.82 (d, 2H), 8.25-2.83 (m, 2H), 8.00-7.94 (m, 2H),
7.42-7.36 (m, 1H), 4.62 (s, 2H).
C. 2,2,2-Trifluoro-N-(2-fluoro-5- i eridin-4- l-benz l -acetamide hydrochloride
By proceeding in a similar manner to the method described in Example 112 1
with 2,2,2-trifluoro-N-(2-fluoro-5-pyridin-4-yl-benzyl)-acetamide as the starting
material, the titled compound is prepared as an amber solid.
H NMR (300 MHz, DMSO-c/6) 5 10.08-1 0.04 (m, 1H), 9.05 (br s, 1H), 7.21-7.1 5 (m,
3H), 4.42 (d, 2H), 3.42-3.32 (m, 2H), 3.03-2.79 (m, 3H), 1.90-1 .73 (m, 4H).
D. 2,2,2-Trifluoro-N-(2-fluoro-5-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
By proceeding in a similar manner to the method described in Example 2 1 with
7-methyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-(2-
fluoro-5-piperidin-4-yl-benzyl)-acetamide hydrochloride as the starting material, the
titled compound is prepared as a white solid.
H NMR (300 MHz, CDCI3) 7.58-7.55 (m, 1H), 7.41 (s, 1H), 7.19-7.14 (m, 2H), 7.1 0-
6.96 (m, 4 H), 4.55-4.51 (m, 6H), 3.70 (t, 2H), 3.30 (s, 3H), 3.05-2.97 (m, 2H), 2.81 -
2.74 (m, 1H), 2.71 (s, 3H), 1.87-1 .83 (m, 2H), 1.73-1 .59 (m, 2H).
E. [4-(3-Aminomethyl-4-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-methyl-
1H-indol-3-yl]-methanone hydrochloride
By proceeding in a similar manner to the method described in Example 3B with
2,2,2-trifluoro-N-(2-fluoro-5-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-acetamide as the starting material, the titled compound is
prepared as an off-white solid.
H NMR (300 MHz, DMSO-c/6) 8.42 (br s, 3H), 7.63 (s, 1H), 7.55-7.52 (m, 2H),
7.38-7.33 (m, 1H), 7.24-7.1 8 (m, 1H), 7.03-6.98 (m, 1H), 6.94-6.92 (m, 1H), 4.57 (t,
2H), 4.40 (br d, 2H), 4.09-4.02 (m, 2H), 3.67 (t, 2H), 3.22 (s, 3H), 3.08-3.00 (m, 2H),
2.88-2.81 (m, 1H), 2.67 (s, 3H), 1.83-1 .79 (m, 2H), 1.67-1 .58 (m, 2H).
MS m/z [M+H] +=424.
EXAMPLE 113
(6-Aminomethyl-3\4\5\6'-tetrahy^^
methyl-1 H-indol-3-yl]-methanone dihydrochloride
A. 6-Aminomethyl-3',6'-dihydro-2'H-[2,4']bipyridinyl-1 '-carboxylic acid tert-butyl ester
The title compound is prepared according to the procedure by Eastwood, P.
R., Tet. Lett, 2000, vol. 4 1, pp. 3705-3708 & WO 2007/092435 (page 140-145) with
(6-bromo-pyridin-2-yl)-methylamine and 4-(4,4,5,5-tetramethyl[1 ,3,2]dioxaborolan-2-
yl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester as the starting materials
to yield a brown oil.
H NMR (300 MHz, CDCI3) 7.59 (t, 1H), 7.21 (d, 1H), 7.08 (d, 1H), 6.64 (br s, 1H),
3.96 (s, 2H), 3.62 (t, 2H), 2.74 (s, 4H), 2.63 (br s, 2H), 1.47 (s, 9H).
B. 6-[(2,2,2-Trifluoro-acetylamino)-methyl]-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-
carboxylic acid tert-butyl ester
By proceeding in a similar manner to the method described in Example 1F with
6-aminomethyl-3',6'-dihydro-2'H-[2,4']bipyridinyl-1 '-carboxylic acid tert-butyl ester as
the starting material, the titled compound is prepared as a yellow solid.
H NMR (300 MHz, CDCI3) 9.55 (br s, H), 8.09-8.05 (t, H), 7.59-7.55 (m, 2H),
6.76 (br s, H), 4.77 (d, 2H), 4.20 (m, 2H), 3.68 (t, 2H), 2.64 (m, 2H), .50 (s, 9 H).
C. 6-[(2,2,2-Trifluoro-acetylamino)-methyl]-3\4\5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1 '-
carboxylic acid tert-butyl ester
6-[(2,2,2-Trifluoro-acetylamino)-methyl]-3',6'-dihydro-2'H-[2,4']bipyridinyl-1 '-
carboxylic acid tert-butyl ester ( 1 .68 g, 4.36 mmol) in methanol and 10% Pd/C (48
mg, 0.04 mmol) is hydrogenated under 1 atm of hydrogen for 30 min. The mixture is
filtered on a Celite bed and rinsed with methanol. The solvent is removed in vacuo to
give the titled compound as a yellow semi-solid.
H NMR (300 MHz, CDCI3) 9.61 (br s, 1H), 8.09-8.04 (m, 1H), 7.60 (d, 1H), 7.43 (d,
1H), 4.73 (d, 2H), 4.29 (br s, 2H), 3.26-3.1 7 (tt, 1H), 2.92-2.84 (m, 2H), 2.00-1 .95 (m,
2H), 1.74-1 .63 (m, 2H), 1.48 (s, 9H).
D. 2,2,2-Tnfluoro-N-(1 \2\3\4\5\6'-hexahydro-[2,4]bipyridinyl-6-ylmethyl)-acetamide
dihydrochloride
By proceeding in a similar manner to the method described in Example 11OK
with 6-[(2,2,2-trifluoro-acetylamino)-methyl]-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-
1'-carboxylic acid tert-butyl ester the titled product is prepared as a beige solid.
H NMR (300 MHz, DMSO-c/6) 10.20 (t, 1H), 9.25 (br s, 1H), 7.98 (t, 1H), 7.34 (dd,
2 H), 4.58 (d, 2H), 3.35 (m, 2H), 3.18-3.10 (m, 1H), 3.05-2.94 (m, 2H), 2.08-1 .88 (m,
4 H).
E. 2,2,2-Trifluoro-N-{1 '-[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-6-ylmethyl}-acetamide
By proceeding in a similar manner to the method described in Example 2 1 with
7-methyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-
( 1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-6-ylmethyl)-acetamide dihydrochloride as
the starting material, the titled compound is prepared as a gum.
H NMR (300 MHz, CDCI3) 8.1 0 (br s, 1H), 7.66 (t, 1H), 7.59 (d, 1H), 7.43 (s, 1H),
7.1 6-7.06 (m, 3H), 6.98 (m, 1H), 4.62-4.52 (m, 6H), 3.71 (t, 2H), 3.30 (s, 3H), 3.14-
2.98 (m, 3H), 2.72 (s, 3H), 2.01 - 1 .98 (m, 2H), 1.91-1 .77 (m, 2H).
F. (6-Aminomethyl-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1 '-yl)-[1 -(2-methoxyethyl)-
7-methyl-1 H-indol-3-yl]-methanone dihydrochloride
By proceeding in a similar manner to the method described in Example 3B with
2,2,2-trifluoro-N-{1 '-[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-6-ylmethyl}-acetamide the titled compound
is prepared as a white solid.
H NMR (300 MHz, DMSO-c/6) 8.38 (br s, 3H), 7.85 (t, H), 7.62 (s, H), 7.53 (d,
H), 7.37 (d, 2H), 7.02-6.97 (m, H), 6.94-6.92 (m, H), 4.57 (t, 2H), 4.42 (br d, 2H),
4.21-4.1 5 (m, 2H), 3.66 (t, 2H), 3.57 (s, 3H), 3.1 6-2.99 (m, 3H), 2.67 (s, 3H), 1.93-
1.73 (m, 4H).
MS m/ z [M+H]+=407.
EXAMPLE 114
[4-(5-Aminomethyl-2-trifluoromethyl-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
meth l-1H-indol-3-yl]-methanone hydrochloride
A. 3-Bromo-4-butoxy-benzonitrile
To a solution of 3-bromo-4-hydroxy-benzonitrile (5.0 g, 25.25 mmol) and
potassium carbonate (7.0 g, 50.5 mmol) in DMF ( 100 ml_) is added 1-bromo-butane.
The reaction mixture is stirred at room temperature overnight. The reaction mixture is
poured into EtOAc, washed with H2O (2X), brine, dried over MgSO , filtered, and
concentrated in vacuo to give the crude product. Purification by flash chromatography
on S1O2 eluting with 10% ethyl acetate / heptane gives the titled compound (5.9 g,
92%).
H NMR (300 MHz, CDCI3) 7.8 (s, 1H), 7.6 (d, 1H), 6.9 (d, 1H), 4.1 (m, 2H), 1.85
(m, 2H), 1.5 (m, 2H), 1.0 (m, 3H).
MS m/z [M+H]+=254
B. 3-Bromo-4-butoxy-benzylamine
To a solution of 3-bromo-4-butoxy-benzonitrile (5.85 g, 23 mmol) in THF (100
ml_) is added a 1.0 M borane.THF solution (28 ml_, 28 mmol). The resulting mixture is
heated to reflux for 3 h and is quenched with 6 N HCI ( 16 ml_, 96 mmol). The resulting
mixture is heated to reflux for 1 h and is stirred at room temperature overnight. The
reaction mixture is diluted with H2O (20 ml_) and the solvent is removed in vacuo. The
aqueous layer is diluted with H2O (20 ml_) and is washed with ethyl acetate, basified
with 6 N NaOH to pH 13 and is extracted with ethyl acetate (2X). The extracts are
combined and is washed with brine, dried over MgSO4, filtered and concentrated in
vacuo to yield the titled compound (3.75 g, 63%).
H NMR (300 MHz, CDCI3) 7.5 (s, 1H), 7.2 (d, 1H), 6.8 (d, 1H), 4.0 (m, 2H), 3.8 (bs,
2H), 1.8 (m, 2H), 1.5 (m, 4H), 1.0 (m, 3H).
MS m/z: [M+H]+=258
C. 4-Butoxy-3-pyridin-4-yl-benzylamine
A flask is charged with NaHCO3 (2.86 g, 34.1 mmol), 3-bromo-4-butoxybenzylamine
(4 g, 15.5 mmol) and pyridine-4-boronic acid (2.1 g, 17.05 mmol) and
isopropyl alcohol (40 ml_) and water (20 ml_) at r.t. The suspension is degassed with
for 1.0 h at 10 °C. Into the mixture is added 1, 1 '-
bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex
(PdCI2dppf-CH 2CI2 (0.5 g, 0.62 mmol). The reaction mixture is heated to 85 °C and
stirred for 10 h. After the reaction is completed (HPLC analysis), the mixture is cooled
to room temperature, and aqueous 1 N HCI (50 ml_) is added, and stirred for 0.5 h.
The solution is washed with EtOAc (2X) and the aqueous phase is basified to pH = 13
with 6 N NaOH, and extracted with ethyl acetate (2X). The extracts are combined and
is washed with brine, dried over MgSO4, filtered and concentrated down in vacuo to
yield the titled compound (4.0 g, 100%).
H NMR (300 MHz, CDCI3) 8.6 (m, 2H), 7.5 (m, 2H), 7.3 (m, 2H), 7.0 (d, 1H), 4.0
(m, 2H), 3.8 (bs, 2H), 1.8 (m, 4H), 1.4 (m, 2H), 0.9 (m, 3H).
D. N-(4-Butoxy-3-pyridin-4-yl-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example
1F using 4-butoxy-3-pyridin-4-yl-benzylamine as the starting material.
H NMR (300 MHz, CDCI3) 8.8 (m, 2H), 8.0 (m, 2H), 7.4 (m, 2H), 7.0 (d, 1H), 6.9
(bs, H), 4.5 (m, 2H), 4.0 (m, 2H), 1.9 (m, 2H), 1.4 (m, 2H), 0.9 (m, 3H).
E. N-(4-Butoxy-3-piperidin-4-yl-benzyl)-2,2,2-trifluoro-acetamide hydrochloride
The title compound is prepared in a similar manner as described in Example 11
using N-(4-butoxy-3-pyridin-4-yl-benzyl)-2,2,2-trifluoro-acetamide as the starting
material.
H NMR (300 MHz, DMSO-c/6) 8.7 (bs, 1H), 8.4 (bs, 1H), 7.2 (m, 2H), 7.0 (m, 1H),
4.3 (m, 2H), 4.0 (m, 2H), 3.4 (m, 4H), 3.1 (m, 3H), 1.9 (m, 2H), 1.8 (m, 2H), 1.4 (m,
2H), 0.9 (m, 3H).
F. N-(4-Butoxy-3-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-piperidin-4-
yl}-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using N-(4-butoxy-3-piperidin-4-yl-benzyl)-2,2,2-trifluoro-acetamide hydrochloride and
1-(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carboxylic acid as the starting materials.
H NMR (300 MHz, CDCI3) 7.6 (d, H), 7.4 (s, 1H), 7.1 (m, 3H), 7.0 (m, 1H), 6.8 (d,
1H), 6.5 (bs, 1H), 4.5 (m, 4H), 4.4 (m, 2H), 4.0 (t, 2H), 3.7 (t, 2H), 3.3 (s, 3H), 3.2 (m,
1H), 3.1 (m, 2H), 2.7 (s, 3H), 1.9-1 .7 (m, 6H), 1.5 (m, 2H), 1.0 (m, 3H).
MS m/z [M+H]+=574
G. [4-(5-Aminomethyl-2-butoxy-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-methyl-
1H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using N-(4-butoxy-3-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-2,2,2-trifluoro-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.1 (bs, 2H), 7.6 (s, 1H), 7.5 (m, 1H), 7.4 (m, 3H),
7.2 (m, 1H), 7.0 (m, 3H), 4.6 (m, 2H), 4.4 (m, 2H), 4.0 (m, 2H), 3.9 (m, 2H), 3.6 (m,
2H), 3.2 (s, 3H), 3.1 (m, 1H), 3.0 (m, 2H), 2.6 (s, 3H), 1.9-1 .7 (m, 6H), 1.4 (m, 2H),
1.0 (m, 3H).
MS m/z: [M+H]+=478
EXAMPLE 115
[4-(5-Aminomethyl-2-phenethyloxy-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
methyl-1 H-indol-3-yl]-methanone hydrochloride
A. 3-Bromo-4-phenethyloxy-benzonitrile
The title compound is prepared in a similar manner as described in Example
115A using (2-bromo-ethyl)-benzene as the starting material.
H NMR (300 MHz, CDCI3) 7.8 (s, H), 7.6 (d, H), 7.4 (m, 5H), 6.8 (d, H), 4.3 (t
2H), 3.2 (t, 2H). MS m/z [M+H]+=303
B. 4-Phenethyloxy-3-pyridin-4-yl-benzonitrile
The title compound is prepared in a similar manner as described in Example
115C using 3-bromo-4-phenethyloxy-benzonitrile as the starting material.
H NMR (300 MHz, CDCI3) 8.6 (d, 2H), 7.7 (d, 2H), 7.6 (s, H), 7.3 (m, 5H), 7.2 (m,
2H), 7.0 (d, H), 4.3 (t, 2H), 3.1 (t, 2H).
MS m/z [M+H]+=301 .
4-Phenethyloxy-3-pyridin-4-yl-benzyla
The title compound is prepared in a similar manner as described in Example
115B using 4-phenethyloxy-3-pyridin-4-yl-benzonitrile as the starting material.
H NMR (300 MHz, CDCI3) 8.6 (d, 2H), 7.7 (d, 2H), 7.6 (s, H), 7.3 (m, 5H), 7.2 (m,
2H), 7.0 (d, H), 4.3 (t, 2H), 4.1 (m, 2H), 3.1 (t, 2H).
D. 2,2,2-Trifluoro-N-(4-phenethyloxy-3-pyridin-4-yl-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example
1F using 4-phenethyloxy-3-pyridin-4-yl-benzylamine as the starting material.
H NMR (300 MHz, CDCI3) 8.6 (d, 2H), 7.8 (d, 2H), 7.6 (m, 1H), 7.3 (m, 5H), 7.2 (m,
2H), 7.0 (d, 1H), 4.5 (m, 2H), 4.3 (t, 2H), 3.1 (t, 2H).
MS m/z: [M+H]+=401
-Trifluoro-N-(4-phenethyloxy-3-piperidin-4-yl-benzyl)-acetamide hydrochloride
The title compound is prepared in a similar manner as described in Example 11
using 2,2,2-trifluoro-N-(4-phenethyloxy-3-pyridin-4-yl-benzyl)-acetamide as the
starting material. Crude material is used in next step without purification.
MS m/z [M+H]+=407
F. 2,2,2-Trifluoro-N-(3-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-phenethyloxy-benzyl)-acetamide
The title compound is prepared in a similar manner as described in Example 2 I
using 2,2,2-trifluoro-N-(4-phenethyloxy-3-piperidin-4-yl-benzyl)-acetamide
hydrochloride and 1-(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carboxylic acid as the
starting materials.
H NMR (300 MHz, CDCI3) 7.6 (d, 1H), 7.4 (s, 1H), 7.3 (m, 5H), 7.1 (m, 3H), 7.0 (m,
1H), 6.8 (d, 1H), 6.4 (bs, 1H), 4.5 (m, 4H), 4.4 (m, 2H), 4.2 (t, 2H), 3.7 (t, 2H), 3.3 (s,
3H), 3.1 (m, 3H), 3.0 (m, 2H), 2.7 (s, 3H), 1.8-1 .6 (m, 4H).
MS m/z: [M+H]+=622
G. [4-(5-Aminomethyl-2-phenethyloxy-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-
methyl-1 H-indol-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using 2,2,2-trifluoro-N-(3-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
piperidin-4-yl}-4-phenethyloxy-benzyl)-acetamide as the starting material.
H NMR (300 MHz, DMSO-c/6) 8.4 (bs, 2H), 7.7(s, 1H), 7.55 (m, 1H), 7.3 (m, 6H),
7.2 (m, H), 7.0 (m, 3H), 4.6 (m, 2H), 4.4 (m, 2H), 4.2 (m, 2H), 3.9 (m, 2H), 3.7 (m,
2H), 3.2 (s, 3H), 3.2 (m, 3H), 3.0 (m, 2H), 2.7 (s, 3H), .7-1 .4 (m, 4H).
MS m/ z [M+H]+=526
EXAMPLE 116
[4-(5-Aminomethyl-3-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-methyl-1 Hindol-
3-yl]-methanone hydrochloride
A. 3-Bromo-5-fluoro-benzylamine
To a solution of 3-bromo-5-fluorobenzonitrile (5.05 g, 25.23 mmol) in
tetrahydrofuran ( 120 mL) is added the borane THF complex (31 mL, 3 1.00 mmol))
dropwise. The resulting mixture is refluxed for ~2 hr, and then 2 N HCI solution is
added. The resulting mixture is refluxed for an additional ~ 1 hr. THF is removed in
vacuo and the aqueous residue is extracted with ethyl acetate. The aqueous layer is
basified with 50% NaOH and the aqueous phase is extracted with ethyl acetate (3x)
and the combined organic phases are washed with brine then separated and dried
(MgSO4) . The organic phase is concentrated in vacuo to afford without purification
the titled compound (2.66 g, 52%) as yellow oil.
H NMR (300 MHz, CDCI3) 7.77 (m, 1H), 7.1 5-7.1 0 (m, 1H), 7.01 -6.98 (m, 1H), 3.86
(s, 2H), 1.51 ( b s, 2H).
B. 3-Fluoro-5-pyridin-4-yl-benzylamine
By proceeding in a similar manner to the method described in Example 112G
using 3-fluoro-5-pyridin-4-yl-benzylamine and 4-pyridineboronic acid as the starting
material, the titled compound is prepared as a brown viscous oil.
H NMR (300 MHz, CDCI3) 8.67 (d, 2H), 7.49 (d, 2H), 7.40 (s, 1H), 7.20 (m, 1H),
7.1 3 (m, 1H), 3.98 (s, 2H), 1.96 (br s, 2H).
C. N-(3-fluoro-5-pyridin-4-yl-benzyl)-2,2,2-trifluoro-acetamide
By proceeding in a similar manner to the method described in Example 1F
using 3-fluoro-5-pyridin-4-yl-benzylamine as the starting material, the titled product is
prepared as a yellow solid.
H NMR (300 MHz, CD3CN) 8.77 (m, 2H), 7.99 (m, 3H), 7.59 (s, H), 7.52 (m, 1H),
7.26 (m, 1H), 4.53 (s, 2 H).
D. N-(3-fluoro-5-piperidin-4-yl-benzyl)-2,2,2-trifluoro-acetamide hydrochloride
By proceeding in a similar manner to the method described in Example 112 1
using N-(3-fluoro-5-pyridin-4-yl-benzyl)-2,2,2-trifluoro-acetamide as the starting
material, the titled product is prepared as a yellow semi-solid and used in the next
step.
E. 2,2,2-Trifluoro-N-(3-fluoro-5-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
By proceeding in a similar manner to the method described in Example 2 1
using 7-methyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and N-(3-fluoro-5-
piperidin-4-yl-benzyl)-2,2,2-trifluoro-acetamide hydrochloride as the starting material,
the titled product is prepared as a white solid.
H NMR (300 MHz, CDCI3) 7.57 (br d, 1H), 7.43 (s, 1H), 7.1 1-7.06 (m, 1H), 6.99-
6.83 (m, 4H), 6.70 (br s, 1H), 4.60-4.94 (m, 6H), 3.71 (t, 2H), 3.31 (s, 3H), 3.07-2.99
(m, 2H), 2.83-2.75 (m, 1H), 2.71 (s, 3H), 1.90-1 .66 (m, 2H), 1.75-1 .61 (m, 2H).
F. [4-(5-Aminomethyl-3-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-methyl-
1H-indol-3-yl]-methanone hydrochloride
By proceeding in a similar manner to the method described in Example 3B with
2,2,2-trifluoro-N-(3-fluoro-5-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
piperidin-4-yl}-benzyl)-acetamide as the starting material, the titled product is
prepared as a white solid.
H NMR (300 MHz, DMSO-c/6) 8.43 (br s, 3H), 7.62 (s, 1H), 7.53 (d, 1H), 7.30 (s,
1H), 7.23-7.1 6 (m, 2H), 7.03-6.98 (m, 1H), 6.94-6.92 (m, 1H), 4.57 (t, 2H), 4.43-3.38
(m, 2H), 4.02 (br s, 2H), 3.67 (t, 2H), 3.22 (s, 3H), 3.07-2.99 (m, 2H), 2.91 -2.83 (m,
1H), 2.67 (s, 3H), 1.85-1 .81 (m, 2H), 1.69-1 .58 (m, 2H).
MS m/z [M+H]+=424
EXAMPLE 117
[4-(3-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-methyl-1 Hindol-
3-yl]-methanone hydrochloride
N-(3-Bromo-2-fluoro-benzyl)-2,2,2-trifluoro-acetamide
By proceeding in a similar manner to the method described in Example 115B
using 3-bromo-2-fluorobenzonitrile as the starting material, 3-bromo-2-
fluorobenzylamine is prepared.
The crude 3-bromo-2-fluorobenzylamine is treated with trifluoroacetic
anhydride following the procedure of Example 1F, to yield the titled compound as a
yellow oil.
H NMR (300 MHz, CDCI3) 1.65 (br s, 1H), 7.56-7.51 (m, 3H), 7.33-7.28 (m, 1H),
7.07-7.01 (m, 1H), 4.59 (d, 2H).
B. 2,2,2-Trifluoro-N-(2-fluoro-3-pyridin-4-yl-benzyl)-acetamide
By proceeding in a similar manner to the method described in Example 112G
using N-(3-bromo-2-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the starting material,
2-fluoro-3-pyridin-4-yl-benzylamine is prepared. The crude 2-fluoro-3-pyridin-4-ylbenzylamine
is treated with trifluoroacetic anhydride following the protocol of Example
1F to give the titled compound as an off-white solid.
H NMR (300 MHz, CD3CN) 8.82 (br s, 1H), 8.00 (br s, 4H), 7.62-7.51 (m, 2H),
7.38-7.32 (m, H), 4.57 (s, 2H).
C. 2,2,2-Trifluoro-N-(2-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride
By proceeding in a similar manner to the method described in Example 112 1
using 2,2,2-trifluoro-N-(2-fluoro-3-pyridin-4-yl-benzyl)-acetamide as the starting
material, the titled product is prepared as an off-white solid and used for the next
step.
D. 2,2,2-Trifluoro-N-(2-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
By proceeding in a similar manner to the method described in Example 2 1 with
7-methyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-(2-
fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride as starting materials, the titled
product is prepared as a brown gum.
H NMR (300 MHz, CDCI3) 7.58 (br d, H), 7.43 (s, H), 7.23-7.20 (m, 2H), 7.14-
7.06 (m, 2H), 6.98 (m, 1H), 6.78 (br s, 1H), 4.59-4.52 (m, 6H), 3.71 (t, 2H), 3.31 (s,
3H), 3.20-3.03 (m, 3H), 2.72 (s, 3H), 1.89-1 .63 (m, 4H).
E. [4-(3-Aminomethyl-2-fluoro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-methyl-
1H-indol-3-yl]-methanone hydrochloride
By proceeding in a similar manner to the method described in Example 3B
using 2,2,2-trifluoro-N-(2-fluoro-3-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material, the titled product
is prepared as a white solid.
H NMR (300 MHz, DMSO-c/6) 8.36 (br s, 3H), 7.63 (s, 1H), 7.53 (d, 1H), 7.46-7.40
(m, 2H), 7.26-7.21 (m, 1H), 7.02-6.98 (m, 1H), 6.94-6.92 (m, 1H), 4.57 (t, 2H), 4.42
(br d , 2H), 4.06 (m, 2H), 3.67 (t, 2H), 3.22 (s, 3H), 3.1 9-2.99 (m, 3H), 2.67 (s, 3H),
1.80-1 .63 (m, 4H).
MS m/z [M+H] +=424.
EXAMPLE 118
[4-(3-Aminomethyl-4-chloro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-methyl-1 Hindol-
3-yl]-methanone hydrochloride
A. N-(5-Bromo-2-chloro-benzyl)-2,2,2-trifluoro-acetamide
The title compound is prepared according to the procedure by Kuramochi, T. et
al., Bioorg. & Med. Chem., 2005, vol. 13, pp. 4022-4036, using 5-bromo-2-
chlorobenzyl alcohol as the starting material, 5-bromo-2-chlorobenzylamine is
obtained as a white semi-solid and used in the next step without further purification.
By proceeding in a similar manner to the method described in Example 1F using 5-
bromo-2-chlorobenzylamine as the starting material, the titled product is prepared as
a white solid.
H NMR (300 MHz, CDCI3) 7.52 (d, 1H), 7.43 (dd, 1H), 7.28 (d, 1H), 6.71 (br s, 1H),
4.59 (d, 2H).
9F NMR (300 MHz, CDCI3) -76.2 (s).
MS m/z [M+H]+=31 3, 3 15, 3 17 .
B. N-(2-Chloro-5-pyridin-4-yl-benzyl)-2,2,2-trifluoro-acetamide
By proceeding in a similar manner to the method described in Example 112G
using N-(5-bromo-2-chloro-benzyl)-2,2,2-trifluoro-acetamide as the starting material,
2-chloro-5-pyridin-4-yl-benzylamine is obtained. The crude 2-chloro-5-pyridin-4-ylbenzylamine
is treated with trifluoroacetic anhydride following the protocol of Example
1F to afford the titled compound as a brownish solid.
H NMR (300 MHz, CD3CN) 8.05 (br s, 3H), 7.82 (m, H), 7.79-7.75 (m, H), 7.63
(d, 1H), 4.63 (d, 2H), 3.1 3 (br s, 2H).
9F NMR (300 MHz, CD3CN) -76.9 (s).
MS m/z [M+H]+=31 5, 3 17 .
C. N-(2-Chloro-5-piperidin-4-yl-benzyl)-2,2,2-trifluoro-acetamide hydrochloride
By proceeding in a similar manner to the method described in Example 112 1
using N-(2-chloro-5-pyridin-4-yl-benzyl)-2,2,2-trifluoro-acetamide as the starting
material, the titled product is prepared as a yellowish solid.
H NMR (300 MHz, DMSO-c/6) 10.05 (t, 1H), 9.1 3 (br s, 1H), 8.99 (br s, 1H), 7.44
(m, 1H), 7.22-7.1 9 (m, 2H), 4.47 (d, 2H), 3.36-3.32 (m, 2H), 3.06-2.73 (m, 3H), 1.94-
1.80 (m, 4H).
9F NMR (300 MHz, DMSO-c/6) -74.6 (s).
MS m/z: [M+H]+=321 , 323.
D. N-(2-Chloro-5-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-piperidin-4-
yl}-benzyl)-2,2,2-trifluoro-acetamide
By proceeding in a similar manner to the method described in Example 2 1
using 7-methyl-1-(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and N-(2-chloro-5-
piperidin-4-yl-benzyl)-2,2,2-trifluoro-acetamide hydrochloride as starting materials, the
titled product is prepared as a white solid.
H NMR (300 MHz, DMSO-c/6) 9.95 (t, H), 7.61 (s, 1H), 7.52 (d, 1H), 7.41 (d, 1H),
7.29-7.26 (m, 2H), 7.02-6.91 (m, 2H), 4.56 (t, 2H), 4.46 (d, 2H), 4.39 (br d, 2H), 3.66
(t, 2H), 3.22 (s, 3H), 3.03 (t, 2H), 2.88-2.80 (m, 1H), 2.67 (s, 3H), 1.82-1 .78 (m, 2H),
1.62-1 .51 (m, 2H).
9F NMR (300 MHz, DMSO-c/6) -74.6 (s).
MS m/z [M+H] +=336, 338.
E. [4-(3-Aminomethyl-4-chloro-phenyl)-piperidin-1 -yl]-[1 -(2-methoxy-ethyl)-7-methyl-
1H-indol-3-yl]-methanone hydrochloride
By proceeding in a similar manner to the method described in Example 3B
using N-(2-chloro-5-{1 -[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-piperidin-
4-yl}-benzyl)-2,2,2-trifluoro-acetamide as the starting material, the titled compound is
prepared as a pale yellow powder.
H NMR (300 MHz, DMSO-c/6) 8.39 (br s, 2H), 7.62 (s, H), 7.56-7.52 (m, 2H), 7.46
(d, H), 7.35 (dd, H), 7.00 (t, H), 6.93 (d, H), 4.57 (t, 2H), 4.41 (br d, 2H), 4.1 2
(dd, 2H), 3.68-3.65 (m, 4H), 3.05 (br t , 2H), 2.90-2.82 (m, 1H), 2.67 (s, 3H), 1.84-1 .80
(m, 2H), 1.68-1 .57 (m, 2H).
MS m/z [M+H] +=440, 442.
EXAMPLE 119
(4-Aminomethyl-3\4\5\6'-tetrahydro-^
meth l-1H-indol-3-yl]-methanone hydrochloride
A. 4-Aminomethyl-3',6'-dihydro-2'H-[2,4']bipyridinyl-1 '-carboxylic acid tert-butyl ester
The title compound is prepared according to the procedure by Eastwood, P.
R., Tet. Lett., 2000, vol. 4 1, pp. 3705-3708 & WO 2007/092435 (p 140-145) using C-
(2-bromopyridin-4-yl)methylamine and 4-(4,4,5,5-tetramethyl[1 ,3,2]dioxaborolan-2-yl)-
3,6-dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester as starting materials to
provide the titled compound as a viscous brown oil.
H NMR (300 MHz, CDCI3) 8.50 (d, 1H), 7.35 (s, 1H), 7.1 3 (d, 1H), 6.61 (br s, 1H),
4.1 6-4.1 1 (m, 2H), 3.91 (s, 2H), 3.65 (t, 2H), 2.66 (br s, 2H), 1.86 (br s, 2H), 1.24 (s,
9H).
MS m/z [M+H]+=290.
B. 4-[(2,2,2-Trifluoro-acetylamino)-methyl]-3^6'-dihydro-2 -[2,4]bipyridinyl-1'-
carboxylic acid tert-butyl ester
By proceeding in a similar manner to the method described in Example 1F
using 4-aminomethyl-3',6'-dihydro-2'H-[2,4']bipyridinyl-1 '-carboxylic acid tert-butyl
ester as the starting material, the titled product is prepared as a viscous brown oil.
H NMR (300 MHz, CDCI3) 8.95 (t, 1H), 8.69 (d, 1H), 7.62 (s, 1H), 7.53 (d, 1H), 6.80
(br s, 1H), 4.67 (d, 2H), 4.1 9 (m, 2H), 3.65 (t, 2H), 2.60 (br s, 2H), 1.48 (s, 9H). 9F
NMR (300 MHz, CDCI3) -76.1 (s).
MS m/z: [M+H]+=386.
C. 4-[(2,2,2-Trifluoro-acetylamino)-methyl]-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-
1'-carboxylic acid tert-butyl ester
By proceeding in a similar manner to the method described in Example 114C
4-[(2,2,2-trifluoro-acetylamino)-methyl]-3',6'-dihydro-2'H-[2,4']bipyridinyl-1 '-
carboxylic acid tert-butyl ester as the starting material, the titled product is prepared
as a brown solid.
H NMR (300 MHz, CDCI3) 8.80 (br s, 1 H), 8.64 (br s, H), 7.53-7.48 (m, 2H), 4.67
(br s, 2H), 4.25 (br d, 2H), 3.20 (m, H), 2.85 (br s, 2H), .92 (m, 2H), .68 (m, 2H),
1.47 (s, 9H).
9F NMR (300 MHz, CDCI3) -76.0 (s).
MS m/z [M+H]+=388.
D. 2,2,2-Trifluoro-N-(1 ',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-4-ylmethyl)-acetamide
dihydrochloride
By proceeding in a similar manner to the method described in Example 1111
using 4-[(2,2,2-trifluoro-acetylamino)-methyl]-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-
1'-carboxylic acid tert-butyl ester as the starting material, the titled product is
prepared as a brown solid.
H NMR (300 MHz, DMSO-c/6) 10.34 (t, 1H), 9.21 (br s, 1H), 9.1 0 (br s, 1H), 8.70
(d, 1H), 7.61 -7.58 (m, 2H), 4.62 (d, 2H), 3.32 (m, 2H), 3.07-2.96 (m, 2H), 2.1 5-2.1 0
(m, 2H), 2.06-1 .93 (m, 2H).
9F NMR (300 MHz, DMSO-c/6) -74.7 (s).
MS m/z: [M+H]+=288.
E. 2,2,2-Trifluoro-N-{1 '-[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-4-ylmethyl}-acetamide
By proceeding in a similar manner to the method described in Example 2 1
using 7-methyl-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 2,2,2-trifluoro-N-
(1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-4-ylmethyl)-acetamide dihydrochloride as
starting materials, the titled product is prepared as a white solid.
H NMR (300 MHz, DMSO-c/6) 10.1 (t, 1H), 8.57 (d, 1H), 7.62 (s, 1H), 7.52 (d,
1H), 7.44 (br s, 1H), 7.31 (m, 1H), 7.0-6.92 (m, 2H), 4.57 (t, 2H), 4.50 (d, 2H), 4.40
(br d, 2H), 3.66 (t, 2H), 3.22 (s, 3H), 3.1 5-2.98 (m, 3H), 2.67 (s, 3H), 1.92-1 .88 (m,
2H), 1.79-1 .67 (m, 2H).
9F NMR (300 MHz, DMSO-c/6) -74.7 (s).
MS m/ z [M+H] +=503.
F. (4-Aminomethyl-3',4',5',6'-tetrahydro-2'H-[2,4']bipyridinyl-1 '-yl)-[1 -(2-methoxyethyl)-
7-methyl-1 H-indol-3-yl]-methanone dihydrochloride
By proceeding in a similar manner to the method described in Example 3B
using 2,2,2-trifluoro-N-{1 '-[1 -(2-methoxy-ethyl)-7-methyl-1 H-indole-3-carbonyl]-
1',2',3',4',5',6'-hexahydro-[2,4']bipyridinyl-4-ylmethyl}-acetamide as the starting
material, the titled product is prepared as an off-white solid.
H NMR (300 MHz, DMSO-c/6) 8.74 (br d, 4H), 7.90 (br s, 1H), 7.72 (m, 1H), 7.64
(s, H), 7.55 (d, H), 7.01 (t, 1H), 6.93 (d, 1H), 4.57 (t, 2H), 4.42 (br d, 2H), 4.23 (dd,
2H), 3.67 (t, 2H), 3.22 (s, 3H), 3.1 0 (t, 2H), 2.68 (s, 3H), 1.99-1 .95 (m, 2H), 1.83-1 .70
(m, 2H).
MS m/ z [M+H] +=407.
EXAMPLE 120
2,3-Dihydro-benzofuran-7-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperidine-1 -car hydrochloride
A. 2,3-Dihydro-benzofuran-7-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoroacetylamino)-
methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-
-amide
The title compound is prepared in a similar manner as described in Example
6E using 7-coumarancarboxylic acid and N-(3-{1-[4-amino-1 -(2-methoxy-ethyl)-1 Hindole-
3-carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the
starting materials.
H NMR (300 MHz, DMSO-c/6) 10.61 (s, 1H), 9.94 (t, 1H), 8.01 (d, 1H), 7.71 (s, 1H),
7.55 (d, 1H), 7.40-7.34 (m, 2H), 7.22 (t, 1H), 7.1 6-7.1 1 (m, 3H), 6.90 (t, 1H), 4.67 (t,
2H), 4.45 (br s, 1H), 4.41-4.37 (m, 3H), 4.33 (d, 2H), 3.65 (t, 2H), 3.30-3.23 (m, 2H),
3.20 (s, 3H), 3.1 0-2.99 (m, 3H), 1.77-1 .73 (m, 2H), 1.61-1 .53 (m, 2H).
9F NMR (300 MHz, DMSO-c/6) -74.8 (s), - 12 1.8 (m).
MS m/z [M+H] +=667.
B. 2,3-Dihydro-benzofuran-7-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperidine-1 -ca hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using 2,3-dihydro-benzofuran-7-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoroacetylamino)-
methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-
yl]-amide as the starting material.
H NMR (300 MHz, DMSO-c/6) 10.63 (s, 1H), 8.20 (br s, 2H), 8.00 (d, 1H), 7.70 (s,
1H), 7.53 (d, 1H), 7.38-7.30 (m, 4H), 7.23-7.1 5 (m, 2H), 6.89 (t, 1H), 4.65 (t, 2H),
4.45-4.37 (m, 3H), 3.94 (br s, 2H), 3.64 (t, 2H), 3.28-3.21 (m, 3H), 3.18 (s, 3H), 3.10-
3.00 (m, 3H), 1.76-1 .72 (m, 2H), 1.59-1 .55 (m, 2H).
9F NMR (300 MHz, DMSO-c/6) - 120.4 (br s).
MS m/z [M+H] +=571 .
EXAMPLE 12 1
7-Methyl-1 H-indole-2-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide dihydrochloride
A. 7-Methyl-1 H-indole-2-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoroacetylamino)-
methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-
-amide
The title compound is prepared in a similar manner as described in Example
6E using 7-methylindole-2-carboxylic acid and N-(3-{1 -[4-amino-1-(2-methoxy-ethyl)-
1H-indole-3-carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide as the
starting materials.
H NMR (300 MHz, DMSO-c/6) .64 (s, 1H), 11.54 (s 1H), 9.87 (t, 1H), 8.24 (d,
1H), 7.86 (s, 1H), 7.49-7.47 (m, 2H), 7.37 (d, 1H), 7.28 (t, 1H), 7.1 9 (d, 1H), 7.1 2-7.1 1
(m, 1H), 7.09 (s, 1H), 7.01 -6.94 (m, 2H), 4.71 (br d, 2H), 4.34 (t, 2H), 4.21 (d, 2H),
3.68 (t, 2H), 3.30-3.14 (m, 6H), 2.54 (s, 3H), 1.90-1 .87 (m, 2H), 1.81 - 1 .69 (m, 2H).
9F NMR (300 MHz, DMSO-c/6) -74.9 (s), - 12 1.9 (m).
MS m/ z [M+H] +=678.
B. 7-Methyl-1 H-indole-2-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide dihydrochloride
The title compound is prepared in a similar manner as described in Example
3B with 7-methyl-1 H-indole-2-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoroacetylamino)-
methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-
yl]-amide as the starting material.
H NMR (300 MHz, DMSO-c/6) 1 .67 (s, 1H), 1 .52 (s 1H), 8.28-8.21 (m, 3H), 7.86
(s, 1H), 7.46-7.44 (m, 3H), 7.37-7.23 (m, 3H), 7.1 6 (t, 1H), 6.99-6.92 (m, 2H), 4.70 (br
d, 2H), 4.42 (t, 2H), 3.86-3.84 (m, 2H), 3.66 (m, 2H), 3.40-3.26 (m, 6H), 2.52 (s, 3H),
1.89-1 .85 (m, 2H), 1.78-1 .71 (m, 2H).
9F NMR (300 MHz, DMSO-c/6) -74.9 (s), - 12 1.9 (m).
MS m/z [M+H] +=678.
EXAMPLE 122
1-Methyl-piperidine-3-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
A. 1-Methyl-piperidine-3-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoroacetylamino)-
methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-
yl]-amide
The title compound is prepared in a similar manner as described in Example
6E using 1-methylpiperidine-3-carboxylic acid hydrochloride and N-(3-{1 -[4-amino-1 -
(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoroacetamide
as the starting materials.
H NMR (300 MHz, DMSO-c/6) 0.80 (s, H), 9.92 (t, H), 7.90 (d, H), 7.78 (s, H),
7.31-7.24 (m, 2H), 7.1 9-7.1 3 (m, 3H), 4.59 (br d, 2H), 4.38 (t, 2H), 4.33 (d, 2H), 3.64
(t, 2H), 3.26-3.1 3 (m, 3H), 3.19 (s, 3H), 2.88 (br d, 1H), 2.66 (br d, 1H), 2.55-2.43 (m,
1H), 2.14 (s, 3H), 2.09-2.02 (m, 1H), 1.87-1 .83 (m, 4H), 1.74-1 .62 (m, 3H), 1.50-1 .40
(m, 2H).
9F NMR (300 MHz, DMSO-c/6) -74.8 (s), - 12 1.6 (m).
MS m/z [M+H] +=646.
B. 1-Methyl-piperidine-3-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-
piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
The title compound is prepared in a similar manner as described in Example
3B using 1-methyl-piperidine-4-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoroacetylamino)-
methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-
yl]-amide as the starting material.
H NMR (300 MHz, DMSO-c/6) 10.95 (s, 1H), 8.50 (br s, 2H), 7.89 (d, 1H), 7.79 (s,
1H), 7.54 (d, 1H), 7.37-7.29 (m, 2H), 7.23-7.14 (m, 2H), 4.58 (br d, 2H), 4.38 (t, 2H),
3.96 (s, 2H), 3.63 (t, 2H), 3.31-3.1 0 (m, 3H), 3.1 8 (s, 3H), 2.92 (br d, 1H), 2.65 (br s,
1H), 2.39 (br s, 4H), 1.96-1 .49 (m, 10H).
9F NMR (300 MHz, DMSO-c/6) - 1 19.4 (br s).
MS m/z [M+H]+=550.
EXAMPLE 123
3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-1 Hindole-
4-carboxylic acid cyclopropylamide hydrochloride
A. 3-(4-{2-Fluoro-5-[(2,2,2-trifluoro-acetylamino)-methyl]-phenyl}-piperidine-1 -
carbonyl)-1 -(2-met cyclopropylamide
The title compound is prepared in a similar manner as described in Example
96A using 3-(4-{2-fluoro-5-[(2,2,2-trifluoro-acetylamino)-methyl]-phenyl}-piperidine-1 -
carbonyl)-1 -(2-methoxy-ethyl)-1 H-indole-4-carboxylic acid and cyclopropylamine as
the starting materials.
H NMR (300 MHz, CDCI3) 7.6 (bs, 1H), 7.5 (m, 3H), 7.4 (s, 1H), 7.3 (m, 1H), 6.95
(m, H), 6.4 (m, H), 4.9 (m, H), 4.5 (m, 2H), 4.3 (t, 2H), 3.7 (t, 2H), 3.3 (s, 3H), 3.2
(m, 2H), 3.0 (m, 2H), .9-1 .70 (m, 4H), 1.6 (m, 2H), 0.8 (m, 4H).
MS m/z [M+H]+=589.
B. 3-[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidine-1 -carbonyl]-1 -(2-methoxy-ethyl)-
1H-indole-4-carboxylic acid cyclopropylamide hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using 3-(4-{2-fluoro-5-[(2,2,2-trifluoro-acetylamino)-methyl]-phenyl}-piperidine-1 -
carbonyl)-1 -(2-methoxy-ethyl)-1 H-indole-4-carboxylic acid cyclopropylamide as the
starting material.
H NMR (300 MHz, DMSO-c/6) 8.4 (bs, 2H), 8.1 (m, 1H), 7.6 (m, 3H), 7.4 (m, 1H),
7.2 (m, 3H), 4.4 (t, 2H), 4.0 (m, 3H), 3.6 (t, 2H), 3.2 (s, 3H), 3.1 - 2.9 (m, 4H), 2.7 (m,
1H), 1.85 (m, 4H), 0.6 (m, 4H).
MS m/z: [M+H]+= 493.
EXAMPLE 124
Oxazole-5-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperidine-1 -
carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
A. Oxazole-5-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoro-acetylamino)-methyl]-
phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide
To a solution of oxazole-5-carboxylic acid ( 108 mg, 0.96 mmol) in DMF ( 10
ml_) is added TBTU (0.37g, 1.15 mmol), triethylamine (0.3 ml, 2.1 1 mmol), and N-(3-
{ 1-[4-amino-1 -(2-methoxy-ethyl)-1 H-indole-3-carbonyl]-piperidin-4-yl}-4-fluorobenzyl)-
2,2,2-trifluoro-acetamide (0.5g, 0.96 mmol). The resulting mixture is stirred at
room temperature overnight. The mixture is diluted with EtOAc and washed with
water, brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by
flash chromatography on S1O2 eluting with 70% ethyl acetate / heptanes affords the
titled compound (0.52 g, 88%).
H NMR (300 MHz, CDCI3) 11.5 (s, 1H), 8.2 (d, 1H), 8.0 (m, 2H), 7.4 (d, 1H), 7.3
(m, 1H), 7.2 (m, 3H), 7.0 (m, 2H), 4.8 (m, 2H), 4.5 (m, 2H), 4.3 (t, 2H), 3.7 (t, 2H), 3.3
(s, 3H), 3.2 (m, 3H), 1.9 (m, 2H), 1.7 (m, 2H).
MS m/z [M+H]+=61 6.
B. Oxazole-5-carboxylic acid [3-[4-(5-aminomethyl-2-fluoro-phenyl)-piperidine-1 -
carbonyl]-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide hydrochloride
The title compound is prepared in a similar manner as described in Example
1K using oxazole-5-carboxylic acid [3-(4-{2-fluoro-5-[(2,2,2-trifluoro-acetylamino)-
methyl]-phenyl}-piperidine-1 -carbonyl)-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-amide as
the starting material.
H NMR (300 MHz, DMSO-c/6) 12.0 (s, 1H), 8.6 (s, 1H), 8.2 (m, 3H), 8.0 (s, 1H), 7.9
(s, H), 7.5-7.2 (m, 5H), 4.7 (m, 2H), 4.4 (m, 2H), 4.0 (m, 2H), 3.7 (m, 2H), 3.3 (m,
3H), 3.2 (s, 3H), .9 (m, 2H), .7 (m, 2H).
MS m/z [M+H]+=520.
Biological Activity
The properties of the compound of the present invention are demonstrated by:
1) its beta-Tryptase Inhibitory Potency (IC50 and K , values).
IN VITRO TEST PROCEDURE
As all the actions of tryptase, as described in the background section, are
dependent on its catalytic activity, then compounds that inhibit its catalytic activity will
potentially inhibit the actions of tryptase. Inhibition of this catalytic activity may be
measured by the in vitro enzyme assay and the cellular assay.
Tryptase inhibition activity is confirmed using either isolated human lung
tryptase or recombinant human beta tryptase expressed in yeast cells. Essentially
equivalent results are obtained using isolated native enzyme or the expressed
enzyme. The assay procedure employs a 96 well microplate (Costar 3590) using Lpyroglutamyl-
L-prolyl-L-arginine-para-nitroanilide (S2366: Quadratech) as substrate
(essentially as described by McEuen et. al. Biochem Pharm, 1996, 52, pages 331-
340). Assays are performed at room temperature using 0.5mM substrate (2 x Km )
and the microplate is read on a microplate reader (Beckman Biomek Plate reader) at
405 nm wavelength.
Materials and Methods for Tryptase primary screen (Chromogenic assay)
Assay buffer
50 mM Tris (pH 8.2), 100 mM NaCI, 0.05% Tween 20, 50 g/mL heparin.
Substrate
S2366 (Stock solutions of 2.5 mM).
Enzyme
Purified recombinant beta Tryptase Stocks of 310 g/mL.
Protocol (Single point determination)
• Add 60 _ of diluted substrate (final concentration of 500 in assay buffer) to
each well
• Add compound in duplicates , final concentration of 20 , volume 20 _
• Add enzyme at a final concentration of 50 ng/mL in a volume of 20 _
• Total volume for each well is 100 _
• Agitate briefly to mix and incubate at room temp in the dark for 30 minutes
• Read absorbencies at 405 nM
Each plate has the following controls:
Totals : 60 _ of substrate, 20 _ of buffer (with 0.2% final concentration of
DMSO),
20 _ of enzyme
Non-specific: 60 _ of substrate, 40 _ of buffer (with 0.2% DMSO)
Totals: 60 _ of substrate, 20 _ of buffer (No DMSO), 20 _ of enzyme
Non-specific: 60 _ of substrate, 40 _ of buffer (No DMSO)
Protocol (ICm and K , determination)
The protocol is essentially the same as above except that the compound is
added in duplicates at the following final concentrations: 0.01 , 0.03, 0.1 , 0.3, 1, 3, 10
(All dilutions carried out manually). For every assay, whether single point or IC50
determination, a standard compound is used to derive IC50 for comparison. From the
IC50 value, the K , can be calculated using the following formula: K , = IC50/(1 +
[Substrate]/K m) .
The compounds of this invention display beta-Tryptase inhibition in the range
of 1 to < 1 nM.
Biological Activity
The compounds of this invention display Ki values in the range of 1 to < 1
nM as shown in Table 1 below.
TABLE 1
EXAMPLE # Tryptase Ki (nM)
1 47
2 234
3 109
4 1303
5 96, 56 (8923:1 1)
6 20
7 139
8 35
9 203
10 175
11 56
12 26
13 75
14 83
15 18
16 97
17 37
18 40
19 94
20 19
2 1 28
22 390
23 42
24 98
25 672
26 306
27 164
28 538
29 331
30 50
3 1 306
32 1280
33 >10 uM
34 10 13
35 8.6
36 1150
37 87
38 66
39 10
40 25
4 1 62
42 123
43 850
44 5 1
45 753
46 94
47 56, 59
48 125
49 291
50 241
5 1 54
52 49
53 289
54 96
55 72
56 9
57 54
58 108
59 32
60 22
6 1 17
62 22
63 46
64 39
65 11
66 164
67 12
68 35
69 400
70 2 1
7 1 49
72 13
73 7
74 26
75 59
76 2 11
77 57
78 117
79 935
80 961
8 1 224
82 6
83 5
84 22
85 9
86 80
87 207
88 239
89 11
90 396
9 1 20 (71 9 54 nM; 8923 28 nM)
92 90
93 160
94 2 1
95 44 (8923 15 nM, 7 19D 47 nM)
96 18
97 28
98 147
99 25
100 17
10 1 11
102 22
103 4 1
104 204
105 100
106 149
107 3 15
108 15
109 142
110 1260
111 10 17
112 998
113 656
114 526
115 390
116 746
117 756
118 832
119 180
120 3
12 1 99
122 44
123 50
124 8
Although the invention has been illustrated by certain of the preceding
examples, it is not to be construed as being limited thereby; but rather, the invention
encompasses the generic area as hereinbefore disclosed. Various modifications and
embodiments can be made without departing from the spirit and scope thereof.
WO 2011/079102 „„„ PCT/US2010/061461
CLAIMS
What is claimed is:
1. A compound of formula (I):
(I)
wherein
R 1 is F, CI, Br, OCH2CO2CH3, OCH2CONW1W2, CH2OH or optionally
substituted alkyl, haloalkyl, alkoxy or haloalkoxy; wherein
W1 and W2 are independently H or alkyl;
R2 is H, F, CI, Br, OH, CH2OH, alkyl or alkoxy;
provided R 1 and R2 are not H at the same time;
R3 is aryl or heteroaryl; or
a salt thereof or an enantiomer or a diastereomer thereof.
The compound according to claim 1, wherein
R 1 is selected from the group consisting of F, CI, Br, OCH CO2CH3 and
CH2OH.
The compound according to claim 1, wherein
R2 is selected from the group consisting of H, F, CI, Br, OH, CH3, OCH3
CH2OH.
4 . The compound according to claim 1, wherein R3 is indolyl that is optionally
substituted.
5 The compound according to claim 1, wherein
wherein
R4 is alkyl optionally substituted by one or more groups selected from hydroxy,
alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, optionally
substituted aryl and heteroaryl, or optionally substituted heteroaryl; and
R5 is H, halo, alkoxy, haloalkoxy, alkyl, amido, carboxyl, ureyl, sulfonyl amido,
sulfonyl urea, alkyl optionally substituted by one or more groups
selected from hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl.
6 . A pharmaceutical composition comprising a compound of formula (I):
wherein
R 1 is F, CI, Br, OCH2CO2CH3, OCH2CONW1W2, CH2OH or optionally
substituted alkyl, haloalkyl, alkoxy or haloalkoxy; wherein
W1 and W2 are independently H or alkyl;
R2 is H, F, CI, Br, OH, CH2OH, alkyl or alkoxy;
provided R 1 and R2 are not H at the same time;
R3 is aryl or heteroaryl; or
a pharmaceutically acceptable salt thereof or an enantiomer or a diastereomer
thereof in combination with at least one pharmaceutically acceptable
excipient, diluent or a carrier.
7 . A method of treating a disease in a patient, said disease selected from the
group consisting of an inflammatory disease, for example, joint inflammation,
including arthritis, rheumatoid arthritis and other arthritic condition such as
rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis,
psoriatic arthritis, osteoarthritis or other chronic inflammatory joint disease, or
diseases of joint cartilage destruction, ocular conjunctivitis, vernal
conjunctivitis, inflammatory bowel disease, asthma, allergic rhinitis, interstitial
lung diseases, fibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis,
myocardial fibrosis, neurofibromas, hypertrophic scars, various dermatological
conditions, for example, atopic dermatitis and psoriasis, myocardial infarction,
stroke, angina or other consequences of atherosclerotic plaque rupture, as
well as periodontal disease, diabetic retinopathy, macular degeneration, acute
macular degeneration, wet , macular degeneration, tumor growth, anaphylaxis,
multiple sclerosis, peptic ulcers, or a syncytial viral infection; comprising
administering to said patient a therapeutically effective amount of a compound
of formula (I):
(I)
wherein
R 1 is F, CI, Br, OCH2CO2CH3, OCH2CONW1W2, CH2OH or optionally
substituted alkyl, haloalkyi, alkoxy or haloalkoxy; wherein
W1 and W2 are independently H or alkyl;
R2 is H, F, CI, Br, OH, CH2OH, alkyl or alkoxy;
provided R 1 and R2 are not H at the same time;
R3 is aryl or heteroaryl; or
a pharmaceutically acceptable salt thereof or an enantiomer or a diastereomer
thereof optionally in combination with one or more pharmaceutically
acceptable excipient, diluent or a carrier.