[4 [4-(5-AMINOMETHYL-2-FLUORO-PHENYL)-PIPERIDIN-l-YL]-(l H-PYRROLOPYRIDIN-
YL)-METHANONE S AND SYNTHESIS THEREOF
FIELD OF THE INVENTION
Provided herein are novel and useful compounds having a tryptase inhibition activity
and the intermediates thereof, pharmaceutical compositions comprising such compounds, and
a method of treating subjects suffering from a condition disease or disorder that can be
ameliorated by the administration of an inhibitor of tryptase including but not limited to for
example asthma and other inflammator diseases.
BACKGROUND OF THE INVENTION
Mast cell mediated inflammatory conditions, in particular asthma, are a growing public
health concern. Asthma is frequently characterized by progressive development of hyperresponsiveness
of the trachea and bronchi to both irnmunospecific 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 secretory
protease of human mast cells. Tryptase has been implicated in a variety of biological
processes, including degradation of vasodilating and bronchorelaxing neuropeptides
(Caughey, et al, J. Pharmacol. Exp. Ther., 1988, 244, pages 133-137; 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 175-179).
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. Timrnerman, Mediators
Inflarnm., 1997, 112, pages 3 11-317), 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 1313-1321) 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 115-122).
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 tumor growth (W.J. Beil et al, Exp. Hematol,
1998 26, pages 158-169). Also, tryptase inhibitors may be useful in the treatment of
anaphylaxis (L.B. Schwarz et al, J. Clin. Invest., 1995, 96, pages 2702-2710), multiple
sclerosis (M. Steinhoff et al, Nat. Med. (N. Y), 2000, 6(2), pages 151-158), peptic ulcers and
syncytial viral infections.
US Patent 6,977,263 discloses compounds including [(benzylamine)-piperidin-l-yl]
(aryl or heteroaryl)methanone as tryptase inhibitors, and describes potential uses for such
compounds due to tryptase being implicated in a variety of biological processes, including
degradation of vasodilating and bronchorelaxing neuropeptides (Caughey, et al, J.
Pharmacol. Exp. Ther., 1988, 244, pages 133, 137; 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 175-179).
US Patent 6,977,263 more particularly discloses the compounds of formula A, their
preparation, and use for treating disease states capable of being modulated by the inhibition
of tryptase. US Patent 6,977,263 also discloses that R1 of formula A may be an aryl or
heteroaryl group. Heteroaryl groups that are exemplified in the US Patent 6,977,263 are
alkylpyridyl, alkylthienyl, and indoyl. However there is no teaching or implication that R1 of
formula A may be a pyrrolo-pyridin-yl substituent. Here in we disclose compounds of
formula 1 wherein one of the X substituents is a nitrogen (N) thus providing pyrrolo-pyridinyl
compounds with unexpected activity against tryptase.
Accordingly, what is needed is a novel and useful compound having particularly
valuable pharmaceutical properties, in its ability to inhibit tryptase. Such a compound should
readily have a 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 vasodilating
and bronchorelaxing neuropeptides.
The present invention further relates to a method for treating or ameliorating macular
degeneration in a patient.
Macular degeneration is the general term for a disorder in which a part of the retina
called the macula deteriorates. Age-related macular degeneration (AMD) is the most common
type of macular degeneration. It has been reported that in the United States, AMD is the
leading cause of blindness in people older than 55. More than 10 million people in the US are
affected by this dease, which includes 23% of people over 90. (www.webmd.com/eyehealth/
macular-degeneration/macular-degeneration-overview).
There are various types of macular degeneration that afflict patients. One type of
macular degeneration is "dry" macular degeneration. Dry macular degeneration is an early
stage of the disorder in which a pigment is deposited on the macula. The deposition of this
pigment may result from aging or thinning of the macular tissues. As a result of this
deposition of pigment, loss of central vision may gradually occur. Many times, AMD begins
with dry macular degeneration.
Another type of AMD is "wet" macular degeneration. Wet macular degeneration is a
neovascular type of degeneration in which blood vessels abnormally grow under the retina and
begin to leak. As a result of this leakage, permanent damage occurs to light-sensitive cells of
the retina which ultimate causes the death of these cells and thus, blind spots. Unlike dry
macular degeneration, in which the vision loss may be minor, the vision loss that occurs in
wet macular degeneration can be severe. Indeed, it has been reported that although only 10%
of those with AMD suffer from wet macular degeneration, 66% of those with AMD suffering
from significant visual loss can directly attribute that loss to wet macular degeneration.
Since the causes for macular degeneration are unknown, there has only be limited
success determining the causes for the disorder. Moreover, treatments for macular
degeneration have met with only limited limited success. To date, there is no FDA-approved
treatment for dry macular degeneration and nutritional intervention is used to prevent the
progression of wet macular degeneration.
Furthermore, in a method of the present invention, administration of a compound to
the patient suffering from macular degeneration modulates the activity of an immunocyte in
the patient. The activity of numerous types of immunocytes can be modulated in a method of
the present invention. Examples of such immunocytes include a natural killer cell (NK cell), a
natural killer T cell (NKT cell), a mast cell, a dendritic cell, and granulocyte selected from the
group consisting of an eosinophil, a basophil and neutrophil. Naturally, the activity of a
combination of these cells can also be modulated in a method of the present invention.
Moreover, a method of the present invention can also be used to treat or ameliorate
choroidal neovascularization, which in turn also treats or ameliorates wet macular
degeneration in the patient.
Accordingly, the present invention relates to a methhod of treating a patient in neeed
of amelioration of AMD with a compound of Formula I .
SUMMARY OF THE INVENTION
The present invention is directed to aminomethyl-2-fluoro-phenyl-piperidin-l-yl]-(l Hpyrrolo-
pyridin-yl)-methanones (compounds of formula I)
(I); to the syntheses of said compounds and or a prodrug, pharmaceutically acceptable
salt, or solvate of said compound to a method of treating patients in need there of.
Furthermore, the present invention is directed to a pharmaceutical composition comprising a
pharmaceutically effective amount of the compound of formula I, and a pharmaceutically
acceptable carrier. Furthermore, the present invention is directed to the use of a compound of
formula I as an inhibitor of tryptase, comprising introducing the compound into a composition
comprising tryptase. In addition, the present invention is directed to the use of a compound of
formula I for treating a patient suffering from, or subject to, a physiological condition in need
of amelioration of an inhibitor of tryptase comprising administering to the patient a
therapeutically effective amount of the compound of Claim 1. The present invention is
directed also to the preparation of a compound of formula I .
DETAILED DESCRIPTION
Definitions
As used above, and throughout the instant specification and appending claims, the following
terms, unless otherwise indicated, shall be understood to have the following meanings:
As used herein, the term "compound of the present invention", and equivalent expressions, are
meant to embrace the compound of formula I, as hereinbefore described, which expression includes
the prodrug, the pharmaceutically acceptable salt and the solvate, e.g., hydrate. Similarly, reference to
intermediates, whether or not they themselves are claimed, is meant to embrace the salts, and solvates,
where the context so permits. For the sake of clarity, particular instances when the context so permits
are sometimes indicated in the text, but these instances are purely illustrative and they are not intended
to exclude other instances when the context so permits.
As used herein, the term "treatment" or "treating" includes prophylactic therapy as well as treatment of
an established condition.
"Patient" means a human or other mammal.
"Effective amount" is meant to describe an amount of a compound effective in producing the
desired therapeutic effect.
"Prodrug" means a compound that is suitable for administration to a patient without undue
toxicity, irritation, allergic response, and the like, and is convertible in vivo by metabolic means (e.g.
by hydrolysis) to the compound of the present invention. A thorough discussion of prodrugs is
provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S.
Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Desiml, American
Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by
reference.
Particular Embodiments
In addition, the present invention is directed to the use of the compound of formula I for
treating a patient suffering from a physiological condition that can be ameliorated by administering to
the patient a therapeutically effective amount of the compound of formula I . Particular embodiments
of physiological conditions that can be treated with the compound of the present invention include, but
certainly are not limited to inflammatory diseases, e.g., 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.
In a particular embodiment, the present invention is directed to the use of a compound of
formula I for treating a patient suffering from asthma, comprising administering to the patient a
physiologically effective amount of the compound.
In another particular embodiment, the present invention is directed to the use of a compound
of formula I for treating a patient suffering from COPD, comprising administering to the patient a
physiologically effective amount of the compound.
In another particular embodiment, the present invention is directed to the use of a compound
of formula I for treating a patient suffering from COPD exacerbations, comprising administering to the
patient a physiologically effective amount of the compound.
In another particular embodiment, the present invention is directed to the use of a compound
of formula I for treating a patient suffering from allergic rhinitis, comprising administering to the
patient a physiologically effective amount of the compound.
In another particular embodiment, the present invention is directed to the use of a compound
of formula I for treating a patient suffering from joint inflammation, comprising administering to the
patient a physiologically effective amount of the compound.
In another particular embodiment, the present invention is directed to the use of a compound
of formula I for treating a patient suffering from macular degenaration, comprising administering to
the patient a physiologically effective amount of the compound.
In another particular embodiment, the present invention is directed to the use of a compound
of formula I for treating a patient suffering from wet macular degenaration, comprising administering
to the patient a physiologically effective amount of the compound.
In another particular embodiment, the present invention is directed to the use of a compound
of formula I for treating a patient suffering from acute macular degenaration, comprising administering
to the patient a physiologically effective amount of the compound.
In addition, the present invention extends to a pharmaceutical composition comprising the
compound of formula I, a second compound selected from the group consisting of a beta andrenergic
agonist, an anticholinergic, an anti-inflammatory corticosteroid, and an anti-inflammatory agent, and a
pharmaceutically acceptable carrier thereof. In such a composition the compound of formula I and the
second compound are present in amounts such that provide a therapeutically efficacious activity, i.e.,
additive or synergistic effect. Particular inflammatory diseases or disorders that can be treated with
such a pharmaceutical composition include, but is not limited to, asthma.
Moreover, the present invention is directed to a method for treating a patient suffering from an
inflammatory disorder, comprising administering to the patient the compound of formula I and a
second compound selected from the group consisting of a beta andrenergic agonist, an anticholinergic,
an anti-inflammatory corticosteroid, and an anti-inflammatory agent. In such a method, the compound
of formula I and the second compound are present in amounts such that provide a therapeutically
efficacious activity, i.e., additive or synergistic effect. In such a method of the present invention, the
compound of the present invention can be administered to the patient before a second compound, a
second compound can be administered to the patient before a compound of the present invention, or a
compound of the present invention and a second compound can be administered concurrently.
Particular examples of andrenergic agonists, anticholinergics, anti-inflammatory corticosteroids, and
anti-inflammatory agents having application according to the method are described infra.
Pharmaceutical Compositions
As explained above, the compound of the present invention exhibits useful pharmacological
activity and accordingly may be incorporated into a pharmaceutical composition and used in the
treatment of patients suffering from certain medical disorders. The present invention thus provides,
according to a further aspect, pharmaceutical compositions comprising the compound of the invention,
and a pharmaceutically acceptable carrier thereof. As used herein, the term "pharmaceutically
acceptable" preferably means approved by a regulatory agency of a government, in particular the
Federal government or a state government, or listed in the U.S. Pharmacopoeia or another generally
recognized pharmacopoeia for use in animals, and more particularly in humans. Suitable
pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.
Pharmaceutical compositions according to the present invention can be prepared according to the
customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The
adjuvants comprise, inter alia, diluents, fillers, binders, disintegrants, glidants, lubricants, surfactants,
sterile aqueous media and the various non-toxic organic solvents. The composition may be presented
in the form of tablets, capsules, pills, sustained release formulations, granules, powders, aqueous
solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents
chosen from the group comprising sweeteners, flavorings, colorings, or stabilizers in order to obtain
pharmaceutically acceptable preparations. The choice of vehicle and the content of active substance in
the vehicle are generally determined in accordance with the solubility and chemical properties of the
active compound, the particular mode of administration and the provisions to be observed in
pharmaceutical practice. For example, excipients such as lactose, microcrystalline cellulose,
pregelatinized starch, unmodified starch, silicified microcrystalline cellulose, rnannitol, sorbitol,
xylitol, dextrates, fructose, sodium citrate, calcium carbonate, dicalcium phosphate dihydrate,
anhydrous dicalcium phosphate, calcium sulfate, along with binders such as polyvinylpyrollidone,
hydroxypropylmethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium
carboxymethyl cellulose, pregelatinized starch, starch, polyethylene glycols, polyethylene oxide,
polycarbophils, gelatin and acacia and disintegrating agents such as sodium croscannellose, sodium
starch glycolate, crospovidone, starch, microcrystalline cellulose, alginic acids and certain complex
silicates combined with lubricants such as magnesium stearate, calcium stearate, stearic acid,
hydrogenated vegetable oil, mineral oil, polyethylene glycols, glyceryl esters of fatty acids, sodium
lauryl sulfate and glidants such as silicon dioxide, talc, starch, along with some suitable wetting agent
such as sodium lauryl sulfate, sorbitan esters, polyoxyethylene fatty acid esters, poloxamer,
polyoxyethylene ether, sodium docusate, polyethoxylated castor oil, and benzalkonium chloride may
be used for preparing tablets. To prepare a capsule, it is advantageous to use fillers such as lactose,
microcrystalline cellulose, pregelatinized starch, unmodified starch, silicified microcrystalline
cellulose alone or a mixture of two or more fillers, with and without binders as described above along
with suitable wetting agent (s), disintegrants, glidants, lubricants, etc. as listed above. When aqueous
suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and
chloroform or mixtures thereof may also be used. Such pharmaceutically acceptable carriers can also
be sterile water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as
peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the
pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and
glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable
pharmaceutical excipients include rnannitol, human serum albumin (HSA), starch, glucose, lactose,
sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium carbonate, magnesium stearate, sodium
stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,
water, ethanol and the like. These compositions can take the form of solutions, suspensions, tablets,
pills, capsules, powders, sustained-release formulations and the like.
Naturally, a pharmaceutical composition of the present invention will contain a therapeutically
effective amount of the active compound together with a suitable amount of carrier so as to provide the
form for proper administration to the patient. While intravenous injection is a very effective form of
administration, other modes can be employed, such as by injection, or by oral, nasal or parenteral
administration, which are discussed infra.
Methods of Treatment
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. 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.
Combination Therapy
As explained above, other pharmaceutically active agents can be employed in combination
with the compound of formula I depending upon the disease being treated. For example, in the
treatment of asthma, beta-adrenergic agonists such as albuterol, terbutaline, formoterol, fenoterol or
prenaline can be included, as can anticholinergics such as ipratropium bromide, anti-inflammatory
corticosteroids such as beclomethasone dipropionate, triamcinolone acetonide, flunisolide or
dexamethasone, and anti-inflammatory agents such as sodium cromoglycate and nedocromil sodium.
Thus, the present invention extends to a pharmaceutical composition comprising the compound of
formula I and a second compound selected from the group consisting of a beta andrenergic agonist, an
anticholinergic, an anti-inflammatory corticosteroid, and an anti-inflammatory agent; and a
pharmaceutically acceptable carrier thereof. Particular pharmaceutical carriers having applications in
this pharmaceutical composition are described herein.
Furthermore, the present invention extends to a method for treating a patient suffering from
asthma, comprising administering the patient the compound of the present invention, and a second
compound selected from the group consisting of a beta andrenergic agonist, an anticholinergic, an anti
inflammatory corticosteroid, and an anti-inflammatory agent. In such a combination method, the
compound of the present invention can be administered prior to the administration of the second
compound, the compound of the present invention can be administered after administration of the
second compound, or the compound of the present invention and the second compound can be
administered concurrently.
Modes of Delivery
According to the invention, the compound of formula I, or a pharmaceutical composition
comprising the compound, may be introduced parenterally, transmucosally, e.g., orally, nasally,
intraocularly, pulmonarily, or rectally, or transdermally to a patient.
Oral Delivery
Contemplated for use herein are oral solid dosage forms, which are described generally in
Remington's Pharmaceutical Sciences, 18th Ed. 1990 (Mack Publishing Co. Easton PA 18042) at
Chapter 89, which is herein incorporated by reference. Solid dosage forms include tablets, capsules,
pills, troches or lozenges, cachets or pellets. Also, liposomal or proteinoid encapsulation may be used
to formulate the present compositions (as, for example, proteinoid microspheres reported in U.S.
Patent No. 4,925,673). Liposomal encapsulation may be used and the liposomes may be derivatized
with various polymers (e.g., U.S. Patent No. 5,013,556). A description of possible solid dosage forms
for a therapeutic is given by Marshall, K. In: Modern Pharmaceutics Edited by G.S. Banker and C.T.
Rhodes Chapter 10, 1979, herein incorporated by reference. In general, the formulation will include a
compound of the present invention, and inert ingredients that allow for protection against the stomach
environment, and release of the biologically active material, i.e., a compound of the present invention,
in the intestine.
Also specifically contemplated are oral dosage forms of the compound of the present
invention. Such a compound may be chemically modified so that oral delivery is more efficacious.
Generally, the chemical modification contemplated is the attachment of at least one moiety to the
component molecule itself, where said moiety permits (a) inhibition of proteolysis; and (b) uptake into
the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the
compound of the present invention, and increase in circulation time in the body. Examples of such
moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol,
carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline.
Abuchowski and Davis, 198 1, "Soluble Polymer-Enzyme Adducts" In: Enzymes as Drugs, Hocenberg
and Roberts, eds., Wiley-Interscience, New York, NY, pp. 367-383; Newmark, et al., 1982, J . Appl.
Biochem. 4:185-189. Other polymers that could be used are poly-l,3-dioxolane and poly- 1,3,6-
tioxocane. Preferred for pharmaceutical usage, as indicated above, are polyethylene glycol moieties.
For the compound of the present invention, the location of release may be the stomach, the
small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art
has available formulations that will not dissolve in the stomach, yet will release the material in the
duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the
stomach environment, either by protection of the compound of the present invention, or by release of
the compound beyond the stomach environment, such as in the intestine.
To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential.
Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate
trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55,
polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP),
Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed films.
A coating or mixture of coatings can also be used on tablets, which are not intended for
protection against the stomach. This can include sugar coatings, or coatings that make the tablet easier
to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic i.e.
powder; for liquid forms, a soft gelatin shell may be used. The shell material of cachets could be thick
starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing
techniques can be used.
The therapeutic can be included in the formulation as fine multi-particulates in the form of
granules or pellets of particle size about 1mm. The formulation of the material for capsule
administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic
could be prepared by compression.
Colorants and flavoring agents may all be included. For example, the compound of the present
invention may be formulated (such as by liposome or microsphere encapsulation) and then further
contained within an edible product, such as a refrigerated beverage containing colorants and flavoring
agents.
One may dilute or increase the volume of the therapeutic with an inert material. These diluents
could include carbohydrates, especially mannitol, alpha-lactose, anhydrous lactose, cellulose, sucrose,
modified dextrans and starch. Certain inorganic salts may be also be used as fillers including calcium
triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are
Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.
Disintegrants may be included in the formulation of the therapeutic into a solid dosage form.
Materials used as disintegrates include, but are not limited to starch, including the commercial
disintegrant based on starch, Explotab sodium starch glycolate, Amberlite, sodium
carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl
cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the
insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and
these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt
are also useful as disintegrants.
Binders may be used to hold the therapeutic agent together to form a hard tablet and include
materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl
cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone
(PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to
granulate the therapeutic.
An anti-frictional agent may be included in the formulation of the therapeutic to prevent
sticking during the formulation process. Lubricants may be used as a layer between the therapeutic
and the die wall, and these can include but are not limited to; stearic acid including its magnesium and
calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble
lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene
glycol of various molecular weights, Carbowax 4000 and 6000.
Glidants that might improve the flow properties of the drug during formulation and to aid
rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic
silica and hydrated silicoaluminate.
To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added
as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl
sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents might be used and could
include benzalkonium chloride or benzethomium chloride. The list of potential non-ionic detergents
that could be included in the formulation as surfactants are lauromacrogol 400, polyoxyl 40 stearate,
polyoxyethylene hydrogenated castor oil 10,50 and 60, glycerol monostearate, polysorbate 40, 60,65
and 80, sucrose fatty acid ester, methyl cellulose and carhoxymethyl cellulose. These surfactants could
be present in the formulation of a compound of the present invention either alone or as a mixture in
different ratios.
Additives that potentially enhance uptake of the compound of the present invention are, for
instance, the fatty acids oleic acid, linoleic acid and linolenic acid. Controlled release oral formulation
may be desirable. The drug could be incorporated into an inert matrix that permits release by either
diffusion or leaching mechanisms, e.g., gums. Slowly degenerating matrices may also be incorporated
into the formulation. Some enteric coatings also have a delayed release effect.
Another form of a controlled release of this therapeutic is by a method based on the Oros
therapeutic system (Alza Corp.), i -e - e drug is enclosed in a semipermeable membrane which allows
water to enter and push drug out through a single small opening due to osmotic effects.
Other coatings may be used for the formulation. These include a variety of sugars that could
be applied in a coating pan. The therapeutic agent could also be given in a film-coated tablet and the
materials used in this instance are divided into 2 groups. The first are the non-enteric materials and
include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, sodium carboxy-niethyl cellulose,
providone and the polyethylene glycols. The second group consists of the enteric materials that are
commonly esters of phthalic acid.
A mix of materials might be used to provide the optimum film coating. Film coating may be
carried out in a pan-coater or in a fluidized bed or by compression coating.
Pulmonary Delivery
Also contemplated herein is pulmonary delivery of the compound of the present invention,
either alone, or in a pharmaceutical composition. The compound is delivered to the lungs of a
mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other
reports of this include Adjei et al., 1990, Pharmaceutical Research, 7:565-569; Adjei et al., 1990,
International Journal of Pharmaceutics, 63: 135-144 (leuprolide acetate); Braquet et al., 1989, Journal
of Cardiovascular Pharmacology, 13(suppl. 5): 143-146 (endothelin-1); Hubbard et al., 1989, Annals
of Internal Medicine, Vol. Ill, pp. 206-212 (al- antitrypsin); Smith et al., 1989, J.Clin. Invest. 84: 1145-
1146 (a- 1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium
on Respiratory Drug Delivery 11, Keystone, Colorado, March, (recombinant human growth hormone);
Debs et al., 1988, J . Immunol. 140:3482-3488 (interferon-y and tumor necrosis factor alpha) and Platz
et al., U.S. Patent No. 5,284,656 (granulocyte colony stimulating factor). A method and composition
for pulmonary delivery of drugs for systemic effect is described in U.S. Patent No. 5,451,569, issued
September 19, 1995 to Wong et al.
Contemplated for use in the practice of this invention are a wide range of mechanical devices
designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers,
metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.
Some specific examples of commercially available devices suitable for the practice of this
invention are the Ultravent nebulizer, manufactured by Wallinckrodt, Inc., St. Louis, Missouri; the
Acom I I nebulizer, manufactured by Marquest Medical Products, Englewood, Colorado; the Ventolin
metered dose inhaler, manufactured by Glaxo Inc., Reseaxch Triangle Park, North Carolina; and the
Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Massachusetts, to name only a few.
All such devices require the use of formulations suitable for the dispensing of the compound of the
present invention. Typically, each formulation is specific to the type of device employed and may
involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or
carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion
complexes, or other types of carriers is contemplated. A chemically modified compound of the present
invention may also be prepared in different formulations depending on the type of chemical
modification or the type of device employed.
Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise
the compound of the present invention dissolved in water at a concentration of about 0.1 to 25 mg of
compound per rnL of solution. The formulation may also include a buffer and a simple sugar (e.g., for
stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a
surfactant, to reduce or prevent surface induced aggregation of the compound caused by atomization of
the solution in forming the aerosol.
Formulations for use with a metered-dose inhaler device will generally comprise a finely
divided powder containing the compound of the invention suspended in a propellant with the aid of a
surfactant. The propellant may be any conventional material employed for this purpose, such as a
chlorofluorocarbon, hydrochlorofluorocarbon, hydro fluorocarbon, a r hydrocarbon, including
trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and
1,1,1 ,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and
soya lecithin. Oleic acid may also be useful as a surfactant.
Formulations for dispensing from a powder inhaler device will comprise a finely divided dry
powder containing the compound of the invention, and may also include a bulking agent, such as
lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the
device, e.g., 50 to 90% by weight of the formulation. The compound of the present invention should
most advantageously be prepared in particulate form with an average particle size of less than 10 mm
(or microns), most preferably 0.5 to 5 mm, for most effective delivery to the distal lung.
Nasal Delivery
Nasal delivery of the compound of the present invention is also contemplated. Nasal delivery
allows the passage of the compound to the blood stream directly after administering the therapeutic
product to the nose, without the necessity for deposition of the product in the lung. Formulations for
nasal delivery include those with dextran or cyclodextran.
Intraocular Delivery
Intraocular delivery of the compound of the present invention is also contemplated. Various
and numerous methods are known in the art for intraoculal administration of a drug. Intraocular
delivery allows the passage of the compound to the intaocular fluid directly after administering the
therapeutic product to the eye, without the necessity for oral administration of the product.
Formulations for intaocular delivery may include, but are not limited to, solutions or suspensions in
aqueous or non-aqueous media.
Transdermal Delivery
Various and numerous methods are known in the art for transdermal administration of a drug,
e.g., via a transdermal patch. Transderma administration methods have applications in the present
invention. Transdermal patches are described in for example, U.S. Patent No. 5,407,713, issued April
L 8, 1995 to Rolando et al.; U.S. Patent No. 5,352,456, issued October 4, 1994 to Fallon et al.; U.S.
Patent No. 5,332,213 issued August 9, 1994 to DAngelo et al.; U.S. Patent No. 5,336,168, issued
August 9, 1994 to Sibalis; U.S. Patent No. 5,290,561, issued March 1, 1994 to Farhadieh et al.; U.S.
Patent No. 5,254,346, issued October 19, 1993 to Tucker et al.; U.S. Patent No. 5,164,189, issued
November 17, 1992 to Berger et al.; U.S. Patent No. 5,163,899, issued November 17, 1992 to Sibalis;
U.S. Patent Nos. 5,088,977 and 5,087,240, both issued February 18, 1992 to Sibalis; U.S. Patent No.
5,008,110, issued April 16, 1991 to Benecke et al.; and U.S. Patent No. 4,921,475, issued May 1, 1990
to Sibalis, the disclosure of each of which is incorporated herein by reference in its entirety.
It can be readily appreciated that a transdermal route of administration may be enhanced by
use of a dermal penetration enhancer, e.g., such as enhancers described in U.S. Patent No. 5, 164, 189
(supra), U.S. Patent No. 5,008,1 10 (supra), and U.S. Patent No. 4,879,1 19, issued November 7, 1989 to
Aruga et al., the disclosure of each of which is incorporated herein by reference in its entirety.
Topical Administration
For topical administration, gels (water or alcohol based), creams or ointments containing
compounds of the invention may be used. Compounds of the invention may also be incorporated in a
gel or matrix base for application in a patch, which would allow a controlled release of compound
through the transdermal barrier.
Rectal Administration
Solid compositions for rectal administration include suppositories formulated in accordance
with known methods and containing the compound of the invention.
Dosages
The percentage of active ingredient in the composition of the invention may be varied, it being
necessary that it should constitute a proportion such that a suitable dosage shall be obtained.
Obviously, several unit dosage forms may be administered at about the same time. The dose employed
will be determined by the physician, and depends upon the desired therapeutic effect, the route of
administration and the duration of the treatment, and the condition of the patient. In the adult, the doses
are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg per kg body weight
per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10,
mg per kg body weight per day by oral administration, and from about 0.001 to about 10, preferably
0.01 to 1, mg per kg body weight per day by intravenous administration. In each particular case, the
doses will be determined in accordance with the factors distinctive to the subject to be treated, such as
age, weight, general state of health and other characteristics which can influence the efficacy of the
medicinal product.
Furthermore, the compound according to the invention may be administered as frequently as
necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a
higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it
may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with
the physiological requirements of each particular patient. Generally, the active product may be
administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe
not more than one or two doses per day.
Naturally, a patient in whom administration of the compound of the present invention is an
effective therapeutic regimen is preferably a human, but can be any animal. Thus, as can be readily
appreciated by one of ordinary skill in the art, the methods and pharmaceutical compositions of the
present invention are particularly suited to administration to any animal, particularly a mammal, and
including, but by no means limited to, domestic animals, such as feline or canine subjects, farm
animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals
(whether in the wild or in a zoological garden), research animals, such as mice, rats, rabbits, goats,
sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc., i.e., for veterinary
medical use.
Preparatory Details
The compound of formula I may be prepared by the application or adaptation of known
methods, by which is meant methods used heretofore or described in the literature, for example those
described by R.C.Larock in Comprehensive Organic Transformations, VCH publishers, 1989, or as
described herein.
In the reactions described hereinafter it may be necessary to protect reactive functional groups,
for example, amino groups, to avoid their unwanted participation in the reactions. Conventional
protecting groups may be used in accordance with standard practice, for examples see T.W. Greene
and P.G.M.Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991. In
particular, the compound of formula I may be prepared as shown through Examples 1-20 below. For
example, the compound of the present invention is an achiral compound whose preparation is
comprised of a convergent synthesis.
As used throughout the specification, the following abbreviations and definitions,
unless otherwise indicated, shall be understood to have the following meanings:
List of Abbreviations
APCI atmospheric pressure chemical ionization
BOC tert-butyl dicarbonate
BOC anhydride di-t rt-butyl dicarbonyl anhydride
t-Bu tert-butyl
t-BuOH tert-butanol
CDC13 deuterated chloroform
CD3OD deuterated methanol
DCM dichloromethane, CH2C 12 or methylenechloride
DMAP 4-dimethylaminopyridine
DMF dimethylformamide
DMSO dimethylsulfoxide
OMSO-d6 dimethyl-d6 sulfoxide
dppf 1,1'-bis(diphenylphosphino)ferrocene
eq equivalent(s)
Et ethyl
Et20 diethyl ether
Et3N triethylamine
EtOH ethanol
EtOAc ethyl acetate
EDCI 1-ethyl-3-(3 '-dimethylaminopropyl)carbodiimide
HPLC high performance liquid chromatography
H2 hydrogen
L Liter
LC/MS liquid chromatography-mass spectrometry
M molar
Me methyl
MeCN acetonitile
MeOH methanol
MgS0 4 magnesium sulfate
MHz megahertz
min minute
OMe methoxide
NaHC0 3 sodium bicarbonate
Na2C0 3 sodium carbonate
NaCl sodium chloride
NaOH sodium hydroxide
Nal sodium iodide
NaOMe sodium methoxide
Na2S0 4 sodium sulfate
n-BuOAc n-butyl acetate
NMR nuclear magnetic resonance
Pd/C Palladium on carbon
Pd(PPh3)4 tetrakistriphenylphosphine palladium
Pd(PPh3)2Cl2 bistriphenylphosphine palladium (II) dichloride
PdCl2dppf l,l'-bis(diphenylphosphino) ferrocene palladium (II) dichloride
Pd(dtbpf)Cl2 (l,l'-bis(di-t-butylphosphino)ferrocene palladium dichloride
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
Pd(OAc)2 palladium(II) acetate
P(Cy)3 tricyclohexylphosphine
t-Bu3P tri-t-butylphosphine
PP 3 triphenylphosphine
PrOH propanol
z-PrOH zso-propanol
Pt/C platinum on carbon
t-BuOK potassium t r t-butoxide
rt room temperature
Rt Retention time
sat saturated
Si0 2 silica
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
Terms
Preparatory Details
The starting materials for preparing compound I according to Scheme 1 below are
commercially available.
EXAMPLE 1
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-(l H-pyrrolo[2,3-b]pyridin-2-yl)-
methanone dihydrochloride
A
A. 2,2,2-Trifluoro -N-(4-fluoro-3-pyridin-4-yl-benzyl)-acetamide hydrochloride
A flask is charged with NaHC0 3 (126 g, 1.5 mol), 3-bromo-4-fluorobenzylamine
hydrochloride (12, 120 g, 0.5 mole) and pyridine-4-boronic acid (13, 67.6 g, 0.55 mmol) and
isopropyl alcohol (750 mL) and water (375 mL) at room temperature. The suspension is
degassed with N2 for 1.0 h at 10 °C. Into the mixture is added 1,1'-
bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex
(PdCl2dppf-CH2Cl2, 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 room temperature, and
aqueous 2 N HC1 (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 mixture 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%
a2C0 3 ( 1.0 L). A solution of 5-6 N HC1 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 room temperature. 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, 50.16; H, 3.08; N, 8.38. MS (ESI)
m/z 299 (M+H). 1H NMR (300 MHz, D 20 ) 8.70 (d, J = 6.9 Hz, 2 H), 8.14 (d, J = 6.9 Hz,
2H), 7.56-7.20 (m, 3H), 4.51 (s, 2H).
B. 2,2,2-trifluoro -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 H2 at 50-60 psi. The mixture is shaken for >48 h while charging H2 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 rt overnight. The suspension is cooled to 10 °C, filtered, and dried in oven at 50 °C
to give 112 g (89%) of desired product as white solid: mp = 134 °C. Anal. Calcd for
C14H10F4N2O-HCI: C, 50.24; H, 3.31; N, 8.37. Found: C, 50.16; H, 3.08; N, 8.38. MS (ESI)
m/z 305.4 (M+H). 1H NMR (300 MHz, D20 ) 7.16-6.98 (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).
C. 2,2,2-Trifluoro -N-{4-fluoro-3-[l-(l H-pyrrolo[2,3-b]pyridine-2-carbonyl)-piperidin-4-yl]-
benzyl} -acetamide
To a suspension of lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (0.43 g, 2.59 mmol), 2,2,2-
trifluoro -N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride (Example IB, 0.88 g,
2.59 mmol), and EDCI (0.88 g, 3.1 1 mmol) in delete CH2C 12 (50 mL) is added Et3N (0.865
mL, 6.22 mmol). The reaction is stirred at room temperature overnight. The reaction mixture
is poured into EtOAc and the organic layer is washed with sat NH4CI, water and brine. The
organic is dried over MgS0 4, filtered and concentrated in vacuo to give the crude product.
Purification by flash chromatography on Si0 2 eluting with 100% EtOAc gives 0.95 g, (82%)
of the desired product.
1H-NMR (CDCI3, 300 MHz) 10.4 (s, H), 8.5 (d, H), 8.0 (d, H), 7.2-7.0 (m, 4H), 6.8 (s, H),
6.7 (bs, H), 4.8 (m, 2H), 4.5 (d, 2H), 3.4-3.0 (m ,3H), 2.7- 2.0(m, 4H). LCMS m/z 449
(M+H).
D. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-(lH-pyrrolo[2,3-b]pyridin-2-yl)-
methanone dihydrochloride
To a solution 2,2,2-trifluoro -N-{4-fluoro-3-[l-(l H-pyrrolo[2,3-b]pyridine-2-carbonyl)-
piperidin-4-yl]-benzyl}-acetamide (0.78 g, 1.74 mmol) in 30 ml MeOH and H20 (12 mL) was
added K2CO3 (2.4 g, 17.4 mmol). The reaction mixture is stirred overnight. The reaction
mixture is concentrated in vacuo to remove most of the methanol. The residue is partitioned
between H20 and EtOAc washed with H20 and brine, dried over MgSC^, filtered, and
concentrated in vacuo. The residue is taken up in 4.0 N HCl/Dioxane (10 mL, 40.0 mmol) and
stirred 10 min The reaction mixture is concentrated in vacuo and Et20 (20 mL) is added. A
solid precipitate forms and the ethereal solution is decanted off. The solid is washed with
additional Et20 and then isolated by filtration to give 0.3 1 g (46%) of the desired product. 1HNMR
(DMSO- , 300 MHz) 12.2 (s, H), 8.4 (s, H), 8.2 (bs, 2H), 8.1 (d, H), 7.5 (d, H), 7.4
(m, H), 7.25 (m, H), 7.19 (m, H), 6.8 (s, H), 4.6 (m, 2H), 4.2-3.8 (m, 3H), 3.2 (m, 2H), 1.85
(m, 2H), 1.7 (m, 2H). LCMS m/z 353 (M+H).
EXAMPLE 2
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[l-(2-methoxy-ethyl)-l H-pyrrolo[2,3-
b]pyridin-2-yl]-methanone dihydrochloride
A.l H-Pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester
A solution of lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (20 g, 123 mmol), H2S0 4 (20 mL)
and EtOH is heated to reflux for 4h. The reaction mixture is concentrated in vacuo, taken up
in EtOAc and washed with sat. NaHC0 3 (2X), H20 and brine, dried over MgS0 4, filtered, and
concentrated in vacuo to yield 14 g (60%) of desired product. 1H-NMR (CDC13, 300 MHz)
11.6 (bs, H), 8.6 (d, H), 8.1 (d, H), 7.2 (m,2 H), 4.45 (m, 2H),1.5 (m, 3H). LCMS m/z 191
(M+H).
. l-(2-Methoxy-ethyl)-l H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester
To a suspension of NaH (0.51 g, 12.63 mmol) in DMF (lOmL) under Ar is added a suspension
of lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester (2 g, 10.53 mmol) in DMF (9 mL).
The reaction mixture is stirred for 20 min, and 2-methoxyethyl bromide ( 1.1 mL, 11.8 mmol)
is added. The reaction mixture is stirred at room temperature overnight. The reaction mixture
is poured into H20 and the resulting precipitate isolated by filtration. Purification by flash
chromatography on Si0 2 eluting with 10%> EtOAc gives 1.27 g, (49%>) of the desired product.
1H-NMR (CDC13, 300 MHz) 8.5 (d, H), 8.0 (d, H), 7.2 (s, H), 7.15 (m, H), 5.0 (t, 2H), 4.4
(t, 2H), 3.75 (t, 2H), 3.3 (s,3H), 1.4(t, 3H). LCMS m/z 249 (M+H).
C. 1-(2-Methoxy-ethyl)- lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid
l-(2-Methoxy-ethyl)-l H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester ( 1 g, 4.03
mmol), EtOH (30 mL), THF (10 mL) and IN NaOH solution (16 mL) are heated to 50 °C for
l h and then stirred at room temperature overnight. The reaction is cooled to room
temperature, acidified to pH=3 with concentrated HCl and extracted with EtOAc (3X). The
organic fractions are combined, dried over MgS0 4, filtered, and concentrated in vacuo to yield
0.73g (83%) of desired product. 1H-NMR (DMSO-d6, 300 MHz) 13.2 (bs, H), 8.45 (d, H),
8.1 (d, H), 7.2 (m, 2H), 4.85 (t, 2H), 3.6 (t, 2H), 3.2 (s, 3H). LCMS m/z 221 (M+H).
D. 2,2,2-Trifluoro -N-(4-fluoro-3-{l-[l-(2-methoxy-ethyl)-l H-pyrrolo[2,3-b]pyridine-2-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as Example 1C using l-(2-methoxyethyl)-
l H-pyrrolo[2,3-b]pyridine-2-carboxylic acid as the starting material. 1H NMR (CDCI3,
300 MHz) 8.4 (d, H), 7.9 (d, H), 7.2-7.0 (m, 5H), 6.55 (s, 2H), 4.75(m, 2H), 4.5 (m, 2H), 3.7
(t, 2H), 3.25 (s, 3H), 2.0-1.8 (m, 4H), 1.55 (m, 4H). LCMS m/z 507 (M+H).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[ 1-(2-methoxy-ethyl)- lH-pyrrolo[2,3-
b]pyridin-2-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as Example ID using l,2,2-trifiuoro -N-(4-
fiuoro-3- {1-[1-(2-methoxy-ethyl)-l H-pyrrolo[2,3-b]pyridine-2-carbonyl]-piperidin-4-yl} -
benzyl)-acetamide as the starting material. 1H NMR (OMSO-d6, 300 MHz) 8.4 (d, H), 8.2
(bs, 2H), 8.0 (d, H), 7.6 (d, H), 7.35 (m, H), 7.3-7.1 (m, 2H), 6.7 (s, 1H), 4.6 (bm, 2H) 4.0
(bm, 2H), 3.6(m, 5H), 3.25-3.15 (m, 5H), 2.0-1.6 (m, 4H). MS m/z 4 11 (M+H).
EXAMPLE 3
[4-(3 -Aminomethyl-phenyl)-piperidin- 1-y1] -[1-(2-methoxy-ethyl)- lH-pyrrolo[2,3 -b]pyridin-
2-yl]-methanone dihydrohydrochloride
A. 4-Oxo-piperidine-l-carboxylic acid 2-trimethylsilanyl-ethyl ester
A solution of 4-piperidone monohydrate hydrochloride (25 g, 88.22 mmol), 2-
trimethylsilylethyl p-nitrophenylcarbonate (50 mL, 359.70 mmol), triethylamine (50 mL,
345.00 mmol) and DMAP (10.78 g, 88.24 mmol) in of 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 1M HC1 (3 X 100 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 MgSC^. The organic phase is concentrated in vacuo to
afford 19.35 g (90%) of the title compound as a colorless oil. 1H NMR (CDC13, 300 MHz) 
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, 9 H).
B. 4-(3-Cyanophenyl)-3,6-dihydro-2 H-pyridine-l-carboxylic acid 2-trimethylsilanyl-ethyl
ester
To a flask containing tetrahydrofuran (50 mL) at -70°C is added 1M lithium
hexamethyldisilazide (60 mL, 60 mmol) dropwise. A solution of 4-oxo-piperidine-lcarboxylic
acid 2-trimethylsilanyl-ethyl ester (13.3 g, 55 mol) 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 THF (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-2 H-pyridine-lcarboxylic
acid 2-trimethyl-silanyl-ethyl ester, is used without further purification.
To a solution of 4-trifluoromethanesulfonyloxy-3,6-dihydro-2 H-pyridine-l-carboxylic acid 2-
trimethyl-silanyl-ethyl ester (20.65 g, 55 mmol) 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 2 M Na2C0 3 (300
mL) then extracted 3X dichloromethane. The organic phase is washed with brine then
separated and dried (MgSC^). The organic phase is concentrated in vacuo and the crude
residue is flash chromatographed over Si0 2 (eluted with heptane:EtOAc:DCM = 5:1:1) to give
10.46 g (58%) of the title compound as a yellow oil. 1H NMR (CDC13, 300 MHz) 7.65-7.52
(m, 3H), 7.44 (t, J =7.7 Hz, 1H), 6.1 1 (bs, 1H), 4.23 (m, 2H), 4.15 (m, 2 H), 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-l-carboxylic acid 2-trimethylsilanyl-ethyl ester
To a slurry of 10% Pd/C (5 g, wet) in ethanol (250 mL) is added concentrated HC1 (2.9 mL,
34.8 mmol) and 4-(3-cyanophenyl)-3,6-dihydro-2 H-pyridine-l-carboxylic acid 2-
trimethylsilanyl-ethyl ester (10.4 g). The mixture is hydrogentated 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 Et20/pentane, then
filtered to give 7.1 g of the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 
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) m/z 336, 335 (M+H, 100), 191.
D. 4-[3 -(t rt-Butoxycarbonylamino-methyl)-phenyl]-piperidine-l-carboxylic acid 2-
trimethylsilanyl-ethyl ester
To a solution of 4-(3-aminomethyl-phenyl)-piperidine-l-carboxylic acid 2-trimethylsilanylethyl
ester ( 11.1 g, 29.93 mmol) in dichloromethane (150 mL) and saturated NaHC0 3 (50 mL)
is added Boc-anhydride (6.54 g, 29.96 mmoL). The mixture is stirred overnight at room
temperature. The organic phase is then separated and washed with water and brine. The
organic phase is then separated, dried (MgS0 4) and concentrated in vacuo to give 13.41 g
(100%) of the title compound as an oil. 1H NMR (CDC13, 300 MHz) 7.26 (m, 1H), 7.10 (m,
3H), 4.85 (bs, 1H), 4.29 (d, J = 5.8 Hz, 4H), 4.19 (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
9H).
E. (3-Piperidin-4-yl-benzyl)-carbamic acid tert-butyl ester
To a solution of 4-(3 -t rt-butoxycarbonylaminomethylphenyl)-piperidine-l-carboxylic acid 2-
trimethylsilanyl-ethyl ester (13.41 g (30.9 mmol) tetrahydrofuran (200 mL) is added tetrabutyl
ammonium fluoride (1M in THF, 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 HC1 and extracted with Et20 . The aqueous phase is made basic with IN
NaOH and extracted 3X with EtOAc. The organic phases are combined, washed with brine,
separated and dried (MgSC^). The organic phase is filtered and concentrated in vacuo to
afford 8.3 g (93%) of the title compound as a yellow oil which is used without further
purification. 1H NMR (CDC13, 300 MHz) 7.25 (m, 1H), 7.07-7.13 (m, 3H), 4.85 (bs, 1H),
4.29 (d, J = 5.1 Hz, 2H), 3.17 (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, 1H), 1.81 (m, 2H), 1.55-1.70 (m, 3H), 1.46 (s, 9H). LCMS m/z 291 (M+H).
F. (3- {1-[1 -(2-Methoxy-ethyl)- lH-pyrrolo[2,3-b]pyridine-2-carbonyl]-piperidin-4-yl} -
benzyl)-carbamic acid tert-but l ester
The title compound is prepared in a similar manner as Example 1C using l-(2-methoxyethyl)-
l H-pyrrolo[2,3-b]pyridine-2-carboxylic acid and (3-piperidin-4-yl-benzyl)-carbamic
acid tert-butyl ester as the starting material. 1H NMR (CDCI3, 300 MHz) 8.4 (d, 1H), 7.95
(d, 1H), 7.3 (m, 2H), 7.2-7.0 (m, 4H), 6.55 (s, 1H), 4.9 (bs, 1H), 4.7(m, 3H), 4.3 (m, 2H),
3.7(t, 2H), 3.3(s, 3H), 2.8 (m, 1H), 1.95 (m, 2H), 1.8(m, 3H), 1.5 (m, 1H), 1.45 (s, 9H). LCMS
m/z 493 (M+H).
G. [4-(3-Aminomethyl-phenyl)-piperidin- 1-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-
b]pyridin-2-yl]-methanone dihydrochloride
3- {1-[1-(2-Methoxy-ethyl)- lH-pyrrolo[2,3-b]pyridine-2-carbonyl]-piperidin-4-yl} -benzyl)-
carbamic acid tert-butyl ester (0.33 g, 0.66 mmol) and 4.0 N HCl/dioxane (8 mL, 32 mmol)
are stirred for 3h. The reaction mixture is concentrated in vacuo and Et20 (2 0 mL) is added.
A solid precipitate forms and the ethereal solution is decanted off. The solid is washed with
additional Et20 and then isolated by filtration to give 0.28 g (98%) of the desired product. 1HNMR
(DMSO- , 300 MHz) 8.4 (d, 1H), 8.3 (bs, 2H), 8.1 (d, 1H), 7.45-7.3 (m, 4H), 7.2
(m, H), 6.7 (s, 1H), 4.8-4.5 (m, 3H), 4.2(m, 4H), 4.0 (m, 2H), 3.2 (s, 3H), 2.9 (m, 2H), 2.0-1.6
(m, 4H). LCMS m/z 393 (M+H).
EXAMPLE 4
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[3,2-
c]pyridin-2-yl]-methanone hydrochloride
A. lH-Pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester
To a solution of lH-pyrrolo[3,2-c]pyridine-2-carbaldehyde (3.24 g, 22.19 mmol) in MeOH at
0°C under argon is added sodium cyanide (5.44 g, 111 mmol) and manganese dioxide (9.65 g,
111 mmol). The reaction mixture is stirred for 5h after which time it is filtered through Celite
and diluted with EtOAc (500mL). The organic layer is washed with water (2x), brine, dried
over sodium carbonate, filtered and concentrated to yield 3.27 g ( 84%) of desired product. 1H
NMR (DMSO- , 300 MHz) 12.3 (bs, 1H), 9.0 (s, 1H), 8.3 (d, 1H), 7.4 (d, 1H), 7.3 (s, 1H),
4.0 (s, 3H). LCMS m/z 177 (M+H).
. l-(2-Methoxy-ethyl)-l H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester
The title compound is prepared in a similar manner as Example 2B using lH-pyrrolo[3,2-
c]pyridine-2-carboxylic acid methyl ester as the starting material. 1H NMR (CDCI3, 300 MHz)
9.0 (s, 1H), 8.2 (bs, 2H), 8.4 (d, 1H), 7.4 (m, 2H), 4.7(t, 2H), 4.0 (s, 3H), 3.8 (t, 2H), 3.3 (s,
3H). LCMS m/z 235 (M+H).
C. l-(2-Methoxy-ethyl)-l H-pyrrolo[3,2-c]pyridine-2-carboxylic acid
To l-(2-methoxy-ethyl)-l H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (0.18 g,
0.77 mmol) MeOH (15 mL) is added 1 N NaOH (5 mL). The resulting solution is stirred at
room temperature overnight. The reaction mixture is acidified to pH= 2 with 1N HCl and is
washed with EtOAc. The aquous layer is lyopholized to dryness and the resulting solid
triturated with MeOH. The MeOH layer is concentrated in vacuo to yield 0.165 g (97%) of
desired product. 1H-NMR (CD3OD, 300 MHz) 13.2 (bs, 1H), 9.3(s, 1H), 8.4 (d, 1H), 8.2 (d,
1H), 7.8 (s, 1H), 4.95 (t, 2H), 3.8 (t, 2H), 3.2 (s, 3H). LCMS m/z 221 (M+H).
D. 2,2,2-Trifluoro -N-(4-fluoro-3-{l-[l-(2-methoxy-ethyl)-l H-pyrrolo[3,2-c]pyridine-2-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as Example 1C using l-(2-methoxyethyl)-
l H-pyrrolo[3,2-c]pyridine-2-carboxylic acid as the starting material.
1H NMR (CDC13, 300 MHz) 8.9 (s, 1H), 8.4 (d, 1H), 7.35 (d, 1H), 7.2 (m, 2H), 6.7 (s, 1H),
4.5 (m, 4H), 3.7 (t, 2H), 3.3 (s, 3H), 3.2 (m, 2H), 1.9 (m, 2H), 1.8 (m, 2H), 1.6 (bs, 4H).
LCMS m/z 507 (M+H).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]- [1-(2-methoxy-ethyl)- lH-pyrrolo [3,2-
c]pyridin-2-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as Example ID using 2,2,2-trifluoro-/V-(4-
fluoro-3-{l-[l-(2-methoxy-ethyl)-l H-pyrrolo[3,2-c]pyridine-2-carbonyl]-piperidin-4-yl}-
benzyl)-acetamide as the starting material.
1H NMR (OMSO-d6, 300 MHz) 9.35 (s, 1H), 8.6 (d, 1H), 8.4 (bs, 2H), 8.2 (d, H), 7.6 (d,
1H), 7.4 (m,l H), 7.3-7.1 (m, 2H), 4.65 (m, 3H), 4.0 (m, 5H), 3.6 (t, 2H), 3.2 (s, 3H), 3.0 (m,
H), 1.9 (m, 2H), 1.8 (m, 2H). LCMS m/z 4 11 (M+H).
EXAMPLE 5
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-(l H-pyrrolo[2,3-c]pyridin-3-yl)-methanone
dihydrochloride
A. 2,2,2-Trichloro-l-(l H-pyrrolo[2,3-c]pyridin-3-yl)-ethanone
To lH-pyrrolo[2,3-c]pyridine (5 g, 42.4 mmol) in CH2CI2 (150 mL) is added aluminum
chloride (42.4 g, 318 mmol). The reaction mixture is heated to 48 °C and trichloroacetyl
chloride (8.1 g, 44.5 mmol) is added dropwise. After heating for 2 h, the reaction mixture is
cooled to 0 °C and is quenched with 200 mL H20 and the resulting precipitate is isolated by
filtration to give 10 g of the desired product (89%). 1H NMR (OMSO-d6, 300 MHz) 9.3 (s,
1H), 9.25 (s, 1H), 8.6 (m, 2H). LCMS m/z 263 (M+H), 265.
B. lH-Pyrrolo[2,3-c]pyridine-3-carboxylic acid
A mixture of 2,2,2-trichloro-l-(l H-pyrrolo[2,3-c]pyridin-3-yl)-ethanone (6.7 g, 25.4 mmol)
and 6N NaOH (150 mL) is heated at reflux for 3 h and then 110 °C overnight. The reaction
mixture is diluted with H20 (200 mL), washed with CH2C 12 (2X) and acidified to pH= 2 with
cone. HC1. The aquous layer is lyopholized to dryness and the resulting solid triturated with
MeOH. The MeOH layer is concentrated in vacuo to yield 3.5g (85%) of desired product. 1HNMR
(DMSO- , 300 MHz) 10.0 (s, 1H), 8.9 (s, 1H), 8.35-8.25 (m, 2H), 8.2 (s, 1H), 8.0
(m, 1H). LCMS m/z 163 (M+H).
C. 2,2,2-Trifluoro -N-{4-fluoro-3-[l-(l H-pyiTolo[2,3-c]pyridine-3-carbonyl)-piperidin-4-yl]-
benzyl} -acetamide
The title compound is prepared in a similar manner as Example 1C using lH-pyrrolo[2,3-
c]pyridine-3-carboxylic acid as the starting material. 1H NMR (OMSO-d6, 300 MHz) 13.4
(s, 1H), 10.0 (m, 1H), 9.3 (bs, 1H), 8.6 (s, 1H), 8.4 (bs, 1H), 8.2 (bs, 1H), 7.3 (m, 1H), 7.2 (d,
2H), 4.4 (m, 3H), 3.2 (m, 3H), 1.8-1.6 (m, 5H). LCMS m/z 449 (M+H).
D. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]-(l H-pyrrolo[2,3-c]pyridin-3-yl)-
methanone dihydrochloride
To a solution 2,2,2-trifluoro -N-{4-fluoro-3-[l-(l H-pyrrolo[2,3-c]pyridine-3-carbonyl)-
piperidin-4-yl]-benzyl}-acetamide (0.58 g, 1.29 mmol) in MeOH (40 mL) and H20 (17 mL) is
added K2CO3 (1.79 g, 12.9 mmol). The reaction mixture is stirred overnight. The reaction is
partitioned between H20 and EtOAc washed with H20 and brine, dried over MgSC^, filtered,
and concentrated in vacuo. The residue is taken up in Et20 (10 mL) and 2.0 N HC1/ Et20 (15
mL, 30.0 mmol) is added. A solid precipitate forms and the ethereal solution is decanted off.
The solid is washed with additional Et20 and then isolated by filtration to give 0.2 g (40%) of
the desired product. 1H-NMR (DMSO- , 300 MHz) 13.5 (s, 1H), 9.2 (s, 1H), 8.6 (s, 1H),
8.5 (d, 1H), 8.4 (bs, 2H), 8.2 (d, 1H), 7.6 (m, 1H), 7.4 (m, 1H), 7.2 (m, 1H), 4.4 (bs, 1H), 4.0
(m, 2H), 3.2 (m, 3H), 1.85 (m, 2H), 1.7 (m, 2H), 1.2 (m, 1H). LCMS m/z 353 (M+H).
EXAMPLE 6
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[l-(2-methoxy-ethyl)-l H-pyrrolo[3,2-
b]pyridin-2-yl]-methanone dihydrochloride
A. l -(2-Methoxy-ethyl)- lH-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester
To a solution of lH-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester ( 1.34 g, 7.04 mmol) [prepared
according to the procedure by Lachance, N. et al. Synthesis 2005, 15, 257 1-2577] in N,Ndimethylacetamide
at rt is added sodium hydride (2 10 mg, 8.3 1 mmol). The resulting mixture is stirred
for 30 minutes at rt. 2-Bromoethylmethyl ether ( 1.4 mL, 14. 15 mmol) is added and the resulting
mixture is stirred at rt overnight. The mixture is diluted with water and EtOAc. The organic is
separated and the aqueous phase is extracted with EtOAc. The organic phase is washed with brine then
separated and dried (MgSO ). The organic phase is concentrated in vacuo and the crude residue is
flash chromatographed over Si0 2 (eluted with heptane:EtOAc = 85: 15) to afford 1.24 g (7 1%) of the
title compound as a yellow oil. NMR (CDC13, 300 MHz) 8.56 (m, 1H), 7.82 (d, 1H), 7.46 (s, 1H),
7.24-7.20 (m, 1H), 4.73 (m, 2H), 4.40 (m, 2H), 3.73 (m, 2H), 3.24 (m, 3H), 1.43 (m, 3H). LCMS m/z
249 (M+H).
l -(2-Methoxy-ethyl)-l H-pyrrolo[3,2-b]pyridine-2-carboxylic acid trifluoroacetate
To a solution of l-(2-methoxy-ethyl)-l H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester
(1.24 g, 5.00 mmol) in a mixture of THF:MeOH:H 20 (1:1:1) (30 mL) is added lithium
hydroxide hydrate (1.1 g, 26.12 mmol). The resulting mixture is stirred for one hour. The
mixture is acidified with 2 N HC1 to pH 2-3. The solvents are removed in vacuo and the
aqueous phase is flash freeze and lyophilized. The solid is flash chromatographed over reverse
phase (Ci8) (eluted with 10% MeCN/0.1%TFA in H20 to 100% MeCN on a 25 minutes ramp)
to afford 1.66 g (99% as a TFA salt) of the title compound as a white solid. 1H NMR (CD3OD,
300 MHz) 8.83 (d, 1H), 8.73 (d, 1H), 7.82 (dd, 1H), 7.48 (s, 1H), 5.00 (t, 2H), 3.77 (t, 2H),
3.22 (s, 3H). LCMS m/z 221 (M+H).
C. 2,2,2-Trifluoro -N-(4-fluoro-3- {1-[1-(2-methoxy-ethyl)- lH-pyrrolo[3,2-b]pyridine-2-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
To a solution of l-(2-methoxy-ethyl)-l H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (434 mg,
1.30 mmol) in dichloromethane (25 mL) and N,N-dimethylformamide ( 1 mL) is added l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295 mg, 1.54 mmol), 1-
Hydroxybenzotriazole (194 mg, 1.44 mmol) and triethylamine (550 , 3.93 mmol). The
resulting mixture is stirred for 20 minutes at rt. 2,2,2-trifluoro -N-(4-fluoro-3-piperidin-4-ylphenyl)-
acetamide hydrochloride (466 mg, 1.37 mmol) is added and heated at 40 °C
overnight. The mixture is poured into water and the organic layer separated. The aqueous
phase is extracted with EtOAc (x3). The organic phases are washed with brine then separated
and dried (MgS0 4) . The organic phase is concentrated in vacuo and the crude residue is flash
chromatographed over Si0 2 (eluted with MeOH:CH2Cl2 = 3:97) to afford 369 mg (56%) of
the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 8.40 (m, 1H), 8.03 (d,
1H), 7.32-7.28 (m, 2H), 7.22-7.17 (m, 1H), 7.09-7.02 (m, 1H), 6.80 (s, 1H), 4.56 (m, 2H),
4.43 (s, 2H), 4.32 (bs, 2H), 3.65 (m, 2H), 3.24 (s, 5H), 3.07-2.99 (m, 2H), 1.89-1.77 (m, 4H)
LCMS m/z 507 (M+H).
D. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]-[l -(2-methoxy-ethyl)- \Hpyrrolo[
3,2-b]pyridin-2-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as Example ID using 2,2,2-trifluoro -N-(4-
fluoro-3-{l-[l-(2-methoxy-ethyl)-l H-pyrrolo[3,2-b]pyridine-2-carbonyl]-piperidin-4-yl}-
benzyl)-acetamide as the starting material. 1H NMR (OMSO-d6, 300 MHz) 8.76-8.71 (m,
2H), 8.42 (bs, 3H), 7.70 (dd, 1H), 7.66-7.63 (m, 1H), 7.43-7.38 (m, 1H), 7.26-7.20 (m, 1H),
7.06 (s, 1H), 4.71-4.63 (m, 3H), 4.02-3.93 (m, 3H), 3.62 (t, 2H) 3.56 (s, 3H), 3.55-3.45 (m,
2H), 3.1 1-2.94 (m, H), 1.94-1.72 (m, 4H). LCMS m/z 4 11 (M+H).
EXAMPLE 7
[4-(3 -Aminomethyl-phenyl)-piperidin- 1-y1] -[1-(2-methoxy-ethyl)- lH-pyrrolo [3,2-b]pyridin-
2-yl]-methanone dihydrochloride
A. (3- {1-[1-(2-Methoxy-ethyl)-l H -pyrrolo[3,2-b]pyridine-2-carbonyl]-piperidin-4-yl} -
benzyl)-carbamic acid tert-but l ester
The title compound is prepared in a similar manner as Example 6C using l-(2-methoxy-ethyl)-l Hpyrrolo[
3,2-b]pyridine-2-carboxylic acid and (3-piperidin-4-yl-benzyl)-carbamic acid tert-butyl ester
as the starting materials. NMR (CD3OD, 300 MHz) 8.40 (d, IH), 8.02 (d, IH), 7.32-7.1 1 (m, 5H),
6.80 (s, IH), 4.55 (t, 2H), 4.22 (br s, 3H), 3.65 (t, 2H), 3.24 (s, 3H), 3.00-2.87 (m, 3H), 1.86-1.72 (m,
3H), 1.45 (br s, 9H), 1.39-1.29 (m, 2H), 0.87 (br s, IH). LCMS m/z 493 (M+H).
B. [4-(3 -Aminomethyl-phenyl)-piperidin- 1-yl] -[1-(2-methoxy-ethyl)- lH -pyrrolo [3,2-
b]pyridin-2-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as Example 3G using (3-{l-[l-(2-
methoxy-ethyl)-l H-pyrrolo[3,2-b]pyridine-2-carbonyl]-piperidin-4-yl}-benzyl)-carbamic acid
ter t-butyl ester as the starting material. 1H NMR (OMSO-d6, 300 MHz) 8.40 (d, 1H), 8.77-
8.71 (m, 2H), 8.40 (br s, 3H), 7.72 (dd, H), 7.48 (s, H), 7.41-7.31 (m, 3H), 7.08 (s, H), 4.64
(m, 2H), 4.00 (m, 3 H), 3.62 (t, 2H), 3.57 (s, 3H), 3.49 (m, H), 3.03-2.87 (m, H), 1.96-1.67 (m,
4H). LCMS m/z 393 (M+H).
EXAMPLE 8
[4-(3 -Aminomethyl-phenyl)-piperidin- 1-y1] -[1-(2-methoxy-ethyl)- lH-pyrrolo [2,3 -c]pyridin-3 -
yl]-methanone dihydrochloride
A. lH-Pyrrolo[2,3-c]pyridine-3-carboxylic acid methyl ester
To a solution of 2,2,2-trichloro-l-(l H-pyrrolo[2,3-c]pyridin-3-yl)-ethanone (7.8 g, 29.6
mmol) in 90 mL MeOH is added a 30% wt solution NaOMe/MeOH (10 mL, 177 mmol). The
reaction mixture is stirred for 2h and is then concentrated in vacuo. The residue is taken up in
EtOAc, washed with H20 and brine, dried over MgSC^, filtered, and concentrated in vacuo to
yield 4g (77%) of desired product. 1H NMR (CDC13, 300 MHz) 8.85 (s, 1H), 8.4 (d, 1H),
8.1 (m, 2H), 3.95 (s, 3H). LCMS m/z 177 (M+H).
B. l-(2-Methoxy-ethyl)-l H-pyrrolo -c]pyridine-3-carboxylic acid methyl ester
The title compound is prepared in a similar manner as Example 2B using lH-pyrrolo[2,3-
c]pyridine-3-carboxylic acid methyl ester as the starting material. 1H NMR (CDCI3, 300 MHz)
8.8 (s, 1H), 8.4 (m, 1H), 8.0 (m, 2H), 4.4 (t, 2H), 3.9 (s, 3H), 3.75 (t, 2H), 3.3 (s, 3H).
LCMS m/z 235 (M+H).
C. l-(2-Methoxy-ethyl)-l H-pyrrolo[2,3-c]pyridine-3-carboxylic acid
To l-(2-methoxy-ethyl)-l H-pyrrolo[2,3-c]pyridine-3-carboxylic acid methyl ester (2 g, 8.5
mmol) in MeOH (25 mL) is added IN NaOH (31 mL). The resulting solution is stirred at
room temperature overnight. The reaction mixture is acidified to pH= 3 with 1N HCl and is
concentrated in vacuo to remove the MeOH. A solid precipitate forms and is isolated by
filtration to give 1.64g (88% yield) of desired product. 1H-NMR (OMSO-d6, 300 MHz) 13.0
(bs, 1H), 9.5 (s, 1H), 8.8 (s, 1H), 8.5 (d, 1H), 8.4 (d, 1H), 4.7 (t, 2H), 3.8 (t, 2H), 3.2 (s, 3H).
GMS m/z 221 (M+H).
D. (3- {1-[1-(2-Methoxy-ethyl)- lH-pyrrolo[2,3-c]pyridine-3-carbonyl]-piperidin-4-yl} -
benzyl)-carbamic acid tert-butyl ester
The title compound is prepared in a similar manner as Example 1C using l-(2-methoxyethyl)-
l H-pyrrolo[2,3-c]pyridine-3-carboxylic acid and (3-piperidin-4-yl-benzyl)-carbamic
acid tert-butyl ester as the starting materials. The material is used in the next step without
further purification.
E. r4-(3-Aminomethyl-phenyl)-piperidin- 1--1-(2-methoxy-ethyl)- lH-pyrrolor2,3-
clpyridin-3-vU-methanone dihydrochloride
A solution of (3-{l-[l-(2-methoxy-ethyl)-lh-pyrrolo[2,3-c]pyridine-3-carbonyl]-piperidin-4-
yl}-benzyl)-carbamic acid tert-butyl ester (0.896g, 1.82 mmol) in a saturated HCl / EtOAc
solution (30 mL) is stirred at room temperature for 4h. The resulting precipitate is isolated by
filtration to give 0.77 g (98%) of desired product. 1H NMR (OMSO-d6, 300 MHz) 9.5 (s,
1H), 8.8 (s, 1H), 8.45 (d, H), 8.4 (bs, 2H), 8.2 (d, 1H), 7.45(s, 1H), 7.35 (m, 3H), 4.7(t, 2H),
4.0 (m, 2H), 3.75 (t, 2H), 3.4 (m, 4H), 3.2 (s, 3H), 2.9 (m, 1H), 1.9 (m, 2H), 1.75(m, 2H).
LCMS m/z 393 (M+H).
EXAMPLE 9
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[l-(2-methoxy-ethyl)-l H-pyrrolo[2,3-
c]pyridin-3-yl]-methanone dihydrochloride
A. 2,2,2-Trifluoro -N-(4-fluoro-3- {1-[1-(2-methoxy-ethyl)- lH-pyrrolo[2,3-c]pyridine-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as Example 1C using 1-(2-methoxyethyl)-
lH-pyrrolo[2,3-c]pyridine-3-carboxylic acid as the starting material. 1H-NMR (CDC13,
300 MHz) 9.4 (s, 1H), 8.35 (d, 1H), 8.15 (d, 1H), 8.1 (s, H), 7.2 (m, 2H), 7.1 (m, 1H), 6.7
(bs, IH), 6.7 (bs, IH), 4.5 (m, 6H), 3.8 (t, 2H), 3.3 (s, 3H), 3.2 (m, 3H), 2.0 (m, 2H), 1.8 (m,
2H). LCMS m/z 507 (M+H)
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]-[ 1-(2-methoxy-ethyl)- \Hpyrrolo[
2,3-c]pyridin-3-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as Example 5D using 2,2,2-trifluoro -N-(4-
fluoro-3- {1-[1-(2-methoxy-ethyl)-l H-pyrrolo[2,3-c]pyridine-3-carbonyl]-piperidin-4-yl} -
benzyl)-acetamide as the starting material. 1H-NMR (DMSO- , 300 MHz) 9.4 (s, IH), 8.5
(s, IH), 8.4 (d, IH), 8.35 (m, 2H), 8.1 (d, IH), 7.6 (d, IH), 7.4 (m, IH), 7.2 (m, IH), 4.7 (t,
2H), 4.4 (bs, IH), 4.0 (m, 2H), 3.4 (m, 2H), 3.8 (t, 2H), 3.2 (s, 3H), 3.1 (m, 2H), 1.8 (m, 2H),
1.7 (m, 2H). LCMS m/z 4 11 (M+H).
EXAMPLE 10
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[3,2-
c]pyridin-3-yl]-methanone dihydrochloride
A. 3-Iodo-l H -pyrrolo[3,2-c]pyridine
The title compound is prepared according to the procedure by Lefoix, M. et al. Synthesis
2005, 20, 3581-3588, 1H NMR (CD 3OD, 300 MHz) 8.54 (s, 1H), 8.20 (d, 1H), 7.21 (s,
7.42 (d, 1H). LCMS m/z 245 (M+H).
B. 3-Iodo- 1-(2-methoxy-ethyl)- lH -pyrrolo[3,2-c]pyridine
The title compound is prepared in a similar manner as Example 6A using 3-iodo-l H-pyrrolo[3,2-
c]pyridine as the starting material. NMR (CDC13, 300 MHz) 8.70 (m, 1H), 8.37 (d, 1H), 7.27 (s,
1H), 7.20 (m, 1H), 4.26 (t, 2H), 3.68 (t, 2H), 3.31 (s, 3H). LCMS m/z 303 (M+H).
C. l-(2-Methoxy-ethyl)-l H -pyrrolo[3,2-c]pyridine-3-carboxylic acid
The title compound is prepared in a similar manner according to the procedure by Lefoix, M. et al.
Synthesis 2005, 20, 3581-3588 using 3-iodo-l -(2-methoxy-ethyl)- lH-pyrrolo[3,2-c]pyridine as the
starting material. ¾ NMR (CD3OD, 300) 9.35 (s, 1H), 8.23 (d, 1H), 7.95 (s, 1H), 7.62 (d, 1H),
4.43 (t, 2H), 3.74 (t, 2H), 3.31 (s, 3H). LCMS m/z 221 (M+H).
D. 2,2,2-Trifluoro -N-(4-fluoro-3- {1-[1-(2-methoxy-ethyl)- lH-pyrrolo[3,2-c]pyridine-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as Example 6C using l-(2-methoxyethyl)-
l H-pyrrolo[3,2-c]pyridine-3-carboxylic acid as the starting material. This material is
used in the next step without further purification.
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]-[ 1-(2-methoxy-ethyl)- \Hpyrrolo[
3,2-c]pyridin-3-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as Example ID using 2,2,2-trifluoro-N-(4-fluoro-3-
{1-[1 -(2-methoxy-ethyl)- lH-pyrrolo[3,2-c]pyridine-3-carbonyl]-piperidin-4-yl} -benzyl)-acetamide as
the starting material. NMR (OMSO-d6, 300 MHz) 8.44 (br s, 3H), 8.35 (s, 1H), 8.23 (br s, 1H),
7.63 (m, 1H), 7.41-7.37 (m, 1H), 7.26-7.19 (m, 1H), 6.1 1 (m, 1H), 6.02 (m, H), 4.62 (t, 2H), 4.45 (br s,
H), 4.00 (m, 2H), 3.74 (t, 2H) 3.22 (s, 3H), 3.08-2.97 (m, 4H), 1.91-1.67 (m, 4H). ) . LCMS m/z 4 11
(M+H).
EXAMPLE 11
[4-(5 -Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl] -[7-(2-methoxy-ethoxy)- 1-(2-methoxyethyl)-
lH-pyrrolo[2,3-c]pyridin-3-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as Example 5A using 7-methoxy-l Hpyrrolo[
2,3-c]pyridine as the starting material. 1H NMR (OMSO-d6, 300 MHZ) 13.4 (bs,
1H), 11.5 (bs, 1H), 8.2 (s, 1H), 7.2 (m, 1H), 7.0 (d, 1H). LCMS m/z 279 (M+H).
B. 7-Hydroxy-l H-pyrrolo[2,3-c]pyridine-3-carboxylic acid methyl ester
The title compound is prepared in a similar manner as Example 8A using 2,2,2-trichloro-l-(7-
hydroxy-l H-pyrrolo[2,3-c]pyridin-3-yl)-ethanone as the starting material. 1H NMR (DMSOd6,
300 MHz) 12.8 (bs, 1H), 11.2 (bs, 1H), 7.8 (s, 1H), 7.0 (m, 1H), 6.8 (d, 1H), 3.8 (s, 3H).
LCMS m/z 193 (M+H).
C. 7-(2-Methoxy-ethoxy)- 1-(2-methoxy-ethyl)- lH-pyrrolo[2,3-c]pyridine-3-carboxylic acid
methyl ester
To 7-hydroxy-l H-pyrrolo[2,3-c]pyridine-3-carboxylic acid methyl ester (0.63 g, 3.28 mmol)
in DMF (10 mL) under Ar is added NaH (0.26 g, 6.60 mmol). The reaction mixture is stirred
for 10 min and 2- methoxyethyl bromide (1.23 mL, 13.12 mmol) is added. The reaction is
stirred at room temperature overnight. The reaction mixture is poured into EtOAc and the
organic layer washed with H20 (2X) water, brine, dried with MgSC^, filtered and
concentrated in vacuo to give the crude product. Purification by flash chromatography on Si0 2
eluting with 100% EtOAc gives 0.74 g (73%) of the desired product. 1H NMR (CDC13, 300
MHz) 7.75 (s, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 4.7 (t, 2H), 4.2 (t, 2H), 3.9 (s, 3H), 3.75 (t, 2H),
3.65 (t, 2H), 3.3(d, 6H). LCMS m/z 309 (M+H).
D. 7-(2-Methoxy-ethoxy)-l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-c]pyridine-3-carboxylic acid
To 7-(2-methoxy-ethoxy)-l-(2-methoxy-ethyl)-l H-pyrrolo[2,3-c]pyridine-3-carboxylic acid
methyl ester (0.59 g, 1.92 mmol) in MeOH (20 mL) is added IN NaOH (20 mL). The
resulting solution is stirred at room temperature overnight. The reaction mixture is acidified
to pH= 3 with IN HC1 and is concentrated in vacuo to remove the MeOH. The aquous layer
is lyopholized to dryness and the resulting solid is triturated with H20 to yield 0.50 g (86%) of
desired product. 1H NMR (OMSO-d6, 300 MHz) 12.3 (s, 1H), 7.8(s, 1H), 7.3 (d, 1H), 6.8
(d, 1H), 4.6 (t, 2H), 4.1 (t, 2H), 3.7 (t, 2H), 3.6 (t, 2H), 3.2 (d, 6H). LCMS m/z 295 (M+H).
E. 2,2,2-Trifluoro -N-(4-fluoro-3- {1-[7-(2-methoxy-ethoxy)- 1-(2-methoxy-ethyl)- \Hpyrrolo[
2,3-c]pyridine-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as Example 1C using 7-(2-methoxyethoxy)-
l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-c]pyridine-3-carboxylic acid as the starting
material. 1H NMR (CDC13, 300 MHz) 7.4 (s, 1H), 7.15 (m, 2H), 7.05 (m, 2H), 6.65 (d, 1H),
6.55 (bs,lH), 4.75 (t, 2H), 4.6 (bs, 1H), 4.45 (m, 3H), 4.2 (t, 2H), 3.75 (t, 2H), 3.7 (t, 2H), 3.3
(s, 6H), 3.1 (m, 3H), 1.9 (m, 2H), 1.8 (m, 2H). LCMS m/z 581 (M+H).
F. [4-(5-Aminomethyl-2-fl uoro-phenyl)-piperidm
ethyl)- lH-pyrrolo[2,3-c]pyridin-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as Example 5D using 2,2,2-trifluoro -N-(4-
fluoro-3- {1-[7-(2-methoxy-ethoxy)-l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-c]pyridine-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide as the starting material. 1H NMR (DMSO-J^,
300 MHz) 8.2 (bs, 2H), 7.7 (s, 1H), 7.5 (m, 1H), 7.35 (m, 1H), 7.2 (m, 2H), 7.1 (m, 1H),
6.5 (d, 1H), 4.7 (t, 2H), 4.4 (bs, 2H), 4.15 (t, 2H), 4.0 (m, 2H), 3.7 (t, 2H), 3.6 (t, 2H), 3.2 (d,
6H), 3.1 (m, 3H), 1.8 (m, 2H), 1.7 (m, 2H). LCMS m/z 485 (M+H).
EXAMPLE 12
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[ 1-(2-methoxy-ethyl)-7-methyl- \Hpyrrolo[
3,2-b]pyridin-3-yl]-methanone dihydrochloride
A. 7-Methyl-l H-pyrrolo[3,2-b]pyridine
The title compound is prepared according to the following procedure: Journal of Organic
Chemistry 2002, 67(7), 2345-2347. 1H NMR (DMSO-d6, 300 MHz) 11.4 (bs, 1H), 8.2 (d,
1H), 7.6 (d, 1H), 6.9 (d, 1H), 6.5 (d, 1H), 3.3 (s, 3H). LCMS m/z 133 (M+H).
B. 3-Iodo-7-methyl-l H-pyrrolo[3,2-b]pyridine
To a solution of 7-methyl-l H-pyrrolo[3,2-b]pyridine (0.50 g, 3.79 mmol) in THF (30 mL) is
added N-iodosuccinimide (0.34 g, 4.2 mmol). The reaction mixture is stirred for 2 h and is
concentrated in vacuo. Purification by flash chromatography on Si0 2 eluting with 50%
EtOAc/heptane gives 0.92 g (94%) of the desired product. 1H NMR (DMSO- , 300 MHz) 
11.9 (bs, 1H), 8.2 (d, 1H), 7.8 (s, 1H), 7.0 (d, 1H), 6.5 (d, 1H), 3.3 (s, 3H). LCMS m/z 259
(M+H).
C. 3-Iodo-l-(2-methoxy-ethyl)-7-methyl-l H-pyrrolo[3,2-b]pyridine
A mixture of powder KOH ( 1.74 g, 31 mmol) in DMSO (60 mL) is stirred at room
temperature for 10 min. 3-Iodo-7-methyl-lH-pyrrolo[3,2-b]pyridine (2.00 g, 7.75 mmol) is
added. The reaction mixture is stirred for l h and then 2-methoxyethyl bromide (1.46 mL, 15.5
mmol) is added. After 3h the reaction mixture is poured into EtOAc and the organic layer
washed with H20 (2X), brine, dried with MgSC^, filtered and concentrated in vacuo.
Purification by flash chromatography on Si0 2 eluting with 50% EtOAc/heptane gives 1.93 g
(79%) of the desired product. 1H NMR (CDC13, 300 MHz) 8.4 (d, 1H), 7.4 (s, 1H), 6.9 (d,
1H), 4.45 (t, 2H), 3.65 (t, 2H), 3.3 (s, 3H), 2.7 (s, 3H). LCMS m/z 317 (M+H).
D. l-(2-Methoxy-ethyl)-7-methyl-l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid trifluoro-acetic
acid salt
The title compound is prepared in a similar manner as Example IOC using 3-iodo-l-(2-
methoxy-ethyl)-7-methyl-lH-pyrrolo[3,2-b]pyridine as the starting material. 1H NMR
(DMSO- ) 8.7 (s, 1H), 8.5 (d, 1H), 7.6 (d, 1H), 4.75 (t, 2H), 3.75 (t, 2H), 3.2 (s, 3H), 2.95
(s, 3H). LCMS m/z 235 (M+H).
E. 2,2,2-Trifluoro -N-(4-fluoro-3- {1-[1-(2-methoxy-ethyl)-7-methyl- lH-pyrrolo[3,2-
b]pyridine-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as Example 1C using l-(2-methoxy
ethyl)-7-methyl-l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid trifiuoroacetic acid salt
as the starting material. 1H NMR (CDC13, 300 MHz) 8.4 (d, IH), 7.8 (s, IH), 7.25-7.1 (m,
2H), 7.0 (m, IH), 6.9 (d, IH), 6.7 (bs, H), 4.5 (m, 4H), 3.75 (t, 2H), 3.3 (s, 3H), 3.15 (m, 2H),
2.7 (s, 3H), 1.9-1.75(m, 4H), 1.6 (m, 3H). LCMS m/z 521 (M+H).
D. [4-(5 -Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl] -[1-(2-methoxy-ethyl)-7-methyl- 1
pyrrolo[3,2-b]pyridin-3-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as Example 5D using 2,2,2-trifluoro -N-(4-
fluoro-3- {1-[1-(2-methoxy-ethyl)-7-methyl- lH-pyrrolo[3,2-b]pyridine-3-carbonyl]-piperidin-
4-yl}-benzyl)-acetamide as the starting material. 1H NMR (OMSO-d6, 300 MHz) 8.6 (m,
2H), 8.4 (bs, 2H), 7.6 (m, 2H), 7.4 (m, IH), 7.2 (m, IH), 4.7 (t, 2H), 4.0 (m, 2H), 3.7 (t, 2H),
3.6-3.3 (m, 4H), 3.2 (m, 4H), 3.0 (s, 3H), 2.0-1.8 (m, 4H). LCMS m/z 425 (M+H).
EXAMPLE 13
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[7-chloro- 1-(2-methoxy-ethyl)- \Hpyrrolo[
2,3-c]pyridin-3-yl]-methanone dihydrochloride
A. 7-Chloro- lH-pyrrolo[2,3-c]pyridine
To a 1L three-necked flask under nitrogen is added commercially available vinylmagnesium
bromide solution ( 1 M in THF, 500 mL, 500 mmol). At 0 °C a solution of of 2-chloro-3-nitropyridine
(25 g, 160 mmol) in THF (100 mL) is added dropwise via addition funnel over 40
minutes. After stirring an additional 40 minutes at 0 °C the reaction is quenched with aqueous
saturated NH4C 1 solution and extracted with EtOAc. The combined organic layers are dried
over MgS0 4, filtered and concentrated in vacuo. The crude material is passed through a plug
of silica gel with CH2Cl2/heptanes (33%) as eluant to give a solid that is recrystallized from
CH2Cl2/heptanes to deliver 6.9 g (28%) of the titled product as a beige solid mp 182- 185 0 C.
1H NMR (CDCI3) 8.60 (br s, 1H), 8.05 (m, 1H), 7.50 (m, 1H), 7.42 (m, 1H), 6.64 (m, 1H).
LCMS m/z 153 (M+H).
B. 7-Chloro- 1-(2-methoxy-ethyl)- lH-pyrrolo[2,3-c]pyridine
To a 0 °C solution of 7-chloro-l H-pyrrolo[2,3-c]pyridine (1.3 g, 8.5 mmol) in DMF (40 mL)
under nitrogen is added sodium hydride (60% suspension in oil, 0.51 g, 12.8 mmol). After
stirring for 10 minutes at 0 °C, 1- bromo-2-methoxy-ethane (1.8 g, 12.8 mmol) is added
followed by a catalytic amount of Na After stirring an additional 2h at 0 °C the reaction is
quenched with aqueous saturated NaHC0 3 solution and extracted with EtOAc. The combined
organic layers are dried over MgS0 4, filtered and concentrated in vacuo. The crude material
is purified on silica gel with 30%> EtOAc /heptanes as eluant to deliver the titled compound as
a clear colorless oil 1.66 g (93%). 1H NMR (CDC13) 7.98 (d, J = 5.4 Hz, 1H), 7.45 (d, J =
5.4 Hz, 1H), 7.31 (d, J = 3.1 Hz, 1H), 6.52 (d, J = 3.1 Hz, 1H), 4.72 (t, J = 5.1 Hz, 2H), 3.76
(t, J = 5.1 Hz, 2H), 3.30 (s, 3H). LCMS m/z 2 11 (M+H).
C. 1-[7-Chloro- 1-(2-methoxy-ethyl)- -pyrrolo[2,3-c]pyridin-3-yl]-2,2,2-trifluoro-ethanone
To a 0 C solution of -7-chloro-l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-c]pyridine (1.5 g, 7.1
mmol) in DMF (10 mL) under nitrogen is added trifluoracetic anhydride (4.5 g, 21.3 mmol).
After stirring for 2 h at 0 °C, an additional trifluoracetic anhydride (4.5 g, 21.3 mmol) is added
and the reaction allowed towarm to rt overnight. At 0 °C the reaction is quenched with
aqueous saturated NaHC0 3 solution and extracted with EtOAc. The combined organic layers
are dried over MgSC^, filtered and concentrated in vacuo. The crude material is recrystallized
from CH2Cl2/heptanes to deliver 1.75 g (80%) as a first crop of the titled product as a beige
solid mp 110-1 12 °C. 1H NMR (CDC13) 8.27 (s, 2 H), 8.09 (s, 1H), 4.82 (t, J = 5.1 Hz, 2H),
3.81 (t, J = 5.1 Hz, 2H), 3.32 (s, 3H). LCMS m/z 307 M+H).
D. 7-Chloro- 1-(2-methoxy-ethyl)- lH-pyrrolo[2,3-c]pyridine-3-carboxylic acid
To a mixture of l-[7-chloro-l-(2-methoxy-ethyl)-l H-pyrrolo[2,3-c]pyridin-3-yl]-2,2,2-
trifluoro-ethanone (1.0 g, 3.27 mmol) in THF (5 mL) and H20 (25 mL) is added lithium
hydroxide ( 1.4 g, 32.7 mmol). After refluxing the mixture for 1.5 h the reaction is cooled to rt
and extracted with Et20 . The aqueous later is acidified with aqueous 10% HCl and extracted
with hot EtOAc. The combined organic layers are dried over MgSC^, filtered and
concentrated in vacuo. The crude material is recrystallized from EtOAc/MeOH to deliver
0.76 g (91%) of the titled compound as a white powder mp 210-203 0 C. 1H NMR (DMSOd6)
12.55 (s, 1H), 8.28 (s, 1H), 8.07 (m, 1H), 7.97 (m, 1H), 4.78 (t, J =5.1 Hz, 2H), 3.73 (t,
J = 5.1 Hz, 2H), 3.32 (s, 3H). LCMS m/z 255 (M+H).
E. N-(3- {1-[7-Chloro- 1-(2-methoxy-ethyl)- lH-pyrrolo[2,3-c]pyridine-3-carbonyl]-piperidin-
4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide
To a mixture of 7-chloro-l-(2-methoxy-ethyl)-l H-pyrrolo[2,3-c]pyridine-3-carboxylic acid
(0.22 g, 0.86 mmol) in THF (10 mL) under nitrogen is added carbonyl diimidazole (0.17, 1.04
mmol). After stirring 6h at ambient temperature 2,2,2-trifluoro -N-(4-fluoro-3-piperidin-4-ylbenzyl)-
acetamide (0.52 g, 1.73 mmol) is added and the reaction is stirred overnight. The
reaction is quenched with aqueous 10% HC1 solution and extracted with EtOAc. The
combined organic layers are washed with aqueous saturated NaHC0 3 solution, dried over
MgS0 4, filtered and concentrated in vacuo to deliver 0.36g (77%) of the titled compound as a
white foam. 1H NMR (CDC13) 8.10 (m, 1H), 7.66 (m, 1 H), 7.61 (m, 1H), 7.10 (m, 4H),
6.50 (br s, 1H), 4.76 (m, 2H), 4.51 (m, 5H), 3.78 (m, 2H), 3.31 (s, 3H), 3.16 (m, 1H), 1.92 (m,
1H) 1.75 (m, 1H). LCMS m/z 541 (M+H).
F. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[7-chloro-l-(2-methoxy-ethyl)-l Hpyrrolo[
2,3-c]pyridin-3-yl]-methanone dihydrochloride
To a mixture of N-(3-{l-[7-chloro-l-(2-methoxy-ethyl)-l H-pyrrolo[2,3-c]pyridine-3-
carbonyl]-piperidin-4-yl}-4-fluoro-benzyl)-2,2,2-trifluoro-acetamide (0.5 g, 0.92 mmol) in (30
mL) and H20 (15 mL) is added of Na2C0 3 (0.98 g, 9.2 mmol). After heating 40 min on a
steam bath the mixture is concentrated in vacuo and extracted with EtOAc/H 20 . The
combined organic layers are dried over MgSC^, filtered and concentrated in vacuo. The crude
material is passed through a plug of silica gel (EtOAc eluant) to remove baseline material.
This material is treated with methanolic HC1. This mixture is concentrated in vacuo. The
resulting hydrochloride salt is recrystallized from MeOH/EtOAc to deliver 0.25g (57%) of the
titled compound as a white powder mp 163-167 0 C. 1H NMR (DMSO- ) 8.23 (m, 3H),
8.04 (m, 1H), 7.70 (m, 1H), 7.56 (m, 1H), 7.38 (m, 1H), 7.26 (m, 1H), 4.78 (m, 2H), 4.40-4.00
(m, 7H), 3.99 (m, 2H), 3.23 (s, 3H), 3.17 (m, 2H), 1.83 (m, 1H) 1.72 (m, 1H). LCMS m/z
445 (M+H).
EXAMPLE 14
[4-(5 -Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl] -[1-(2-methoxy-ethyl)-7-methyl-
1H-pyrrolo [2,3-c]pyridin-3 -y1] -methanone
A. 2,2,2-Trifluoro- 1-[1-(2-methoxy-ethyl)-7-methyl-l H-pyrrolo[2,3-c]pyridin-3-yl]-ethanone
To a mixture of l-[7-chloro-l-(2-methoxy-ethyl)-l H-pyrrolo[2,3-c]pyridin-3-yl]-2,2,2-
trifluoro-ethanone (1.40 g, 4.57 mmol) in dioxane (40 mL) under nitrogen is added
methylboronic acid (0.83, 13.7 mmol), K2CO3 (1.90 g, 13.7 mmol) and
tetrakis(triphenylphosphine)palladium (0) (0.21 g, 0.18 mmol). After refluxing the reaction
5h silica gel was is added and the mixture concentrated in vacuo. The resulting powder was
added to the top of a silica plug and eluted with EtOAc. Appropriate fractions are
concentrated to give a solid which is recrystallized from CH2Cl2/heptanes to deliver 1.20 g
(92%) of the titled product as a beige solid mp 125-127 0 C.) 1H NMR (CDC13) 8.39 (m, 1
H), 8.18 (m, 1H), 8.05 (m, 1H), 4.64 (t, J = 5.1 Hz, 2H), 3.77 (t, J = 5.1 Hz, 2H), 3.33 (s, 3H),
2.94 (s, 3H). LCMS m/z 287 (M+H).
B. l-(2-Methoxy-ethyl)-7-methyl-l -pyrrolo[2,3-c]pyridine-3-carboxylic acid
A suspension of 2,2,2-trifluoro-l-[l-(2-methoxy-ethyl)-7-methyl-l H-pyrrolo[2,3-c]pyridin-3-
yl]-ethanone (0.70 g, 2.40 mmol) in 6 N NaOH solution (6 mL) is heated to reflux for 15
minutes. The resulting clear solution is cooled to 0 °C and acidified with 10%> aqueous HCl.
This mixture is concentrated in vacuo. The resulting crude product is passed through a silica
gel plug (3% AcOH/20% MeOH/CH 2Cl2 as eluant). Concentration in vacuo delivers 0.33 g
(59%) of the titled compound as a white powder mp 215-225 0 C. 1H NMR (DMSO- ) 
8.02 (m, 1 H), 7.92 (m, 1H), 7.88 (m, 1H), 4.60 (t, J =5.3 Hz, 2H), 3.68 (t, J =5.3 Hz, 2H),
3.22 (s, 3H), 1.88 (s, 3H). LCMS m/z 235 (M+H).
C. 2,2,2-Trifluoro -N-(4-fluoro-3- {1-[1-(2-methoxy-ethyl)-7-methyl- lH-pyrrolo[2,3-
c]pyridine-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
To a mixture of l-(2-methoxy-ethyl)-7-methyl-l H-pyrrolo[2,3-c]pyridine-3-carboxylic acid
(0.50 g, 2.1 mmol) in THF (15 mLO under nitrogen is added carbonyl diimidazole (0.69 g,
4.27 mmol). After stirring l h at ambient temperature 2,2,2-trifluoro -N-(4-fluoro-3-piperidin-
4-yl-benzyl)-acetamide (2.6 g, 8.5 mmol) is added and the reaction is heated to reflux
overnight. The reaction is quenched with saturated aqueous NH4C 1 solution and extracted
with EtOAc. The combined organic layers are dried over MgSC^, filtered and concentrated in
vacuo. The crude product is purified on silica gel (2.5% MeOH/CH 2Cl2 eluant) to deliver
0.36g (77%) of the titled compound as a white foam. 1H NMR (CDC13) 8.21 (m, 1H), 7.52
(m, 1H), 7.2-7.0 (m, 4H), 6.62 (br s, 1H), 4.58 (m, 2H), 4.49 (m, 6H), 3.73 (m, 2H), 3.31 (s,
3H), 3.10 (m, 2H), 2.93 (s, 3H), 1.9-1.6 (m, 3H). LCMS m/z 521 (M+H).
D. [4-(5 -Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl] -[1-(2-methoxy-ethyl)-7-methyllH-
pyrrolo[2,3-c]pyridin-3-yl]-methanone
To a mixture of 2,2,2-trifluoro -N-(4-fluoro-3-{l-[l-(2-methoxy-ethyl)-7-methyl-l Hpyrrolo[
2,3-c]pyridine-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (0.42 g, 0.81 mmol) in
MeOH (8 mL) and H20 (2 mL) is added of aqueous 50% NaOH solution (1.0 mL). After
stirring at ambient temperature for l h the mixture is concentrated in vacuo, diluted with
MeOH and adsorbed onto silica gel. This material is purified on silica gel (CH2C 12, 5%MeOH/
CH2CL2 and finally 5% 7N NH3/MeOH: 95% CH2C 12 as eluant). Concentration of
appropriate fractions delivers 0.25g (73%) of the titled compound as a white foam. 1H NMR
(CDC13) 8.22 (m, 1H), 7.68 (m, 1H), 7.59 (m, 2H), 7.26-6.96 (m, 4H), 4.58 (m, 3H), 3.85
(m, 2H), 3.73 (m, 2H), 3.31 (s, 3H), 3.10 (m, 3H), 2.93 (s, 3H), 1.90-1.60 (m, 5H). LCMS
m/z 425 (M+H).
EXAMPLE 15
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[7-methoxy- 1-(2-methoxy-ethyl)- \Hpyrrolo[
3,2-b]pyridin-3-yl]-methanone dihydrochloride
A. 4-Methoxy-3-nitro-pyridine
To cone. H2SO4 (5 mL) chilled in an ice bathm is added 4-methoxypyridine (0.5 mL, 4.9
mmol) dropwise over a 20 s period. Cone. Fuming nitric acid (5 mL) is added, and the
reaction mixture is heated at 70 °C for 2.5 days. This mixture is cooled to rt, and then is
poured into ice. Soild K2CO3 is added until the pH of the mixture is basic. The mixture is
partitioned between H20 and EtOAc. The two layers is separated, and the aqueous layer is
extracted with EtOAc once. The combined organic layers are washed with H2O and brine,
dried over MgS0 4, filtered, and concentrated in vacuo to yield 0.7 g (92%) of the product a
yellow powder. 1H NMR (CDC13, 300 MHz) 9.02 (s, 1H), 8.65 (d, J = 5.8, 1 H), 7.04 (d, J
= 5.9, 1H), 4.05 (s, 3H). LC Rt: 0.5 min; LCMS m/z 155 (M+l, 100%).
B. 4-Methoxy-pyridin-3-ylamine
A mixture of 4-methoxy-3-nitro-pyridine (19.2 g, 0.13 mol) and Pd/C (10%, 1.5 g) in MeOH
(150 mL) is hydrogenated at 40 psi for 5 h or until no more ¾ is consumed. The mixture is
filtered through Celite, and the filtrate is concentrated in vacuo. The residue is dissolved in
CH2CI2, and the resulting solution is dried over MgS0 4, filtered, and concentrated in vacuo to
yield 15.0 g of the product as a yellow liquid. 1H NMR (CDC13, 300 MHz) 8.00 (s, 1H),
7.98 (d, J = 5.5, 1H), 6.70 (d, J =5.4, 1H) 3.90 (s, 3H), 3.71 (br s, 2H). LC Rt: 0.57 min;
LCMS m/z 125 (M+l, 100%).
C. 2-Bromo-4-methoxy-pyridin-3 -ylamine
To a solution of 4-methoxy-pyridin-3-ylamine (6.76 g, 54.5 mmol) in cone. HC1 (50 mL) is
added Br2 (3.36 mL, 65.4 mmol) dropwise over a 30 s period. This mixture is stirred at rt for
1 h,and then heated at 55 °C overnight. The mixture is cooled to rt, and then poured into ice.
Cone. NH4OH is added until the pH of the solution is basic. The resulting suspension is
partitioned between H20 and EtOAc. The two layers are separated, and the aqueous layer is
extracted with EtOAc (2X). The combined organic layers are washed with H20 and brine,
dried over MgS0 4, filtered, and concentrated in vacuo. The crude material is purified on
silica gelwith EtOAc/MeOH (lOO/o to 80/20) as elant to yield 9.18 g (82%) of the product as a
white powder. 1H NMR (CDC13, 300 MHz) 7.75 (d, J =5.3, 1H), 6.68 (d, J
(br s, 2H), 3.91 (s, 3H). LC Rt: 0.89 min; LCMS m/z 203 (M+l, 100%).
D. (2-Bromo-4-methoxy-pyridin-3-yl)-carbamic acid ethyl ester
To a solution of 2-bromo-4-methoxy-pyridin-3-ylamine (540 mg, 2.66 mmol) in pyridine (20
mL) at 0 °C is added ethyl chloroformate (0.38 mL, 3.99 mmol). After 30 min, more
chloro formate is added (~18 mmol) is added until the reaction goes to completion. The
mixture is partitioned between sat. NaHC0 3 and EtOAc. The two layers are separated, and the
aqueous layer is extracted with EtOAc once. The combined organic layers are washed with
H20 and brine, dried over MgS0 4, filterd, and concentrated in vacuo. The crude material is
purified on silica gel with EtOAc/MeOH (100/0 to 90/10) as eluant to yield 0.54 g of the
product as a white crystalline solid. 1H NMR (CDC13, 300 MHz) 8.18 (d, J =5.6, 1H), 6.84
(d, J = 5.7, 1H), 6.02 (br s, 1H), 4.23 (q, J = 7.0, 2H), 3.92 (s, 3H), 1.31 (t, J = 7.2, 3H). LC
Rt: 1.89 min; LCMS m/z 275 (M+l, 100%).
E. (4-Methoxy-2-trimethylsilanylethynyl-pyridin-3-yl)-carbamic acid ethyl ester
A mixture of (2-bromo-4-methoxy-pyridin-3-yl)-carbamic acid ethyl ester (540 mg, 1.96
mmol), Et3N (0.54 mL, 3.9 mmol), Pd(PPh) 2Cl2 (69 mg, 5% mol), Cul (30 m g, 8% mol), and
TMS-acetylene (0.56 mL, 3.9 mmol) in degassed THF (10 mL) is heated at 60 °C overnight.
The mixture is cooled to rt, and then partitioned between H20 and EtOAc. This mixture is
filtered through Celite to remove the insoluble material. The two layers of the filtrate are
separated, and the organic layer is washed H20 and brine, dried over MgS0 4, filtered, and
concentrated in vacuo. The crude material is purified on silica gel with heptane/EtOAc (50/50
to 0/100) as eluant to give 460 mg (80%) of the product as a beige solid. 1H NMR (CDC13,
300 MHz) 8.32 (d, J = 5.6, 1 H), 6.81 (d, J =5.7, 1H), 6.16 (br s, 1H), 4.22 (q, J = 7.0, 2H),
3.90 (s, 3H), 1.30 (t, J = 7.2, 3H), 0.26 (s, 9H). LC Rt 2.63 min; LCMS m/z 293 (M+l, 100%).
F. 7-Methoxy-l H-pyrrolo[3,2-b]pyridi
A mixture of (4-methoxy-2-trimethylsilanylethynyl-pyridin-3-yl)-carbamic acid ethyl ester
(460 mg, 1.57 mmol) and KOH (353 mg, 6.29 mmol) in t-BuOH (20 mL) is heated at 60 °C
for 6 h, and then stirred at rt overnight. The mixture is concentrated in vacuo. The residue is
partitioned between H20 and EtOAc. The two layers are separated, and the organic layer is
washed with brine, dried over MgS0 4, filtered, and concentrated in vacuo. The crude material
is purified on silica gel with EtOAc/MeOH (90/10 to 80*20) as eluant toyield 127 mg (54%)
of the product as a white powder. 1H NMR (CD3OD, 300 MHz) 8.17 (d, J =5.5, 1 H), 7.42
(d, J =3.2, 1H), 6.75 (d, J =5.5, 1H), 6.53 (d, J = 3.2, 1H), 4.85 (s, 3H). LC Rt 0.39 min;
LCMS m/z 149 (M+l, 100%).
The title compound is prepared in a similar manner as Example 12C using 7-methoxy-l Hpyrrolo[
3,2-b]pyridine as the starting material. 1H NMR (CDCI3, 300 MHz) 8.29 (d, J = 5.5,
1 H), 7.23 (d, J =3.1, 1H), 6.61 (d, J = 3.1, 1H), 6.56 (d, J =5.5, 1H), 4.50 (t, J = 5.7, 2H),
3.97 (s, 3H), 3.68 (t, J = 5.5, 2H), 3.29 (s, 3H). LC Rt 2.51 min; MS m/z 207 (M+l, 100%).
H. 3-Iodo-7-methoxy- 1-(2-methoxy-ethyl)- lH-pyrrolo[3,2-b]pyridine
A mixture of 7-methoxy-l-(2-methoxy-ethyl)-l H-pyrrolo[3,2-b]pyridine (256 mg, 1.24
mmol) and N-iodosuccimide (536 mg, 1.61 mmol) in degassed THF (20 mL) is stirred at 60
°C for 1.5 h. The mixture is cooled to rt,and then partitioned between 0.1 M NaOH and
EtOAc. The two layers are separated, and the organic layer is washed with H20 and brine,
dried over MgS0 4, filtered, and concentrated in vacuo. The crude material is purified on
silica gel with heptane/EtOAc (40/60 to 0/100) as eluant to yield 272 mg (66%) of the product
as a yellow gum. 1H NMR (CDC13, 300 MHz) 8.41 (d, J = 5.5, 1 H), 7.35 (s, 1H), 6.63 (d, J
= 5.5, 1H), 4.51 (t, J = 5.3, 2H), 3.99 (s, 3H), 3.67 (t, J =5.3, 2H), 3.30 (s, 3H); LC Rt 1.43
min; MS m/z 333 (M+l, 100%).
7-Methoxy-l-(2-methoxy-ethyl)-l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid ethyl ester
To a solution of 3-iodo-7-methoxy-l-(2-methoxy-ethyl)-l H-pyrrolo[3,2-b]pyridine (272 mg,
0.82 mmol) in THF (5 mL) at -78 °C is added -BuLi (2.0 M in pentane, 0.62 mL, 1.24
mmol). After 15 min, diethyl carbonate (0.30 mL, 2.45 mmol) is added. After 30 min, sat.
NH4C1 is added, and the mixture is partitioned between H20 and EtOAc. The two layers are
separated, and the aqueous is extracted with EtOAc once. The combined organic layers are
washed with H20 and brine, dried over MgS04, filtered, and concentrated in vacuo. The
crude material is purified on silica gel with EtOAc/MeOH (100/0 to 80/20) as eluant to give
108 mg (47%) of the product (contaminated with ~20 % of the de-iodinated starting material)
as a clear colorless film. This material is used in the next sep without further purification. 1H
NMR (CDC13, 300 MHz) 8.51 (d, J = 5.4, 1 H), 7.91 (s, 1H), 6.64 (d, J = 5.5, 1H), 4.55-4.35
(m, 4H), (t, J =5.3, 2H), 3.99 (s, 3H), 3.70 (t, J =5.2, 2H), 3.29 (s, 3H), 1.41 (t, J = 7.1, 3H).
LC Rt 0.50 min; MS m/z 279 (M+l, 100%).
J . 7-Methoxy-l-(2-methoxy-ethyl)-l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid
hydrochloride
A mixture of 7-methoxy-l-(2-methoxy-ethyl)-l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid
ethyl ester (108 mg, 0.39 mmol) in MeOH (5 mL) and NaOH (1.0 M, 2 mL) is heated at 45 °C
overnight and then at 60 °C for 3 h. The mixture is cooled to rt, and then partitioned between
H20 and EtOAc. The two layers are separated, and the aqueous is extracted with EtOAc once.
The aqueous layer is acidified to pH 2 with 3 M HCl. This acidified solution is concentrated
to dryness. The residue is suspended in toluene and then concentrated to dryness. The
resulting white solid was dried in vacuo for 1 h, and then is use in the next step with further
purification. LC Rt 0.3 1 min; MS m/z 251 (M+ 1, 100%).
K. 2,2,2-Trifluoro-N-(4-fluoro-3- {1-[7-methoxy- 1-(2-methoxy-ethyl)- lH-pyrrolo[3,2-
b]pyridine-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as Example 1C using 7-methoxy- 1-(2-
methoxy-ethyl)-l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid hydrochloride as the starting
material. 1H NMR (CDC13, 300 MHz) 8.37 (d, J =5.4, 1H), 7.68 (s, 1H), 7.25-7.05 (m, 2H),
7.05-6.95 (m, 1H), 6.71 (br s, 1H), 6.62 (d, J = 5.4, 1H), 4.70 (br s, 1H), 4.60-4.30 (m, 4H),
3.99 (s, 3H), 3.72 (t, J = 5.5, 2H), 3.33 (s, 3H), 3.30-2.85 (m, 4H), 2.00-1.70 (m, 4H); 1 F
NMR (CDC13, 282 MHz) -75.29 (s, 3F), - 119.18 (s, IF). LC Rt 2.47 min; MS m/z 537
(M+l, 100%).
L. [4-(5 -Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl] -[7-methoxy- 1-(2-methoxy-ethyl)- 1Hpyrrolo[
3,2-b]pyridin-3-yl]-methanone dihydrochloride
The title compound is prepared in a similar manner as Example ID using 2,2,2-trifluoro -N-(4-
fluoro-3- {1-[7-methoxy- 1-(2-methoxy-ethyl)- lH-pyrrolo[3,2-b]pyridine-3-carbonyl]-
piperidin-4-yl}-benzyl)-acetamide as the starting material. 1H NMR (OMSO-d6, 300 MHz) 
8.53 (d, J =6.5, 1H), 8.45 (br,s 3H), 8.34 (s, 1H), 7.61 (d, J =6.4, 1H), 7.50-7.30 (m, 3H),
7.30-7.10 (m, 1H), 4.80-4.55 (m, 2H), 4.50 (br m, 1H), 4.42 (s, 3H), 4.10-3.90 (m, 2H), 3.90-
3.60 (m, 3H), 3.55-3.40 (m, 1H), 3.23 (s, 3H), 3.20-3.10 (m, 2H), 2.00-1.60 (m, 4H); 1 F
NMR (OMSO-d6, 282 MHz) - 119.58 (s, IF). LC 1.39 min; MS m/z 441 (M+l), 233 (100%).
EXAMPLE 16
[4-(5 -Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl] -(1-phenethyl- lH-pyrrolo [3,2-b]pyridin-
3-yl)-methanone dihydrochloride
A. 1-Phenethyl- lH-pyrrolo[3 ,2-b]pyridine
The title compound is prepared in a similar manner as Example 12C using lH-pyrrolo[3,2-
b]pyridine and phenethyl bromide as the starting materials. 1H NMR (CDCI3, 300 MHz) 
8.25 (d, 1H), 7.50 (d, 1H), 7.50-6.90 (m, 7H), 6.65 (s, 1H), 4.35 (s, 2H), 3.10 (s, 3H). LC 1.62
min; MS m/z 223 (M+l, 100%).
B 3-Iodo-l-phenethyl-l H-pyrrolo[3,2-b]pyridine
To a solution of l-phenethyl-l H-pyrrolo[3,2-b]pyridine (400 mg, 1.8 mmol) in THF (6 mL)
is added N-iodosuccimide (526 mg, 1.3 mmol). This reaction mixture is stirred at rt for 2 h
and then at 45 °C for 2 h. The solvent is removed in vacuo, and the residue is dissolved in
Et20 , washed with 0.5 M NaOH (2X), H20 , and brine, dried over Na2S0 4, filtered, and
concentrated in vacuo to yield 540 mg (86%) of the product as a yellow solid. 1H NMR
(CDCI3, 300 MHz) 8.55 (s, 1H), 7.45 (d, 1H), 7.15-7.05 (m, 1H), 7.09-6.65 (m, 1H), 4.35
(s, 2H), 3.10 (s, 3H). LC 0.77 min; MS m/z 249 (M+l, 100%).
C. l-Phenethyl-l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid ethyl ester
The title compound is prepared in a similar manner as Example 151 using 3-iodo-l-phenethyllH-
pyrrolo[3,2-b]pyridine as the starting material. 1H NMR (CDC13, 300 MHz) 8.65 (s,
1H), 7.85 (s, 1H), 7.50 (d, 1H), 7.40-6.80 (m, 6H), 4.60-4.25 (m, 4H), 3.20-2.95 (m, 2H),
1.40 (t, 3H). LC 0.65 min; MS m/z 295 (M+l, 100%).
D. l-Phenethyl-l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid hydrochloride
A mixture of l-phenethyl-l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid ethyl ester (290 mg,
0.98 mmol) in MeOH (2.9 mL) and NaOH ( 1 M, 2.9 mL) is stirred at rt for 2.5 h and then at
70 °C for 1 h. The pH of the reaction is adjusted to ~2 withl M HCl. The resulting solution is
concentrated to dryness in vacuo. The crude material is used in the next setp without further
purification. LC 0.55 min; MS m/z 267 (M+l).
E. 2,2,2-Trifluoro -N-{4-fluoro-3-[l-(l-phenethyl-l H-pyrrolo[3,2-b]pyridine-3-carbonyl)-
piperidin-4-yl]-benzyl}-acetamide
The title compound is prepared in a similar manner as Example 1C using 1-phenethyl- 1Hpyrrolo[
3,2-b]pyridine-3-carboxylic acid hydrochloride as the starting material. 1H NMR
(CDC13, 300 MHz) 8.60-8.50 (m, 1H), 7.62 (s, 1H), 7.60-7.50 (m, 1H), 7.40-6.90 (m, 9H),
6.65 (br s, 1H), 4.60 (br m, 1H), 4.50 (d, 2H), 4.38 (t, 2H), 3.40-2.85 (m, 6H), 2.00-1.70 (m,
4H). LC Rt 0.82 min; MS m/z 553 (M+l).
F. 4- -Aminomethyl-2-fluoro-phenyl)-piperidin- 1- l - 1-phenethyl- lH-pyrrolo 3,2-
blpyridin-3 -yl)-methanone dihydrochloride
The title compound is prepared in a similar manner as Example ID using 2,2,2-trifluoro -N-{4-
fluoro-3-[ 1-(1 -phenethyl- lH-pyrrolo[3,2-b]pyridine-3-carbonyl)-piperidin-4-yl]-benzyl} -
acetamide as the starting material. 1H NMR (OMSO-d6, 300 MHz) 8.79 (d, 1H), 8.61 (d,
1H), 8.55-8.30 (m, 4H), 7.75-7.55 (m, 2H), 7.45-7.30 (m, 1H), 7.30-6.95 (m, 7H), 4.80-4.65
(m, 2H), 4.55 (br m, 1H), 4.10-3.90 (m, 2H), 3.30-2.90 (m, 6H), 1.95-1.55 (m, 4H). LC 0.58
min; MS m/z 457 (M+l), 241.
EXAMPLE 17
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[ 1-(2-piperidin- 1-yl-ethyl)- \Hpyrrolo
[3,2-b]pyridin-3 -yl]-methanone trihydrochloride
A. 3-Iodo-l H-pyrrolor3,2-b1pyridine
To a solution of lH-pyrrolo[3,2-b]pyridine (1.94 g, 16.4 mmol) in THF (10 mL) is added Niodosuccimide
(4.06 g, 18.1 mmol). Preciptation occurs after a few minutes. The reaction is
continued to stri at rt overnight. The preciptate is collected by filtration and is washed with a
smalll amount of THF and heptane. The resultin white solid is dried in vacuo. The yeild of
the reaction is 4.1 g (quantitative). 1H NMR (OMSO-d6, 300 MHz) 8.40 (s, 1H), 7.90-7.70
(m, 2H), 7.15 (d, 1H). LC 0.41 min; MS m/z 245 (M+l).
B. 3-Iodo- 1-(2-piperidin- 1-yl-ethyl)- lH-pyrrolo [3,2-b]pyridine
The title compound is prepared in a similar manner as Example 12C using 3-iodo-l Hpyrrolo[
3,2-b]pyridine and N-(2-chloroethyl)piperdine hydrochloride as the starting materials.
1H NMR (CDCI3, 300 MHz) 8.60 (s, 1H), 7.65 (d, 1H), 7.55 (s, 1H), 7.15 (d, 1H), 4.20 (t,
2H), 3.65 (t, 2H), 2.50-2.30 (m, 4H), 1.70-1.35 (m, 6H). LC 0.43 min; MS m/z 356 (M+l).
C. l-(2-Piperidin-l-yl-ethyl)-l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid ethyl ester
The title compound is prepared in a similar manner as Example 151 using 3-iodo-l-(2-
piperidin-l-yl-ethyl)-l H-pyrrolo[3,2-b]pyridine as the starting material. 1H NMR (CDCI3, 300
MHz) 8.65 (d, 1H), 8.10 (s, 1H), 7.70 (d, 1H), 7.20-7.10 (m, 1H), 4.45 (q, 2H), 4.20 (t, 2H),
3.70 (t, 2H), 2.50-2.30 (m, 4H), 1.65-1.35 (m, 9H). LC 0.41 min; MS m/z 302 (M+l).
D. l-(2-Piperidin-l-yl-ethyl)-l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid dihydrochloride
A mixture of 1-(2-piperidin-1 -yl-ethyl)- lH-pyrrolo [3,2-b]pyridine-3-carboxylic acid ethyl
ester ( 110 mg, 0.36 mmol) in MeOH ( 1.1 mL) and NaOH ( 1 M, 1.1 mL) is stirred at rt for 2.5
h and then at 70 °C for 1 h. The reaction mixture is concentrated in vacuo to remove the
methanol. The pH of the resulting mixture is ajusted to ~4 with3 M HCl. The resulting
solution is concentrated to dryness in vacuo. The crude material is used in the next setp
without further purification.
E. 2,2,2-Trifluoro -N-(4-fluoro-3- ( 1- I -(2-piperidin- 1-yl-ethyl)- lH-pyrrolor3,2-b1pyridine-3-
carbonyl -piperidin-4- -benz l)-acetamide
The title compound is prepared in a similar manner as Example 1C using 1-(2-piperidin-1 -ylethyl)-
l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid dihydrochloride as the starting material.
1H NMR (CDC13, 300 MHz) 8.60-8.50 (m, 1H), 7.62 (s, 1H), 7.75-7.65 (m, 1H), 7.25-6.95
(m, 4H), 6.60 (br s, 1H), 4.70 (br m, 1H), 4.59 (d, 2H), 4.24 (t, 2H), 3.35-2.85 (m, 4H), 2.73
(t, 2H), 2.55-2.35 (m, 4H), 2.00-1.75 (m, 4H), 1.70-1.35 (m, 6H). LC Rt 0.63 min; MS m/z
560 (M+l), 281.
F. 4- -Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl - 1-(2-piperidin- 1-yl-ethyl)- \Hpyrrolo
[3,2-blpyridin- -yl -methanone trihydrochloride
To a mixture of 2,2,2-trifluoro -N-(4-fluoro-3-{l-[l-(2-piperidin-l-yl-ethyl)-l H-pyrrolo[3,2-
b]pyridine-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide (85 mg, 0.15 mmol) in MeOH (5
mL) is added aqueous K2CO3 (168 mg, 1.21 mmol, dissolved in 1mL H20). This mixture is
stirred at rt 1 h and then 45 °C for 1.5 h. LC/MS indicates the reaction is completed. The
reaction mixture is concentrated in vacuo to remove most of the methanol, and the residue is
dissolved in H20 . The solution is acidified to pH 3 with 3 M HCl. The resulting solution is
filtered, and the filtrate is purified by HPLC to give 42 mg (48%) of the product as a white
solid. 1H NMR (DMSO- , 300 MHz) 10.8 (br s, 1H), 8.51 (d, 1H), 8.45-8.10 (m, 6H),
7.60-7.45 (m, 1H), 7.45-7.30 (m, 2H), 7.30-7.15 (m, 1H), 4.90-4.80 (m, 2H), 4.70 (br m, 1H),
4.10-3.90 (m, 2H), 3.25-2.75 (m, 6H), 2.50-2.30 (m, 4H), 1.90-1.50 (m, 8H), 1.50-1.25 (m,
2H). LC 0.40 min; MS m/z 464 (M+l), 192.
EXAMPLE 18
r4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin- 1--1-(2-pyrrolidin- 1-yl-ethyl)- \Hpyrrolo
[3,2-blpyridin-3 -yl]-methanone trihydrochloride
A. 3-Iodo- 1-(2-pyrrolidin- 1-yl-ethyl)- lH-pyrroloP ,2-blpyridine
The title compound is prepared in a similar manner as Example 12C using 3-iodo-l Hpyrrolo[
3,2-b]pyridine and N-(2-chloroethyl)piperdine hydrochloride as the starting materials.
1H NMR (CDCI3, 300 MHz) 8.65 (s, 1H), 7.65 (d, 1H), 7.55 (s, 1H), 7.15 (d, 1H), 4.25 (t,
2H), 2.80 (t, 2H), 2.70-2.50 (m, 4H), 1.90-1.70 (m, 4H). LC 0.54 min; MS m/z 342 (M+l),
192.
B. l-(2-Pyrrolidin-l-yl-ethyl)-l H-pyrrolor3,2-b1pyridine-3-carboxylic acid ethyl ester
The title compound is prepared in a similar manner as Example 151 using 3-iodo-l-(2-
pyrrolidin-l-yl-ethyl)-l H-pyrrolo[3,2-b]pyridine as the starting material. 1H NMR (CDCI3,
300 MHz) 8.70 (d, 1H), 8.10 (s, 1H), 7.75 (d, 1H), 7.25-7.10 (m, 1H), 4.45 (q, 2H), 4.25 (t,
2H), 2.90 (t, 2H), 2.60-2.40 (m, 4H), 1.85-1 .70 (m, 4H), 1.45 (t, 3H). LC 0.55 min; MS m/z
288 (M+l), 165.
C. l-(2-Pyrrolidin-l-yl-ethyl)-l H-pyrrolo[3,2-blpyridine-3-carboxylic acid dihydrochloride
A mixture of l-(2-pyrrolidin-l-yl-ethyl)-l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid ethyl
ester (105 mg, 0.44 mmol) in MeOH (1.1 mL) andNaOH ( 1 M, 1.1 mL) is stirred at at 70 °C
for 1 h. The reaction mixture is concentrated in vacuo to remove the methanol. The pH of the
resulting mixture is adjusted to ~4 with 3M HC1. The resulting solution is concentrated to
dryness in vacuo. The crude material is used in the next setp without further purification.
D . 2,2,2-Trifluoro -N-(4-fluoro-3-(l-ri-(2-pyrrolidin-l-yl-ethyl)-l H-pyrrolor3,2-b1pyridine-3-
carbonyl1-piperidin-4-yl|-benzyl)-acetamide
The title compound is prepared in a similar manner as Example 1C using l-(2-pyrrolidin-l-ylethyl)-
l H-pyrrolo[3,2-b]pyridine-3-carboxylic acid dihydrochloride as the starting material.
1H NMR (CDCI3, 300 MHz) 8.60-8.50 (m, 1H), 7.88 (s, 1H), 7.75-7.65(m, 1H), 7.25-6.95
(m, 4H), 6.70 (br m, 1H), 4.75 (br m, 1H), 4.49 (d, 2H), 4.28 (t, 2H), 3.35-3.30 (m, 4H), 2.93
(t, 2H), 2.50-2.30 (m, 4H), 2.05-1.65 (m, 8H). LC Rt 0.62 min; MS m/z 546 (M+l), 217.
E. r4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yll- 1-(2-pyrrolidin- 1-yl-ethyl)- \Hpyrrolo
[3,2-blpyridin-3 -yl -methanone trihydrochloride
To a mixture of 2,2,2-trifluoro -N-(4-fluoro-3-{l-[l-(2-pyrrolidin-l-yl-ethyl)-l H-pyrrolo[3,2-
b]pyridine-3-carbonyl]-piperidin-4-yl}-benzyl)-acetamide ( 110 mg, 0.20 mmol) in MeOH (5
mL) is added aqueous K2CO3 (61 mg, 1.61 mmol, dissolved in 1mL H20). This mixture is
stirred at rt 1 h and then 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, and the residue is
dissolved in H20 . The solution is acidified to pH 3 with 3 M HCl. The resulting solution is
filtered, and the filtrate is purified by HPLC to give 112 mg (quantitative) of the product as a
light yellow solid. 1H NMR (DMSO- , 300 MHz) 10.2 (br s, 1H), 8.55 (d, 1H), 8.41 (d,
1H), 8.33 9s, 1H), 8.19 (br s, 4H), 7.60-7.40 (m, 2H), 7.40-7.30 (m, 1H), 7.10-6.95 (m, 1H),
4.80-4.60 (m, 2H), 4.30 (br m, 1H), 4.10-3.95 (m, 2H), 3.90-3.65 (m, 2H), 3.65-3.45 (m, 2H),
3.20-2.80 (m, 4H), 2.15-1.50 (m, 10H). LC 0.378 min; MS m/z 450 (M+l).
EXAMPLE 19
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-(l H-pyrrolo[2,3-b]pyridin-3-yl)-
methanone dihydrochloride
A. 2,2,2-Trifluoro -N-{4-fluoro-3-[l-(l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-piperidin-4-yl]-
benzyl} -acetamide
The title compound is prepared in a similar manner as Example 1C using lH-pyrrolo[2,3-
b]pyridine-3-carboxylic acid as the starting material. 1H-NMR (CDC13, 300 MHz) 9.8 (bs,
1H), 8.4 (m, 1H), 8.2 (m, 1H), 7.6 (d, 1H), 7.3-7.0 (m, 3H), 6.75 (bs, 1H), 4.6 (m, 2H), 4.45
(m, 2H), 3.2 (m, 3H), 2.5 (m, 1H), 1.9 (m, 2H), 1.8 (m, 2H). LCMS m/z 449 (M+H).
B. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-(lH-pyrrolo[2,3-b]pyridin-3-yl)-
methanone dihydrochloride
The title compound is prepared in a similar manner as Example 5D using 2,2,2-trifluoro -N-{4-
fluoro-3-[l-(l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-piperidin-4-yl]-benzyl}-acetamide as the
starting material. 1H NMR (DMSO- , 300 MHz) 12.4 (bs, 1H), 8.4 (bs, 2H), 8.2 (m, 1H),
7.9 (m, 1H), 7.6 (m, 1H), 7.4 (m, 1H), 7.2 (m, 2H), 4.4 (m, 2H), 4.0 (m, 2H), 3.2 (m, 3H),
1.95-1.8 (m, 4H). LCMS m/z 353 (M+H).
EXAMPLE 20
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-
b]pyridin-3-yl]-methanone dihydrochloride
A. lH-Pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester
The title compound is prepared in a similar manner as Example 2A using lH-pyrrolo[2,3-
b]pyridine-3-carboxylic acid as the starting material. 1H-NMR (CDC13, 300 MHz) 10.5 (bs,
1H), 8.5 (m, 1H), 8.4 (m, 1H), 8.1 (m, 1H), 7.2 (m, 1H), 3.95 (s, 3H). LCMS m/z 177 (M+H).
B. l-(2-Methoxy-ethyl)-l H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester
The title compound is prepared in a similar manner as Example 2B using lH-pyrrolo[2,3-
b]pyridine-3-carboxylic acid methyl ester as the starting material. 1H-NMR (CDCI3, 300
MHz) 8.4 (m, 2H), 8.1 (s, 1H), 7.2 (m, 1H), 4.5 (t, 2H), 3.9 (s, 3H), 3.8 (t, 2H), 3.3 (s, 3H).
LCMS m/z 235 (M+H).
C. 1-(2-Methoxy-ethyl)- lH-pyrrolo[2,3-b]pyridine-3-carboxylic acid
The title compound is prepared in a similar manner as Example 8C using l-(2-methoxyethyl)-
l H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester as the starting material. 1HNMR
(DMSO- , 300 MHz) 8.3 (m, 2H), 8.2 (s, 1H), 7.3 (m, 1H), 4.5 (t, 2H), 3.75 (t, 2H),
3.2 (s, 3H). LCMS m/z 221 (M+H).
D. 2,2,2-Trifluoro-N-(4-fluoro-3- {1-[1-(2-methoxy-ethyl)- lH-pyrrolo[2, 3-b]pyridine-3-
carbonyl]-piperidin-4-yl}-benzyl)-acetamide
The title compound is prepared in a similar manner as Example 1C using 1-(2-methoxyethyl)-
lH-pyrrolo[2,3-b]pyridine-3-carboxylic acid as the starting material. 1H-NMR (CDCI3,
300 MHz) 8.35 (m, 1H), 8.1 (m, 1H), 7.7 (s, H), 7.2 (m, 3H), 7.1 (m, 1H), 6.6 (bs, 1H), 4.65
(m, 2H), 4.5 (m, 4H), 3.8 (m, 2H), 3.3 (s, 3H), 3.15 (m, 3H), 1.9 (m, 2H), 1.8 (m, 2H). LCMS
m/z 507 (M+H).
E. [4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]- [1-(2-methoxy-ethyl)- lH-pyrrolo [2,3 -
b]pyridin-3-yl]-methanone hydrochloride
The title compound is prepared in a similar manner as Example 5D using 2,2,2-trifluoro -N-(4-
fluoro-3- {1-[1-(2-methoxy-ethyl)-l H-pyrrolo[2,3-b]pyridine-3-carbonyl]-piperidin-4-yl} -
benzyl)-acetamide as the starting material. 1H NMR (OMSO-d6, 300 MHz) 8.4 (m, 1H), 8.2
(bs, 2H), 8.1 (m, 1H), 7.9 (s, 1H), 7.6 (m, 1H), 7.4 (m, 1H), 7.2 (m, 2H), 4.5 (m, 4H), 4.0 (m,
2H), 3.7 (m, 2H), 3.25 (s, 3H), 3.2 (m, 3H), 1.9 (m,2H), 1.75 (m, 2H). LCMS m/z 4 11
(M+H).
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 L-pyroglutamyl-L-prolyl-L-arginine-/?aranitroanilide
(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 NaCl, 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 x of diluted substrate (final concentration of 500 in assay buffer) to each
well
• Add compound in duplicates , final concentration of 20 , volume 20 ΐ
• Add enzyme at a final concentration of 50 ng/mL in a volume of 20 ΐ
• 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 IC _n 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 IC 0 for comparison. From the IC 0 value, the can be calculated
using the following formula: Ki = IC o/(l + [Substrate]/K m) .
The beta-Tryptase inhibitory potency for the compound of formula I is Ki value of 26
nM.
Table 1: Activity of compounds against beta-Tryptase
We Claim :
1 . A compound of formula (I):
such that Ar is an aryl or a heteroaryl, and the
group is beta to the
on the aryl
wherein,
is a single or a double bond;
X is independently chosen from the group consisting of N and C-R5;
R1 and R2 are each independently hydrogen or lower alkyl;
R is aryl, arylalkenyl, cycloalkenyl, cycloalkyl, heteroaryl, heteroarylalkenyl,
heterocycloalkenyl, a carbon linked heterocycloalkyl or alkyl optionally substituted by one or
more groups selected from hydroxy, alkoxy, alkyloxycarbonylamino, cycloalkyl,
heterocycloalkyl, R6,—OR6,—S(0)mR 6 or —C(=0) —R6;
R4 is hydrogen, acyl, alkoxy, alkyloxycarbonyl, carboxy, hydroxy, —C(=0) —NY Y2 or alkyl
optionally substituted with alkoxy, alkylcarbonylamino, alkylsulfonylamino, hydroxy, —
S(0)m-alkyl or —NY Y2;
R5 is hydrogen, alkoxy, alkyloxycarbonyl, or alkyl optionally substituted with alkoxy,
alkylcarbonylamino, alkylsulfonylamino, hydroxy, —S(0)m-alkyl or —NY Y2;
R6 is aryl or heteroaryl;
Y1 and Y2 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl,
heteroarylalkyl or heterocycloalkyl; or the group —NY Y2 may form a cyclic amine; and
n is 2; or
an N-oxide of said compound, a prodrug of said compound, a pharmaceutically acceptable salt
of said compound, a solvate of said compound or a hydrate of said compound.
2. The compound in claim 1 wherein R1 or R2 is hydrogen or R1 and R2 are hydrogen.
3. The compound in claim 1 wherein R is a hydrogen or a cyano group.
4. The compound in claim 1, wherein:
Ar comprises a phenyl group;
R1 and R2 are both hydrogen;
R is hydrogen; and
is a single bond.
5. The compound of formula la
wherein,
is a single or a double bond;
X is independently chosen from the group consisting of N and C-R5;
R1 and R2 are each independently hydrogen or lower alkyl;
R is aryl, arylalkenyl, cycloalkenyl, cycloalkyl, heteroaryl, heteroarylalkenyl,
heterocycloalkenyl, a carbon linked heterocycloalkyl or alkyl optionally substituted by one or
more groups selected from hydroxy, alkoxy, alkyloxycarbonylamino, cycloalkyl,
heterocycloalkyl, R6,—OR6,—S(0)mR 6 or —C(=0) —R6;
R4 is hydrogen, acyl, alkoxy, alkyloxycarbonyl, carboxy, hydroxy, —C(=0) —NY Y2 or alkyl
optionally substituted with alkoxy, alkylcarbonylamino, alkylsulfonylamino, hydroxy, —
S(0)m-alkyl or —NY Y2;
R5 is hydrogen, alkoxy, alkyloxycarbonyl, or alkyl optionally substituted with alkoxy,
alkylcarbonylamino, alkylsulfonylamino, hydroxy, —S(0)m-alkyl or —NY Y2;
R6 is aryl or heteroaryl;
R7 is selected from the group consisting of hydrogen or halogen;
Y1 and Y2 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl,
heteroarylalkyl or heterocycloalkyl; or the group —NY Y2 may form a cyclic amine;
m is zero or an integer 1 to 2; and
n is 2; or
an N-oxide of said compound, a prodrug of said compound, a pharmaceutically acceptable salt
of said compound, a solvate of said compound or a hydrate of said compound.
6. The compound in claim 5 wherein R1 or R2 is hydrogen or R1 and R2 are hydrogen.
7. The compound in claim 5 wherein R is a hydrogen or a cyano group.
8. The compound in claim 5, wherein:
R1 and R2 are both hydrogen;
R is hydrogen; and
is a single bond.
9. The compound of claim 5 wherein:
R1 and R2 are both hydrogen;
R3 is hydrogen;
is a single bond;
and
R5 is hydrogen, alkoxy, alkyloxycarbonyl, or alkyl optionally substituted with alkoxy,
alkylcarbonylamino.
10. The compound in claim 1 that is selected from the group consisting of:
[4-(5 -aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]-[ 1-(2-methoxy-ethyl)-7-methyl- \Hpyrrolo
[3,2-b]pyridin-3-yl]-methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[7-chloro-l-(2-methoxy-ethyl)-
pyrrolo[2,3 -c]pyridin-3-yl]-methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]-[7-methyl-1-(2-methoxy-ethyl)- 1Hpyrrolo[
2,3 -c]pyridin-3-yl]-methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-(l-phenethyl-l H-prrolo[3,2-b]pyridin-3-
yl)-methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-
c]pyridin-3-yl]-methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-
b]pyridin-3-yl]-methanone,
[4-(3-aminomethyl-phenyl)-piperidin- 1-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-c]pyridin-3-
yl]-methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]-[7-(2-methoxy-ethoxy)- 1-(2-methoxyethyl)-
l H-pyrrolo[2,3-c]pyridin-3-yl]-methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[7-methoxy- 1-(2-methoxy-ethyl)- \Hpyrrolo[
3,2-b]pyridin-3-yl]-methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[3,2-
c]pyridin-3-yl]-methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-(l H-pyrrolo[2,3-b]pyridin-3-yl)-
methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl] -( lH-pyrrolo[2,3 -c]pyridin-3-yl)-
methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-(l H-pyrrolo[2,3-b]pyridin-2-yl)-
methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]-[ 1-(2-pyrrolidin-1-yl-ethyl)- 1Hpyrrolo[
3,2-b]pyridin-3-yl]-methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[ 1-(2-piperidin- 1-yl-ethyl)- 1Hpyrrolo[
3,2-b]pyridin-3-yl]-methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-
b]pyridin-2-yl]-methanone,
[4-(3-aminomethyl-phenyl)-piperidin- 1-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-b]pyridin-2-
yl]-methanone,
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidm
c]pyridin-2-yl]-methanone,
[4-(3-aminomethyl-phenyl)-piperidin- 1-yl] -[1-(2-methoxy-ethyl)- IH-pyrrolo[3,2-b]pyridin-2-
yl]-methanone, and
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[3,2-
b]pyridin-2-yl]-methanone.
11. The compound in claim 1 that is selected from the group consisting of:
[4-(3 -Aminomethyl-phenyl)-piperidin- 1-y1] -[1-(2-methoxy-ethyl)- IH-pyrrolo[2,3 -c]pyridin-3-
yl]-methanone,
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-(l H-pyrrolo[2,3-b]pyridin-3-yl)-
methanone,
[4-(5 -Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl] -(1-phenethyl- lH-prrolo [3,2-b]pyridin-3-
yl)-methanone,
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-
b]pyridin-3-yl]-methanone,
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[2,3-
c]pyridin-3-yl]-methanone,
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[l -(2-methoxy-ethyl)- lH-pyrrolo[3,2-
c]pyridin-3-yl]-methanone,
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[ 1-(2-methoxy-ethyl)-7-methyl- \Hpyrrolo[
3,2-b]pyridin-3-yl]-methanone,
[4-(5 -Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl]-[7-(2-methoxy-ethoxy)- 1-(2-methoxyethyl)-
l H-pyrrolo[2,3-c]pyridin-3-yl]-methanone,
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[7-chloro- 1-(2-methoxy-ethyl)- \Hpyrrolo[
2,3 -c]pyridin-3-yl]-methanone,
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[7-methoxy- 1-(2-methoxy-ethyl)- \Hpyrrolo[
3,2-b]pyridin-3-yl]-methanone, and
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[7-methyl- 1-(2-methoxy-ethyl)- \Hpyrrolo[
2,3 -c]pyridin-3-yl]-methanone.
12. The compound in claim 1that is selected from the group consisting of:
[4-(5 -Aminomethyl-2-fluoro-phenyl)-piperidin- 1-yl] -(1-phenethyl- lH-prrolo [3,2-b]pyridin-3-
yl)-methanone;
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperi^
c]pyridin-3-yl]-methanone;
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[ 1-(2-methoxy-ethyl)-7-methyl- \Hpyrrolo
[3,2-b]pyridin-3 -yl]-methanone;
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l-yl]-[7-chloro-l-(2-methoxy-ethyl)-l Hpyrrolo
[2,3 -c]pyridin-3 -yl]-methanone;
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[7-methoxy- 1-(2-methoxy-ethyl)- \Hpyrrolo[
3,2-b]pyridin-3-yl]-methanone; and
[4-(5-Aminomethyl-2-fluoro-phenyl)-piperidin-l -yl]-[7-methyl- 1-(2-methoxy-ethyl)- \Hpyrrolo[
2,3-c]pyridin-3-yl]-methanone.
13. A pharmaceutical composition comprising one or more of compounds of formula 1 as
recited in claim 1 in a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising one or more of compounds of formula 1 as
recited in claim 1 and one or more additional pharmaceutically active compounds which are
useful in the treatment of inflammatory diseases.
15. A pharmaceutical composition as recited in claim 14 in a pharmaceutically acceptable
carrier.
16. The pharmaceutical composition in claim 14 wherein said one or more additional
pharmaceutically active compounds are chosen from the group consisting of known anti
inflammatory agents.
17. The pharmaceutical composition in claim 16 wherein said one or more additional
pharmaceutically active compounds are chosen from the group consisting of compounds
known to treat airway inflammation.
18. The pharmaceutical composition in claim 16 wherein said one or more additional
pharmaceutically active compounds are chosen from the group consisting of compounds
known to treat joint inflammation.
19. The method of treatment and/or prevention of inflammatory diseases by the
administration one or more of the compounds of formula 1 as recited in claim 1.
20. The method of treatment and/or prevention of inflammatory diseases by the
administration one or more of the compounds of formula 1 as recited in claim 1 and a
pharmaceutically acceptable carrier.
21. The method of treatment and/or prevention of inflammatory diseases by the
administration one or more of the compounds of formula 1 as recited in claim 1, a known anti
inflammatory agent and a pharmaceutically acceptable carrier.