Title of Invention

A SUBSTITUTED TETRAHYDROCARBAZOLE COMPOUND USEFUL AS ANDROGEN RECEPTOR MODULATORS (SARM) AND PHARMACEUTICAL COMPOSITION THEREOF

Abstract The present invention provides a compound of the formula : Formula (I) or a pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising an effective amount of a compound of Formula (1) in combination with a suitable carrier, diluent, or excipient; and methods for treating physiological disorders, particularly frailty, osteoporosis, osteopenia, and male and female sexual dysfunction comprising administering to a patient in need thereof an effective amount of a compound of Formula (I).s
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TETRAHYDROCARBAZOLE DERIVATIVES USEFUL AS ANDROGEN
RECEPTOR MODULATORS
TECHNICAL FIELD OF INVENTION
The present invention relates to tetrahydrocarbazole compounds that are
useful as therapeutic agents, to pharmaceutical compositions comprising the
compounds, to methods of using the compounds to treat disorders in patients, and to
intermediates and processes useful in the synthesis of the compounds.
BACKGROUND OF THE INVENTION
Nuclear hormone receptors are an evolutionarily conserved class of
intracellular receptor proteins which have been termed "ligand dependent
transcription factors". Evans et al., SCIENCE, 240: 889 (1988). The nuclear
hormone receptor gene superfamily encodes structurally-related receptor proteins
for glucocorticoids (e.g. Cortisol, corticosterone, cortisone), androgens,
mineralocorticoids (e.g. aldosterone), progestins, estrogen, and thyroid hormone.
Also included within this superfamily of nuclear receptors are receptor proteins for
vitamin D, retinoic acid, 9-cis retinoic acid, as well as those receptors for which no
cognate ligands have been identified ("orphan receptors") Ribeiro et al., Annual
Rev. Med., 46:443-453 (1995); Nature Rev. Drug Discovery, 3: 950-964 (Nov.
2004). Steroid hormone receptors represent a subset of the nuclear hormone
receptor superfamily. So named according to the cognate ligand which complexes
with the receptor in its native state, the steroid hormone nuclear receptors include
the glucocorticoid receptor (GR), the androgen receptor (AR), the mineralocorticoid
receptor (MR), the estrogen receptor (ER), and the progesterone receptor (PR).
Tenbaum et al., Int. J. Biochem. Cell. Bio., 29(12):1325-1341(1997).
In contrast to membrane bound receptors, nuclear hormone receptors
encounter their respective ligands following entry of the ligand into the cell. Once
ligand binding occurs, the ligand-receptor complex modulates transcription of target
genes within the cell nucleus. For example, most ligand-free nuclear receptors are
bound in a complex with heat shock proteins (hsps) in the cytoplasm. Following
entry of circulating hormone into the cell, binding elicits a conformational change in

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the receptor, dissociating the receptor from the hsp. The ligand bound receptors
translocate to the nucleus, where they act as monomers as well as hetero-and
homodimers in binding to particular hormone response elements (HREs) in the
promoter regions of target genes. The HRE-receptor complex then, in turn,
regulates transcription of proximally-located genes (see Ribeiro et al., supra.). On
the other hand, thyroid hormone receptors (TRs) and other non-steroid receptors
such as vitamin D receptor (VDR) and retinoic acid receptors (RAR) are bound to
their respective HRE in the absence of hsps and/or cognate ligand. Hormones
released from the circulation enter the cell, binding in the nucleus to these receptors
which, in turn, hetero-dimerize to other nuclear receptors such as 9-cis retinoic acid
(RXR). As with the steroid hormone nuclear receptors, following ligand binding,
the ligand-bound receptor complex again regulates transcription of neighboring
genes.
Androgens exert profound influences on a multitude of physiological
functions by virtue of their diverse roles in inter alia male sexual development and
function, maintenance of muscle mass and strength in both males and females,
maintenance of bone mass, erythropoeisis, memory and cognition, and maintenance
of sexual behaviour (e.g. libido and potency). The actions of androgens
(testosterone and 5a-dihydrotestosterone (DHT)) are mediated by the AR which,
upon androgen binding, translocates to the cell nucleus where it binds to specific
DNA sequences termed androgen respone elements (AREs) to initiate or repress
transcription of target genes. The effects of androgens can be generally
characterized as anabolic or androgenic in nature. Anabolic (i.e. tissue building)
effects of androgens include increasing muscle mass and strength and bone mass,
whereas androgenic (i.e. masculinizing) effects include the development of male
secondary sexual characteristics such as the internal reproductive tissues (i.e.
prostate and seminal vesicle), the external genetalia (penis and scrotum), libido, and
hair growth patterns.
Reductions in bioavailable serum androgen levels that occur with aging can
have serious physiological effects in both males and females. In males, for
example, decreases in androgen levels are associated with loss of libido, erectile
dysfunction, depression, decreased cognitive ability, lethargy, osteoporosis, and loss

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of muscle mass and strength. Rajfer (2003), Rev, Urol, 5 (Suppl. 1): S1-S2. In
addition, as men age and testosterone levels decline, bones weaken, diabetes and
cardiovascular disease rates increase, and the ratio of muscle mass to fat decreases.
Vastag, B. (2003), JAMA; 289: 971-972. In females, low plasma levels of
circulating testosterone are associated with diminished libido, unexplained fatigue,
and general lack of well being. Davis, S.R. (1999), Medical J. Australia; 170: 545-
549. Clinically, the principal application of androgen therapy has been in the
treatment of hypogonadism in men. Significantly, androgen replacement therapy in
hypogonadal men has also been shown to decrease bone resorption and increase
bone mass. Katznelon, L., et al., J. Clin. Endocrinol Metab.; 81: 4358 (1996).
Other indications for which androgens have been used clinically include treatment
of delayed puberty in boys, anemia, primary osteoporosis, and muscle wasting
diseases. In addition, androgen replacement therapy has been used recently in aging
men and for the regulation of male fertility. T.R. Brown, Endocrinology; 145(12):
5417-5419 (2004). In females, androgen therapy has been used clinically for the
treatment of sexual dysfunction or diminished libido. W. Arlt, Euro. J. Endocrinol.;
154(1)1-11(2006).
However, activation of AR in certain tissues is also associated with serious
deleterious consequences. For example, unwanted side effects of steroidal
androgen therapy include growth stiumulation of the prostate and seminal vesicles.
Feldkom et al, J. Steroid Bichem and Mol. Biol; 94(5): 481-487 (2005). Prostate
cancers, for example, depend on AR for growth and development. Gegory, C.W. et
al. (2001), Cancer Res., June 1; 61(11):4315-4319; and Jenster, G. (1999), Semin.
Oncol, August; 26(4): 407-421. Androgen therapy has also been associated with
sleep apnea, stimulation of prostate tumors and elevations in prostate specific
antigen (PSA), an indication of increased prostate cancer risk. Vastag, B. (2003),
JAMA; 289: 971-972. In addition, use of androgen agonists have specifically been
associated with liver damage, adverse effects on male sexual function, adverse
effects associated with cardiovascular and erythropoetic function, prostate
enlargement, hisutism, and virilization, (see Published International Patent
Applications WO 03/011824 and WO 03/034987). Furthermore, preparations of
unmodified and modified steroidal androgens have been found to suffer from rapid

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degradation in the liver leading to poor oral bioavailability and short duration of
activity following parenteral administration, variations in plasma levels,
hepatotoxicity, or cross reactivity with other steroid hormone receptors (e.g. the
glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the
progesterone receptor (PR) which have ligand binding domains homologous to AR)
Yin et al., JPET; 304(3): 1323-1333 (2003). Furthermore, in females, the use of
steroidal androgens may lead to hirsutism or virilization.
Thus, there remains a need in the art for alternatives to classical steroidal
androgen therapy which possess the beneficial pharmacological properties of
steroidal androgens, but with a reduced likelihood or incidence of the typical
limitations associated with steroidal androgen therapy. Recent efforts to identify
suitable replacements for steroidal androgens have focused on identifying tissue
selective androgen receptor modulators (SARMs) which display a differentiated
profile of activity in androgenic tissues. In particular, such agents preferably
display androgen agonist activity in anabolic tissues such as muscle or bone, yet are
only partial agonists or even antagonists in androgenic tissues such as the prostate
or seminal vesicles.
Ligands used to modulate (i.e., agonize, partially agonize, partially
antagonize, or antagonize) the transcriptional activity of AR display androgenic or
antiandrogenic activity (or anabolic or antianabolic activity) and, further, may be
steroidal or nonsteroidal in structure. Androgenic agents (AR Agonists or partial
AR agonists) mimic the effects of natural androgens in either activating or
repressing the transcriptional activity of AR, whereas antiandrogenic agents (AR
antagonists or partial AR antagonists) block androgen mediated transactivation or
transrepression of AR. Further, the AR ligand-AR complex has also been reported
to influence the recruitment of cofactor proteins to the enhancer and or promoter
sites. Shang et al. (March 2002), Mol. Cell. 9(3): 601-610. In addition to their
effects on target gene transcription, ligands for AR may also induce "non-
genotropic" effects. For example, ligands can bind to AR localized in non-nuclear
compartments such as the endoplasmic reticulum, outer cell membrane, or
cytoplasm and induce biochemical changes that are mediated by adaptor proteins
such as phosphatidylinositol-3-kinase (PI3K), extracellular regulated kinases

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(ERKs), mitogen activated protein kinases (MAPKs), or p38/stress activated protein
kinase/c-Jun N-terminal kinases (p38/SAP/JNK). These "non-genotropic" effects
encompass a wide array of physiological changes including the triggering of
antiapoptotic and survival pathways, (see Bowen, R. L. (2001), JAMA 286(7): 790-
1; Gouras, G. K., H. Xu, et al. (2000), Proc. Natl. Acad. Sci. U S A 97(3): 1202-5;
Kousteni, S., T. Bellido,et al (2001), Cell 104(5): 719-30; and Kousteni, S., L.
Han, et al. (2003) [comment] Journal of Clinical Investigation 111(11): 1651-64.)
Thus, it is clear that a ligand which has affinity for AR could be used to
modulate receptor activity and thereby influence a multitude of physiological effects
related to alterations in androgen levels and/or AR activity. Furthermore, the
effects of such agents can be accomplished by both classical conventional HRE-
mediated (e.g. "genotropic") or non-genotropic mechanisms. Preferably such
agents function as selective androgen receptor modulators (SARMs) displaying
androgenic effects in tissues such as muscle and/or bone, while concomitantly
displaying antiandrogenic properties in tissues such as the prostate, liver, and those
responsible for virilization in females. Alternatively, SARMs may display tissue
selectivity with regard to their androgenic effects functioning as, for example,
agonists in anabolic tissue such as muscle or bone but only partial agonists or
antagonists in tissues such as the prostate or seminal vesicles. In addition, such
ligands are preferably non-steroidal in nature thus avoiding many of the undesired
pharmacological, physiochemical and pharmacokinetic properties of their steroidal
counterparts, including poor oral bioavailability, rapid hepatic metabolism, and
cross activation of other steroid receptors. He, Y, et al. (2002), Eur. J. Med. Chem.
37: 619-634.
Several physiological disorders are believed to be susceptible to AR
modulation, and in particular, modulation by SARMs. Frailty represents one such
disorder. Frailty is a geriatric condition which results in a reduction in one's reserve
capacity to the extent that multiple physiological systems are close to, or past the
threshold of symptomatic clinical failure. As a consequence, the frail person is at
an increased risk of disability and death from minor external stresses (e.g. disease or
life events). Campbell, A.J., et al. (1997), Age and Ageing; 26(4): 315-318. Frailty
represents a complex syndrome characterized by numerous musculoskeletal

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symptoms including declines in muscle mass and strength, decreased range of
motion, slowness and paucity of movement, balance and gait abnormalities, weight
loss and reduced food intake, weakness and fatigue, decreased exercise tolerance,
and sarcopenia (loss of lean body mass). Brown, M., et al. (2000), J. of
Gerontology; 55(6): M350-M355; and Fried, L. and Watson, J. (1999), Principles
of Geriatric Medicine and Gerontolgy, 1387-1402, New York: McGraw Hill. As
such, an agent with androgenic properties in tissues such as muscle and bone would
be expected to have utility in treating the frail patient.
Other physiological disorders are also suitable for AR modulation. For
example, it is now well known that hypogonadism is associated with osteoporosis in
men. Kaufman, J.M., et al.,Ann. Rheum. Dis:, Oct; 59(10): 765-772 (2000).
Furthermore, In men with prostate cancer, androgen deprivation therapy increased
the rate of bone mineral density loss. Preston, D.M., et al, Prostate Cancer
Prostatic Dis.; 5(4): 304-310 (2002). In addition, androgen replacement therapy in
hypogonadal men decreases bone resorption and increases bone mass. Katznelon,
L., et al, J. Clin. Endocrinol Metab.; 81: 4358 (1996). As such, AR modulators are
believed to be useful in the treatment of osteoporosis (either as a monotherapy or in
combination with other inhibitors of bone resorption including, but not limited to
estrogens, bisphosphonates, and selective estrogen receptor modulators). In fact,
small clinical trials have in fact shown that testosterone replacement therapy in
older men may help delay or reverse osteoporosis, possibly preventing hip and
vertebral fractures. Vastag, B., JAMA; 289: 971-972 (2003).
Moreover, AR modulators, can be used to enhance performance in the
treatment of male and female sexual dysfunction (see Morley, J.E. and Perry, H..M.,
J. Steroid Biochem. Mol. Biol; June; 85(2-5): 367-373 (2003) and Medical J.
Australia; 170: 545-549 (1999), supra). Other indications or physiological
disorders or for which an AR modulator is believed to have utility include
maintenance of muscle mass, strength and function; as bone anabolic agents in the
treatment of osteoporosis or osteopenia; restoration of bone either independently or
as an adjunct to androgen deprivation therapy in the treatment of prostate or
pancreatic cancer; as an agent to accelerate bone repair (e.g. bone fractures); as a
treatment for sarcopenia or Age Related Functional Decline (ARFD); as an agent to

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increase energy (e.g. reduce lethargy) and libido; or as a treatment for
hypogonadism. In addition, AR modulators can be used for the treatment of
prostate cancer.
Thus, it is an object of the present invention to provide nonsteroidal AR
ligands which possess androgen receptor modulating activity. In particular, it is an
object of the present invention to provide nonsteroidal AR ligands which possess
androgen receptor agonist activity. More particularly, it is a preferred embodiment
of the present invention to provide nonsteroidal androgen agonists which bind to
AR with greater affinity relative to the other steroid hormone receptors. Even more
particularly, it is a preferred embodiment of the present invention to provide tissue
selective androgen receptor modulators (SARMs) which display androgen agonist
activity in muscle or bone, but only partial agonist, partial antagonist or antagonist
activity in other androgenic tissues such as the prostate or seminal vesicle.
The following references provide some examples of the state of the art as it
relates to the present invention.
He et al., Eur. J. Med. Chem.; 37: 619-634 (2002) discloses bicalutamide
analogs as nonsteroidal Androgen receptor ligands.
Published International PCT Application WO 03/051837 discloses tricyclic
derivatives as gonodotropin-releasing hormone antagonists.
Published International PCT Application WO 03/011302 Al discloses
androstene derivative compounds as androgen receptor modulators.
Published International PCT Application WO 03/077919 A1 discloses
azasteroid derivative compounds as androgen receptor modulators.
Published International PCT Application WO 02/16310 A1 discloses
bicalutamide analogs as nonsteroidal Androgen receptor ligands.
Published International PCT Application WO 03/034987 A2 discloses
tricyclic derivatives as as androgen receptor modulators.
Published International PCT Application WO 03/011824 Al discloses
bicyclic modulators of the androgen receptor.
Published International PCT Application WO 04/041782 discloses indole
derivative molecules as modulators of the androgen receptor.

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Published International PCT Application WO 03/0114420 discloses fused
heterocyclic derivative molecules as modulators of the androgen receptor.
Published International PCT Application WO 03/096980 discloses N-aryl
hydantoin derivative molecules as modulators of the androgen receptor.
Published International PCT Application 03/011824 discloses N-naphthyl
hydantoin derivative molecules as modulators of the androgen receptor.
Published International PCT Application 04/016576 discloses N-naphthyl
pyrrolidine derivative molecules as modulators of the androgen receptor.
Published International PCT Application 05/000795 discloses aniline
derivative molecules as modulators of the androgen receptor.
SUMMARY OF THE INVENTION
The present invention is directed to the discovery that certain
tetrahydocarbazole derivative compounds, as defined below, are modulators of the
androgen receptor. Accordingly, the present invention provides a compound of the
formula:

wherein,
R1 represents hydrogen, hydroxy, cyano, halo, nito, (C1-C4)alkyl, halo(C1-
C4)alkyl, halo(C1-C4)alkoxy, SCH3, C(=S)NH2, CH=NOCH3, CH=NOCH2CH3,
C(NOCH3)CH3, C(NOCH2CH3)CH3, CH=NOH, CORla, OR1b, S02R1c, NHCORld,
or a 5 to 6 membered heteroaryl group optionally substituted with 1 or 2
substituents selected from the group consisting of amino, cyano, (C1-C4)alkyl, (C1-
C4)alkoxy, halo, halo(C1-C4)alkyl, or halo(C1-C4)alkoxy;

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Rla represents hydrogen, amino, hydroxy, (C1-C4)alkyl, (C1-C4)aIkoxy, or
haIo(C1-C4)alkyl;
RIb represents (C1-C4)alkyl, cyclopropyl, or cyclopropylmethyl;
Rlc represents amino or (C1-C4)alkyl;
Rld represents (C1-C4)alkoxy;
R2 represents hydrogen, halo, (C1-C4)alkyl, or (C1-C4)alkoxy, or R1 and R2
together form a group of the formula

R3 represents NHCOR3" or NHS02R3b;
R3a and R3b each independently represent at each occurrence (C1-C6)alkyl,
halo(C1-C4)alkyl, (C1-C4)alkoxy, cyclopropyl, cyclobutyl, NH-(C1-C4)alkylamine,
NJN-(C1-C6)dialkylamine, or N(CH3)OCH3; and
R4 represents a phenyl group optionally substituted with 1 or 2 substituents
selected from the group consisting of amino, hydroxy, cyano, halo, nitro, (C1-
C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, NH-(C1-
C4)alkylamine, N,N-(C1-C4)dialkylamine, NHSO2CH3, or COOCH3; or a 5 to 6
memebered heteroaryl group optionally substituted with 1 or 2 substituents
independently selected from the group consisting of amino, (C1-C4)alkyl, halo, or
hydroxy
or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a method of treating
a disorder or condition susceptible to androgen receptor modulation, comprising
administering to a patient in need thereof an effective amount of a compound of
Formula I, or a pharmaceutically acceptable salt thereof. More particularly, the
present invention provides a method of treating reduced muscle mass or strength,
frailty, hypogonadism, osteoporosis, osteopenia, reduced bone mass or density (as
occurs independently or as a result of androgen deprivation therapy), bone fractures,
sarcopenia, Age Related Functional Decline (ARFD), reduced libido, male or

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female sexual dysfunction, erectile dysfunction, depression, prostate cancer,
decreased cognitive ability, or lethargy, comprising administereing to a patient in
need thereof an effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof. As a more particular aspect, the present
invention provides a method for treating frailty, osteoporosis, osteopenia, prostate
cancer, and male or female sexual dysfunction comprising administereing to a
patient in need thereof an effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof.
Further, the present invention provides the use of a compound of Formula I,
or a pharmaceutically acceptable salt thereof, as an agent for the treatment of
reduced muscle mass or strength, frailty, hypogonadism, osteoporosis, osteopenia,
reduced bone mass or density (as occurs independently or as a result of androgen
deprivation therapy), bone fractures, sarcopenia, Age Related Functional Decline
(ARFD), reduced libido, male or female sexual dysfunction, erectile dysfunction,
depression, prostate cancer, decreased cognitive ability, or lethargy. More
particularly, the invention provides the use of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, as an agent for the treatment of frailty,
osteoporosis, osteopenia, or male or female sexual dysfunction.
In another embodiment, the present invention provides the use of a
compound of Formula I, or a pharmaceutically acceptable salt thereof, for the
manufacture of a medicament for the treatment of a disorder or condition
susceptible to androgen receptor modulation. In particular, the present invention
provides the use of a compound of Formula I, or a pharmaceutically acceptable salt
thereof, for the manufacture of a medicament for the treatment of reduced muscle
mass or strength, frailty, hypogonadism, osteoporosis, osteopenia, reduced bone
mass or density (as occurs independently or as a result of androgen deprivation
therapy), bone fractures, sarcopenia, Age Related Functional Decline (ARFD),
reduced libido, male or female sexual dysfunction, erectile dysfunction, depression,
prostate cancer, decreased cognitive ability, or lethargy. More particularly, the
present invention provides the use of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for

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the treatment of frailty, osteoporosis, osteopenia, or male or female sexual
dysfunction.
In addition, the present invention provides pharmaceutical compositions
comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof,
in combination with a pharmaceutically acceptable carrier, diluent or excipient.
More particularly, the present invention provides pharmaceutical compositions for
the treatment of frailty, osteoporosis, osteopenia, or male or female sexual
dysfunction, comprising a compound of Formula I, or a pharmaceutically acceptable
salt thereof, in combination with a pharmaceutically acceptable carrier, diluent or
excipient.
The present invention also encompasses novel intermediates, reagents, and
processes useful for the synthesis of the compounds of Formula I as well as a
compound of Formula I for use in therapy.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds with affinity for AR, which
could be used to modulate (i.e., agonize, partially agonize, partially antagonize, or
antagonize) receptor activity and gene expression, thereby influencing physiological
functions related to Androgen hormone levels and/or AR activity. In particular,
compounds of Formula (I) are potent AR ligands, which preferably agonize the
androgen receptor. In addition, particularly preferred compounds of Formula (I)
selectively bind to AR with greater affinity relative to the other steroid hormone
receptors. More particularly, the compounds of the present invention are selective
androgen receptor modulators (SARMs) which display both androgenic and
antiandrogenic properties, acting as agonists of AR in some tissues while
antagonizing AR in yet other tissues. Alternatively, the present invention provides
as a more partiuclar embodiment SARMs which display agonist activity in tissues
such as muscle or bone, yet only partial agonist activity in tissues such as the
prostate or seminal vesicles. In this regard, such ligands are believed to be useful in
treating or preventing a multitude of disorders and conditions susceptible to AR
modulation. Thus, methods for the treatment or prevention of disorders or
conditions susceptible to AR modulation constitute an important embodiment of the

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present invention. As a particularly preferred aspect, the present invention provides
compounds useful as SARMs.
It is also understood that many of the compounds of the present invention
may exist as pharmaceutically acceptable salts and, as such, pharmaceutically
acceptable salts are therefore included within the scope of the present invention.
The term "pharmaceutically acceptable salt" as used herein, refers to salts of the
compounds of the present invention, which are substantially non-toxic to living
organisms. Typical pharmaceutically acceptable salts include those salts prepared
by reaction of the compounds of the present invention with a pharmaceutically
acceptable mineral or organic acid or an organic or inorganic base. Such salts are
known as acid addition and base addition salts. It is further understood by the
skilled reader that salt forms of pharmaceutical compounds are commonly used
because they are often more readily crystallized, or more readily purified, than are
the free bases. In all cases, the use of the pharmaceutical compounds of the present
invention as salts is contemplated in the description herein. Hence, it is understood
that where compounds of the present invention are capable of forming salts, the
pharmaceutically acceptable salts and isoforms thereof are encompassed in the
names or structures provided herein. Acids and bases suitable for the preparation of
pharmaceutically acceptable salts, as well as procedures for preparing such salts, are
well within the knowledge of those skilled in the art. See for example, Stahl et al.,
"Handbook of Pharmaceutical Salts: Properties, Selection and Use," VCHA/Wiley-
VCH, (2002); Gould, P.L., "Salt selection for basic drugs," International Journal of
Pharmaceutics, 33: 201-217 (1986); Berge et al, "Pharmaceutical Salts," Journal
of Pharmaceutical Sciences, 66, No. 1, (January 1977); Bastin et al. "Salt Selection
and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic
Process Research and Development, 4: 427-435 (2000).
As used herein, the term "stereoisomer" refers to a compound made up of
the same atoms bonded by the same bonds but having different three-dimensional
structures which are not interchangeable. The three-dimensional structures are
called configurations. As used herein, the term "enantiomer" refers to one of two
stereoisomers whose molecules are nonsuperimposable mirror images of one
another. The term "chiral center" refers to a carbon atom to which four different

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groups are attached. As used herein, the term "diastereomers" refers to
stereoisomers which are not enantiomers. In addition, two diastereomers which
have a different configuration at only one chiral center are referred to herein as
"epimers". The terms "racemate", "racemic mixture" or "racemic modification"
refer to a mixture of equal parts of enantiomers.
The compounds of the present invention may have one or more chiral
centers and may, therefore, exist in a variety of stereoisomeric configurations. As a
consequence of these chiral centers the compounds of the present invention may
occur as racemates, mixtures of enantiomers, and as individual enantiomers as well
as diastereomers and mixtures of diastereomers. All such racemates, enantiomers,
and diastereomers are within the scope of the present invention. Enantiomers of the
compounds provided by the present invention can be resolved, for example, by one
of ordinary skill in the art using standard techniques such as those described by J.
Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons,
Inc., 1981. The terms "R" and "S" are used herein as commonly used in organic
chemistry to denote specific configuration of a chiral center. The term "R" (rectus)
refers to that configuration of a chiral center with a clockwise relationship of group
priorities (highest to second lowest) when viewed along the bond from the chiral
carbon toward the lowest priority group. The term "S" (sinister) refers to that
configuration of a chiral center with a counterclockwise relationship of group
priorities (highest to second lowest) when viewed along the bond from the chiral
carbon toward the lowest priority group. The priority of groups is based upon their
atomic number (in order of decreasing atomic number). A partial list of priorities
and a discussion of stereochemistry is contained in "Nomenclature of Organic
Compounds: Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages
103-120.
The specific stereoisomers and enantiomers of compounds of the present
invention can be prepared by one of ordinary skill in the an utilizing well known
techniques and processes, such as those disclosed by Eliel and Wilen,
"Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, Chapter
7; Separation of Stereoisomers, Resolution, Racemization; and by Collet and Wilen,
"Enantiomers, Racemates, and Resolutions", John Wiley & Sons, Inc., 1981. For

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example, specific stereoisomers and ehantiomers can be prepared by stereospecific
syntheses using enantiomerically and geometrically pure, or enantiomerically or
geometrically enriched starting materials. In addition, the specific stereoisomers
and enantiomers can be resolved and recovered by techniques such as
chromatography on chiral stationary phases, enzymatic resolution or fractional
recrystallization of addition salts formed by reagents used for that purpose.
The term "enantiomeric enrichment" as used herein refers to the increase in
the amount of one enantiomer as compared to the other. A convenient method of
expressing the enantiomeric enrichment achieved is the concept of enantiomeric
excess, or "ee", which is found using the following equation:

wherein E1 is the amount of the first enantiomer and E2 is the amount of the second
enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is
present in a racemic mixture, and an enantiomeric enrichment sufficient to produce
a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%.
However, if the final ratio is 90:10, the ee with respect to the first enantiomer is
80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most
preferred and an ee of greater than 99% is most especially preferred. Enantiomeric
enrichment is readily determined by one of ordinary skill in the art using standard
techniques and procedures, such as gas or high performance liquid chromatography
with a chiral column. Choice of the appropriate chiral column, eluent and
conditions necessary to effect separation of the enantiomeric pair is well within the
knowledge of one of ordinary skill in the art. In addition, the enantiomers of
compounds of Formula I can be resolved by one of ordinary skill in the art using
standard techniques well known in the art, such as those described by J. Jacques, et
al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981.
Where used herein, the term "Pg" refers to a suitable oxygen or nitrogen
protecting group. Suitable oxygen or nitrogen protecting groups, as used herein,
refers to those groups intended to protect or block the oxygen or nitrogen group
against undesirable reactions during synthetic procedures. Whether the term "Pg",

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as used herein, represents an oxygen protecting group or a nitrogen protecting group
will be readily apparent to the ordinarily skilled artisan. The suitability of the
oxygen or nitrogen protecting group used will depend upon the conditions that will
be employed in subsequent reaction steps wherein protection is required, and is well
within the knowledge of one of ordinary skill in the art. Commonly used nitrogen
and oxygen protecting groups are disclosed in Greene, "Protective Groups In
Organic Synthesis, 3rd Edition" (John Wiley & Sons, New York (1999)).
As used herein, the following terms have the meanings indicated: "i.v."
refers to intravenously; "p.o." refers to orally; "i.p." refers to intraperitoneally;
"s.c." refers to subcutaneously; "eq" or "equiv." refers to equivalents; "g" refers to
grams; "Kg" refers to kilograms; "mg" refers to milligrams; "µg" refers to
micrograms; "L" refers to liters; "mL" refers to milliliters; "µL" refers to
microliters; "mol" refers to moles; "mmol" refers to millimoles; "M" refers to
molar; "mM" refers to millimolar; "nM" refers to nanomolar; "µM" refers to
micromolar; "N" refers to normal; "psi" refers to pounds per square inch; "mm Hg"
refers to millimeters of mercury; "min" refers to minutes; "h" or "hr" or "hrs."
refers to hours; "°C" refers to degrees Celsius; "5" refers to part per million down-
field from tetramethylsilane; "MHz" refers to megahertz; "TLC" refers to thin layer
chromatography; "HPLC" refers to high performance liquid chromatography; "Rt"
refers to retention time; "UV" refers to ultraviolet; "nm" refers to nanometer;
"Anal" refers to analytical; "Calcd" refers to calculated; "mp" or "m.p." refers to
melting point; "CDCl3" refers to chloroform-d; "THF" refers to tetrahydrofuran;
"DMF" refers to N,N-dimethylforrnamide; "DMSO" refers to dimethyl sulfoxide;
"DMSO-d6" refers to dimethyl-d6-sulfoxide; "EtOAc" refers to ethyl acetate;
"MeOH" refers to methanol; "EtOH" refers to ethanol; "i-PrOH" refers to
isopropanol; "Et2O" refers to diethyl ether; "MTBE" refers to tert-butyl methyl
ether; "DMEA" refers to N,.N-dimethylethylamine; "Na2SO4" refers to sodium
sulfate; "MgSO4" refers to magnesium sulfate; "Na2CO3" refers to sodium
carbonate; "K2CO3" refers to potassium carbonate; "NaHCO3 refers to sodium
bicarbonate; Na2S2O3 refers to sodium thiosulfate; "NaOH" refers to sodium
hydroxide; "HCl" refers to hydrogen chloride or hydrochloric acid; "H2O2" refers to
hydrogen peroxide; "NaH" refers to sodium hydride; "LDA" refers to lithium

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diisopropylamide; "CH2Cl2" refers to dichloromethane; "NH4OH" refers to
ammonium hydroxide; "NH4Cl" refers to ammonium chloride; "NH3" refers to
ammonia; and "Al-Ni" refers to aluminum-nickel.
Also as used herein, "Kd" refers to the equilibrium dissociation constant for
a ligand-receptor complex; "Ki" refers to the equilibrium dissociation constant for
drug-receptor complex, and is an indication of concentration of drug that will bind
to half the binding sites at equilibrium; "IC50" refers to the concentration of an
agent which produces 50 % of the maximal inhibitory response possible for that
agent; "IC50" also refers to the concentration of an agent which produces 50%
displacement of ligand binding to the receptor; "EC50" refers to the concentration
of an agent which produces 50% of the maximal response possible for that agent;
and "ED50" refers to the dose of an administered therapeutic agent which produces
50% the maximal response for that agent..
As used herein the term "(C1-C4)alkyl" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not
limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term "(C1-C6)alkyl" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not
limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-
hexyl, and the like. It is understood that the term "(C1-C4)alkyl" is included within
the definition of "(C1-C6)alkyl".
As used herein, the terms "Me", "Et", "Pr", "i-Pr", "Bu" and "t-Bu" refer to
methyl, ethyl, propyl, isopropyl, butyl and tert-butyl respectively.
As used herein, the term "(C1-C4)alkoxy" refers to an oxygen atom bearing
a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms
and includes, but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-
butoxy, and the like. As used herein the term "(C1-C6)alkoxy" refers to an oxygen
atom bearing a straight or branched, monovalent, saturated aliphatic chain of 1 to 6
carbon atoms and includes, but is not limited to methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, n-pentoxy, n-hexoxy, and the like. It is understood that the
term "(C1-C4)alkoxy" is included within the definition of "(C1-C6)alkoxy".

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As used herein, the terms "halo", "halide" or "hal" or "Hal" refer to a
chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein.
As used herein, the term "halo(C1-C4)alkyr' refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 4 carbon atoms bearing one or more
halo groups attached to one or more of the carbon atoms. As used herein, the term
"halo(C1-C6)alkyl" refers to a straight or branched, monovalent, saturated aliphatic
chain of 1 to 6 carbon atoms bearing one or more halo groups attached to one or
more of the carbon atoms. It is understood that the term "halo(C1-C4)alkyl" is
included within the definition of "halo(C1-C6)alkyl". Typical examples of
"halo(C1-C4)alkyl" or "halo(C1-C6)alkyl" include CF3, CHF2, CH2F, and the like.
As used herein, the term "halo(C1-C4)alkoxy" refers to an oxygen atom bearing a
straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms,
further bearing one or more halo groups attached to one or more of the carbon
atoms. As used herein, the term "halo(C1-C6)alkoxy" refers to an oxygen atom
bearing a straight or branched, monovalent, saturated aliphatic chain of 1 to 6
carbon atoms, further bearing one or more halo groups attached to one or more of
the carbon atoms. It is understood that the term "halo(C1-C4)a]koxy" is included
within the definition of "halo(C1-C6)alkoxy". Typical examples of "halo(C1-
C4)alkoxy" or "halo(C1-C6)alkoxy" include OCF3, OCHF2, OCH2F, and the like.
As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic
radical and includes groups such as phenyl, naphthyl and the like.
As used herein, the term "heteroaryl" refers to a 5 to 6 membered
monovalent monocyclic aromatic radical containing one to four heteroatoms each
independently selected from the group consisting of oxygen, sulfur, and nitrogen. It
is understood that the remaining atoms of the radical are carbon and that the radical
may be attached, for example to the structure of Formula I, through any atom of the
cyclic system which provides for a stable structure. Examples of typical
heterocyclic groups include furanyl, thiophenyl, pyrrolyl, tetrazolyl, thiazolyl,
isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl,
pyrazolyl, pyridinyl, pyradazinyl, pyrimidinyl, pyrazinlyl, and triazinyl, and the like.
As used herein the term "N,N-(C1-C4)dialkylamine" refers to a nitrogen
atom substituted with two straight or branched, monovalent, saturated aliphatic

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chains of 1 to 4 carbon atoms. Included within the term "N,N-(C1-C6)dialkylamine"
are -N(CH3)2, -N(CH3)CH2CH3, -N(CH2CH3)2, -N(CH2CH2CH3)2, -
N(CH2CH2CH2CH3)2, and the like. The term "NH-(C1-C4) alkylamine" refers to a
nitrogen atom substituted with a single straight or branched, monovalent, saturated
aliphatic chains of 1 to 4 carbon atoms.
As will be appreciated by one of ordinary skill in the art, some of the
heterocyclic moieties of the compounds of Formula I may exist as positional
isomers and as tautomeric forms. For example, tetrazole is known to exist as
tautomeric structures:

Similarly, triazoles exist in two positional isomeric forms, the 1,2,4-triazole
and the 1,2,3-triazole. Each form of which may exist as tautomeric structures. The
present invention contemplates all positional isomers, individual tautomeric forms,
as well as any combination thereof.
The designation " " refers to a bond that protrudes forward out of the
plane of the page.
The designation " """"II " refers to a bond that protrudes backward out of
the plane of the page.
As used herein the term "androgen receptor" or "AR" refers to the androgen
receptor subtype, of the larger class of nuclear hormone receptors, which binds the
androgen hormone testosterone, as its cognate ligand. The term "androgen receptor
modulator" or "androgen modulator" or "AR modulator" as used herein, refers to
those nuclear hormone receptor ligands which bind to the AR subtype and modulate
(i.e. agonize, partially agonize, partially antagonize, antagonize) the receptor
activity. As a particular embodiment, the present invention provides selective
androgen receptor modulators (SARMs) which display androgenic properties in
certain tissues (e.g. muscle and/or bone) while concomitantly displaying
antiandrogenic effects in other tissues such as the prostate or liver. Alternatively,
SARMs of the present invention may display agonist activity in anabolic tissues

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20
such as muscle or bone, yet display only parital agonist activity or antagonist
activity in tissues such as the prostate or seminal vesicles.
As appreciated by one of skill in the art, physiological disorders may present
as a "chronic" condition, or an "acute" episode. The term "chronic", as used herein,
means a condition of slow progress and long continuance. As such, a chronic
condition is treated when it is diagnosed and treatment continued throughout the
course of the disease. Conversely, the term "acute" means an exacerbated event or
attack, of short course, followed by a period of remission. Thus, the treatment of
pathological disorders contemplates both acute events and chronic conditions. In an
acute event, compound is administered at the onset of symptoms and discontinued
when the symptoms disappear. As described above, a chronic condition is treated
throughout the course of the disease.
As used herein the term "patient" refers to a mammal, such a mouse, gerbil,
guinea pig, rat, dog or human. It is understood, however, that the preferred patient
i:s a human. As used herein, the terms "treating", "treatment", or "to treat" each
mean to alleviate symptoms, eliminate the causation of resultant symptoms either
on a temporary or permanent basis, and to prevent, slow the appearance, or reverse
the progression or severity of resultant symptoms of the named disorder or
condition. As such, the methods of treatment provided by this invention encompass
both therapeutic and prophylactic administration.
As used herein the term "effective amount" refers to the amount or dose of
the compound, upon single or multiple dose administration to the patient, which
provides the desired effect in the patient undergoing diagnosis or treatment. An
effective amount can be readily determined by the attending diagnostician, as one
skilled in the art, by the use of known techniques and by observing results obtained
under analogous circumstances. In determining the effective amount or dose of
compound administered, a number of factors are considered by the attending
diagnostician, including, but not limited to: the species of mammal; its size, age,
and general health; the degree of involvement or the severity of the disease
involved; the response of the individual patient; the particular compound
administered; the mode of administration; the bioavailability characteristics of the

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preparation administered; the dose regimen selected; the use of concomitant
medication; and other relevant circumstances.
A typical daily dose will contain as an effective amount about 0.001 mg/kg
to about 100 mg/kg of an active compound of the present invention. Preferably, the
daily dose will contain as an effective amount about 0.05 mg/kg to about 50 mg/kg
of the compound of the present invention.
Oral administration is a preferred route of administering the compounds
employed in the present invention whether administered alone, or in combination
with other therapeutic agents. Oral administration, however, is not the only route,
nor even the only preferred route. Other preferred routes of administration include
transdermal, percutaneous or subcutaneous, pulmonary, intravenous, intramuscular,
intranasal, intraperitoneal, buccal, sublingual, or intrarectal routes. Where the AR
modulator is administered in combination with other compounds, one of the
compounds may be administered by one route, such as oral, and the other may be
administered by the transdermal, percutaneous or subcutaneous, pulmonary,
intravenous, intramuscular, intranasal, intraperitoneal, buccal, sublingual, or
intrarectal route, as particular circumstances require. The route of administration
may be varied in any way, limited by the physical properties of the compounds and
me convenience of the patient and the caregiver.
The compounds employed in the present invention may be administered as
pharmaceutical compositions and, therefore, pharmaceutical compositions
incorporating compounds of the present invention are important embodiments of
the present invention. Such compositions may take any physical form that is
pharmaceutically acceptable, but orally administered pharmaceutical compositions
are particularly preferred. Such pharmaceutical compositions contain, as an active
ingredient, an effective amount of a compound of Formula I, including the
pharmaceutically acceptable salts and hydrates thereof, which effective amount is
related to the daily dose of the compound to be administered. Each dosage unit may
contain the daily dose of a given compound, or may contain a fraction of the daily
dose, such as one-half or one-third of the dose. The amount of each compound to be
contained in each dosage unit depends on the identity of the particular compound
chosen for the therapy, and other factors such as the indication for which it is given.

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The pharmaceutical compositions of the present invention may be formulated so as
to provide quick, sustained, or delayed release of the active ingredient after
administration to the patient by employing well known procedures.
The following discussion provides typical procedures for preparing
pharmaceutical compositions incorporating the compounds of the present invention.
However, the following is in no way intended to limit the scope of the
pharmaceutical compositions provided by the present invention.
Compositions are preferably formulated in a unit dosage form, each dosage
containing from about 1 to about 500 mg of each compound individually or in a
single unit dosage form, more preferably about 5 to about 300 mg (for example 25
mg). The term "unit dosage form" refers to a physically discrete unit suitable as
unitary dosages for a patient, each unit containing a predetermined quantity of
active material calculated to produce the desired therapeutic effect, in association
with a suitable pharmaceutical carrier, diluent, or excipient.
The composition of the present invention is a synergistic composition and
exhibits surprising and unexpected results.
The inert ingredients and manner of formulation of the pharmaceutical
compositions are conventional. The usual methods of formulation used in
pharmaceutical science may be used here. All of the usual types of compositions
may be used, including tablets, chewable tablets, capsules, solutions, parenteral
solutions, intranasal sprays or powders, troches, suppositories, transdermal patches
and suspensions. In general, compositions contain from about 0.5% to about 50%
of the compound in total, depending on the desired doses and the type of
composition to be used. The amount of the compound, however, is best defined as
the "effective amount", that is, the amount or dose of each compound which
provides the desired effect to the patient in need of such treatment. The activity of
the compounds employed in the present invention does not depend on the nature of
the composition, hence, the compositions are chosen and formulated solely for
convenience and economy.
Capsules are prepared by mixing the compound with a suitable diluent and
lolling the proper amount of the mixture in capsules. The usual diluents include
inert powdered substances such as starches, powdered cellulose especially
crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and
sucrose, grain flours, and similar edible powders.

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Tablets are prepared by direct compression, by wet granulation, or by dry
granulation. Their formulations usually incorporate diluents, binders, lubricants and
disintegrators as well as the compound. Typical diluents include, for example,
various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate,
inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose
derivatives are also useful. Typical tablet binders are substances such as starch,
gelatin and sugars such as lactose, fructose, glucose and the like. Natural and
synthetic gums are also convenient, including acacia, alginates, methylcellulose,
polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes
can also serve as binders.
Tablets are often coated with sugar as a flavor and sealant. The compounds
may also be formulated as chewable tablets, by using large amounts of pleasant-
tasting substances such as mannitol in the formulation, as is now well-established
practice. Instantly dissolving tablet-like formulations are also now frequently used
to assure that the patient consumes the dosage form, and to avoid the difficulty in
swallowing solid objects that bothers some patients.
A lubricant is often necessary in a tablet formulation to prevent the tablet
and punches from sticking in the die. The lubricant is chosen from such slippery
solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated
vegetable oils.
Tablet disintegrators are substances which swell when wetted to break up
the tablet and release the compound. They include starches, clays, celluloses, algins
and gums. More particularly, corn and potato starches, methylcellulose, agar,
bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic
acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used,
as well as sodium lauryl sulfate.
Enteric formulations are often used to protect an active ingredient from the
strongly acid contents of the stomach. Such formulations are created by coating a
solid dosage form with a film of a polymer which is insoluble in acid environments,
and soluble in basic environments. Exemplary films are cellulose acetate phthalate,
polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and
hydroxypropyl methylcellulose acetate succinate.

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When it is desired to administer the compound as a suppository, the usual
bases may be used. Cocoa butter is a traditional suppository base, which may be
modified by addition of waxes to raise its melting point slightly. Water-miscible
suppository bases comprising, particularly, polyethylene glycols of various
molecular weights are in wide use, also.
Transdermal patches have become popular recently. Typically they
comprise a resinous composition in which the drugs will dissolve, or partially
dissolve, which is held in contact with the skin by a film which protects the
composition. Many patents have appeared in the field recently. Other, more
complicated patch compositions are also in use, particularly those having a
membrane pierced with innumerable pores through which the drugs are pumped by
osmotic action.
It is understood by one of ordinary skill in the art that the procedures as
described above can also be readily applied to a method of treating disorders
susceptible to androgen receptor modulation, and particularly frailty, osteoporosis,
osteopenia, and male or female sexual dysfunction.
When used in conjunction with the methods and uses of the present
invention, the compounds and compositions of the present invention may be
administered either alone, or in combination with conventional therapeutic agents
used to treat the particular disorder or condition. Where the compounds or
compositions of the present invention are used as part of a combination, the
compound or composition comprising Formula I may be administered separately or
as part of a formulation comprising the therapeutic agent with which it is to be
combined.
Combination therapy for Osteoporosis:
Conventional therapeutic agents for the treatment of osteoporosis may
advantageously be combined with the compounds of Formula I, or compositions
comprising a compound of Formula I. Conventional agents for the treatment of
osteoporosis include hormone replacement therapies such as conjugated equine
estrogen (Premarin®), synthetic conjugated estrogen (Cenestin®), esterified
estrogen (Estratab® or Menest®), estropiate (Ogen® or Ortho-est®); as well as

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transdermal estradiol preparations such as Alora®, Climara®, Estraderm®, and
Vivelle®. Combination estrogen-progestin formulations are also available for the
treatment of osteoporosis including Prempro® (conjugated equine estrogen and
medroxyprogesterone acetate), Premphase® (conjugated equine estrogen and
norgestimate), Ortho-Prefest® (estradiol and norgestimate), Femhrt® (ethinyl
estradiol and norethindrone acetate), and Combipatch (transdermal estradiol and
norethindrone acetate). Other conventional osteoporosis treatments which may be
combined with the compounds or compositions of the present invention include
bisphosphonates such as alendronate (Fosamax®), risedronate (Actonel®), and
pamidronate (Aredia®); selective estrogen receptor modulators (SERMs) such as
raloxifene (Evista®); calcitonin (Calcimar® or Miacalcin®); parathyroid hormone
(Forteo®); calcium; Vitamin D; diuretics (to reduce Ca2+ excretion); fluoride; and
androgens (testosterone or 5α-dihydrotestosterone).
Thus, a formulation for combination therapy in treating osteoporosis
comprises:
Ingredient (A1): a compound of formula I;
Ingredient (A2): one or more co-agents that are conventional for
the treatment of osteoporosis selected from the group consisting of
Premarin®, Cenestin®, Estratab®, Menest®, Ogen®, Ortho-est®,
Alora®, Climara®, Estraderm®, Vivelle®, Prempro®, Premphase®,
Ortho-Prefest®, Femhrt®, Combipatch®, Fosamax®), Actonel®,
Aredia®); Evista®; Calcimar®, Miacalcin®, Forteo®, calcium,
Vitamin D, diuretics, fluoride, testosterone, and 5a-dihydrotestosterone;
and optionally
Ingredient (A3): a pharmaceutically acceptable carrier, diluent or
excipient.
Particular Aspects of the Invention
The following lists set out several groupings of particular substituents and
particular variables for compounds of Formula I. It will be understood that

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26
compounds of Formula I having such particular substituents or variables, as well as
methods and uses employing such compounds, represent particular aspects of the
present invention. It will be further understood that each of these groupings of
particular substituents and particular variables may be combined with other
provided groupings, to create still additional particular aspects of the compounds,
methods and uses of the present invention.
Thus, a particular aspect of the present invention is one wherein the
compound of Formula I, is one wherein
(a) R1 represents cyano, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, halo(C1-
C4)alkoxy, C(=S)NH2, CH=NOCH3, CH=NOCH2CH3,
C(NOCH3)CH3, C(NOCH2CH3)CH3, CORla, ORlb, S02R,c,
NHCORld, or a 5 to 6 membered heteroaryl group optionally
substituted with 1 or 2 substituents independently selected from the
group consisting of amino, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, halo,
halo(C1-C4)alkyl, or halo(C1-C4)alkoxy;
(b) R1 represents cyano, halo, (C1-C4)alkyl, CF3, OCF3, CHF2, OCHF2)
CH=NOCH3, CH=NOCH2CH3, C(NOCH3)CH3,
C(NOCH2CH3)CH3, CORla, ORlb, S02R,c, NHCORld, or a 5 to 6
membered heteroaryl group optionally substituted with 1 or 2
substituents independently selected from the group consisting of
amino, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, halo, halo(C1-C4)alkyl,
or halo(C1-C4)alkoxy;
(c) R1 represents cyano, halo, (C1-C4)alkyl, CF3, OCF3, CHF2, OCHF2,
CH=NOCH3, CH=NOCH2CH3, C(NOCH3)CH3,
C(NOCH2CH3)CH3, CORla wherein Rla represents hydrogen,
hydroxyl, methyl, methoxy, ethoxy, amino, or trifluoromethyl; OR!b
wherein Rlb represents methyl, ethyl, propyl, isopropyl, cyclopropyl,
or cyclopropylmethyl; S02R1c wherein Rlc represents methyl or
ethyl; NHCORld wherein Rld represents methoxy or ethoxy; or a 5 to
6 membered heteroaryl group optionally substituted with 1 or 2
substituents independently selected from the group consisting of

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amino, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, halo, halo(Ct-C4)alkyl,
or halo(C1-C4)alkoxy;
(d) R1 represents cyano, halo, (C1-C4)alkyl, CF3, OCF3, CHF2, OCHF2)
CH=NOCH3, CH=NOCH2CH3, C(NOCH3)CH3,
C(NOCH2CH3)CH3, CORla wherein Rla represents hydrogen,
hydroxyl, methyl, methoxy, ethoxy, amino, or trifluoromethyl; ORlb
wherein Rlb represents methyl, ethyl, propyl, isopropyl, cyclopropyl,
or cyclopropylmethyl; SO2R1c wherein Rlc represents methyl or
ethyl; NHCORld wherein Rld represents methoxy or ethoxy; or a 5 to
6 membered heteroaryl group selected from the group consisting of
furanyl, thiophenyl, pyrrolyl, tetrazolyl, thiazolyl, isothiazolyl,
oxadiazolyl, triazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl,
pyrazolyl, pyridinyl, pyradazinyl, pyrimidinyl, pyrazinlyl, and
triazinyl, each optionally substituted with 1 or 2 substituents
independently selected from the group consisting of amino, cyano,
(C1-C4)alkyl, (C1-C4)alkoxy, halo, halo(C1-C4)aIkyl, or halo(C1-
C4)alkoxy;
(e) R1 represents cyano, halo, (C1-C4)alkyl, CF3, OCF3, CHF2, OCHF2,
CH=NOCH3, CH=NOCH2CH3, C(NOCH3)CH3,
C(NOCH2CH3)CH3, COR1a wherein R1a represents hydrogen,
hydroxyl, methyl, methoxy, ethoxy, amino, or trifluoromethyl; ORlb
wherein Rlb represents methyl, ethyl, propyl, isopropyl, cyclopropyl,
or cyclopropylmethyl; S02Rlc wherein R1,C represents methyl or
ethyl; NHCOR1d wherein R1d represents methoxy or ethoxy; or a 5 to
6 membered heteroaryl group selected from the group consisting of
thiazolyl, thiadiazolyl, isoxazolyl, pyridinyl, pyradazinyl,
pyrimidinyl, each optionally substituted with 1 or 2 substituents
independently selected from the group consisting of amino cyano,
(C1-C4)alkyl, (C1-C4)alkoxy, halo, halo(C1-C4)alkyl, or halo(C1-
C4)alkoxy;
(f) Rl represents cyano, bromo, chloro, fluoro, methyl, CF3, OCF3,
CHF2, OCHF2, CH=NOCH3, CH=NOCH2CH3, C(NOCH3)CH3,

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-28-
C(NOCH2CH3)CH3, CORla wherein Rla represents hydrogen,
hydroxyl, methyl, methoxy, ethoxy, amino, or trifluoromethyl; OR,b
wherein RIb represents methyl, ethyl, propyl, isopropyl, cyclopropyl,
or cyclopropylmethyl; SO2R1c wherein R1c represents methyl or
ethyl; NHCORld wherein Rld represents methoxy or ethoxy; or a 5 to
6 membered heteroaryl group selected from the group consisting of
thiazolyl, thiadiazolyl, isoxazolyl, pyridinyl, pyradazinyl,
pyrimidinyl, each optionally substituted with a first substituent
selected from the group consisting of cyano, amino, (C1-C4) alkyl, or
halo and a second substituent that is (C1-C4)alkyl;
(g) R1 represents cyano, bromo, chloro, fluoro, methyl, CF3, OCF3,
CHF2, OCHF2, CH=NOCH3, CH=NOCH2CH3, C(NOCH3)CH3,
CCNOCH2CH3)CH3, CORla wherein Rla represents hydrogen,
hydroxyl, methyl, methoxy, ethoxy, amino, or trifluoromethyl; ORIb
wherein R1b represents methyl, ethyl, propyl, isopropyl, cyclopropyl,
or cyclopropylmethyl; SO2R1c wherein R1c represents methyl or
ethyl; NHCORld wherein Rld represents methoxy or ethoxy; or a 5 to
6 membered heteroaryl group selected from the group consisting of
thiazolyl, thiadiazolyl, isoxazolyl, pyridinyl, pyradazinyl,
pyrimidinyl, each optionally substituted with a first substituent
selected from the group consisting of amino, methyl, or fluoro and a
second substituent that is methyl;
Additional particular aspects of the present invention are provided by
compounds of Formula I wherein:
(a) R2 represents hydrogen, methyl, ethyl, propyl, isopropyl, methoxy,
ethoxy, fluoro, bromo, chloro, or R1 and R2 together to form a group
of the formula a group of the formula


WO 2007/002181 PCT/US2006/024122
(b) R2 represents hydrogen, methyl, fluoro, bromo, chloro, or R1 and R2
together to form a group of the formula a group of the formula

(c) R2 represents hydrogen, methyl, ethyl, propyl, isopropyl, methoxy,
ethoxy, fluoro, bromo, or chloro; or
(d) R2 represents hydrogen, methyl, fluoro, bromo, or chloro;
Yet Additional particular aspects of the present invention are provided by
compounds of Formula I wherein:
(a) R3 represents NHCOR3a or NHSO2R3, wherein
R3a and R3b each independently represent at each occurrence methyl,
ethyl, isopropyl, CH(C2H5)2, CH(CH3)CH2CH3, CF3, CHF2,
methoxy, ethoxy, cyclopropyl, cyclobutyl, NH(CH3), N(CH3)2, or
N(CH3)OCH3;
(b) R3 represents NHCOR3a wherein R3a represents at each occurrence
methyl, ethyl, isopropyl, CH(C2H5)2, CH(CH3)CH2CH3, CF3,
methoxy, ethoxy, cyclopropyl, cyclobutyl, NH(CH3), or N(CH3)2; or
R3 represents NHSO2R3b, wherein R3b represents at each occurrence
cyclopropyl, NH(CH3), N(CH3)2, or N(CH3)OCH3; or
(c) R3 represents NHCOR3a wherein R3a represents isopropyl;
Still additional particular aspects of the present invention are provided by
compounds of Formula I wherein:
(a) R4 represents a phenyl group optionally substituted with 1 or 2
substituents independently selected from the group consisting of
amino, hydroxy, cyano, halo, nitro, methyl, methoxy, CF3, OCF3,
CHF2, OCHF2, NH(CH3), NH(C2H5), N(CH3)2, NHSO2CH3, or
COOCH3; or a 5 to 6 membered heteroaryl group optionally
substituted with 1 or 2 substituents independently selected from the
group consisting of amino, (C1-C4)alkyl, or halo;

WO 2007/002181 PCT/US2006/024122
(b) R represents a phenyl group optionally substituted with 1 or 2
substituents independently selected from the group consisting of
amino, hydroxy, cyano, halo, nitro, methyl, methoxy, CF3, OCF3,
CHF2, OCHF2, NH(CH3), NH(C2H5), N(CH3)2, NHSO2CH3, or
COOCH3; or a 5 to 6 membered heteroaryl group selected from the
group consisting of furanyl, thiophenyl, pyrrolyl, tetrazolyl, thiazolyl,
isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, oxazolyl, isoxazolyl,
imidazolyl, pyrazolyl, pyridinyl, pyradazinyl, pyrimidinyl, pyrazinlyl,
and triazinyl, optionally substituted with one or two substituents
independently selected from the group consisting of amino, (C1-
C4)alkyl, or halo;
(c) R4 represents a phenyl group optionally substituted with 1 or 2
substituents independently selected from the group consisting of
amino, hydroxy, cyano, halo, nitro, methyl, methoxy, CF3, OCF3,
CHF2, OCHF2, NH(CH3), NH(C2H5), N(CH3)2, NHSO2CH3, or
COOCH3; or a 5 to 6 membered heteroaryl group selected from the
group consisting of thiophenyl, thiazolyl, pyridinyl, or pyrazinyl,
each optionally substituted with one or two substituents
independently selected from the group consisting of amino, (C1-
C4)alkyl, or halo;
(d) R4 represents a phenyl group optionally substituted with 1 or 2
substituents independently selected from the group consisting of
amino, hydroxy, cyano, halo, nitro, methyl, methoxy, CF3, OCF3,
CHF2, OCHF2, NH(CH3), NH(C2H5), N(CH3)2, NHSO2CH3, or
COOCH3; or a 5 to 6 membered heteroaryl group selected from the
group consisting of thiophenyl, thiazolyl, pyridinyl, or pyrazinyl,
each optionally substituted with one or two substituents
independently selected from the group consisting of amino, methyl,
fluoro, or chloro;
(e) R4 represents a phenyl group optionally substituted with 1 or 2
substituents independently selected from the group consisting of
amino, hydroxy, cyano, halo, nitro, methyl, methoxy, CF3, OCF3,

WO 2007/002181 PCT/US2006/024122
CHF2, OCHF2, NH(CH3), NH(C2H5), N(CH3)2, NHSO2CH3, or
COOCH3; or a 5 to 6 membered heteroaryl group selected from the
group consisting of thiophenyl, thiazolyl, pyridinyl, or pyrazinyl,
each optionally substituted with a substituent independently selected
from the group consisting of amino, methyl, fluoro, or chloro;
Even more particular embodiments of the present invention are provided by
the compounds of Formula I(a), I(b), and I(c), below:

wherein,
R1 represents cyano, halo, (C1-C4)alkoxy, halo(C1-C4)alkoxy, CH=NOCH3,
CH=NOCH2CH3, C(NOCH3)CH3, C(NOCH2CH3)CH3, or COH;
R3 represents NHCOR3a;
R3a represents (C1-C6)alkyl, (C1-C6)alkoxy, cyclopropyl, cyclobutyl, NH-
(C1-C4)alkylamine, or N,N-(C1-C6)dialkylamine; and
R4 represents a 5 to 6 membered heteroaryl group optionally substituted with
1 or 2 substituents independently selected from the group consisting of amino, (C1-
C4)alkyl, or halo, or a pharmaceutically acceptable salt thereof.
More particular aspects of the compound Formula 1(a) are provided by
compounds wherein:
(a) R1 represents cyano, fluoro, bromo, chloro, methoxy, OCF3, OCHF2,
CH=NOCH3, CH=NOCH2CH3, C(NOCH3)CH3,
C(NOCH2CH3)CH3, or COH;
(b) R1 represents cyano, fluoro, bromo, chloro, methoxy, OCF3,
CH=NOCH3,orCOH;

WO 2007/002181 PCT/US2006/024122
(c) Rl represents cyano, bromo, methoxy, OCF3, CH=NOCH3, or COH;
(d) R1 represents cyano, methoxy, OCF3, CH=NOCH3, or COH;
(e) R1 represents cyano;
(f) R1 represents methoxy;
(g) R1 represents OCF3;
(h) R1 represents CH=NOCH3; or
(i) R1 represents COH.
Additional particular aspects of the compound Formula 1(a) are provided by
compounds wherein:
(a) R3 represents NHCOR3a wherein R3a represents (C1-C6)alkyl, (Cr
C6)alkoxy, cyclopropyl, or N,N-(C1-C6)diaUcylamine;
(b) R3 represents NHCOR3a, wherein R3a represents isopropyl,
methoxy, cyclopropyl, or N(CH3)2;
(c) R3 represents NHCOR3a, wherein R3a represents isopropyl;
(d) R3 represents NHCOR3a, wherein R3a represents methoxy;
(e) R3 represents NHCOR3a, wherein R3a represents cyclopropyl; or
(f) R3 represents NHCOR3a, wherein R3a represents N(CH3)2
Yet additional particular aspects of the compound Formula 1(a) are provided
by compounds wherein:
(a) R4 represents a 5 to 6 membered heteroaryl group seleceted from the
group consisting of furanyl, thiophenyl, pyrrolyl, tetrazolyl, thiazolyl,
isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, oxazolyl, isoxazolyl,
imidazolyl, pyrazolyl, pyridinyl, pyradazinyl, pyrimidinyl, pyrazinlyl,
and triazinyl, each optionally substituted with 1 or 2 substituents
independently selected from the group consisting of amino, (C1-
C4)alkyl, or halo;
(b) R4 represents a 5 to 6 membered heteroaryl group seleceted from the
group consisting of thiophenyl, thiazolyl, pyridinyl, or pyrazinyl
each optionally substituted with 1 or 2 substituents independently
selected from the group consisting of amino, (C1-C4)alkyl, or halo;

WO 2007/002181 PCTAJS2006/024122
(c) R4 represents a 5 to 6 membered heteroaryl group seleceted from the
group consisting of thiophenyl, thiazolyl, pyridinyl, or pyrazinyl,
each optionally substituted with 1 or 2 substituents independently
selected from the group consisting of amino, methyl, chloro, or
fluoro;
(d) R4 represents a 5 to 6 membered heteroaryl group seleceted from the
group consisting of thiophenyl, thiazolyl, pyridinyl, or pyrazinyl,
each optionally substituted with a substituent selected from the group
consisting of amino, methyl, chloro, or fluoro;
(e) R4 represents a group of the following

WO 2007/002181 PCT/US2G06/024122

Even more particular embodiments of the present invention are provided by
5 the compounds of Formula 1(b), below:

WO 2007/002181 PCT/US2006/024122
wherein,
R! represents hydrogen, hydroxy, cyano, halo, nitro, (C1-C4)alkyl,
halo(C1-C4)alkyl, halo(C1-C4)alkoxy, C(=S)NH2, CH=NOCH3, CH=NOH, CORla,
OR,b, SO2Rlc, NHCORld;
Rla represents hydrogen, amino, hydroxy, (C1-GOalkyl, (C1-
C4)alkoxy, or halo(C1-C4) alkyl;
R1b represents (C1-C4)alkyl, cyclopropyl, or cyclopropylmethyl;
R1c represents (C1-C4) alkyl;
R1d represents (C1-C4)alkoxy;
R2 represents hydrogen halo, (C1-C4)alkyl, or (C1-C4)alkoxy, or R1
and R2 together represent a group of the formula

R3 represents NHCOR3a or NHSO2R3b;
R3a and R3b each independently represent at each occurrence (C1-
C6)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, cyclopropyl, c'yclobutyl, NH-(C1-
C4)alkylamine, N,N-(C1-C6)dialkylamine, or N(CH3)OCH3; and
R4 represents a phenyl group optionally substituted with 1 or 2
substituents independently selected from the group consisting of amino, hydroxy,
cyano, halo, nitro, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-
C4)alkoxy, NH-(C1-C4)alkylamine, N,N-(C1-C6)dialkylamine, NHSO2CH3, or
COOCH3;

WO 2007/002181

PCT/US2006/024122

Additional particular aspects of the compound Formula 1(b) are provided by
compounds wherein:
(a) R1 represents hydroxy, cyano, halo, nitro, (C1-C4)alkyl,
halo(C1-C4)alkyl, halo(C1-C4)alkoxy, CH=NOCH3,
CH=NOCH2CH3, C(NOCH3)CH3, C(NOCH2CH3)CH3,
CORla, OR1b, SO2Rlc, orNHCOR1d;
(b) R1 represents hydroxy, cyano, fiuoro, chloro, bromo, nitro,
methyl, CF3, CHF2) OCF3, OCHF2, CH=NOCH3,
CH=NOCH2CH3, C(NOCH3)CH3) C(NOCH2CH3)CH3)
CORla, OR1b, SO2R1c, or NHCORld;
(c) R1 represents hydroxy, cyano, fiuoro, chloro, bromo, nitro,
methyl, CF3, CHF2, OCF3, OCHF2, CH=NOCH3,
CH=NOCH2CH3, C(NOCH3)CH3, C(NOCH2CH3)CH3,
CORla wherein R1a represents hydrogen, hydroxyl, amino,
methyl, methoxy, ethoxy, or CF3,; OR1b wherein Rlb
represents methyl, ethyl,propyl, isopropyl, cyclopropyl, or
cyclopropylmethyl; SO2RIc wherein Rlc represents methyl;
or NHCOR1d wherein Rld represents methoxy or ethoxy;
(d) R1 represents cyano, fiuoro, chloro, bromo, methyl, CF3,
CHF2, OCF3, OCHF2, CH=NOCH3, CH=NOCH2CH3,
C(NOCH3)CH3, C(NOCH2CH3)CH3, CORla wherein Rla
represents hydrogen, hydroxyl, amino, methyl, methoxy,
ethoxy, or CF3; ORlb wherein Rlb represents methyl, ethyl,
propyl, isopropyl, cyclopropyl, or cyclopropylmethyl;
SO2Rlc wherein Rlc represents methyl; or NHCORld
wherein Rld represents methoxy or ethoxy;
(e) R1 represents cyano, fiuoro, chloro, bromo, CH=NOCH3,
CH=NOCH2CH3, C(NOCH3)CH3, C(NOCH2CH3)CH3, or
OR1b wherein R1b represents methyl, ethyl, propyl, isopropyl,
cyclopropyl, or cyclopropylmethyl;
(f) R1 represents cyano;
(g) R1 represents fiuoro, bromo, or chloro;

WO 2007/002181 PCT/US2006/024122
(h) R1 represents CH=NOCH3, CH=NOCH2CH3,
C(NOCH3)CH3, or C(NOCH2CH3)CH3;
(i) R1 represents ORIb wherein Rlb represents methyl, ethyl,
propyl, isopropyl, cyclopropyl, or cyclopropylmethyl;
Yet Additional particular aspects of the compounds of Formula 1(b) are
provided by compounds wherein:
(a) R2 represents hydrogen bromo, chloro, fluoro, methyl, or
methoxy, or R1 and R2 together represent a group of the
formula

(b) R2 represents hydrogen, bromo, chloro, or fluoro;
(c) R2 represents hydrogen, methyl or methoxy;
(d) R2 represents hydrogen or R1 and R2 together represent a
group of the formula

(e) R2 represents hydrogen.
Yet Additional particular aspects of the compounds of Formula 1(b) are
provided by compounds wherein:
(a) R3 represents NHCOR3a or NHSO2R3b, wherein R3! and R3b
each independently represent at each occurrence methyl,
ethyl, isopropyl, CH(C2H5)2, CH(CH3)CH2CH3, CF3, CHF2,
methoxy, ethoxy, cyclopropyl, cyclobutyl, NH(CH3),
N(CH3)2,or N(CH3)OCH3;
(b) R3 represents NHCOR3a wherein R3a represents at each
occurrence methyl, ethyl, isopropyl, CH(C2H5)2,
CH(CH3)CH2CH3, CF3, methoxy, ethoxy, cyclopropyl,
cyclobutyl, NH(CH3), or N(CH3)2; or R3 represents

WO 2007/002181 PCT/US2006/024122
NHSO2R , wherein R represents at each occurrence
cyclopropyl, NH(CH3), N(CH3)2, or N(CH3)OCH3;
(c) R3 represents NHCOR3a wherein R3° represents methyl, ethyl,
isopropyl, cyclopropyl, or cyclobutyl;
(d) R3 represents NHCOR3a wherein R3a isopropyl;
Further particular aspects of the compound of formula 1(b) are provided by
compounds whererin:
(a) R4 represents a phenyl group optionally substituted with 1 or
2 substituents independently selected from the group
consisting of amino, hydroxy, cyano, bromo, chloro, fluoro,
nitro, methyl, methoxy, CF3, CHF2, OCF3, OCHF2,
NH(C2H5), N(CH3)2, NHSO2CH3, or COOCH3;
(b) R4 represents a phenyl group optionally substituted with a
first subsitutent selected from the group consisting of amino,
hydroxy, cyano, bromo, chloro, fluoro, nitro, methyl,
methoxy, CF3, CHF2, OCF3, OCHF2, NH(C2H5), N(CH3)2,
NHSO2CH3, or COOCH3 and a second subsitutent selected
from the group consisting of bromo, chloro, fluoro, or
methyl;
(c) R4 represents a phenyl group optionally substituted with a
first subsitutent selected from the group consisting of cyano,
bromo, chloro, fluoro, methyl, or methoxy, and a second
subsitutent that is fluoro;
(d) R4 represents a phenyl group optionally substituted with a a
subsitutent selected from the group consisting of cyano,
bromo, chloro, fluoro, methyl, or methoxy,
(e) R4 represents a phenyl group optionally substituted with a
cyano group;
(f) R4 represents a phenyl group optionally substituted with a
fluoro group;

WO 2007/002181 PCT/US2006/024122
(g) R4 represents a phenyl group optionally substituted with a
methyl group; or
(h) R4 represents a phenyl group optionally substituted with a
methoxy group;
Additonal particular aspects of the present invention are provided by
compounds of Formula 1(c)

wherein,
R1 represents a 5 to 6 membered heteroaryl group optionally substituted with
1 or 2 substituents independently selected from the group consisting of amino, (C1-
C4)alkyl, or halo;
R3a represents (C1-C6)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, cyclopropyl,
cyclobutyl, NH-(C1-C4)alkylamine, N,N-(C1-C6)dialkylamine, or N(CH3)OCH3;
and
R4 represents a phenyl group optionally substituted with 1 or 2 substituents
independently selected from the group consisting of amino, hydroxy, cyano, halo,
nitro, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, NH-(C1-
C4)alkylamine, N,N-(C1-C6)dialkylamine, NHSO2CH3, or COOCH3;
or a pharmaceutically acceptable salt thereof
Other particular aspects of the compound of Formula 1(c) are provided by
compounds whererin:
(a) R1 represents a 5 to 6 membered heteroaryl selected from the
group consisting of furanyl, thiophenyl, pyrrolyl, tetrazolyl,
thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,
oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridinyl,

WO 2007/002181

PCT/US2006/024122

40
pyradazinyl, pyrimidinyl, pyrazinlyl, and triazinyl, each
optionally substituted with 1 or 2 substituents independently
selected from the group consisting of amino, cyano, (C1-
C4)alkyl, (C1-C4)alkoxy, halo, halo(C1-C4)alkyl, or halo(C1-
C4)alkoxy;
(b) R1 represents a 5 to 6 membered heteroaryl selected from the
group consisting of thiazolyl, thiadiazolyl, isoxazoly],
pyridinyl, pyradazinyl, pyrimidinyl, each optionally
substituted with 1 or 2 substituents independently selected
from the group consisting of amino, cyano, (C1-C4)alkyl, (C1-
C4)alkoxy, halo, CF3, CHF2, OCF3, or OCHF2;
(c) R1 represents a 5 to 6 membered heteroaryl selected from the
group consisting of thiazolyl, thiadiazolyl, isoxazolyl,
pyridinyl, pyradazinyl, pyrimidinyl, each optionally
substituted with 1 or 2 substituents independently selected
from the group consisting of amino, methyl, or fluoro;
(d) R1 represents a 5 to 6 membered heteroaryl selected from the
group consisting of thiazolyl, thiadiazolyl, isoxazolyl,
pyridinyl, pyradazinyl, pyrimidinyl, each optionally
substituted with a first substituent selected from the group
consisting of amino, methyl, or fluoro, and a second
substitutnt that is methyl;
(e) R1 represents a group of the formula

WO 2007/002181 PCT/US2006/024122

More particular aspects of the compound of Formula 1(c) are provided by
compounds whererin:
(a) R3a represents (C1-C6)alkyl, cyclopropyl, or cyclobutyl;
(b) R3a represents methyl, ethyl, propyl, isopropyl, cyclopropyl,
or cyclobutyl;

WO 2007/002181

PCT/US2006/024122

(c) R3n represents isopropyl, cyclopropyl, or cyclobutyl; or
(d) R3a represents isopropyl
More particular aspects of the compound of Formula 1(c) are provided by
compounds whererin:
(a) R4 represents a phenyl group optionally substituted with 1 or
2 substituents independently selected from the group
consisting of amino, hydroxy, cyano, halo, nitro, (C1-
C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-
C4)alkoxy, NH-(C1-C4)alkylamine, N,N-(C1-C6)dialkylamine,
NHSO2CH3, or COOCH3;
(b) R4 represents a phenyl group optionally substituted with 1 or
2 substituents independently selected from the group
consisting of cyano, halo, (C1-C4)alkyl, or (C1-C4)alkoxy;
(c) R4 represents a phenyl group optionally substituted with 1 or
2 substituents independently selected from the group
consisting of cyano, fluoro, methyl, or methoxy;
(d) R4 represents a phenyl group optionally substituted with a
substituent selected from the group consisting of cyano,
fiuoro, methyl, or methoxy;
(e) R4 represents a phenyl group optionally substituted with a
cyano group;
(f) R represents a phenyl group optionally substituted with a
fiuoro group;
(g) R4 represents a phenyl group optionally substituted with a
methyl group; or
(h) R4 represents a phenyl group optionally substituted with a
methoxy group.
As an especially particular aspect, the present invention provides the
compound of Formula I(a),wherein
R1 represents cyano, halo, or CH=NOCH3;

WO 2007/002181

PCT/US2006/024122

43
R3 represents NHCOR3a;
R3a represents (C1-C6)alkyl, (C1-C6)alkoxy, cyclopropyl, or NH-(C1-
C4)alkylamine; and
R4 represents a 5 to 6 membered heteroaryl group optionally substituted with
a substituent selected from the group consisting of amino, methyl, ethyl, isopropyl,
and fluoro, or a pharmaceutically acceptable salt thereof.
As a most particular aspect, the present invention provides the compound of
Formula 1(a), wherein
R1 represents cyano or CH=NOCH3;
R3 represents NHCOR3a;
R3a represents methyl, ethyl, isopropyl, or cyclopropyl; and
R4 represents a pyridine, thiazole, or pyrazine group optionally substituted
with a substituent selected from the group consisting of amino, methyl and fluoro,
or a pharmaceutically acceptable salt thereof.
As yet an additional especially particular aspect, the present invention
provides the compound of Formula I(b),wherein
R1 represents cyano, halo, or CH=NOCH3;
R2 represents hydrogen;
R3 represents NHCOR3";
R3a represents (C1-C6)alkyl, (C1-C6) alkoxy, cyclopropyl, or NH-(C1-
C4) alkylamine; and
R4 represents a phenyl group optionally substituted with 1 or 2 substituents
selected from the group consisting of amino, hydroxyl, cyano, methyl, fluoro, and
chloro, or a pharmaceutically acceptable salt thereof.
As a most especially particular aspect, the present invention provides the
compound of Formula I(b),wherein
R1 represents cyano or CH=NOCH3,
R2 represents hydrogen;
R3 represents NHCOR3a;
R3a represents methyl, ethyl, isopropyl, or cyclopropyl; and

WO 2007/002181

PCT7US2006/024122

R4 represents a phenyl group optionally substituted with a substituent
selected from the group consisting of cyano, methyl, and fluoro, or a
pharmaceutically acceptable salt thereof.
As yet an additional especially particular aspect, the present invention
provides the compound of Formula I(c),wherein
R represents a 5 to 6 membered heteroaryl selected from the group
consisting of thiazolyl, thiadiazolyl, isoxazolyl, pyridinyl, pyradazinyl, and
pyrimidinyl, each optionally substituted with 1 or 2 substituents independently
selected from the group consisting of amino, methyl, and fluoro;
R3a represents (C1-C6)alkyl, (C1-C6)alkoxy, cyclopropyl, or NH-(C1-
C4)alkylamine; and
R represents a phenyl group optionally substituted with 1 or 2 substituents
independently selected from the group consisting of amino, hydroxyl, cyano,
methyl, fluoro, and chloro, or a pharmaceutically acceptable salt thereof.
As a most particular aspect, the present invention provides the compound of
Formula 1(c) wherein
R1 represents a 5 to 6 membered heteroaryl selected from the group
consisting of thiazolyl, thiadiazolyl, isoxazolyl, pyridinyl, pyradazinyl, and
pyrimidinyl, each optionally substituted with a substituent selected from the group
consisting of amino, methyl, and fluoro;
R3a represents methyl, ethyl, isopropyl, or cyclopropyl; and
R4 represents a phenyl group optionally substituted with a substituent
selected from the group consisting of cyano, methyl, and fluoro, or a
pharmaceutically acceptable salt thereof.

WO 2007/002181 PCT/US2006/024122
In addition, it will be understood a most particular aspect of the present
invention is provided by those compounds of Formula I, Formula 1(a), Formula 1(b),
and Formula 1(c) exemplified herein. Furthermore, the methods, uses, and
compositions comprising the herein exemplified compounds of Formula I, Formula
1(a), Formula 1(b), and Formula 1(c), are also a most particular aspect of the present
invention.
All of the compounds of the present invention can be chemically prepared,
for example, by following the synthetic routes set forth in the Schemes and /or the
Preparations and Examples below. However, the following discussion is not
intended to be limiting to the scope of the present invention in any way. For
example, the specific synthetic steps for each of the routes described may be
combined in different ways, or in conjunction with steps from different schemes, to
prepare additional compounds of Formula I.
All substituents, unless otherwise indicated, are as previously defined. The
reagents and starting materials are readily available to one of ordinary skill in the
art. For example, certain reagents or starting materials can be prepared by one of
ordinary skill in the art following procedures disclosed in Khanna, I.K., et al., J.
Med. Chem. (2000) 43, 3168-3185; Erlenmeyer, H., et al. Helv. Chim. Acta (1944),
27,1437-1438; McElhinney, R.S., et al., J. Med. Chem. (1998) 41, 5265-5271;
Yang, L., et al., Bioorg. Med. Chem. Lett. (1999) 9,1761-1766; Hermitage, S. A,
Cardwell, K. S., Chapman, T., Cooke, J. W. B., Newton, R., Org. Process Res.
Dev., (2001) 5(1), 37-44; R Frenette et al, Bioorg. Med. Chem. Lett., (1999) 9(16)
2391-2396; Campaigne, E., Thompson, R. L., Van Werth, I E., Journal of
Medicinal & Pharmaceutical Chemistry, (1959) 1,577-600; Kikelj, D. and Urleb,
U., Science of Synthesis, (2002) 11,627-833; Tsunoda, T., et al., Tetrahedron Lett.
(1996) 37, 2459-2462. Tetrahydrocarbazoles can be prepared by one of ordinary
skill in the art using the Fischer indole synthesis as reviewed by Hughes, OPPI
(1993), 25(6), 607-32. Additional reagents, starting materials, or useful procedures
may be found in WO99/55302. Other necessary reagents and starting materials may
be made by procedures which are selected from standard techniques of organic and
heterocyclic chemistry, techniques which are analogous to the syntheses of known

WO 2007/002181 PCT/US2006/024122
structurally similar compounds, and the procedures described in the Examples
below, including any novel procedures.

In Scheme I, Step A, an acid chloride or anhydride, such as isobutyric
anhydride is reacted with a substituted or unsubstitutued transA-
aminocyclohexanol (1) and triethylamine in an inert solvent such as tetrahydrofuran
or dioxane at about 0 to 50 °C for about 10 to 48 hours. The amide product of
formula (2) (wherein Z represents for example a small alkyl, such as isopropyl. or
cycloalkyl, O-Bn, or alkoxy) may be isolated by diluting with water, and washing
with diethyl ether to remove by-products. The amide (2) may then be salted out by
adding sodium chloride and extracted with dichloromethane. In addition, amide (2)
that precipitates out of the aqueous can also be isolated by filtration.
Another preferred method of performing Step A, uses an inorganic base
such as potassium carbonate in a protic solvent such as methanol with an acid
chloride, with cyclopropylcarbonyl chloride being preferred. The reaction is
conducted at about 0 to 50 °C for about 10 to 48 hours. The product may be
isolated by concentration of the reaction and resuspension in methanol/
dichloromethane chloride to remove the inorganic salts.
In Scheme I, Step A, wherein the product (2) has Z = O-benzyl, the preferred
method is that of Janda, K. D. and Ashley, J. A. Synth. Comm. (1990) 20,1073-
1082.
In Scheme I, Step B, a derivative of formula (2) is oxidized to a ketone of
formula (3) using an oxidizing agent such as pyridinium chlorochromate in an inert
solvent such as dichloromethane and strring at about 0 to 50 °C for about 10 to 48

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hours. The reaction is mixed with a large amount of silica and filtered over a silica
pad eluting with an appropriate solvent such as dichloromethane and ethyl
acetate/hexane to obtain a cyclic keto amide of formula (3).
Alternatively, particulary wherein Z = O-benzyl, a Swern oxidation is the
preferred method to obtain the ketone of formula (3). The Swern oxidation uses
conditions well known to those skilled in the art, such as treatment with oxalyl
chloride in the presence of DMSO in an inert solvent such as dichloromethane at a
temperature of about -80 to -60 °C for about 1 to 2 hours, followed by treatment
with triethylamine at -80 °C to room temperature for about 1 to 24 hours. The
product is isolated using standard extraction techniques.

In Scheme II, Step A, a phenylhydrazine salt (for example the hydrochloride
salt) of formula (4), is reacted with a cyclic ketone of formula (3) in a Fischer indole
synthesis to provide a tetrahydrocarbazole of formula (5). The hydrazine and
ketone are reacted in ethanol saturated with hydrogen chloride gas at reflux for
about 10 to 48 hours and isolated using standard aqueous workup techniques.
Alternatively the reaction can be accomplished without the hydrogen chloride gas
simply by using a phenyl hydrazine hydrochloride salt of formula (4) with a ketone
of formula (3) in ethanol at about 50 to 85 °C for about 10 to 72 hours. In yet
another procedure a phenylhydrazine hydrochloride salt of formula (4) and a ketone
of formula (3) can be reacted as a vigorously stirred heterogeneous mixture in water
and concentrated hydrochloric acid at about 80 to 100 °C for about 4 to 8 hours as
essentially described in U.S. Patent No. 6,359,146B1. The tetrahydrocarbazole can

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then be isolated by filtration. Using yet another variation, acetyl chloride and
absolute ethanol are stirred at 0 °C to room temperature for about 1 to 2 hours. A
phenylhydrazine hydrochloride salt of formula (4) and a ketone of formula (3) are
then added to the ethanol/HCl and reluxed for about 10 to 72 hours.
It will be recognized by one skilled in the art that phenyl hydrazines of
formula (4) can be obtained from the corresponding aniline by treatment with
nitrous acid to form the diazonium salt, followed by reduction with tin(II) chloride.
Isolation of the tetrahydrocarbazole derivative of formula (6) is
accomplished by adding water directly and filtering the resulting precipitate or by
using standard techniques of an aqueous workup and extraction with an organic
solvent. The (R) and (S) enantiomers of tetrahydrocarbazoles of formula (6) are
obtained by chiral chromatography using standard techniques common to one
skilled in the art. The enantiomers are used in subsequent reactions as described in
Scheme m through Scheme VIII.
In Scheme II, Step B, tetrahydrocarbazoles of formula (6) can be obtained by
a palladium-catalyzed annulation reaction between a cyclic ketone of formula (3)
and an iodoaniline of formula (5) as generally described in Chen, C, et. al., J. Org.
Chem. (1997), 62, 2676-2677. The ketone and iodoaniline are reacted in an inert
solvent such as dimethylformamide in the presence of a palladium catalyst such as
palladium acetate and an amine base such as l,4-diazobicyclo[2.2.2]octane
(DABCO). The reaction is heated under anhydrous conditions at a temperature of
about 80 to 150 °C for 6 to 48 hours. The product can be isolated by common
extractive techniques and purified by silica gel chromatography.

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In Scheme III, Step A, an aldehyde of formula (7), is reduced to an alcohol
of formula (10). A vast array of methods for reducing aldehydes are well known to
those skilled in the art and can be found in the text of R.C. Larock in
"Comprehensive Organic Transformations", VCH Publishers, 1989, p. 528 - 534.
The preferred method is reduction with sodium borohydride in ethanol or methanol
at room temperature to 60 °C for about 30 min to 24 hours.
Alternatively, as shown in Scheme III, Step B, the alcohol is obtained by
reducing an ester of formula (8). Numerous methods for reducing carboxylic esters
to alcohols are well known to those skilled in the art and can be found in the text of
R.C. Larock in "Comprehensive Organic Transformations", VCH Publishers, 1989,
p. 549 - 551. The preferred method is reduction with lithium borohydride in an
aprotic solvent such as tetrahydrofuran or dioxane at room temperature to reflux
temperature for about 1 to 48 hours.
In Scheme III, Step C, a compound of formula (9), wherein R4 is aryl or
heteroaryl, is halogenated to provide an alkyl halide of formula (11). The
compound of formul (9) is treated with a free radical initiator such as benzoyl
peroxide or 1,1'-azobisisobutyronitrile or 1,1'-azobis(cyclohexanecarbonitrile) in
carbon tetrachloride with N-chlorosuccinimide or N-bromosuccinimide under
irradiation from a UV light. The preferred method is treatment with 1,1'-
azobis(cyclohexanecarbonitrile) and N-bromosuccinimide at about room
temperature to the refluxing temperature of carbon tetrachloride, for about 4 to 48

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hours. The product may then be purified using standard techniques such as
filtration of insoluable components, followed by silica gel chromatography.
In Scheme III, Step D, An alcohol of formula (10) is converted to an alkyl
halide of formula (11), wherein X represents, for example, Br or Cl, with Br being
preferred. A variety of methods for this transformation are known to those skilled
in the art such as the following: 47% hydrogen bromide in acetic acid,
dibromotriphenylphosphorane with triethylamine, thionyl chloride, phosphorous
tribromide, N-chlorosuccinimide or N-bromosuccinimide with methyl sulfide, or
acetyl bromide. The preferred method is treatment with acetyl bromide at -78 °C to
50 °C with the preferred temperature at 0 °C to room temperature, for about 1 to 48
hours. The product is isolated using an ethyl acetate, sodium bicarbonate workup
and may be purified by standard techniques such as silica gel chromatography.
Another preferred method is treatment of the alcohol with thionyl chloride at about
0°C for 30 minutes to 4 hours to give an alkyl halide of formula (IT), wherein X
represents Cl.
Alternatively, in Scheme m, Step E, an alcohol of formula (10) is converted
to a methylsulfonic acid ester of formula (12). The alcohol is combined with an
organic base such as triethylamine or diisopropylethylamine and treated with
methanesulfonylchloride in an inert solvent such as dichloromethane. The reaction
is maintained at 0 °C to room temperature for 15 minutes to 4 hours. The product is
isolated by extractive techniques known to one skilled in the art.

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In Scheme IV, Step A, a tetrahydrocarbazole of formula (6) is alkylated with
a alkylating agent of formula (11) wherein X is bromide or chloride, or with an
agent of formula (12) to give a N-substituted tetrahydrocarbazole of formula (14).
The anion of the tetrahydrocarbazole is generated in an inert solvent such as
dimethylformamide, N-methylpyrrolidinone, tetrahydrofuran, dioxane, or toluene
with a base such as sodium hydride, potassium hydride, potassium or sodium
bis(trimethylsilyl)amide, or cesium carbonate. Preferred solvents are
dimethylformamide and tetrahydrofuran with sodium hydride and potassium
bis(trimethylsilyl)amide being the preferred bases. After about 10 to 60 minutes
treatment with base, the anion is treated with a benzyl halide, at about -78 to 23 °C
and continuing for about 4 to 48 hours. When using cesium carbonate the base and
benzyl halide can be added directly and the reaction heated for about 50 to 100 °C
for about 10 to 72 hours.
In Scheme IV, Step B, a tetrahydrocarbazole of formula (6), is reacted with
an alcohol of formula (10), in a Mitsunobu reaction to provide a tetrahydrocarbazole
of formula (14). Common redox systems, known to those skilled in the art, such as
diethyl azodicarboxylate (DEAD)/triphenylphospine, N,N,N,'N'-
tetramethylazodicarboxamide (TMAD)/tributylphosphine or 1,1'-
(azodicarbonyl)dipiperidine (ADDP)/tributylphosphine are used to effect the
transformation, with the latter being the preferred redox system. The product is

WO 2007/002181 PCT/US2006/024122
isolated by solvent evaporation and dissolution of the crude material in ethyl
acetate/water. The mixture is eluted over a solid-phase extraction cartridge with
ethyl acetate and may then be purified using standard techniques such as silica gel
chromatography.
Alternatively, stabilized trialkylphosphoranes, such as (cyano-
methylene)tributylphosphorane (CMBP) or (cyano-methylene)trimethylphosphorane
(CMMP) (prepared as described in Tsunoda, T., et al., Tetrahedron Lett. (1996) 37,
2459-2462) can be used with alcohols of formula (6) to prepare a
tetrahydrocarbazole of formula (11) (see Bobrun, A. and Casi, G., Tetrahedron Lett.
(2002)43,2187-2190).
In Scheme IV, Step C, is provided yet an additional route to obtain
tetrahydrocarbazoles of formula (14), wherein the tetrahydrocarbazole is
constructed with the benzyl group attached to the phenyl hydrazine as in formula
(13). N-benzyl-N-phenylhydrazines are obtained as described by Audrieth, L. F.,
Weisiger, J. R., Carter, H. E., J. Org. Chem. (1941) 6, 417-420. The ketone of
formula (3) and the N-benzyl-N-phenylhydrazine of formula (13) are stirred in
acetic acid at 50 °C to reflux temperature for about 1 to 24 hours. The product is
isolated by dilution with water and extraction with benzene or toluene and then
purified by recrystillization.

In Scheme V, a methoxy tetrahydrocarbazole of formula (15) is
demethylated to give a phenol of formula (16). Conversion of a methoxy aryl to a
phenol is accomplished by a variety of methods known to those skilled in the art.
These include: sodium ethanethiolate in DMF, 48% HBr in acetic acid, neat
pyridine hydrochloride at high temperature, and boron tribromide. The methoxy
tetrahydrocarbazole is preferably treated with boron tribromide in an inert solvent
such as dichloromethane at a temperature of 0 to 40 °C for about 4 to 48 hours. The

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product is isolated by solvent evaporation in the presence of methanol and may be
purified by silica gel chromatography.
In Scheme V, Step B, a phenol of formula (16) is alkylated to give a
tetrahydrocarbazole of formula (17) using an alkyl halide and an inorganic base
such as potassium carbonate, cesium carbonate or sodium hydride in an inert
solvent such as acetone, dimethylformamide or N-methylpyrrolidinone. Preferred
conditions use cesium carbonate or sodium hydride in dimethylformamide at room
temperature to 50 °C for about 4 to 48 hours. The product is isolated by extractive
techniques and may be purified by silica gel chromatography.

In Scheme VI, a methoxybenzyl tetrahydrocarbazole of formula (18), is
converted to a phenol of formula (19), a reaction which can be accomplished by a
variety of methods well-known to those skilled in the art, as described in Scheme V,
Step A. The preferred method is treatment with boron tribromide in an inert solvent
such as dichloromethane at a temperature of 0 to 40 °C for about 4 to 48 hours. The
product is isolated by solvent evaporation in the presence of methanol or by
common extractive tenchniques using water and an organic solvent. Purification is
accomplished by silica gel chromatography.

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In Scheme VII, the nitro group is further elaborated to amines and amine
derivatives using chemistry well known to those skilled in the art. Thus in Scheme
VII, Step A, a nitro benzyl tetrahydrocarbazole of formula (20) is reduced to an
aniline of formula (21). There are a variety of methods for reducing arylnitro
groups which are well known to those skilled in the art and can be found in the text
of R.C. Larock in "Comprehensive Organic Transformations", VCH Publishers,
1989, p. 412 - 415. The preferred method is reduction with tin(II)chloride
dihydrate in a mixture of a protic solvent, such as ethanol, and concentrated
hydrochloric acid at a temperature of 40 to 80 °C for about 30 minutes to 24 hours.
The product is isolated by taking the reaction alkaline with sodium hydroxide and
extracting with an organic solvent. The product is purified by silica gel
chromatography.

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Alternatively, another preferred method for doing the reduction is is with
sulfided platinum, 5% wt. on carbon in a solvent such as methanol or ethanol, on a
Parr shaker under 55 psi hydrogen. The hydrogenation is preformed at room
temperature for about 4 to 24 hours. The product is isolated by filtration techniques
common to those skilled in the art and purified by silica gel chromatography.
In Scheme VII, Step B, the aniline of formula (21) can be converted to other
derivatives, such as the sulfonamide of formula (22). The aniline is reacted with a
sulfonyl chloride in an inert solvent such as dichloromethane or dimethylformamide
with an organic base such as pyridine. The reaction is performed at a temperature
of 0 to 40 °C for about 4 to 48 hours. The product can be isolated by common
extractive techniques and purified by silica gel chromatography.
In Scheme VII, Step C, an aniline of formula (21) is acylated to form an
amide of formula (23). The aniline is reacted with an acid chloride in an inert
solvent such as dichloromethane or tetrahydrofuran in the presence of an organic
base such as triethyl amine or diisopropylethylamine. The reaction is performed at
a temperature of 0 to 40 °C for about 4 to 48 hours. The product can be isolated by
common extractive techniques and purified by silica gel chromatography.
In Scheme VII, Step D, an aniline of formula (21) is converted to an alkyl
amine of formula (24) (one or both of R5 and R6 represent an alkyl group) in a
reductive amination. Methods for reductive amination are well known to those
skilled in the art and are and can be found in the text of R.C. Larock in
"Comprehensive Organic Transformations", VCH Publishers, 1989, p. 421 - 423.
A preferred method to obtain an alkylamine of formula (24) is reaction with an
aldehyde in an inert solvent such as tetrahydrofuran or dimethylformamide in the
presence of sodium triacetoxyborohydride and acetic acid. The reaction is heated
40 to 100 °C for 4 to 48 hours with additional amounts of reagents as needed. The
product can be isolated by common extractive techniques and purified by silica gel
chromatography.
Alternatively the reduction can be accomplished with sodium
cyanoborohydride in an inert solvent such as acetonitrile, dimethylformamide, or
tetrahydrofuran. An alkyl aldehyde such as formaldehyde can be used in excess to
obtain a dimethyl aniline of formula (24) (R5 and R6 each represent methyl). The

WO 2007/002181 PCT/US2006/024122
56
reaction is accomplished at room temperture to the reflux temperature of the solvent
for about 4 to 48 hours. The product can be isolated by common extractive
techniques and purified by silica gel chromatography.

In Scheme VIII, Step A, a nitrile tetrahydrocarbazole, of formula (25) is
cyclized with thiosemicarbazide to give an aminothiadiazole of formula (26). The
nitrile and thiosemicarbazide are heated at about 40 to 120 °C for about 4 to 48
hours in an organic acid such as trifluoroacetic acid. The reaction mixture is
poured onto dilute ammonium hydroxide and the precipitate filtered to obtain the
product (26). Alternatively the product (26) is isolated by standard extractive
techniques and may then be purified by silica gel chromatography.
In Scheme IV, Step B, the aminothiadiazole may be deaminated using
isoamylnitrite to give an unsubstituted thiadiazole derivative of formula (27). The
aminothiadiazole (26) is treated with isoamylnitrite in a solvent such as
dimethylformamide or N-methylpyrrolidinone at ambient temperature to 100 °C for
about 0.5 to 16 hours. The product is isolated using standard extractive techniques
with water and ethyl acetate and may be purified by silica gel chromatography.


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In Scheme IX, Step A, a nitrile tetrahydrocarbazole of formula (25) is
converted to a primary thioamide of formula (28). The nitrile is treated with
thioacetamide in refluxing 4 N hydrochloric acid in dioxane for about 4 to 48 hours.
The product mixture is neutralized with sodium bicarbonate and the product (28)
isolated by standard techniques, such as filtration.
In Scheme V, Step B, a primary thioamide of formula (28) is reacted with an
alpha haloketone wherein X represents Cl or Br and R' and R" each independently
represent, for example, H or alkyl, to provide a thiazole of formula (29). The
thioamide is treated with the alpha haloketone in a solvent such as
dimethylformamide, N-methylpyrrolidinone, tetrahydrofuran, dioxane, toluene,
ethanol, or isopropanol at about 50 to 120 °C for about 4 to 48 hours. Upon cooling
the reaction is mixed with water and the precipitate collected. Alternatively, the
product (29) can be isolated by standard extractive techniques and purified by silica
gel chromatography.

In Scheme X, Step A, a bromotetrahydrocarbazole of formula (30), prepared
for example, as described in Schemes II - IV, is reacted with a boronate ester such
as bis(pinacoloto)borane, a phosphine ligand, such as tricyclohexylphosphine, a
palladium catalyst such as tris(benzyIideneacetone)dipalladium, and a base such as
potassium acetate. An inert solvent such as dimethyl sulfoxide or dimethyl
formamide is used and the reaction heated under argon or nitrogen at 50 to 120 °C
for 4 to 48 hours. The reaction is poured into water and isolated using standard
extractive techniques. The product may then be purified by eluting over neutral
alumina to provide a boronate ester of formula (31).

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In Scheme X, Step B, the boronate ester of formula (31) is coupled to a
unsubstituted or substituted haloheteroaryl (Hetero-X, where X represents a halo
group and Hetero represents unsubstituted or substituted heteroaryl) using a Suzuki
reaction with a palladium catalyst such as tetrakis(triphenylphosphine)palladium
(0),and a base such as 2M potassium carbonate. An inert solvent is used such as
tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidinone, or ethylene
glycol dimethyl ether, with dioxane being preferred. The reaction is heated under
an inert atmosphere of argon or nitrogen at 50 to 120 °C for 4 to 48 hours. The
reaction is poured into water and isolated using standard extractive techniques. The
product may then be purified by silica gel chromatography to provide a
heterocyclic-substituted tetrahydrocarbazole of formula (32).

In Scheme XI, Step A, an aminohaloheteroaryl of formula (33), wherein Q
represents O, S, N, or CH=CH, is reacted with hexane-2,5-dione with sodium

WO 2007/002181 PCT/US2006/024122
carbonate and acetic acid in an inert solvent such as benzene. The reaction is
refluxed with a Dean-Stark trap for 4 to 48 hours according to a procedure similar
to that described by Macor, J. E., Chenard, B. L., Post, R. J. J. Org. Chem.(l994)
59,7496-7498. The reaction is concentrated and the product may then be purified
by silica gel chromatography to give the amino protected heteroaryl of formula (34).
In Scheme XI, Step B, the protected aminoheteroaryl of formula (34) is
coupled to the boronate ester of formula (31) using conditions as essentially
described for Scheme X, Step B, above to give a heteroaryl-substituted
tetrahydrocarbazole of formula (35). A preferred palladium catalyst for this
reaction is dichloro[1,1'-bis(diphenylphosphino)ferrocene] palladium (H)
dichloromethane adduct using 2M sodium carbonate in dioxane.
In Scheme XI, Step C, the protected heteroaryl of formula (35) is
deprotected using about a ten fold excess of hydroxylamine hydrochloride,
triethylamine and 1 molar sodium hydroxide in refluxing ethanol for about 4 to 48
hours. The product is isolated using standard extractive techniques to give the
aminoheteroaryl-substituted tetrahydrocarbazole of formula (36).

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In Scheme XII, Step A, a substituted tetrahydrocarbazole of formula (37),
where Z = OBn is deprotected to provide the amine substituted tetrahydrocarbazole
of formula (38). Common deprotection conditions for removing a carboxybenzyl
(CBZ) group are well know by those skilled in the art and can be found in the text
of T. W. Green and P. G. M. Wuts in "Protective Groups in Organic Synthesis",
John Wiley & Sons, Inc., 1991,335-338. Preferred conditions use a solvent
mixture of ethanol and tetrahydrofuran at room temperature with 5% or 10%
palladium on carbon under hydrogen gas at normal atmospheric pressure.

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In Scheme XII, Step B, a tetrahydrocarbazole of formula (37), wherein the
amide is protected as a tert-butyl carbamate (BOC) (Z = O-t-butyl), is deprotected
to give a provide the amine substituted tetrahydrocarbazole of formula (38).
Common deprotection conditions for removing a BOC group are well know by
those skilled in the art and can be found in the text of T. W. Green and P. G. M.
Wuts in "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., 1991,
328-330. Preferred conditions use 4N hydrogen chloride in dioxane at a
temperature of about 0 °C to room temperature for about 10 minutes to 24 hours.
The product can be isolated as the HC1 salt by filtration.
In Scheme XII, Step C, a tetrahydrocarbazole of formula (37) wherein Z =
Me is hydrolyzed to an amino substituted tetrahydrocarbazole of formula (38) as the
maleic acid salt. The amide is treated with potassium hydroxide pellets in a mixture
of 2-methoxyethanol and water and heated at 90 °C to reflux temperature for about
4 to 48 hours. The product is isolated by removal of solvent in vacuo and extraction
with water and an organic solvent. The product is purified by recrystillization with
maleic acid to give a compound of formula (38) as the maleic acid salt.
In Scheme XII, Step D, a tetrahydrocarbazole amine of formula (38) is
sulfonylated to give a sulfonamide of formula (39) by reaction with a sulfonyl
halide or a sulfamoyl chloride. The free amine or the salt of the amine is combined
with an excess of an amine base such as triethylamine or diisopropylethylamine in
an inert solvent such as tetrahydrofuran, dichloroethane or dichloromethane. The
reaction is stirred at a temperature of 0 to 40 °C for 1 to 24 hours. The product is
isolated by common extractive techniques and may be purified by recrystillization
or by silica gel chromatography.
In Scheme XII, Step E, a tetrahydrocarbazole amine of formula (38) is
acylated with a compound of structure (42) (wherein X represents halogen and RY
represents, for example, R3a or OPh-p-NO2) to give an amide of formula (40). It is
recognized by one skilled in the art that there are an immense number of methods
for acylating amines using carboxylic acids. Such methods are well known to those
skilled in the art and can be found in the text of R.C. Larock in "Comprehensive
Organic Transformations", VCH Publishers, 1989, p. 972 - 976. The preferred
method to obtain a tetrahydrocarbazole of formula (40) is by acylation with an acid

WO 2007/002181 PCT/US2006/024122
chloride (X represents, for example Cl), a carbamoyl chloride, or a chloroformate
using conditions well known to those skilled in the art. The free amine or a salt of
the amine is combined with an excess of an organic amine base such as
triethylamine or diisopropylethylamine in an inert solvent such as tetrahydrofuran,
dichloroethane or dichloromethane, N-methylpyrrolidinone, or N,N-
dimethylformamide, or a mixture thereof. The reaction is stirred at a temperature of
0 to 40 °C for 1 to 72 hours. The product is isolated by common extractive
techniques and may be purified by recrystillization or by silica gel chromatography.
In Scheme XII, Step F, a tetrahydrocarbazole amine of formula (39),
wherein RY represents O-Ph-p-NO2 (p-nitrophenyloxy) is reacted with an alkyl
amine or an N.O-dialkylhydroxyamine to give tetrahydrocarbazole ureas of formula
(41). The p-nitrophenylcarbamate is combined with an excess of an organic amine
base such as triethylamine or diisopropylethylamine in a inert aprotic solvent such
as tetrahydrofuran, dioxane, N-methylpyrrolidinone, or N,N-dimethylformamide.
The preferred method uses tetrahydrofuran with the hydrochloride salt of
methylamine of N.O-dimethylhydroxylamine at a temperature of 0 to 60 °C for
about 1 to 48. The product is isolated by common extractive techniques and may be
purified by recrystillization or by silica gel chromatography.

In SchemeXIII, Step A, a bromo tetrahydrocarbazole of formula (30) is
converted to a nitrile tetrahydrocarbazole of formula (25). The bromide is treated

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with 1 to 5 equivalents of copper(I) cyanide and 1 to 5 equivalents of copper(I)
iodide at a temperature of 70 - 150 °C in an inert solvent such as 1-methyl-2-
pyrolidinone for about 1 to 5 days. The product is isolated using extractive
techniques with ethyl acetate and water with ethylene diamine to remove the copper
salts. The product may then be purified by silica gel chromatography.
In Scheme XIII, Step B, a nitrile tetrahydrocarbazole of formula (25) is
converted to an acetyl tetrahydrocarbazole of formula (43) by a Grignard reaction
with methyl magnesium halide. The nitrile is treated, preferably with methyl
maganesium bromide in an inert solvent such as diethyl ether or tetrahydrofuran.
The preferred method uses tetrahydrofuran at a temperature of 0 to 50 °C for about
1 to 24 hours. The reaction is quenched with an alcohol, such as methanol, the
solids removed and the filtrate concentrated. The material is treated with refluxing
1N hydrochloric acid/tetrahydrofuran for about 1 to 5 hours. A water immiscible
organic solvent, such as ethyl acetate, is added and the resulting precipitate
discarded to leave the product.
In Scheme XIII, Step C, an acetyl tetrahydrocarbazole of formula (43) is
converted to the isoxazole substituted tetrahydrocarbazole of formula (44). The
acetyl is treated neat with dimethylformamide dimethylacetal at a temperature of 80
to 100 °C for about 12 hours to 4 days. After concentrating, the intermediate
enamine is treated with hydroxylamine hydrochloride in an inert solvent such as
dioxane or THF at a temperature of room temperature to 50 °C for about 30 min to
12 hours. Water is added and the isoxazole of formula (44) collected by filtration.

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In Scheme XIV, Step A, a bromo tetrahydrocarbazole of formula (30) is
carbonylated to provide an ester substituted tetrahydrocarbazole of formula (45).
The bromide is combined with an acetate salt such as sodium acetate in an alcoholic
solvent such as methanol in the presence of a palladium catalyst under an
atmosphere of carbon monoxide. The preferred method uses dichloro[l,l'-
bis(diphenyl-phosphino)ferrocene]pa]ladium (IT) dichloromethane adduct on a Pan-
reactor with the reaction vessel charged with 55 psi of carbon monoxide at a
temperature of 50 to 100 °C for about 4 to 48 hours. The product can be isolated
directly by silica gel chromotagraphy.
In Scheme XIV, Step B, an ester substituted tetrahydrocarbazole of formula
(45) is hydrolyzed to an acid of formula (46). It will be recognized by one skilled in
the art that ester hydrolysis is a common organic transformation and that there are
numerous methods for effecting this reaction such as various aqueous inorganic
bases. Specific methods for methyl ester hydrolysis can be found in T. W. Green
and P. G. M. Nuts, "Protective Groups in Organic Chemistry" John Wiley & Sons,
Inc.,2nd edition, 1991, p. 231 - 234. The preferred method uses an excess of lithium
hydroxide in a solvent mixture of water, a protic solvent, such as methanol, and an
inert water miscible organic solvent such as tetrahydrofuran. The reaction is
preformed at a temperature of 0 °C to the reflux temperature of the solvent for a
period of about 1 to 48 hours. The product is isolated by common extractive
techniques, such as acidification followed by extraction with an organic solvent.

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65
In Scheme XIV, Step C, the acid substituted tetrahydrocarbazole of formula
(46) is converted to a carbamate of formula (47) using a Curtius rearrangement.
Curtius rearrangements are well-known to those skilled in the art and there are
numerous protocols to effect this transformation as found in the text of R.C. Larock
in "Comprehensive Organic Transformations", VCH Publishers, 1989, p. 431-432.
The preferred method uses an azide transfer reagent, such as
diphenylphosphorylazide and an organic amine base, such as triethylamine in an
inert aromatic solvent, such as benzene or toluene. The reaction is preformed at a
temperature of 50 °C to the reflux temperature of the solvent for about 4 to 24 hours
to effect rearrangement to the isocyanate. The isocyanate is reacted in situ with an
alcohol, such as methanol or ethanol to provide compounds of formula (47). The
product is isolated and purified using common extractive techniques and silica gel
chromatography.

In Scheme XV, Step A, a nitrile tetrahydrocarbazole of formula (25), is
reduced to a formyl tetrahydrocarbazole of formula (48). The nitrile is treated with
aluminum-nickel catalyst in 90 to 95% formic acid at room to reflux temperature
for about 2 to 48 hour. The product is isolated by addition of a protic solvent such
as methanol, followed by filtration and concentration of the filtrate. The residue is
further purified by common extractive techniques such as with sodium bicarbonate
solution and ethyl acetate to provide the aldehyde of formula (48).

WO 2007/002181 PCT/US2006/024122
In Scheme XV, Step B, a formyl tetrahydrocarbazole of formula (48) is
converted by addition of hydroxylamine or alkoxyamine to give an oxime
tetrahydrocarbazole of formula (49). The aldehyde is treated with the hydrochloride
salt of hydroxylamine or methoxyamine in pyridine at 0 to 100 °C for about 2 to 48
hour. The product is isolated using common isolation and extractive techniques
known to those skilled in the art.
Alternatively, Step B, is accomplished in the presence of an inorganic base
such as sodium or potassium hydroxide. The aldehyde of formula (48) is treated
with hydroxylamine or alkoxyamine with sodium hydroxide in a protic solvent such
as aqueous methanol or ethanol, with aqueous ethanol being preferred, at about
room temperature to 50 °C for a period of about 2 to 48 hours. The product is
isolated by common extractive techniques and purified over silica gel.
In Scheme XV, Step C, an oxime of Formula (49), wherin Y = H, is oxidized
to a nitrile oxide and then reacted in situ in a 1,3-dipolar cycloaddition a with an
alkyne dipolarophile such as propyne to give an isoxazole tetrahydrocarbazole of
formula (50). It will be recognized by one skilled in the art that there are various
reagents used for effecting the conversion of oximes to nitrile oxides. Such
reagents include chlorine, N-chlorosuccinimide, N-bromosuccinimide, nitrosyl
chloride or sodium hypochlorite. The preferred method uses propyne gas in a
solution with a solvent such as dichloromethane with a solution of sodium
hypochlorite or bleach. The reaction is preferably preformed in a sealed tube at -30
to 50 °C, with 23 °C being preferred for a time of about 1 to 48 hours. The product
can be isolated and purified by common techniques such as extraction and silica gel
chromatography.
In Scheme XV, Step D, a formyl tetrahydrocarbazole of formula (48) is
converted via deoxo-fluorination to a difluoromethyl tetrahydrocarbazole of formula
(51) using a nucleophilic fluorinating reagent. It will be recognized by one skilled
in the art that dialklylaminosulfur trifluoride reagents, such as diethylaminosulfur
trifluoride (DAST) or [bis(2-mefhoxyethyl)amino]sulfur trifluoride (Deoxofluor)
are routinely used for introducing fluorine into organic molecules. The preferred
conditions use 5 to 25 equivalents of Deoxofluor in an aprotic halogenated solvent,
such as dichloroethane, but preferably dichloromethane, at a temperature of 0 to 80

WO 2007/002181 PCT/US2006/024122
°C for 1 to 48 hours. The product can be isolated and purified by common
techniques such as neutralization with an inorganic base and extraction, followed by
silica gel chromatography.

Scheme XVI describes syntheses wherein functionalization at R1 occurs
prior to alkylation at the indole nitrogen with X-CH2R4. In Step A, a compound of
formula (6), wherein R1 = Br is converted to a nitrile tetrahydrocarbazole of
formula (52) using conditions as essentially described for Scheme XIII, Step A.
In Scheme XVI, Step B, a nitrile of formula (52) is reduced to a formyl
tetrahydrocarbazole of formula (53), using conditions as essentially described in
Scheme XV, Step A.
In Scheme XVI, Step C, a formyl tetrahydrocarbazole of formula (53) is
converted by addition of methoxyamine, to give a methoxime tetrahydrocarbazole
of formula (54), using conditions as essentially described for Scheme XV, Step B.
In Scheme XVI, Step D, a methoxime tetrahydrocarbazole of formula (54),
is alkylated to give a tetrahydrocarbazole of formula (55), using alkylating agents
prepared as described in Scheme III, and using alkylating conditions as essentially
described in Scheme IV, Step A or alternatively using Mitsunobu conditions as
described in Scheme IV, Step B.

WO 2007/002181 PCT/US2006/024122

Scheme XVII describes syntheses wherein the Fisher-Indole reaction is
performed with protecting groups on the amine functionality to provide versatility
in the synthetic sequence.
In Scheme XVII, Step A, a phenylhydrazine salt (for example the
hydrochloride salt) of formula (4), is reacted with a cyclic ketone of formula (3),
wherein Z = OBn, in a Fischer indole reaction to provide a tetrahydrocarbazole of
formula (5). The hydrazine and ketone are reacted in acetic acid and heated at about
60 to 110 °C, for about 4 to 48 hours. The product is isolated by removal of the

WO 2007/002181 PCT/US2006/024122
acetic acid under reduced pressure and trituration of the material in an inert solvent,
preferably dichloromethane. After filtration, the filtrate is concentrated and the
resulting material purified using standard techniques such as recrystillization or
silica gel chromatography.
In Scheme XVII, Step B, a benzyl carbamate tetrahydrocarbazole of formula
(56) is deprotected to provide the amine tetrahydrocarbazole of formula (57) using
conditions essentially as described for Scheme XII, Step A.
Alternatively, in Scheme XVII, Step C, an amine tetrahydrocarbazole of
formula (57) is obtained directly from the Fisher-Indole reaction of a substituted
phenyl hydrazine of formula (4) with a ketone of formula (3), wherein Z = O-t-
butyl. The tert-butoxycarbonyl (BOC) protecting group is cleaved under the acidic
reaction conditions. The preferred method uses 1 volume of concentrated
hydrochloric acid and 2 volumes of water at a temperature of 50 °C to the reflux
temperature of the solvent for a period of about 4 to 48 hours. The product can be
isolated by cooling the reaction and collecting the precipitate. The solid precipitate
is washed with an inorganic aqueous base such as potassium carbonate or sodium
carbonate and then azeotroped sequentially with chloroform, ethanol and then
chloroform.
In yet another method, the BOC protecting group is employed by reacting a
ketone of formula (3), wherein Z = O-t-butyl, with an iodoaniline of formula (5,) as
previously described in Scheme n, Step B. The BOC group is then removed in a
subsequent reaction as previously described in Scheme XII, Step B.
In Scheme XVII, Step D, an amine tetrahydrocarbazole of formula (57) is
acylated essentially as described in Scheme XII, Step E with an acid chloride, a
carbamoyl chloride, or a chloroformate using conditions well known to those skilled
in the art which will allow selective reaction at the more nucleophilic amine verses
the indole nitrogen. The preferred conditions use an insert solvent such as
dirnethylformamide or DMSO with an organic base such as diisopropylethylamine
or triethylamine and the reaction stirred at a temperature of 0 to 50 °C for a period
of 5 minutes to 1 hour.

WO 2007/002181 PCT/US2006/024122
70
In Scheme XVII, Step E, a tetrahydrocarbazole of formula (58) is alkylated
with an alkylating agent of formula (10), (11), or (12) as described in Scheme IV,
Steps A or B to give a tetrahydrocarbazole of formula (14).
Determination of Biological Activity
To demonstrate that compounds of the present invention have affinity for
the androgen receptor, and thus have the capacity to modulate androgen receptor
activity, nuclear hormone receptor binding assays are first performed. All ligands,
radioligands, solvents, and reagents employed in the binding assays are readily
available from commercial sources, or can be readily synthesized by the ordinarily
skilled artisan.
Steroid Hormone Nuclear Receptor Binding Assay:
Cell lysates from 293 cells overexpressing human GR (glucocorticoid
receptor), AR (androgen receptor), MR (mineralocorticoid receptor) or PR
(progesterone receptor) are used for competition binding assays to determine Ki
values for test compounds. Briefly, competition binding assays are run in a buffer
containing 20mM Hepes, pH 7.6,0.2 mM EDTA, 75 mM NaCl, 1.5 mM MgC12,
20% glycerol, 20mM sodium molybdate, 0.2 mM DTT, 20 µg/ml aprotinin and 20
µg/ml leupeptin, using either 0.3 nM 3H-dexamethasone for GR binding, 0.36 nM
3H-methyltrienolone for AR binding, 0.25 nM 3H-aldosterone for MR binding, or
0.29 nM 3H-methyltrienoIone for PR binding, and either 20 ug 293-GR lysate, 22
µg 293-AR lysate, 20µg 293-MR lysate or 40 µg 293-PR lysate per well. Competing
compounds are added at various concentrations ranging from about O.OlnM to
10µM. Non-specific binding is determined in the presence of 500 nM
dexamethasone for GR binding, 500 nM aldosterone for MR binding, or 500 nM
methyltrienolone for AR and PR binding,. The binding reaction (140 µl) is
incubated for overnight at 4°C, then 70 µl of cold charcoal-dextran buffer
(containing per 50 ml of assay buffer, 0.75 g of charcoal and 0.25 g of dextran) is
added to each reaction. Plates are mixed 8 minutes on an orbital shaker at 4°C.
Plates are then centrifuged at 3,000 rpm at 4°C for 10 minutes. An aliquot of 120 µl
of the mix is transferred to another 96-well plate and 175 µl of Wallac Optiphase

WO 2007/002181

PCT/US2006/024122

"Hisafe 3" scintillation fluid is added to each well. Plates are sealed and shaken
vigorously on an orbital shaker. After an incubation of 2hrs, plates are read in a
Wallac Microbeta counter. The data is used to calculate an ICso and % Inhibition at
00µM. The Kd for 3H-dexamethasone for GR binding, 3H-methyltrienolone for AR
binding, 3H-aldosterone for MR binding, or 3H-methyltrienolone for PR binding, is
determined by saturation binding. The ICso values for test compounds are converted
to Kj using Cheng-Prusoff equation and the Kd determined by saturation binding
assay.
Binding assay protocols for steroid hormone nuclear receptors similar to
those described above can be readily designed by the ordinarily skilled artisan.
Representative compounds of the present invention have a Ki in the AR binding
assay of ≤ 5 µM. Furthermore, exemplified compounds of the present invention
have a Ki in the AR binding assay of ≤ 1.5 µM. More particularly, preferred
compounds of the present invention have a Ki in the AR binding assay of ≤ 1 µM.
Even more particularly, more preferred compounds of the present invention have a
Ki in the AR binding assay of ≤ 500 nM. More particular still, especially preferred
compounds of the present invention have have a Ki in the AR binding assay of ≤
100 nM. Table I (see below) provides AR binding data for a representative sample
of the exemplified compounds of the present invention. In addition, the most
particularly preferred compounds of the present invention selectively bind to the
androgen receptor with greater affinity relative to the other steroid hormone
receptors (MR, GR, and PR)
To demonstrate the ability of compounds of the present invention to
modulate the activity of the androgen receptor (i.e. either agonize, partially agonize,
partially antagonize, or antagonize), bioassays are performed which detect
modulation of target gene expression in cells transiently transfected with a nuclear
receptor protein and a hormone response element-reporter gene construct. The
solvents, reagents, and ligands employed in the functional assay are readily
available from commercial sources, or can be synthesized by one of ordinary skill in
the art.
Functional Assay of Steroid Hormone Nuclear Receptor Modulation:

WO 2007/002181 PCT/US2006/024122
Human embryonic kidney hEK293 cells are co-transfected using
FuGENE™. Briefly, the reporter plasmid containing two copies of probasin ARE
(androgen response element5'GGTTCTTGGAGTACT3') (SEQ ID NO:1) and TK
promoter upstream of the luciferase reporter cDNA, is transfected with a plasmid
constitutively expressing human androgen receptor (AR) using viral CMV
promoter. The reporter plasmid containing two copies of GRE (glucocorticoid
response element 5TGTACAGGATGTTCT3) (SEQ ID NO:2) and TK promoter
upstream of the luciferase reporter cDNA, is transfected with a plasmid
constitutively expressing either human glucocorticoid receptor (GR), human
mineralocorticoid receptor (MR), or human progesterone receptor (PR), using viral
CMV promoter. Cells are transfected in T150 cm2 flasks in DMEM media with 5%
charcoal-stripped Fetal Bovine Serum (FBS). After an overnight incubation,
transfected cells are trypsinized, plated in 96 well dishes in DMEM media
containing 5% charcoal-stripped FBS, incubated for 4h and then exposed to various
concentrations of test compounds ranging from about 0.01nM to 10µM. In the
antagonist assays low concentrations of agonist for each respective receptor are
added to the media (0.25nM dexamethosone for GR, 0.3 nM of methyltrienolone
for AR, 0.05nM of promegestone for PR and 0.05nM aldosterone for MR). After
24 h of incubations with compounds, cells are lysed and luciferase activity is
determined.
Data are fitted to a four parameter-fit logistic curve fit to determine EC50
values The percentage efficacy (compounds with saturated maximum responses) or
the percent maximum stimulations (compounds with maximum responses that do
not saturate) are determined relative to maximum stimulation obtained with the
.following reference agonists: 100nM methyltrienolone for AR assay, with 30nM
promegestone for PR assay, with 30nM aldosterone for MR assay and with lOOnM
dexamethasone for GR assay. IC50 values may be determined similarly using
antagonist mode assay data. In the antagonist mode, percent inhibitions are
determined by comparing test compound activity in the presence of low
concentration of agonist (0.25nM dexamethasone for GR, 0.3 nM of
methyltrienolone for AR, 0.05nM of promegestone for PR and 0.05nM aldosterone

WO 2007/002181 PCT/US2006/024122
for MR) to the response produced by the same low concentration of agonist in the
absence of test compound.
C2C12 AR/ARE reporter assay:
As an indicator of agonist activity in muscle tissue, the C2C12 AR/ARE
reporter assay is performed. Briefly, mouse myoblast C2C12 cells are co-
transfected using FuGENE™. A reporter plasmid containing a GRE/ARE
(glucocorticoid response element/androgen response element
5TGTACAGGATGTTCT3) (SEQ ID NO:3) and TK promoter upstream of the
luciferase reporter cDNA, is transfected with a plasmid constitutively expressing
human androgen receptor (AR) using viral CMV promoter. Cells are transfected in
T150 cm2 flasks in DMEM media with 4% or 10% Fetal Bovine Serum (FBS).
After a 5 hour incubation, transfected cells are trypsinized, plated in 96 well dishes
in DMEM media containing 10% charcoal-stripped FBS, incubated for 2h and then
exposed to various concentrations of test compounds ranging from about 0.01 nM to
10µM. After 48 h of incubations with compounds, cells are lysed and luciferase
activity is determined using standard techniques. Data is fit to a 4 parameter-fit
logistics to determine EC50 values. The % efficacy is determined versus maximum
stimulation obtained with 10nM methyltrienolone.
Functional assays of nuclear hormone receptor modulation similar to those
described above can be readily designed by the ordinarily skilled artisan. Table I
(see below) provides average EC50 and % Efficacy data in the C2C12 AR/ARE
reporter assay for a representative sample of the exemplified compounds of the
present invention.
In vivo Mouse Model of Efficacy and Selectivity:
Male ICR mice (8 weeks old) are castrated according to approved
procedures (Taconic, NY) and allowed to waste for eight weeks. Age-matched
sham-operated mice are also prepared. (Sham-operated mice are animals that have
been exposed to the same surgical procedures as castrated animals except their
testes are not removed.) Animals are housed in a temperature-controlled room

WO 2007/002181 PCT/US2006/024122
(24°C) with a reversed 12 hour light/dark cycle (dark 10:00/22:00) and water and
food are available ad libitum.
In order to demonstrate in vivo efficacy, compounds of the present invention
are administered daily by oral gavage or subcutaneous injection to the castrated
sixteen week old mice (body weight about 48-50 g). Test compounds are
administered to the animals using conventional vehicles. For example, for oral
dosing 1% Sodium Carboxymethylcellulose (CMC) + 0.25% Tween 80 in sterile
H2O can be used for oral formulation and 6% Ethyl-alcohol (EtOH) + 94%
cyclodexitrane (CDX) can be used for subcutaneous injections. Castrated mice
treated with Testosteron Enanthate (TE) (10 mg/kg/d) are used as a treatment
positive control whereas castrated mice treated only with vehicle are used as
treatment negative control. In addition, sham-operated mice treated with vehicle
only are used as control for the surgical method.
Test animals are dosed over a two week timeframe, orally or
subcutaneously, with, for example, 0.3,1, 3,10 or 30 mg/kg/day of a compound of
the present invention. After the two-week treatment, as an indicator of activity the
wet weight of the Levator Ani muscle in the test group is determined and compared
to the weight in the castrated, vehicle-only control group. The percent efficacy is
then calculated as follows:
(Wet weight in treatment group / Wet weight in control group) X 100
As an indicator of tissue selective activity, the wet weight of the seminal vesicle
from test animals is similarly compared to the weight of the seminal vesicles from
the castrated, vehicle-only group. In addition, a comparison of the wet weight of the
prostate glands from the drug-treated group, to the wet weight of the prostate glands
removed from the castrated, vehicle-only group, may also be used as an indicator of
tissue selective activity.
Table II (see below) provides % efficacy data for a select sample of
exemplified compounds of the present invention. Animal models of efficacy and
selectivity similar to those described above can be readily designed and perfomed
by the ordinarily skilled artisan, for example, Eisenberg and Gilbert, J Pharmacol

WO 2007/002181 PCT/US2006/024122
Exp Ther. 1950,99(1), 38-44, provides an alternative rat model that may be
employed to show in vivo efficacy.
In vivo Models of Disorders associated with bone loss:
To demonstrate that compounds of the present invention have the capacity
to treat disorders associated with bone loss, such as osteoporosis or osteopenia,
animal models well known to those in the art may be employed. Examples of such
models are provided in Y. L. Ma et al., Japanese Journal of Bone and Mineral
Metabolism 23 (Suppl.): 62-68 (2005); Y.L. Ma et al., Endocrinology 144:2008-
2015 (2003); and K. Hanada et al, Biol. Pharm. Bull. 26(11): 1563-1569 (2003).
As will be appreciated by one of ordinary skill in the art, the animal model
protocols described in the references above may be readily adapted for use in
conjunction with the compounds and methods of the present invention.
The following preparations and examples further illustrate the invention and
represent typical synthesis of the compounds of Formula I, including any novel
compounds, as described generally above. The reagents and starting materials are
readily available to, or may be readily synthesized by, one of ordinary skill in the
art. Where the synthesis of the compound is not explicitly stated, a reference to a
previous Example or representative Scheme describing procedures for the synthesis
of the compound is provided. It should be understood that the Preparations and
Examples are set forth by way of illustration and not limitation, and that various
modifications may be made by one of ordinary skill in the art.
Proton nuclear magnetic resonance (1H NMR) spectra are collected on a
Bruker Avance 300 MHz or a Varian 400 MHz spectrometer. Chemical shift values
are reported in parts per million (ppm) 5 values, relative to TMS as the internal
standard (bs, broad singlet; s, singlet; d, doublet; t, triplet; q, quartet). Melting
points are determined on a MelTemp II, model 1001, or a Mettler Toledo FP62
melting point apparatus and are uncorrected. All products are a racemic mixture of
R and S stereoisomers unless indicated otherwise.
HPLC analysis is preformed using the following methods: Agilent Zorbax
SB-C18,5 µm column (4.6 x 250 mm). Method A: Elution system consists of an
isocratic elution of acetonitrile:0.03 M phosphate buffer (80:20) for 10 minutes.

WO 2007/002181 PCT/US2006/024122
The flow rate is 1.5 mL/min. UV detection is performed at 220 nm. Method B:
Elution system consists of an isocratic elution of acetonitrile:0.03 M phosphate
buffer (60:40) for 10 minutes. The flow rate is 1.5 mL/min. UV detection is
performed at 220 nm. HPLC analyses are performed using Method A if not
otherwise noted.
Mass spectral analyses are conducted on one of the following: 1)
ThermoFinnigen aQa using electrospray ionization (ESI); 2) Applied Biosystems
API150EX mass spectrometer using atmospheric chemical ionization (APCI); 3)
Micromass ZMD equipped with a Waters autosampler and using electrospray
ionization (ES); 4) LCMS-APCI analysis is preformed on a Hewlett Packard
LC/MSD using an Agilent Eclipse Zorbax SDB-C8, 5.0 µm column (4.6 x 150
mm). The flow rate is 0.5 mL/min. UV detection is performed at 254 nm. On of
the following methods was utilized. Method C: An isocratic elution of 70:30
methanol/10mM ammonium acetate buffer (pH 5.5) for 10 min. Method D: An
isocratic elution of 80:20 methanol/10mM ammonium acetate buffer (pH 5.5) for
10 min. Method E: A gradient elution beginning with 80:20 methanol/1mM
ammonium acetate buffer (pH 6.0), for 1 min, adjusting the solvent composition in
even gradient to 100% methanol over 2 min, then holding at 100% methanol for 7
min.; or 5) Agilent 1100 series LCMSD with atmospheric pressure electrospray
(APES) using the following method: Waters Exterra C18, 3.5 (im column (2.1 x 50
mm). The elution system consists of solvent A = 0.2% aqueous ammonium
formate, B = ammonium formate in 50% methanol/acetonitrile solution. The
elution system consists of a gradient elution beginning with 5% B for 1 min,
adjusting the solvent composition in even gradient to 100% B over 6 min, then
holding at 100% B for 1 min. The flow rate is 1.0 mL/min. UV detection is
performed at 214 nm.
Preparations and Examples
Preparation 1
N-(4-Hydroxycyclohexyl)isobutyramide

WO 2007/002181 PCT/US2006/024122

Add isobutyric anhydride (317.3 g, 2.01 mol) dropwise over three hours to
trans-4-aminocyclohexanol (210.0 g, 1.82 mol) and triethylamine (279 mL, 2.01
mol) in tetrahydrofuran (4500 mL) in a twelve liter mechanically stirred flask. Stir
at 23 - 30 °C under nitrogen for 18 h. Dilute with water (4500 mL) and wash with
diethyl ether (2 x 2000 mL) to remove by-products. Add sodium chloride (700 g)
and wash with CH2Cl2 (5000 mL) to extract out product. Remove organic portion
and filter the aqueous to collect precipitated solids. Add the filtrate to water and
extract with additional CH2Cl2 (2 x 2500 mL). Dry the organic portion (Na2SO4),
filter, concentrate in vacuo and combine with the collected precipitate to give 219.5
g of a white solid (65%). MS (ES): m/z 186 (M+l); 'H NMR(DMSO-d6): δ 5.23
(br s, 1H, NH), 3.75 (m, 1H), 3.59 (m, 1H), 2.27 (septet, 1H), 2.00 (m, 5H), 1.40
(m,2H), 1.22 (m, 2H), 1.07 (d, 6H).
Preparation 2
N-(4-Oxocyclohexyl)isobutyramide

Add pyridinium chlorochromate (561.6 g, 2.61 mol) to N-(4-
hydroxycyclohexyl) isobutyramide (323.8 g, 1.74 mol) in CH2Cl2 (8000 mL) and
stir mechanically for 24 h under nitrogen. Add silica gel (2000 g), stir, and filter
through a silica pad (6000 g). Elute with CH2Cl2 followed by 75 -100%
EtOAc/hexanes to obtain 210 g of a light brown solid (66%). MS (ES): m/z 184
(M+l); 1H NMR(DMSO-d6): δ. 5.54 (br s, NH), 4.27 (septet, 1H), 2.20-2.60 (m,
7H), 1.78 (m,2H), 1.15 (d,6H).
Preparation 3
N-(6-Cyano-2,3,4,9-tetrahydro-lH-carbazol-3-yl)isobutyramide

WO 2007/002181 PCT/US2006/024122

Method 1. Combine p-cyanophenylhydrazine hydrochloride (38.00 g, 224
mmol) and N-(4-oxo-cyclohexyl)isobutyramide (41.06 g, 224 mmol) in absolute
ethanol (500 mL) and heat at 70 - 85 °C under nitrogen for 48 - 64 h. Concentrate
in vacuo and partition between CH2Cl2/i-PrOH and water. Dry the organic portion
(Na2SO4), filter, and evaporate to give 55.7 g (88%) of a yellow solid. MS (ES):
m/z 282 (M+1). Alternatively, the titled compound can be prepared as described
below.
Method 2. Combine 4-cyanophenylhydrazine hydrochloride (51.95 g, 306.3
mmol) and N-(4-oxo-cyclohexyl)-isobutyramide (56.13 g, 306.3 mmol) in water
(100 mL) and concentrated hydrochloric acid (140 mL). Vigorously stir the thick
suspension at 90 °C for 5.5 h. Allow to cool to room temperature and then cool to 5
°C with continued stirring for 30 min. Filter and dry at 45 °C for 18 h on house
vacuum. Suspend the resulting solid powder in water/THF (200 mL/100 mL) and
take alkaline with 1N NaOH (10 mL). Stir for 2 h and filter, washing liberally with
water. Dry under house vacuum at 45 °C for 3 days to obtain 71.97 g (83%) of a
light brown powder. MS (ES): m/z 282 (M+l), 280 (M-1); 1H NMR(DMSO-d6): δ
11.39 (s, 1H), 7.88 (m, 2H), 7.42 (d, 1H, J=8.4 Hz), 7.37 (dd, 1H, J=8.4,1.3 Hz),
4.06 (m, 1H), 2.96 (dd, 1H, J=15.4, 5.3 Hz), 2.83 (m, 2H), 2.50 (m, 1H), 2.41 (m,
1H), 1.98 (m, 1H), 1.81 (m, 1H), 1.04 (d, 3H, J=2.2 Hz), 1.02 (d, 3H, J=1.8 Hz).
Preparation 4
(N-(9-Benzyl-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide

WO 2007/002181 PCT/US2006/024122
^
Combine p-bromophenylhydrazine hydrochloride (10.0 g, 44.7 mmol) and
N-(4-oxo-cyclohexyl)isobutyramide (8.20g, 44.7 mmol) in saturated ethanolic HC1
(180 mL) and heat at reflux under nitrogen for 18 h. Concentrate in vacuo to
remove about 1/2 of the EtOH, then dilute with water (300 mL). Collect the
resulting solid, slurry in EtOAc and recollect to give 11.5 g (77%) of a beige solid.
MS (ES): 335 (M+1), 337 (M+H+2). 1H NMR(DMSO-d6): δ 10.93 (s, 1H, NH),
7.80 (d, 1H, J=7.9 Hz), 7.48 (s, 1H), 7.19 (d, 1H, J=8.8 Hz), 7.07 (d, 1H, J=8.4 Hz),
4.00 (m, 1H), 2.86 (dd, 1H, J=15.2,5.1 Hz), 2.77 (m, 2H), 2.46 - 2.32 (m, 2H),
1.93 (m, 1H), 1.75 (m, 1H), 0.99 (d, 6H, J=6.6 Hz).
Preparation 4a
N-(6-Fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide

Combine p-fluorophenylhydrazine hydrochloride (5.00 g, 30.7 mmol) and
N-(4-oxo-cyclohexyl)isobutyramide (5.64 g, 30.7 mmol) in ethanolic HC1 (125 mL)
and heat at reflux under nitrogen for 18 h. Concentrate the reaction in vacuo to
remove most of the EtOH, dilute with water and extract with EtOAc. Wash the
EtOAc extracts with water and brine, dry over Na2SO4, and evaporate to give 7.1 g
(56%) of a beige solid. MS (ES): m/z 275 (M+1); 1H NMR(DMSO-d6): δ 10.79 (s,
1H, NH), 7.81 (d, 1H, 7 = 7.5 Hz), 7.19 (dd, 1H, 7 = 8.6,4.6 Hz), 7.07 (d, 1H, 7 =
10.1 Hz), 6.79 (dt, 1H, 7 = 8.9,1.8 Hz), 4.00 (m, 1H), 2.85 (dd, 1H, 7 = 15.0,5.3
Hz), 2.76 (m, 2H), 2.39 (m, 2H), 1.93 (m, 1H), 1.75 (m, 1H), 0.99 (d, 6H, 7 = 6.6
Hz).

WO 2007/002181 PCT/US2006/024122
Example 1
N-(9-Benzyl-6-bromo-2,3.4,9-tetrahydro-1H-carbazoI-3-yl)isobutyramide

Add N-(6-bromo -2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (0.25
g, 0.75 mraol) to a suspension of sodium hydride (0.036 g, 0.90 mmol of a 60%
dispersion in mineral oil) in DMF (3 mL) and stir for 15 min. Add 3-
fluorobenzylbromide (0.10 mL, 0.90 mmol) and stir for 18 - 72 h. Dilute with
water and collect the precipitate by filtration. Purify by silica gel chromatography
eluting with 20 -100% EtOAc/hexanes gradient to give 0.23 g of a white solid
(71%). MS (ES): m/z 443 (M+1), 445 (M+H+2); HPLC: R, = 3.71 min (97.1%);
m.p. = 177 -179 °C.
Using the appropriate tetrahydrocarbazole derivative, prepared essentially as
described in Preparations 3,4, or 4a above, Examples 2 - 60, in the Table below,
are prepared by alkylating the tetrahydrocarbazole with the appropriate benzylhalide
essentially as described in Example 1.






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Example 61
N-[9-(3-Fluorobenzyl)-6-nitro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]isobutyramide

Heatp-nitrophenylhydrazine hydrochloride (5.00 g, 26.4 mmol) and N-(4-
oxo-cyclohexyl)isobutyramide (5.31 g, 29.0 mmol) in absolute EtOH (105 mL) at
70 °C for 2 h. Collect the yellow hydrazone product by filtration and rinse with
EtOH to yield 7.2 g (86%). Transfer the hydrazone to a solution of benzene and
treat with p-toluenesulfonic acid (2 equiv) at reflux for 18 h to afford the
tetrahydrocarbazole. Alkylate with 3-fluorobenzylbromide using cesium carbonate
(1.2 eq) as base at 23 °C for 18 h. Pour the reaction mixture onto water and filter
the precipitate. Purify the material by silica gel chromatography, eluting with 20 -
80% EtOAc/hexanes gradient to obtain the title compound. MS (ES): m/z 410
(M+1); HPLC: Rt = 2.60 min, (100%).
Example 62
N-[6-Dimethylamino-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-lH-carbazol-3-yl]-
isobutyramide

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In a sealed tube, heat N-[6-bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-
lH-carbazol-3-yl]-isobutyramide (Example 35) (200 rag, 0.45 mmol), dimethyl
amine (2.0 M in tetrahydrofuran, 0.45 mL, 0.90 mmol), palladium acetate (5 mg,
0.002 mmol), sodium tert-butoxide (133 mg, 1.38 mmol), and 1,2,3,4,5-
pentaphenyl-1'-(di-r-butylphosphino)ferrocene ligand (60 mg, 0.008 mmol) in
toluene (5 mL) at 70 °C overnight. Cool to room temperature, dilute with ethyl
acetate/10% potassium carbonate, and filter off the red suspension. Wash the
organic portion with 10% aqueous potassium carbonate (2x), dry over anhydrous
sodium sulfate, filter, and concentrate. Purify the residue by silica gel column
chromatography eluting with 40 to 100% ethyl acetate/hexanes to obtain the title
compound (135 mg, 74%). MS (ES): m/z 408 (M+1); 1H NMR (CD3OD): δ 7.25
(m, 1H), 7.18 (d, 1H), 7.01 (s, 1H), 6.96 (t, 1H), 6.89 (d, 1H), 6.81 (d, 1H), 6.65 (d,
1H), 5.30 (s, 2H), 4.19 (m, 1H), 3.08 (dd, 1H), 2.88 (s, 6H), 2.77 (m, 2H), 2.63 (m,
1H), 2.50 (m, 1H), 2.12 (m, 1H), 1.97 (m, 1H), 1.18 (m, 6H).
Example 63
9-(3-Fluorobenzyl)-6-isobutyrylamino-6,7,8,9-tetrahydro-5H-carbazole-3-
carboxylic acid amide

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Add K2CO3 (0.26 g, 1.93 mmol) and 30% H2O2 (2.0 mL) portionwise to N-
(6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide
(Example 51) (1.50 g, 3.85 mmol) in DMSO while cooling in an ice bath. Stir for
18 h and add more H2O2 with warming to 50 °C if needed to facilitate complete
reaction. Dilute with water and collect the precipitate by filtration (1.45 g, 92%).
Recrystallize from EtOAc to yield a white solid. MS (ES): m/z 408 (M+1); m.p. =
192-194 °C.
Example 64
N-(9-(3-Fluorobenzyl)-6-thiocarbamoyl-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)isobutyramide

Heat N-(6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)isobutyramide (Example 51) (1.00 g, 2.57 mmol) with thioacetamide (0.386 g,
5.14 mmol) at reflux temperature in 4N HC1 in dioxane (30 mL) for 4 h. Allow to
cool, pour onto water and neutralize with NaHCO3. Collect 0.98 g (90%) of a
precipitate. Purify a portion of the material by silica gel chromatography (25 -

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80%EtOAc/hexanes gradient) to give a yellow solid. MS (ES): m/z 424 (M+1);
HPLC:Rt = 1.90min,(95%).
Example 65
N-(9-Benzyl-6-methoxy-2,3-4,9-tetrahydro-1H-carbazol-3-yl)-acetarnide

Add N-benzyl-N-(4-methoxy-phenyl)-hydrazine (9.1 g, 0.04 mol) (prepare
as in Shaw, E., J. Am. Chem. Soc. (1955), 77,4319-4324) to N-(4-oxo-cyclohexyl)-
acetamide (6.2 g, 0.04 mol) (prepare as in Dionne, G., Hymbe, L. G., Asselin, A.,
McQuillan, J. and Treasureywala, A. M., J. Med. Chem., (1986), 29,1452-1457) in
acetic acid (60 mL) and reflux for 2 h. Pour in water, extract with hot benzene and
remove the solvent in vacuo. Recrystillize the resulting solid from
benzene/cyclohexane to give 10.4 g of a crystalline solid, m.p = 184-185 °C.
Recrystillize from the same solvents to obtain an analytically pure sample. Anal.
Caled for C22H24N2O2: C, 75.83; H, 6.94; N, 8.04. Found: C, 75.71; H, 7.01; N,
7.89.
Preparation 5
9-Benzyl-6-methoxy-2,34,9-tetrahydro-1H-carbazol-3-ylamine maleic acid salt

Add N-(9-benzyl-6-methoxy-2,3-4,9-tetrahydro- 1H-carbazol-3-yl)-
acetamide (6.5 g 0.020 mol) and potassium hydroxide pellets (35 g, 0.62 mol) to 2-
methoxyethanol (130 mL) and water (35 mL). Reflux for 18 h. Remove the solvent
in vacuo and dilute the resulting residue with water and extract with hot benzene.

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Combine the organic portions and wash with water until the wash is neutral, then
dry (MgSCO4), and concentrate in vacuo to obtain 6.25 g of a viscous oil. Dissolve
the residue in warm methanol (25 mL) and add a solution of maleic acid (2.5 g,
0.0215 mol) in absolute methanol (7 mL). Cool and filter to obtain 6.2 g fine
crystalline needles, m.p. = 167-168.5 °C. Obtained a second crop from the mother
liquor of 0.35 g to give a combined yield of 80.5%. m.p. = 163-165 °C. Obtain an
analytical sample by recrystillization from absolute methanol. Anal. Calcd for
C24H26N2O5: C, 68.23; H, 6.20; N, 6.63. Found: C, 68.07; H, 6.04; N, 6.92.
Example 66
N-(9-Benzyl-6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-propionamide

Suspend 9-benzyl-6-methoxy-2,34,9-tetrahydro-1H-carbazol-3-ylamine
maleic acid salt (100 mg, 0.237 mmol) in dichloromethane (2 mL) under nitrogen
and add triethylamine (0.099 mL, 0.711 mmol) followed by propionyl chloride
(0.021 mL, 0.237 mmol). Stir the reaction at room temperature for 16 h.
Concentrate in vacuo and purify the residue directly by silica gel chromatography,
eluting with 25% ethyl acetate/hexanes followed by 60% ethyl acetate/hexanes to
obtain 61 mg (71%) of a solid. MS (ES): m/z 363 (M+1), 361 (M-1); 1H
NMR(DMSO-d6): δ 7.90 (d, 1H, J= 7.5 Hz), 7.33-7.20 (m, 4H), 7.02 (d, 2H, J =
7.0 Hz), 6.92 (d, 1H, J= 2.2 Hz), 6.67 (dd, 1H, J= 8.8,2.2 Hz), 5.29 (s, 2H), 3.95
(m, 1H), 3.72 (s, 3H), 2.95 (dd, 1H, J = 15.0,5.3 Hz), 2.80 (m, 1H), 2.79 (m, 1H),
2.42 (m, 2H), 2.11 (q, 2H, J = 7.6 Hz), 1.99 (m, 1H), 1.79 (m, 1H), 1.02 (t, 3H, J =
7.5 Hz).
Prepare Examples 67 and 68, below, as essentially described in Example 66,
using isobutryl chloride and cyclopropane carbonyl chloride respectively with 9-
benzyl-6-methoxy-2,34,9-tetrahydro-1H-carbazol-3-ylamine maleic acid salt.

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Example 67
N-(9-Benzyl-6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide

MS (ES): m/z 377 (M+1); 'H NMR(DMSO-d6): δ 7.84 (d, 1H, J= 7.5 Hz),
7.32-7.19 (m, 4H), 7.02 (d, 2H, J = 7.0 Hz), 6.92 (d, 1H, J = 2.2 Hz), 6.67 (dd, 1H,
J= 8.8,2.2 Hz), 5.29 (s, 2H), 4.00 (m, 1H), 3.75 (s, 3H), 2.95 (dd, 1H, J = 15.2,5.1
Hz), 2.83-2.63 (m, 2H), 2.52-2.36 (m, 2H), 1.97 (m, 1H), 1.80 (m, 1H), 1.02 (m,
6H).
Example 68
Cyclopropanecarboxylic acid(9-benzyl-6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-
3-yl)-amide

MS (ES): m/z 375 (M+1); 1H NMR(DMSO-d6): δ 8.21 (d, 1H, J= 7.5 Hz),
7.32-7.20 (m, 4H), 7.03 (d, 2H, J = 7.5 Hz), 6.92 (d, 1H, J = 2.2 Hz), 6.67 (dd, 1H,
J - 8.8,2.2 Hz), 5.29 (s, 2H), 4.03 (m, 1H), 3.75 (s, 3H), 2.96 (dd, 1H, J= 15.2, 5.1
Hz), 2.86-2.77 (m, 1H), 2.74-2.63 (m, 1H), 2.00 (m, 1H), 1.80 (m, 1H), 1.60 (m,
1H), 0.66 (m, 4H).
Preparation 6
N-(6-methoxy-2,3,4,9-tetrahydro-li/-carbazol-3-yl)-isobutyramide

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Add acetyl chloride (8.5 mL, 120 ramol) to absolute ethanol (30 mL) and
stir for 1 h. Add 4-methoxyphenylhydrazine hydrochloride (1.74 g, 10 mmol) and
N-(4-oxo-cyclohexyl)-isobutyramide (Preparation 2) (1.83 g, 120 mmol) and reflux
with stirring for 56 h. Cool to room temperature, dilute with ethyl acetate (100 mL)
and wash with sodium bicarbonate solution (2 x 50 mL), brine, dry (MgSO4), filter
and concentrate in vacuo. Dissolve the residue in dichloromethane and pass over a
silica pad, eluting with 20% ethyl acetate/dichloromethane to obtain 2.32 g of a
solid. Triturate the solid in diethyl ether with a small amount of dichloromethane,
filter and dry under house vacuum to obtain 2.14 g (75%) of an off-white solid. MS
(ES): m/z 287 (M+1), 285 (M-1); !H NMR(DMSO-d6): δ 10.52 (s, 1H), 7.83 (d,
IH, J= 7.5 Hz), 7.13 (d, 1H, J= 8.8 Hz), 6.85 (s, 1H), 6.64 (dd, 1H, J = 8.8, 2.2
Hz), 4.02 (m, IH), 3.75 (m, 3H), 2.90 (dd, IH, J = 15.0, 5.3 Hz), 2.78 (m, 2H), 2.42
(m, 2H), 1.96 (m, IH), 1.79 (m, IH), 1.03 (d, 6H, J = 6.6 Hz).
Preparation 7
N-(8-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide

Add acetyl chloride (34.1 mL, 480 mmol) portionwise to absolute ethanol
(120 mL) cooled in an ice bath and stir for 2 h. Add 4-methoxyphenylhydrazine
hydrochloride (1.74 g, 10 mmol) and N(4-oxo-cyclohexyl)-isobutyramide
(Preparation 2) (1.83 g, 120 mmol) and reflux with stirring for 18 h. Follow the
procedures essentially as described in Preparation 6, above, to give 6.0 g green gum
after workup. Pass over a silica pad eluting with dichloromethane/25% ethyl
acetate to provide 1.29 g of a brown foam. Further purify the residue by flash

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chromatography, eluting with dichloromethane, dichloromethane/25% ethyl acetate
and then a gradient up to dichloromethane/40% ethyl acetate to obtain a pale tan
solid. Triturate in diethyl ether with a bit of hexane to give 421 mg (4%) of an off-
white solid. MS (ES): m/z 287 (M+1), 285 (M-1); 'H NMR(DMSO-d6): δ 10.77 (s,
1H), 7.83 (d, 1H, J = 7.5 Hz), 6.95 (d, 1H, J = 7.9 Hz), 6.86 (t, 1H, J = 7.7 Hz),
6.61 (d, 1H, J = 7.5 Hz), 4.02 (m, 1H), 3.90 (s, 3H), 2.89 (dd, 1H, J = 15.0, 5.3
Hz), 2.76 (m, 2H), 2.50-2.34 (m, 3H), 1.95 (m, 1H), 1.76 (m, 1H), 1.03 (d, 6H, J =
7.0 Hz).
Preparation 8
N-(7-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide

Follow the procedures essentially as described in Preparation 6, above, using
acetyl chloride (26 mL, 360 mmol) and absolute ethanol (90 mL) with 3-
methoxyphenylhydrazine hydrochloride (5.24 g, 30 mmol) and N-(4-oxo-
cyclohexyl)-isobutyramide (5.50 g, 30 mmol). When complete, dilute the reaction
with ethyl acetate (200 mL) and wash with 0.5N NaOH and sodium bicarbonate
solution. Filter the solids in the organic phase, triturate in dichloromethane and
filter to give 2.67 g (31%) gray solid. MS (ES): m/z 287 (M+1), 285 (M-1); 1H
NMR(DMSO-d6): δ 10.52 (s, 1H), 7.83 (d, 1H, J = 7.5 Hz), 7.21 (d, 1H, J = 8.4
Hz), 6.78 (s, 1H), 6.60 (d, 1H, J = 8.4 Hz), 4.00 (m, 1H), 3.75 (s, 3H), 2.87 (dd, 1H,
J = 14.8, 5.1 Hz), 2.76 (m, 2H), 2.48-2.36 (m, 2H), 2.48-2.36 (m, 2H), 1.76 (m,
1H), 1.03 (d, 6H, J = 6.6 Hz).
Example 69
N-[9-(2-Chloro-benzyl)-6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

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Dissolve N-(6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide
(Preparation 6) (100 mg, 0.35 mmol) in anhydrous tetrahydrofuran (4 mL) under
nitrogen. Add dropwise potassium bis(trimethylsilyl)amide (0.77 mL, 0.385 mmol,
0.5N in toluene) and stir 25 min. Add slowly 2-chlorobenzylbromide (0.050 mL,
0.385 mmol) and stir at ambient temperature for 18 h. Quench with saturated
ammonium chloride solution (0.5 mL) and dilute with a volume of dichloromethane
and water (1 mL). Pass over a Varian Chem Elut column to remove aqueous
portion and concentrate in vacuo. Alternatively, workup with ethyl acetate/water
and dry over MgSO4. Purify the resulting residue by flash chromatography, eluting
with dichloromethane with a gradient up to 10% ethyl acetate/dichloromethane to
obtain 99 mg (69%) of a white solid. MS (ES): m/z 411,413 (M+1); 1H
NMR(DMSO-d6): δ 7.86 (d, 1H, J = 7.5 Hz), 7.52 (d, 1H, / = 8.4 Hz), 7.28 (t, 1H,
J = 7.7 Hz), 7.17 (m, 2H), 6.97 (d, 1H, J = 2.2 Hz), 6.68 (dd, 1H, J = 8.8, 2.2 Hz),
6.24 (d, 1H, J = 7.9 Hz), 5.36 (s, 2H), 4.02 (m, 1H), 3.77 (s, 3H), 2.98 (dd, 1H, J =
15.2, 5.1 Hz), 2.75-2.61 (m, 2H), 2.41 (m, 1H), 1.96 (m, 1H), 1.81 (m, 1H), 2.52
(m, 1H).
Using the appropriate tetrahydrocarbazole derivative from Preparations 3,6,
7, or 8 above or as prepared essentially as described in Preparations 4 or 4a above,
Examples 70-89, in the Table below, are prepared by alkylating the
tetrahydrocarbazole with the appropriate benzylhalide essentially as described in
Example 69.

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Example 90
A^-[9-(3-Amino-benzyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Add sulfided platinum (5 wt % on carbon) (120 mg) to a solution of N-[6-
cyano-9-(3-nitro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide
(Example 88) (470 mg, 1.1 mmol) and methanol (50 mL). Purge and fill the
reaction vessel with nitrogen (3x), then with hydrogen (3x, 55 psi). Seal the
reaction vessel at about 55 psi, and stir the mixture at room temperature overnight.
Filter the reaction mixture through a Celite® pad, and wash the filter cake with
methanol. Concentrate under reduced pressure and purify the crude residue by flash
chromatography (2.5% methanol/methylene chloride) to give the title compound.
LCMS (Method D): m/z 387.1 (M+l, APCI); !H NMR (DMSO-ds): 8 7.97 (d, 1H),
7.88 (d, 1H), 7.57 (d, 1H), 7.42 (dd, 1H), 6.94 (t, 1H), 6.24 (d, 1H), 6.20 (m, 1H),

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5.26 (s, 2H), 5.07 (s, 2H), 4.03-4.06 (m, 1H), 3.01 (dd, 1H), 2.72-2.86 (m, 2H), 2.55
(dd, 1H), 2.38-2.46 (m, 1H), 1.98-2.02 (m, 2H), 1.79-1.87 (m, 1H), 1.04 (d, 3H).
1.02 (d,3H).
Example 91
N-[9-(3-Fluoro-benzyl)-6-hydroxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Add a solution of boron tribromide in dichloromethane (1.0M, 33 mL, 33
mmol)to N-[9-(3-fIuoro-benzyl)-6-methoxy-2,3.4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide (Example 79) (2.60 g, 6.59 mmol) and stir at room temperature
overnight. Quench slowly with methanol and concentrate under high vacuum.
Purify the residue by silica chromatography (15% methanol in ethyl acetate) to
obtain the title compound as a yellow solid (1.34 g, 53%). MS (ES): m/z
381(M+1); 1HNMR(CD3OD): δ7.28 (m, 1H), 7.07 (d, 1H), 6.97 (m, 1H), 6.78-
6.85 (m, 2H), 6.65 (d, 1H), 5.28 (s, 2H), 4.18 (m, 1H), 3.05 (dd, 1H), 2.76 (m, 2H),
2.47-2.67 (m, 2H), 2.13 (m, 1H), 1.92 (m, 1H), 1.17 (d, 6H).
Example 92
N-[6-Cyclopropylmethoxy-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide

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Stir N-[9-(3-fluoro-benzyl)-6-hydroxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide (167 mg, 0.44 mmol), cyclopropylmethyl bromide (59 mg, 0.44
mmol), and cesium carbonate (172 mg, 0.53 mmol) in dimethylformamide (1.5 mL)
at room temperature under nitrogen overnight. Dilute the reaction with ethyl
acetate, wash with water (2x), dry over sodium sulfate, filter, and concentrate.
Purify the residue by silica chromatography eluting with 10 to 100% ethyl
acetate/hexanes to obtain the title compound (101 mg, 53%). MS (ES): m/z 435
(M+1); 1H NMR (CDCl3): 8 7.28 (m, 1H), 7.13 (d, 1H), 6.98 (s, 1H), 6.95 (m, 1H),
6.85 (d, 1H), 6.79 (d, 1H), 6.65 (d, 1H), 5.60 (broad s, 1H, NH), 5.22 (s, 2H), 4.43
(m, 1H), 3.87 (d, 2H), 3.15 (dd, 1H), 2.60-2.81 (m, 3H), 2.34 (m, 1H), 2.18 (m,
2H), 1.34 (m, 1H), 1.18 (m, 6H), 0.65 (d, 2H), 0.39 (d, 2H).
Example 93
N-[6-Ethoxy-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Add N-[9-(3-fluoro-benzy3)-6-hydroxy-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide (175 mg, 0.46 mmol), ethyl iodide (72 mg 0.46 mmol), and
sodium hydride (60% suspension in mineral oil, 37 rag, 0.92 mmol) to

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dimethylformamide (1 mL) and stir at room temperature overnight. Dilute the
reaction with ethyl acetate, wash with water (2x), dry over sodium sulfate, and
concentrate. Recrystallize from ethyl acetate/hexanes to obtain the title compound
(107 mg, 57%): MS (ES): m/z (M+1); 1H NMR (CDCl3): 8 7.28 (m, 1H), 7.11 (d,
1H), 6.98 (s, 1H), 6.97 (m, 1H), 6.82 (d, 1H), 6.79 (d, 1H), 6.65 (d, 1H), 5.58 (broad
s, 1H, NH), 5.22 (s, 2H), 4.44 (m, 1H), 4.09 (q, 2H), 3.15 (dd, 1H), 2.60-2.81 (m,
3H), 2.33 (m, 1H), 2.15 (m, 2H), 1.45 (t, 1H), 1.18 (m, 6H).
Prepare Examples 94 and 95, below, by essentially following the procedures
as described in Example 93 using the appropriate alkyl halide and N-[9-(3-fluoro-
benzyl)-6-hydroxy-2,3,4,9-tetrahydro-1 H-carbazol-3-yl] -i sobutyramide.
Example 94
N-[9-(3-Fluoro-benzyl)-6-isopropoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

MS (ES): m/z 423 (M+1); !HNMR (CDCl3): 5 7.23 (m, 1H), 7.11 (d, 1H),
7.00 (s, 1H), 6.96 (m, 1H), 6.82 (m, 2H), 6.68 (d, 1H), 5.58 (broad s, 1H, NH), 5.22
(s, 2H), 4.54 (m, 1H), 4.44 (m, 1H), 3.15 (dd, IH), 2.60-2.81 (m, 3H), 2.35 (m, 1H),
2.17 (m, 2H), 1.39 (d, 6H), 1.18 (m, 6H).
Example 95
N-[9-(3-Fluoro-benzyl)-6-propoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

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MS (ES): m/z 423(M+1); 1H NMR (CD3OD): 5 7.99 (s,1H, NH), 7.26 (m.
1H), 7.11 (d, 1H), 6.96 (m, 2H), 6.81 (d, 1H), 6.77 (d, 1H), 6.65 (d, 1H), 5.27 (s,
2H), 4.18 (m, 1H), 3.96 (t, 2H), 3.08 (dd, 1H), 2.75 (m, 2H), 2.62 (m, 1H), 2.50 (m,
1H), 2.10 (m, 2H), 1.79-1.97 (m, 3H), 1.18 (m, 6H), 1.09 (t, 3H).
Preparation 9
iV-(6,7,8,9-Tetrahydro-5H-1,3-dioxa-9-aza-cyclopenta[b]fluoren-6-yl)-
isobutyramide

Add N-(4-oxo-cyclohexyl)-isobutyramide (974 mg, 5.32 mmol) a
suspension of benzo[l,3]dioxol-5-yl-hydrazine hydrochloride salt (Clemo, G. R.;
Weiss, J. J. Chan. Soc. (1945), 702.) (1.00 g, 5.32 mmol) to water (7 mL) and
concentrated hydrochloric acid (3 mL). Heat the reaction to 90 °C for 12 h and cool
to ambient temperature. Collect the resultant solid by vacuum filtration, rinse with
water and place under high vacuum for 12 h to afford the titled compound (1.20 g,
75%) as a dark brown solid, m.p. = 198-200 °C; 1H NMR (300 MHz, CDCl3): δ
7.77 (br s, 1H), 6.81 (s, 1H), 6.78 (s, 1), 5.91 (s, 2H), 5.57 (br s, 1H), 4.40 (br s,
1H), 3.00 (dd, J= 15.4,5.1 Hz, 1H), 2.80-2.69 (m, 2H), 2.50 (dd, J = 15.4,6.5 Hz,
1H), 2.30 (septet, J = 6.9 Hz, 1H), 2.05-1.96 (m, 2H), 1.14 (d, /= 6.9 Hz, 6H).

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Preparation 10
(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-hydrazine hydrochloride salt

Add slowly a solution of sodium nitrite (1.40 g, 20.3 mmol) in water (11
mL) to a flask containing 2,2-difluoro-benzo[l,3]dioxol-5-ylamine (3.41 g, 19.7
mmol), water (14 mL), and concentrated hydrochloric acid (5 mL) at -5 °C. Cool
the reaction to -10 °C then add tin(II) chloride (11.20 g, 49.6 mmol) in concentrated
hydrochloric acid (9 mL). Stir the reaction for one hour and collect the resultant
solid by filtration. Dissolve the solid in methylene chloride (20 mL) and treat with
acetone (5 mL). Wash the resultant organic solution with water (50 mL), dry over
magnesium sulfate, filter, and evaporate under reduced pressure. Stir the resultant
oil with 2N hydrochloric acid (100 mL) for 12 h. Collect a solid by Filtration, wash
with water and dry in a vacuum oven at 40 °C overnight to give the subtitled
compound (1.14 g, 26%) as a red powder. 1H NMR (300 MHz, DMSO-4): δ 10.32
(br s, 3H), 8.45 (br s, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.11 (d, J= 2.3 Hz, 1H). 6.79
(dd, J = 8.7,2.3 Hz, 1H).
Preparation 11
N-(2,2-Difluoro-6,7,8,9-tetrahydro-5H-l,3-dioxa-9-aza-cyclopenta[b]fluoren-6-yl)-
isobutyramide

Add N-(4-oxo-cyclohexyl)-isobutyramide (933 mg, 5.09 mmol) to a
suspension of (2,2-difluoro-benzo[1,3]dioxol-5-yl)-hydrazine hydrochloride salt
(1.14 g, 5.09 mmol), water (7 mL) and concentrated hydrochloric acid (3 mL). Heat
the reaction to 90 °C for 12 h with stirring and cool to ambient temperature. Collect
the resultant solid by vacuum filtration, rinse with water and place in a vacuum

WO 2007/002181 PCT/US2006/024122
oven for 5 h to afford the subtitled compound (732 mg, 43%) as a tan solid. 1H
NMR (300 MHz, CDCl3): δ 7.96 (br s, 1H), 7.00 (s, 1H), 6.98 (s, 1H), 5.54 (br d, J
= 7.5 Hz, 1H), 4.40 (br s, 1H), 3.03 (dd, J= 15.3,5.1 Hz, 1H), 2.88-2.71 (m, 2H),
2.51 (dd, J = 15.3,7.0 Hz, 1H), 2.33 (pentet, J = 6.9 Hz, 1H), 2.12-1.91 (m, 2H),
1.16 (d, J =6.9 Hz, 6H).
Example 96
N-[6-Cyano-9-(2-trifluoromethyl-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Suspend sodium hydride (60% in oil, 48 mg, 1.20 mmol) in N, N-
dimethylformamide (2.5 mL) and chill to 0 °C. Add slowly a solution of N-(6-
cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (281 mg, 1.00 mmol) in
Nt N-dimethylformamide (2.5 mL) via syringe, and stir 10 min before warming to
ambient temperature for 30 min. Add 2-(trifluoromethyl)benzyl bromide (263 mg,
1.10 mmol) and stir approximately 16 h. Add ethyl acetate (75 mL), wash with
water (50 mL) and brine (2 x 50 mL). Dry the organic phase over magnesium
sulfate, filter, and evaporate under reduced pressure. Triturate the residue with 2:1
hexanes:methylene chloride to afford the title compound (333 mg, 76%). MS (ES):
m/z 440 (M+1); 1H NMR (300 MHz, CDCl3): δ7.83 (s, 1H), 7.73 (d, J= 7.2 Hz,
1H), 7.39-7.29 (m, 3H), 7.16 (d, J= 8.4 Hz, 1H), 6.27 (d, J = 7.4 Hz, 1H), 5.53-
5.51 (m, 1H), 5.46 (s, 2H), 4.47-4.30 (m, 1H), 3.21-3.15 (m, 1H), 2.67-2.59 (m,
3H), 2.33 (septet, 7 = 6.8 Hz, 1H), 2.16-2.11 (m, 1H), 2.03-1.93 (m, 1H), 1.16 (d, 7
= 6.8 Hz, 3H), 1.15 (d, J s 6.8 Hz, 3H); m.p. = 222-225 °C.

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Prepare Examples 97 to 100 below using tetrahydrocarbazoles as prepared
in Preparations 3, 9, and 11, and the appropriate benzylhalide, by essentially
following the procedures as described in Example 96, above.
Example 97
N-[6-Cyano-9-(2-difluoromethoxy-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylj-
isobutyramide

MS (ES): m/z 438 (M+1); 1H NMR (300 MHz, CDCl3): δ 7.81 (s, 1H),
7.37-7.15 (m, 4H), 7.03 (t, 7 = 7.5 Hz, 1H), 6.62 (t, 7 = 73.4 Hz, 1H), 6.38 (d, 7 =
8.1 Hz, 1H), 5.52 (br d, 7 = 7.8 Hz, 1H), 5.32 (s, 2H), 4.38 (br t, 7 = 8.2 Hz, 1H),
3.16 (dd, 7 = 15.4, 5.1 Hz, 1H), 2.74-2.59 (m, 3H), 2.33 (septet, 7 = 6.9 Hz, 1H),
2.17-1.97 (m, 2H), 1.15 (d, 7 = 6.9 Hz, 6H); m.p. = 217-219 °C.
Example 98
N-[9-(3-Fluoro-benzyl)-6,7,8,9-tetrahydro-5H-1,3-dioxa-9-aza-
cyclopenta[b]fluoren-6-yl]-isobutyramide

MS (ES): m/z 409(M+1); 1HNMR (300 MHz, CDCl3): δ7.28-7.20 (m, 1H),
6.95-6.86 (m, 2H), 6.75 (d, J = 7.7 Hz, 1H), 6.65-6.60 (m, 2H), 5.90 (s, 2H), 5.51
(br d, J= 7.7 Hz, 1H), 5.14 (s, 2H), 4.40 (br s, 1H), 3.05 (dd, J= 15.4,5.0 Hz, 1H),

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2.95-2.53 (m, 3H), 2.32 (septet, J = 6.9 Hz, 1H), 2.17-1.98 (m, 2H), 1.15 (d, J=
6.9 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H); m.p. = 250-255 °C.
Example 99
N-[2,2-difluoro- 9-(3-fluoro-benzyl)-6,7,8,9-tetrahydro-5H-1,3-dioxa-9-aza-
cyclopenta[b]fluoren-6-yl]-isobutyramide

MS (ES): m/z 445 (M+1); 1H NMR (300 MHz, CDCl3): δ 7.29-7.22 (m,
1H), 7.07 (s, 1H), 6.94 (t, 7 = 8.3 Hz, 1H), 6.83 (s, 1H), 6.73 (d, J = 7.8 Hz, 1H),
6.60 (d, J= 9.3 Hz, 1H), 5.50 (br d, J = 7.7 Hz, 1H), 5.19 (s, 2H), 4.40 (br s, 1H),
3.09 (dd, J = 15.3,5.0 Hz, 1H), 2.75-2.54 (m, 3H), 2.32 (septet, J= 6.9 Hz, 1H),
2.12-1.97 (m, 2H), 1.14 (d, J= 6.9 Hz, 3H), 1.12 (d, J= 6.9 Hz, 3H); m.p. = 197-
199 °C.
Example 100
N-[6-Cyano-9-(2-trifluorometboxy-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

MS (ES): m/z 456 (M+1); 1H NMR (300 MHz, CDCl3): δ 7.81 (d, J= 1.0
Hz, 1H), 7.36 (dd, J= 8.5,1.5 Hz, 1H), 7.32-7.30 (m, 2H), 7.18 (d, J= 8.5 Hz,
1H), 7.13-7.07 (m, 1H), 6.36 (d, J= 7.7 Hz, 1H), 5.58-5.51 (m, 1H), 5.34 (s, 2H),

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4.46-4.33 (m, 1H), 3.22-3.10 (m, 1H), 2.78-2.57 (m, 3H), 2.33 (septet, J= 6.9 Hz,
1H), 2.19-2.07 (m, 1H), 2.05-1.90 (m, 1H), 1.16 (d, J = 6.9 Hz, 3H), 1.15 (d, J=
6.9 Hz, 3H); m.p. = 224-225 °C.
Example 101
N-[6-Chloro-9-(2-hydroxy-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Dissolve N-[6-chloro-9-(2-methoxy-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-
3-yl]-isobutyramide (Example 19) (100 mg, 0.24 mmol) in anhydrous
dichloromethane (3 mL) under nitrogen and cool in a brine/ice bath to 0 °C. Slowly
add boron tribromide (1M in dichloromethane, 1.22 mL, 1.22 mmol). After 30 min
remove the ice bath and allow to warm to ambient temperature over 4 h. Dilute
with ethyl acetate (12 mL) and wash with water. Extract aqueous portion with ethyl
acetate (3x). Combine all organic portions, wash with water, brine, dry (MgSCU),
and concentrate in vacuo to obtain a residue. Elute the residue over a silica pad
with 25% ethyl acetate/dichloromethane to obtain 93 mg (96%) of a tan solid. MS
(ES): m/z 397, 399 (M+1), 395, 397 (M-1); 1H NMR(DMSO-d6): δ 9.83 (s, 1H),
7.85 (d, 1H, J = 7.9 Hz), 7.45 (s, 1H), 7.33 (d, 1H, J= 8.4 Hz), 7.04 (m, 2H), 6.86
(d, 1H, J = 7.9 Hz), 6.63 (t, 1H, J = 7.3 Hz), 6.32 (d, 1H, J = 7.5 Hz), 5.23 (s, 2H),
4.02 (m, 1H), 2.95 (dd, 1H, J = 15.2,5.1 Hz), 2.84-2.66 (m, 2H), 2.52 (m, 1H), 2.40
(m, 1H), 1.97 (m, 1H), 1.80 (m, 1H), 1.02 (m, 7H).
Prepare Examples 102 and 103, using the appropriate methoxybenzyl
precursor from Examples 23 and 27, by essentially following procedures as
described in Example 101.

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Example 102
N-[6-Chloro-9-(3-hydroxy-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

MS (ES): m/z 397, 399 (M+1), 395,397 (M-1); 1H NMRCDMSO-d6):δ 9.36
(s, 1H), 7.85 (d, 1H, J = 7.9 Hz), 7.46 (d, 1H, J = 1.8 Hz), 7.38 (d, 1H, J = 8.4 Hz),
7.12-7.03 (m, 2H), 6.62 (m, 1H), 6.50 (d, 1H, J = 7.5 Hz), 6.35 (s, 1H), 5.27 (s,
2H), 4.01 (m, 1H), 2.95 (dd, 1H, J = 15.0, 4.8 Hz), 2.85-2.64 (m, 2H), 2.51 (m,
1H), 2.40 (m, 1H), 1.98 (m, 1H), 1.80 (m, 1H), 1.02 (m, 6H).
Example 103
N-[6-Chloro-9-(4-hydroxy-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

MS (ES): m/z 397, 399 (M+1), 395,397 (M-1); 1H NMR(DMSO-d6): δ 9.36
(s, 1H), 7.84 (d, 1H, J = 7.5 Hz), 7.44 (d, 1H, J= 2.2 Hz), 7.41 (d, 1H, J = 8.4 Hz),
7.04 (dd, 1H, J = 8.6,2.0 Hz), 6.90 (d, 2H, J = 8.4 Hz), 6.68 (d, 2H, J= 8.4 Hz),
5.21 (s, 2H), 4.01 (m, 1H), 2.93 (dd, 1H, J = 15.0,4.8 Hz), 2.77 (m, 2H), 2.49 (m,
1H), 2.40 (m, 1H), 1.97 (m, 1H), 1.80 (m, 1H), 1.02 (d, 6H, J = 6.6 Hz).
Example 104

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N-[6-Chloro-9-(2-nitro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide

Suspend sodium hydride (60%, 120 mg, 3 mmol) in anhydrous DMF (2.5
mL) under nitrogen and cool in an ice bath. Slowly add N-(6-chIoro-2,3,4,9-
tetrahydro-1H-carbazol-3-yl)-isobutyramide (prepare essentially as described in
Preparation 4)(727 mg, 2.5 mmol) dissolved in DMF (8 mL). After 10 min remove
ice bath and allow the reaction to warm to ambient temperature over 1 h. Add DMF
(25 mL) and cool in a dry ice/acetone bath. Add dropwise a solution of 2-
nitrobenzylbromide (648 mg, 3 mmol) in DMF (2.5 mL). Stir for 18 h, allowing to
warm to ambient temperature. Pour into water and extract with ethyl acetate/diethyl
ether (100 mL/50 mL). Separate and wash the aqueous portion with ethyl acetate
(50 mL). Combine organics and wash with 1N hydrochloric acid (2 x 100 mL),
brine (2 x 100 mL), dry (MgS04), and concentrate in vacuo to obtain a yellow solid.
Purify by flash chromatography eluting with dichloromethane and then a gradient
up to 10% ethyl acetate/dichloromethane to obtain 833 mg (79%) of a yellow solid.
MS (ES): m/z 426,428 (M+1), 424,426 (M-1); 1H NMR(DMSO-d6): δ 8.21 (dd,
1H, J = 7.9,1.3 Hz), 7.86 (d, 1H, J = 7.9 Hz), 7.60-7.51 (m, 3H), 7.40 (d, 1H, J =
8.8 Hz), 7.03 (dd, 1H, J = 8.6,2.0 Hz), 6.18 (d, 1H, J = 7.0 Hz), 5.75 (s, 2H), 4.05
(m, 1H), 2.99 (dd, 1H, J = 15.2, 5.1 Hz), 2.74-2.53 (m, 3H), 2.40 (m, 1H), 1.95 (m,
1H), 1.82 (m, 1H), 1.01 (m, 6H).
Example 105
N-[6-Cyano-9-(2-methoxy-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

WO 2007/002181 PCT/US2006/024122

Follow the procedures essentially as described in Example 104, above, using
N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (3.38 g, 12 mmol)
and treating with sodium hydride (580 mg, 14.4 mmol). Cool the formed sodium
salt in a dry ice/acetonitrile bath and add 2-methoxybenzylchloride (1.84 mL, 13.2
mmol) in DMF (2 mL) at -35 to -30° C. Remove the bath and allow the reaction to
warm to ambient temperature over 3 h with stirring. Add water (250 mL) dropwise,
cooling in an ice bath while stirring for 30 min. Filter the resulting precipitate and
dry under house vacuum at 45 °C for 18 h. Triturate and sonicate the material in
diethyl ether for 1.5 h, filter and dry to provide 3.98 g (83%) of an off-white solid.
MS (ES): m/z 402 (M+1), 400 (M-1); 'H NMR(DMSO-d6): δ 7.98 (s, 1H), 7.87 (d,
1H, J = 7.5 Hz), 7.50 (d, 1H, J = 8.4 Hz), 7.40 (dd, 1H, J = 8.3,1.3 Hz), 7.26 (t,
1H, J = 7.9 Hz), 7.06 (d, 1H, J = 8.4 Hz), 6.80 (t, 1H, J = 7.5 Hz), 6.40 (d, 1H, J =
7.5 Hz), 5.34 (s, 2H), 4.03 (m, 1H), 3.87 (s, 3H), 3.02 (dd, 1H, J = 15.4, 5.3 Hz),
2.84-2.65 (m, 2H), 2.40 (m, 1H), 2.57 (dd, 1H, J= 15.3, 8.6 Hz), 1.98 (m, 1H), 1.82
(m, 1H), 1.02 (m, 6H).
Example 106
N-[9-(2-Amino-benzyl)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide


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Dissolve tin(II) chloride dihydrate (2.15 g, 9.5 mmol) in absolute ethanol (10
mL) and add it to N-(6-chloro-9-(2-nitro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide (Example 104) (810 mg, 1.9 mmol) in concentrated hydrochloric
acid (10 mL). Heat the reaction at 60 °C for 1.5 h. Allow to cool and add 5N
NaOH (27 mL) until pH = 11-12. Extract the suspended solids into ethyl acetate
(4x). Combine the organic portions and wash with water, brine, dry (MgSO4), and
concentrate in vacuo to obtain a solid. Pass over a silica pad eluting with 25% ethyl
acetate/dichloromethane to obtain 640 mg (85%). MS (ES): m/z 396, 398 (M+1),
394 (M-1); 1H NMR(DMSO-d6): δ 7.86 (d, 1H, J = 7.5 Hz), 7.49 (d, 1H, J = 1.8
Hz), 7.24 (d, 1H, J = 8.8 Hz), 7.04 (dd, 1H, J = 8.6, 2.0 Hz), 6.93 (dt, 1H, J = 7.5,
1.3 Hz), 6.71 (dd, 1H, J = 8.1, 1.1 Hz), 6.37 (dt, 1H, J = 7.5, 1.3 Hz), 5.89 (d, 1H, J
= 7.0 Hz), 5.14 (m, 4H), 4.03 (m, 1H), 2.98 (dd, 1H, J = 15.2,5.1 Hz), 2.75-2.60
(m, 2H), 2.55 (m, 1H), 2.41 (m, 1H), 1.97 (m, 1H), 1.81 (m, 1H), 1.03 (d, 3H, J =
4.0 Hz), 1.02 (d,3H, 7 = 4.4 Hz).
Example 107
N-[6-Cyano-9-(2-hydroxy-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Follow the procedures essentially as described in Example 101, above, using
N-[6-cyano-9-(2-methoxy-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide (Example 105) (3.90 g, 9.71 mmol) to provide, after workup, 4.4 g of
a solid. Partially dissolve in dichloromethane/THF/acetone and a small amount of
methanol. Filter and dissolve the remaining solids in THF/methanol. Apply the
two solutions to a large silica pad and elute with dichloromethane, 25% ethyl
acetate/dichloromethane and 50% ethyl acetate/dichloromethane for a total volume
of 3-4 L. Concentrate in vacuo to give a brown solid. Triturate the solid in

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dichloromethane and filter to provide 3.15 g (84%) of a white solid. MS (ES): m/z
388 (M+1), 386 (M-1); 1H NMR(DMSO-d6): δ 9.87 (s, 1H), 7.97 (s, 1H), 7.88 (d,
1H, J = 7.5 Hz), 7.53 (d, 1H, J = 8.8 Hz), 7.40 (m, 1H), 7.08 (t, 1H, J = 7.7 Hz),
6.86 (d, 1H, J = 7.9 Hz), 6.65 (t, 1H, J = 7.3 Hz), 6.40 (d, 1H, J = 7.5 Hz), 5.30 (s,
2H), 4.03 (m, 1H), 3.01 (dd, 1H, J = 15.4,4.8 Hz), 2.88-2.68 (m, 2H), 2.56 (m,
1H), 2.40 (m, 1H), 1.98 (m, 1H), 1.82 (m, 1H), 1.02 (m, 6H).
Example 108
N-[6-Cyano-9-(2-nitro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide

Prepare the title compound by essentially following the procedures as
described in Example 104, using N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-
isobutyramide (Preparation 3) (5.63 g, 20 mmol), sodium hydride (0.96 g, 24 mmol)
and 2-nitrobenzyl bromide (5.18 g, 24 mmol). After workup, concentrate the
solution in vacuo and when the volume is a slurry, filter and dry under house
vacuum to obtain 6.33 g (76%) of a yellow solid which is used without further
purification. MS (ES): m/z 417 (M+1), 415 (M-1); 1H NMR(DMSO-d6): δ 8.22
(dd, 1H, J = 7.3,2.0 Hz), 8.05 (s, 1H), 7.88 (d, 1H, J = 7.5 Hz), 7.62-7.52 (m, 3H),
7.41 (dd, 1H, J = 8.4,1.3 Hz), 6.20 (d, 1H, J - 7.0 Hz), 5.83 (s, 2H), 4.07 (m, 1H),
3.05 (dd, 1H, J = 15.4, 4.8 Hz), 2.77-2.57 (m, 3H), 2.41 (m, 1H), 1.96 (m, 1H), 1.85
(m,1H), 1.02 (m,6H).
Example 109
7Y-[9-(2-Amino-benzyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

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Dissolve tin(II) chloride dihydrate (16.70 g, 74.0 mmol) in absolute ethanol
(35 mL) and add it to N[6-cyano-9-(2-nitro-benzyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-isobutyramide (6.18 g, 14.8 mmol). Add concentrated hydrochloric
acid (35 mL) and heat at 60 °C for 2 h. Allow to cool and add 5N NaOH (80 mL).
Extract the suspended solids into ethyl acetate (150 mL). Add more 5N NaOH (5
mL) and extract with ethyl acetate (200 mL). Combine the organic portions and
wash with water (2 x 200 mL), brine (150 mL), dry (MgSO4), filter and concentrate
in vacuo to obtain 3.45 g. Triturate the material in dichloromethane, filter, and dry
under house vacuum to obtain 1.71 g (30%) of a white solid. MS (ES): m/z 387
(M+1); 1HNMR(DMSO-d6): δ 8.00 (s, 1H), 7.88 (d, 1H, J = 7.9 Hz), 7.42 (m, 2H),
6.94 (t, 1H, J = 7.6 Hz), 6.72 (dd, 1H, J = 7.9,0.9 Hz), 6.37 (dt, 1H, J = 7.4,0.9
Hz), 5.90 (d, 1H, J = 7.0 Hz), 5.19 (m, 4H), 4.05 (m, 1H), 3.03 (dd, 1H, J = 15.2,
5.1 Hz), 2.71 (m, 2H), 2.59 (dd, 1H, J = 15.9, 8.4 Hz), 2.41 (m, 1H), 1.98 (m, 1H),
1.83 (m, 1H), 1.03 (d, 3H, J = 4.4 Hz), 1.01 (d, 3H, J = 4.4 Hz); HPLC: Rt = 1.95
min, (93%).
Obtain more product by making the aqueous portion basic with 5N NaOH
and extracting with two large volumes of ethyl acetate. Combine organic portions,
wash with brine, dry (MgSO4), filter, and concentrate in vacuo to obtain 1.36 g off-
white solid which was 92.6% by HPLC. Combine with the mother liquor from the
above trituration and absorb on silica with THF/dichloromethane and apply to a
silica pad. Elute with a large volume of 1 dichloromethane/ethyl acetate, 2
dichloromethane/3 ethyl acetate, 1 dichloromethane/2 ethyl acetate and then straight
ethyl acetate to obtain 1.96 g (34%) of product as a light brown solid. 1H
NMR(DMSO-d6) was consistent with that given above. HPLC: R, = 1.99 min,
(96%).

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Example 110
R-N-[9-(2-Amino-benzyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yI]-
isobutyramide

Separate racemic N-[9-(2-amino-benzyl)-6-cyano-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-isobutyramide (1.50 g) by chiral chromatography. Use a Chiralpak
AD column of 4.6 x 150 mm and elute with heptane/isopropylalcohol (60/40) at a
flow rate of 0.6 mL/min with UV detection set at 300 nm. Obtain 640 mg of the
titled compound as Isomer 1 with ee = 98.4%.
Example 111
S-N-[9-(2-Amino-benzyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Use conditions in Example 110 to obtain 623 mg of the titled compound as
Isomer 2 from chiral chromatography with ee = 94.9%.
Example 112
N-[6-Cyano-9-(2-ethylamino-benzyl)-2,3,4,9-tetrahydro-1H-carbazo]-3-yl]-
isobutyramide

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Dissolve N-[9-(2-armno-benzyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide (Example 109) (193 mg, 0.5 mmol) in anhydrous DMF (2 mL)
under nitrogen. Add acetaldhyde (0.34 mL, 0.6 mmol), sodium
triacetoxyborohydride (191 mg, 0.9 mmol) and acetic acid (0.072 mL, 1.25 mmol)
and heat at 40 °C for 6 h. Take TLC (1 hexane/3 ethyl acetate) and observe starting
material is still present. Add more acetaldehyde (0.010 mL, 0.18 mmol), sodium
triacetoxyborohydride (60 mg, 0.3 mmol) and acetic acid (0.030 mL, 0.5 mmol) and
heat at 40 °C for 18 h. Observe TLC which shows the reaction still not complete
but new by-product is forming. Allow the reaction to cool, dilute with water (20
mL), and extract with ethyl acetate (3 x 20 mL). Combine the organic portions and
wash with brine (40 mL), dry (MgSO4), filter, and concentrate in vacuo to give 416
mg of a brown solid. Absorb on silica with THF and a small amount of methanol
and purify by flash chromatography. Elute with dichloromethane, then 10% ethyl
acetate/dichloromethane with a gradient up to 50% ethyl acetate/dichloromethane to
obtain 103 mg (50%) of a white solid. MS (ES): m/z 415 (M+1), 413 (M-1); 1H
NMR(DMSO-d6): δ 8.02 (s, 1H), 7.88 (d, 1H, J = 7.5 Hz), 7.41 (d, 2H, J = 0.9 Hz),
7.07 (t, 1H, J = 7.7 Hz), 6.67 (d, 1H, J = 7.9 Hz), 6.42 (t, 1H, J = 7.6 Hz), 5.85 (d,
1H, J = 7.4 Hz), 5.25 (s, 2H), 5.06 (t, 1H, J = 5.3 Hz), 4.04 (m, 1H), 3.17 (m, 2H),
3.04 (dd, 1H, J = 15.4, 5.3 Hz), 2.74-2.55 (m, 3H), 2.41 (m, 1H), 1.97 (m. 1H), 1.83
(m, 1H), 1.28 (t, 3H, J = 7.0 Hz), 1.02 (m, 6H).
Example 113
N-[6-Cyano-9-(2-methanesulfonylamino-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide

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Suspend N-[9-(2-amino-benzyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide (Example 109) (116 mg, 0.3 mmol) in anhydrous
dichloromethane (3 mL) under nitrogen. Add methanesulfonyl chloride (0.028 mL,
0.36 mmol) and pyridine (0.032 mL, 0.39 mmol), followed by anhydrous DMF (2
mL) to effect solution. Stir 5.5 h at room temperature. Add additional
methanesulfonyl chloride (0.010 mL, 0.13 mmol) and pyridine (0.010 mL, 0.12
mmol) and stir 18 h at room temperature. Dilute with dichloromethane and wash
with 1N hydrochloric acid. Backwash the aqueous portion with dichloromethane.
Combine the organic portions and wash with brine, dry (MgSO4), filter, and
concentrate in vacuo to provide 74 mg of a yellow oil. Absorb the oil on silica with
THF and a small amount of methanol and purify by flash chromatography. Elute
with a step gradient of 10% ethyl acetate/dichloromethane, 25% ethyl
acetate/dichloromethane, and 50% ethyl acetate/dichloromethane to obtain 19 mg
(14%) of a light yellow solid. MS (ES): m/z 465 (M+1), 463 (M-1); lH
NMR(DMSO-d6): δ 9.43 (s, 1H), 8.02 (s, 1H), 7.88 (d, 1H, J = 7.5 Hz), 7.43-7.36
(m, 3H), 7.31 (dt, 1H, J = 7.6,1.0 Hz), 7.12 (dt, 1H, J = 7.5,0.9 Hz), 6.21 (d, 1H, J
= 7.5 Hz), 5.54 (s, 2H), 4.06 (m, 1H), 3.12 (s, 3H), 3.04 (dd, 1H, J = 15.4, 5.3 Hz),
2.70 (m, 2H), 2.59 (dd, 1H, J = 15.4,8.4 Hz), 2.41 (m, 1H), 1.97 (m, 1H), 1.85 (m,
1H), 1.02 (m,6H).
Example 114
N-[6-Cyano-9-furan-(2-dimethylamino-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide

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Add sodium cyanoborohydride (0.030g, 0.48 mmol), to N-[9-(2-
aminobenzyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide
(Example 109) (0.116 g, 0.3 mmol) and 37% formaldehyde (0.112 ml, 1.5 mmol) in
acetonitrile (5 ml). Stir at ambient temperature for 16 h after addition of acetic acid,
one drop after 1 hr, two drops after 1.5 h. Carefully quench the reaction with 1N
sodium hydroxide (5 ml). Dilute the reaction with water and extract with ethyl
acetate. Wash the ethyl acetate extract with water, dry with magnesium sulfate,
filter and evaporate at reduced pressure. Purify the resulting residue with silica gel
chromatography, eluting with ethyl acetate/hexanes to obtain product (36 mg, 29%
yield). LCMS(Method D):m/z415(M+l, APCI). Good for C26H30N4O, MW
414.56. 1H NMR(DMSOd6): δ 7.98 (s, 1H), 7.87 (d, 1H, J = 7.9 Hz), 7.42 (m, 2H),
7.22 (m, 2H), 6.87 (m, 1H), 6.30 (d, 1H, J = 7.5 Hz), 5.42 (s, 2H), 4.03 (m, 1H),
3.79 (s, 6H), 3.02 (dd, 1H, J= 15.2, 5.1 Hz), 2.73-2.56 (m, 3H), 2.40 (m, 1H),
2.00-1.92 (m, 1H), 1.86-1.76 (m, 1H), 1.02 (dd, 6H, J = 6.8, 3.7 Hz).
Preparation 12
(4-Bromo-3-fluoro-phenyl)-hydrazine

Convert 4-bromo-3-fluoroaniline to the title compound in 71% yield
according to the procedure of Street, L.J.; et al. J. Med, Chem. (1993) 36, 1529-
1538. 1H NMR (CDCl3): 8 7.32 (m, 1H), 6.71 (dd, 1H, J = 10.8, 2.4 Hz), 6.51 (dd,

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1H, J= 8.8,2.6 Hz), 6.51 (dd, 1H, J= 8.8, 2.6 Hz), 6.51 (dd, 1H, J - 8.5, 2.5 Hz),
5.33 (br s, 1H), 3.62 (br s, 2H); HPLC: R, = 1.89 min, (96%).
Prepare the following phenylhydrazines (Preparations 13 to 15) using
commercially available anilines by essentially following the procedures of Street et.
al., J. Med. Chem. (1993) 36,1529-1538.

Preparation 16
N-(6-Bromo-7-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide and N-(6-

Prepare the title compounds by essentially following the procedure as
described in Preparation 4 (Method 2) with (4-bromo-3-fluoro-phenyl)-hydrazine
(Preparation 12) and N-(4-oxo-cyclohexyl)-isobutyramide, to obtain a tan solid
containing a 65:35 mixture of isomers in 20% overall yield. MS (ES): m/z 353,355
(M+H), 351, 353 (M-H); HPLC (Method A): Rt = 2.22 min, (95%).
Preparation 17
N-(7-Chloro-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide and N-(5-
chloro-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide


WO2007/002181 PCT/US2006/024122
Prepare the title compounds by essentially following the procedure as
described in Preparation 4 (Method 2) with 3-chloro-4-cyanophenylhydrazine-(1/3
Et3N-HCl) (Preparation 15) and N-(4-oxo-cyclohexyl)-isobutyramide, to obtain a
brown solid containing a 50:50 mixture of isomers in 52% overall yield. MS (ES):
m/2 316 (M+H), 314 (M-H); HPLC (Method A): Rt = 1.83 min, (82%).
Preparation 18
N-(8-Chloro-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide

Prepare the title compound by essentially following the procedure as
described in Preparation 4 (Method 2) with 2-chloro-4-cyanophenylhydrazine
(Preparation 13) and N-(4-oxo-cyclohexyl)-isobutyramide, to obtain the title
compound as a pink powder in 50% yield. MS (ES): m/z 316 (M+H), 314 (M-H);
HPLC (Method A): R, = 1.96, (90%).
Preparation 19
N-(6-Bromo-8-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide

Prepare the title compound by essentially following the procedure as
described in Preparation 4 (Method 2) with 2-fluoro-4-bromophenylhydrazine
(Preparation 14) and N-(4-oxo-cyclohexyl)-isobutyramide, to obtain the title
compound as a tan foam in 32% yield. MS (ES): m/z 353, 355 (M+H), 351,
353(M-H); HPLC (Method A): R, = 2.34, (89%).

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Preparation 20
N-[6-Bromo-7-fluoro-9-(3-fluoro-benzyl-2,3,4,9-tetraliydro-1H-carbazol-3-yl]-
isobutyramide and N-[6-bromo-5-fluoro-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-isobutyramide

Prepare the title compounds by essentially following procedures as
described in Example 96 with N-(6-bromo-7-fluoro-2,3,4,9-tetrahydro-1H-carbazol-
3-yl)-isobutyramide and N-(6-bromo-5-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-
isobutyramide (65:35 mixture) and 3-fluorobenzyl bromide, to obtain a white solid
containing a mixture of isomers in 78% overall yield. MS (ES): m/z 461,463
(M+1), 459,461 (M-1); HPLC: Rt = 3.67 min, (59%); R, = 3.92 min, (38%).
Example 115
N-[6-Cyano-7-fluoro-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Dissolve a 65:35 mixture of N-[6-bromo-7-fluoro-9-(3-fluoro-benzyl)-
2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyrarnide and N-[6-bromo-5-fluoro-9-(3-
fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (500 mg, 1.08
mmol; Preparation 20) in N-methylpyrrolidinone (10 mL). Sparge the resulting

WO 2007/002181 PCT/US2006/024122
solution with nitrogen for 30 min, then add copper(I) cyanide (291 mg, 3.25 mmol)
and copper(I) iodide (619 mg, 3.25 mmol). Heat to 130 °C for three days, then cool
to room temperature. Dilute the reaction mixture with EtOAc (200 mL) and water
(100 mL). Add ethylene diamine until all the solids are dissolved (about 20 mL).
Separate the layers, then wash the organic layer with water (3 x 75 mL). Dry the
organic portion (MgSO4), filter, and concentrate the organic layer to afford 474 mg
of crude product. Separate the title compound from this mixture by silica gel
chromatography (0-10% EtOAc/CHCl3), affording the title compound as a white
solid in 20% yield. MS (ES): m/z 408 (M+1), 406 (M-1); HPLC: Rt = 2.51 min,
(96%).
Example 116
N-[6-Cyano-5-fluoro-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

From the mixture obtained in Example 115, separate the title compound by
silica gel chromatography (0-10% EtOAc/CHCl3), affording the title compound in
7% yield. MS (ES): m/z 408 (M+1), 406 (M-1); HPLC: R, = 2.60 min, (97%).
Example 117
N-[5-Chloro-6-cyano-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

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Prepare the title compound by essentially following the procedure as
described in Example 96 with N-(7-chloro-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-
3-yl)-isobutyramide and N-(5-chloro-6-cyano-2,3,4-,9-tetrahydro-1H-carbazol-3-yl)-
isobutyramide (50:50 mixture - Preparation 17) and 3-fluorobenzyl bromide, to
obtain a mixture of regioisomers. Separate the title compound from this mixture of
regioisomers using silica gel chromatography (0-20% EtOAc/CHCl3), to afford the
title compound in 5% yield. MS (ES): m/z 424 (M+1), 422 (M-1); HPLC (Method
B):Rt = 6.87 min,(97%).
Example 118
N-[7-Chloro-6-cyano-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Separate the title compound from the mixture of regioisomers obtained in
Example 117 using silica gel chromatography (0-20% EtOAc/CHCl3), to afford the
title compound in 3% yield. MS (ES): m/z 424 (M+H), 422 (M-H); HPLC (Method
B): Rt = 7.16 min, (100%).

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Example 119
Ar-[8-Chloro-6-cyano-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Prepare the title compound by essentially following the procedure as
described in Example 96 with N-(8-chloro-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-
3-yl)-isobutyramide (Preparation 18) and 3-fluorobenzyl bromide, to obtain the title
compound as a white solid in 10% yield. MS (ES): 424 (M+1), 422 (M-1); HPLC
(Method A): Rt = 3.18 (92%).
Example 120
N-[6-Bromo-8-fluoro-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Prepare the title compound by essentially following the procedure as
described in Example 96 with N-(6-bromo-8-fluoro-2,3,4,9-tetrahydro-1H-carbazol-
3-yl)-isobutyramide (Preparation 19) and 3-fluorobenzyl bromide, to obtain the title
compound as a white solid in 36% yield. MS (ES): m/z 461,463 (M+1), 459,461
(M-1); HPLC (Method A): Rt = 4.60 (92%).

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Example 121
N-[6-Cyano-8-fluoro-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Following procedures essentially as described in Example 115 using N-[6-
bromo-8-fluoro-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide, the title compound is prepared as a white solid in 29% yield. MS
(ES) 408 (M+1), 406 (M-1); HPLC (Method A): Rt = 2.75 (97%).
Preparation 21
(R)-N-(6-Bromo-2,3,4,9-tetxahydro-1H-carbazol-3-yl)isobutyrarnide

Resolve N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide via
chiral chromatography using a 0.46 x 15 cm Chiralpak AD-H column eluting with
100%MeOH. Flow rate = 0.6 mL/min. Purify using Steady State Recycle (SSR)
with dimethylethylamine to improve resolution to afford e.e. >98%. First to elute is
Isomer 1 (S isomer) while second isomer to elute gives the R isomer as the title
compound. MS (ES): m/z 335 (M+1), 337 (M+1+2).
Example 122
(R)-N-(9-Benzyl-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide

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Alkylate (R)-N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)isobutyramidewith 1-bromomethyl-3-fluorobenzene using procedures essentially
as described in Example 1 to give the title compound. MS (ES): m/z 443 (M+1),
445 (M+1+2); m.p. = 204-207 °C. (Alkylate the S isomer in a similar fashion to
obtain (S)-N-(9-Benzyl-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)isobutyramide.)
Example 123
(R)-N-(6-Cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)isobutyramide

N-(6-Cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)isobutyramide (Example 51), is resolved into its enantiomers via chiral
chromatography using a 0.46 x 15 cm Chiralpak AD-H column eluting with
EtOH/MeOH/heptanes: 15/10/75. Flow rate = 0.6 mL/min. First to elute is Isomer
1 (R), as the title compound with e.e. >99.5%. MS (ES): m/z 390 (M+1); m.p. =
223-225 °C.

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Example 124
(5)-N-(6-Cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)isobutyramide

Obtain the title compound from chiral chromatography as described for
Example 123. Second isomer to elute is (S) isomer. MS (ES): m/z 390 (M+1);
m.p. = 223-225 °C.
Example 125
N-[6-(5-Aniino[l,3,4]thiadiazol-2-yl)-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]isobutyramide

Heat a mixture of N-[6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]isobutyramide (Example 51) (0.500 g, 1.28 mmol) and
thiosemicarbazide (0.129 g, 1.41 mmol) in trifluoroacetic acid (5 ml) at 70 °C under
nitrogen for 18 h. Pour the mixture onto dilute NH4OH solution and collect 0.510 g
of the resultant precipitate by filtration. Azetrope the precipitate with absolute
EtOH and purify by silica chromatography eluting with 0.05% NH4OH in EtOAc to

WO 2007/002181 PCT/US2006/024122
give 0.10 g of a white solid. MS (ES): m/z 464 (M+1); HPLC: Rt = 1.89 min,
(100%); m.p. = 251-254 °C.
Example 126
(R)-N-[6-(5-Amino[1,3,4]thiadiazol-2-yl)-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]isobutyramide

Prepare the title compound in a manner essentially as described for Example
125, starting with(R)-N-(6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl)isobutyramide (Example 123) to give a white solid. MS (ES): m/z
464 (M+1); HPLC: R, = 1.88 min (95.6%).
Example 127
(R)-N-[9-(3-Huorobenzyl)-6-[l,3,4]thiadiazole-2-yl-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]isobutyramide

Add(R)-N-[6-(5-Amino[1,3,4]thiadiazole-2-yl)-9-(3-fluorobenzyl)-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]isobutyramide (Example 126) (0.104 g, 0.224 mmol)
to a solution of isoamylnitrite (0.039 g, 0.337 mmol) in DMF at 60 °C and heat for
1 h. Quench reaction onto water and extract with EtOAc to give 80 mg of a yellow

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solid. Purify over silica eluting with 25 - 90% EtOAc/hexanes gradient to give 20
mg (20%). MS (ES) m/z 449 (M+1); 'H NMR (DMSO-d6): δ 9.56 (s, 1H), 8.08 (s,
1H), 7.89 (d, 1H), 7.77 (d, 1H), 7.57 (d, 1H), 7.38 (dd, 1H), 7.12 (dd, 2H), 6.84-
6.94 (m, 2H), 5.44 (s, 2H), 4.05 (m, 1H), 3.07 (dd, 1H), 2.70-2.84 (m, 2H), 2.63 (m,
2H), 2.41 (septet, 1H), 2.00 (m, 1H), 1.88 (m, 1H), 1.04 (dd, 6H).
Preparation 22
(R)-N-(9-(3-Fluorobenzyl)-6-thiocarbamoyl-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)isobutyramide

Heat (R)-N-(6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro- 1H-carbazol-3-
yl)isobutyramide (Example 127) (4.00 g, 10.3 mmol) with thioacetamide (1.54 g,
20.5 mmol) at reflux in 4N HCl in dioxane (100 mL) for 16 h. Cool the reaction,
pour onto water, and neutralize with NaHCO3. Extract with EtOAc and evaporate
to 4.2 g of a red foam. Purify using silica gel chromatography, eluting with 25-
100% EtOAc/hexanes gradient to give 2.6 g (60%) of a yellow solid. MS (ES): m/z
424 (M+1); HPLC: Rt= 1.90 min (95%).
Example 128
(R-N-9-(3-Fluorobenzyl)-6-(4-methylthiazol-2-yl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yr]sobutyramide

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Combine chloroacetone (0.197 g, 2.13 rnmol) and (R)-N-(9-(3-
fluorobenzyl)-6-thiocarbamoyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramie
(Preparation 22) (0.300 g, 0.708 rnmol) and heat at 80 °C in DMF under nitrogen
for 2.5 h. Upon cooling, dilute the mixture with water and collect the precipitate by
filtration. Slurry the precipitate in hot EtOAc to give 0.278 g of a yellow solid. MS
(ES): m/z 462 (M+1); HPLC: Rt = 3.33 min (100%).
Example 129
(R)-N-[9-(3-Fluorobenzyl)-6-(3,4-dimethylthiazol-2-yl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]isobutyramide

Combine 3-bromo-2-butanone (0.224 g, 1.48 mmol) and (R)-N-(9-(3-
fluorobenzyl)-6-thiocarbamoyl-2,3.4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide
(Preparation 22) (0.209 g, 0.493 mmol) and heat in DMF at 80 °C under nitrogen
for 2 h. Upon cooling, dilute the mixture with water and collect the precipitate by
filtration. Recrystallize from absolute EtOH to give yellow crystals: MS (ES): m/z
476 (M+1); HPLC: Rt = 3.87 min (100%).

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Preparation 23
N-[9-(3-Flourobenzyl)-6-(4,4,5,5-tetramethyl[l,3,2]dioxaborolan-2-yl)-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]isobutyramide

Combine N-[6-bromo-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide (Example 1) (3.00 g, 6.77 mmol), bis(pinacoloto)borane (1.89 g,
7.44 mmol), tricyclophosphine (0.270 g, 0.961 mmol), potassium acetate (1.99 g,
20.3 mmol), tris(benzylideneacetone)dipalladium (0.366 g, 0.399 mmol) in DMSO
(15 mL), purge with argon in a sealed tube and heat at 95 °C for 24 h. Upon
cooling, pour the mixture onto water and extract with EtOAc. Wash the EtOAc
extracts with water and brine, dry (Na2SO4), filter, and evaporate. Chromatograph
over neutral alumina eluting with 20 - 40% EtOAc/hexanes to give 2.2 g (66%) of a
yellow foam. MS (ES): m/z 491(M+1).
Preparation 24
(R)-N-[9-(3-Flourobenzyl)-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]isobutyramide


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Prepare essentially as described in Preparation 23 from (R)-N-(9-BenzyI-6-
bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Example 122). MS
(ES): 491 (M+1); m.p. = 93-96 °C;
Example 130
N-[9-(3-Fluorobenzyl)-6-thiazol-2-yl-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]isobutyramide

Combine N- [9-(3-fluorobenzyl)-6-(4,4,5,5-tetramethyl [1,3,2] dioxaborolan-
2-yl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]isobutyramide (Preparation 23), 2-
bromothiazole (0.0602 g, 0.367 mmol, tetrakis(triphenylphosphine)palladium(0)
(0.0353 g, 0.031 mmol), and K2CO3 (2 mL of a 2 M solution) in 1,4-dioxane (4
mL), purge with argon, and heat at 95 °C for 18 h. Upon cooling, pour the mixture
onto water and extract with EtOAc. Wash EtOAc extracts with brine, dry
(Na2SO4), filter, and evaporate to give a brown solid. Chromatograph over silica
gel with 20 - 80% EtOAc/hexanes to yield 0.050 g (37%) of an off-white solid. MS
(ES): m/z 448; m.p. = 221-225 °C.
Example 131
N-[9-(3-Fluorobenzyl)-6-pyridin-2-yl-2,3,4,9-tetrahydro-1H-carbazo]-3-
yl]isobutyramide

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Prepare the title compound essentially as described in Example 130 using N-
[9-(3-fluorobenzyl)-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]isobutyramide (Preparation 23) (0.200 g, 408 mmol),
2-chloropyridine (0.0556 g, 0.489 mmol), tetrakis(triphenyl-phosphine)palladium(0)
(0.0471 g, 0.041 mmol), and K2CO3 (2 mL of a 2 M solution) in 1,4-dioxane (4
mL), to obtain, after workup and chromatography, 0.039 g (22%) of a beige solid.
MS (ES): m/z 442; m.p. = 228-230 °C.
Examples 132 to 138, contained in the table below, are prepared essentially
as described in Example 136, starting with the appropriate haloheteroaryl and N-[9-
(3-flourobenzyl)-6-(4,4,5,5-tetramethyl[l,3,2]dioxaborolan-2-yl)-2,3,4,9-tetrahydro-
1H-carbazoI-3-yl]isobutyramide (Preparation 23) (for Examples 132,134 to 138) or
(R)-N-[9-(3-flourobenzyl)-6-(4,4,5,5-tetramethyl[l,3,2]dioxaborolan-2-yl)-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]isobutyramide (Preparation 24) (for Example 133).




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Example 139
N-[9-(3-Fluoro-benzyl)-6-(6-methyl-pyridazin-3-yl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-isobutyramide

Dissolve N-[9-(3-flourobenzyl)-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-
yI)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]isobutyramide (Preparation 23) (150 mg,
0.31 mmol) and 3-chloro-6-methylpyridazine (39 mg, 0.31 mmol) in dioxane (2.5
mL) and 2M Na2CO3 (388 µL). Sparge the solution with nitrogen for 5 min, add
dichlorobis(triphenylphosphine)palladium (II) (11 mg, 0.016 mmol) and seal the
reaction vessel. Heat to 140 °C in a microwave reactor for 30 min, then dilute with
water (20 mL). Extract into EtOAc (3 x 25 mL), dry organics (MgSO4), filter, and
concentrate in-vacuo to give the crude product (179 mg) as a brown solid. Purify
the crude product on silica gel (12 g), eluting with 25-70% (4% (2M
NH3/MeOH)/CH2Cl2)/hexanes to afford 35 mg (25%) of the title compound as a
white solid. MS (ES): m/z 457 (M+1), 455 (M-1); HPLC (Method B) R, = 3.37 min
(100%).
Preparation 25
5-Bromo-2-(2,5-dimethylpyrrol-1 -yl)thiazole

Neutralize 2-amino-5-bromothiazole hydrobromide (2.90 g, 16.2 mmol of
free amine) by treating with Na2CO3 and then add it to a mixture of hexane-2,5-
dione (2.04 g, 17.8 mmol) and acetic acid (1.1 mL) in benzene. Heat the mixture

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for 18 h in a flask equipped with a Dean-Stark trap. Filter and concentrate in vacuo
to give a dark oil. Chromatograph the oil over silica eluting with 20 - 80%
EtOAc/hexanes to yield 2.95 g (71%) of a yellow oil. MS (ES): 259 (M+1), 261
(M+H+2).
Preparation 26
N-[9-[2-(2,5-dimethylpyrrol-l-yl)thiazol-5-yl]-9-(3-fluorobenzyl)-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]isobutyramide

Combine N-[9-(3-flourobenzyl)-6-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-
2-yl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]isobutyramide (Preparation 20) (0.458 g,
0.934 mmol), 5-bromo-2-(2,5-dimethylpyrrol-l-yl)thiazole (Preparation 22) (0.312
g, 1.21 mmol), dichloro[l,2-bis(diphenylphosphino)-ferrocene]palladiumll
dichloromethane complex (0.137 g, 0.168 mmol), 2 M Na2CO3 (10 mL), and
dioxane (12 mL) and purge with argon for five minutes. Heat the mixture at reflux
for 18 h. Pour onto water, extract with EtOAc, and chromatograph over silica to
give the title compound as a tan solid. MS (ES): m/z 541 (M+1); HPLC R, = 5.87
min, (97%).
Example 140
N-[9-[2-(Aminothiazol-5-yl]-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]isobutyramide

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Treat N-[9-[2-(2,5-dimethylpyrrol-l-yl)thiazol-5-yl]-9-(3-fluorobenzyl)-
2,3,4,9-tetrahydro-ltf-carbazol-3-yl]isobutyramide (Preparation 26) (0.200 g, 0.370
mmol) with hydroxylamine hydrochloride (0.257 g, 3.70 mmol), triethylamine (0.15
mL, 1.1 mmol), and 1 M NaOH (1.1 ml) in absolute EtOH (2 mL) and heat at reflux
until complete by TLC (70% EtOAc/hexanes). Extract and evaporate to give the
title compound. MS (ES): m/z 463 (M+1).
Example 141
(R)-N-[9-[2-(Aminothiazol-5-yl]-9-(3-fluorobenzyI)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]isobutyr amide

Prepare chiral product essentially as described in Example 140, starting with
(R)-N-[9-(3-flourobenzyl)-6-(4,4,5,5-tetramethyl[l,3,2]dioxaborolan-2-yl)-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]isobutyramide (Preparation 24). MS (ES): m/z 363
(M+1); HPLC: R, = 1.90 min (97%).
Preparation 27
5-Bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine

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Prepare using procedures essentially as described for 5-bromo-2-(2,5-
dimethylpyrrol-l-yl)thiazole (Preparation 25) starting with 2-amino-5-
bromopyridine. MS (ES): m/z 252 (M+1).
Preparation 28
N-[6-[6-(2)5-Dimethylpyrrol-l-yl)-pyridin-3-yl]-9-(3-fluorobenzyl)-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]isobutyramide

Prepare the title compound using procedures essentially as described in
Preparation 26, to give an off-white solid. MS (ES): m/z 535 (M+1); HPLC: Rt =
4.32 min, (100%).
Example 142
N-[6-(6-(Amino-pyridin-3-yl)-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]isobutyramide

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133

Prepare the title compound from N-[6-[6-(2,5-dimethylpyrrol-l-yl)-pyridin-
3-yl]-9-(3-fluorobenzyl)-23,4,94etrahydro-1H-carbazol-3-yl]isobutyramide
(Preparation 28) essentially as described in Example 140, above. MS (ES): m/z 457
(M+1); HPLC: Rt = 1.79 min, (95%).
Preparation 29
N-(6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide

Add acetyl chloride (8.5 mL, 120 mmol) to absolute ethanol (30 mL) and
stir for 1 h. Add 4-methoxyphenylhydrazine hydrochloride (1.74 g, 10 mmol) and
N-(4-oxo-cyclohexyl)-isobutyramide (Preparation 2) (1.83 g, 120 mmol) and reflux
with stirring for 56 h. Cool to room temperature, dilute with ethyl acetate (100 mL)
and wash with sodium bicarbonate solution (2 x 50 mL), and brine. Dry the organic
portion(MgSO4), filter, and concentrate in vacuo. Dissolve in dichloromethane and
pass over a silica pad, eluting with 20% ethyl acetate/dichloromethane. Obtain 2.32
g of a solid. Triturate the solid in diethyl ether with a small amount of
dichloromethane, filter and dry under house vacuum to obtain 2.14 g (75%) of an
off-white solid. MS (ES): m/z 287 (M+1)\ 285 (M-1); 1H NMR(DMSO-d6): δ
10.52 (s, 1H), 7.83 (d, 1H, J=7.5 Hz), 7.13 (d, 1H, J=8.8 Hz), 6.85 (s, 1H), 6.64 (dd,
1H, J=8.8,2.2 Hz), 4.02 (m, 1H), 3.75 (m, 3H), 2.90 (dd, 1H, J=15.0,5.3 Hz), 2.78
(m, 2H), 2.42 (m, 2H), 1.96 (m, 1H), 1.79 (m, 1H), 1.03 (d, 6H, J=6.6 Hz),

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Example 143
N-(6-methoxy-9-pyridin-2-ylmethyI-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-
isobutyramide

Dissolve N-(6-methoxy-2,3,4,9-tetrahydro-1H-carbazoi-3-yl)-isobutyramide
(200 mg, 0.70 mmol) in anhydrous tetrahydrofuran (6 mL) under nitrogen. Add
dropwise potassium bis(trimethylsilyl)amide (3.2 mL, 1.6 mmol, 0.5M in toluene)
and stir 30 min. Add slowly 2-(chloromethy])pyridine hydrochloride (131 mg, 0.80
mmol) in THF/DMF (0.4 mL/1.3 mL) and stir at ambient temperature for 18 h.
Quench with saturated ammonium chloride solution (0.5 mL) and partition between
ethyl acetate and water. Separate the two phases and wash the aqueous phase with
ethyl acetate (2x). Dry the combined organic portions (MgSO4), filter, and
concentrate in vacuo to obtain a residue. Purify the material by silica gel
chromatography, eluting with 50% ethyl acetate/dichloromethane with a gradient up
to 80% ethyl acetate/dichloromethane to obtain 199 mg (75%) of a light yellow
solid. MS (ES): m/z 378 (M+1); 1H NMR(DMSO-d6): δ 8.50 (dd, 1H, J=4.8, 0.9
Hz), 7.82 (d, 1H, J=7.5 Hz), 7.65 (dt, 1H, J=7.6,1.6 Hz), 7.22 (m, 2H), 6.89 (d, 1H,
J=2.2 Hz), 6.77 (d, 1H, J=7.9 Hz), 6.63 (dd, 1H, J=8.6,2.4 Hz), 5.32 (s, 2H), 3.97
(m, 1H), 3.72 (s, 3H), 2.91 (dd, 1H, J=15.0, 5.3 Hz), 2.85-2.76 (m, 1H), 2.74-2.64
(ra, 1H), 2.45 (m, 1H), 2.37 (m, 1H), 1.94 (m, 1H), 1.77 (m, 1H), 0.99 (m, 6H).
Examples 144 to 146, in the table below, are prepared essentially as
described in Example 143, above, using the following heteromethyl reagents
respectively: 3-(chloromethyl)pyridine hydrochloride, 4-(chloromethyl)pyridine
hydrochloride, and 2-(chloromethyl)pyridine hydrochloride.


WO 2007/002181 PCT/US2006/024122

Method A: Dissolve 4-methyl-thiazole-2-carbaldehyde (prepare in 92%
yield according to the procedures essentially as described in Khanna, I.K., et al., J.
Med. Chem. (2000)43, 3168-3185)(15.0g, 118mmol)inEtOH(250mL)andadd
sodium borohydride (2.23 g, 59.0 mmol). Stir at room temperature for 1 h, then
cautiously add aqueous NH4CI (50 mL) to the reaction mixture. Concentrate in
vacuo at 45 °C to remove EtOH. Dilute with water (50 mL) and extract into EtOAc
(3 x 100mL). Dry the combined organic portions (MgSO4), filter, and concentrate
in vacuo at 45 °C to give 14.39 g (94%) of the title compound as a yellow oil. MS
(ES): 130 (M+1); 1H NMR (CDCl3): 8 6.88 (s, 1H), 4.94 (s, 2H), 3.16 (s, 1H), 2.46
(s,3H).
Method B: Alternatively, dissolve 4-methyl-thiazole-2-carboxylic acid ethyl
ester (prepare in 27% yield according to the procedures essentially as described in
Erlenmeyer, H., et al., Helv. Chim. Acta (1944), 27, 1437-1438) (1.52 g, 8.88 mmol)
in THF (60mL) and add lithium borohydride (2.0M solution in THF, 9 mL, 17.8

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mmol). Heat at reflux temperature for 18 h. Allow to cool to room temperature and
dilute the reaction mixture with water (20 mL). Extract into ethyl acetate (3 x 50
mL). Dry the combined organic portions (MgSO4), filter, and concentrate in vacuo
at 45 °C. Purify the crude product on silica gel (40 g) with 40 - 80%
EtOAc/hexanes to give 690 mg (60%) of the title compound as a colorless oil.
Preparation 31
Thiazol-5-yl-methanoI

Prepare the title compound according to literature procedures (McElhinney,
R.S., et al., J. Med. Chem. (1998) 41,5265-5271).
Preparation 32
(2-Chloro-thiazol-4-yl)-methanol

Prepare the title compound by essentially following the procedures as
described in Preparation 27 (Method B), using 2-chloro-thiazole-4-carboxylic acid
ethyl ester (prepare according to the procedures essentially as reported by
Erlenmeyer, H., et al., Helv. Chim. Acta (1944) 27,1432-1436). MS (ES): m/z 150
(M+1); 1H NMR (CDCl3): 8 7.16 (t, 1H, J=1.0 Hz), 4.75 (d, 2H, J=0.9 Hz), 2.48 (s,
1H).
Preparation 33
(5-chloro-thiophen-2-yl)-methanol

Add dropwise a solution of 5-chloro-thiophene-2-carboxylic acid ethyl ester
(5.0 g, 28 mmol) in Et2O (100 mL) to a mixture of lithium aluminum hydride (1.1 g,
28 mmol) in Et2O. Stir at room temperature for 18 h, then quench the reaction with

WO 2007/002181 PCT/US2006/024122
water and 20% aqueous NaOH. Extract into Et20/EtOAc, dry (Na2SO4), filter, and
concentrate the organic portion to give the crude product. Purify by vacuum
distillation to give 3.4 g of an oil, boiling point 160 °C/20 mm Hg. MS [FD] 148;
Anal. Calcd for C5H5CIOS: C, 40.41; H, 3.39. Found: C, 39.59; H 3.59.
Preparation 34
Methanesulfonic acid 4-methyl-thiazol-2-ylmethyl ester

Combine 4-methyl-thiazol-2-yl)-methanol (Preparation 30) (1.00 g, 7.74
mmol) and triethylamine (1.25 g, 1.73 mL, 12.4 mmol) in dichloromethane (30 mL)
with stirring and cool to 0 °C under nitrogen. Add methanesulfonyl chloride (931
mg, 633 µL, 8.13 mmol) to the reaction mixture and stir at 0 °C for 30 min. Warm
to room temperature over 30 min, then dilute with water (40 mL) and
dichloromethane (40 mL). Separate the layers, dry the organic portion (MgSO4),
filter, and concentrate in vacuo at 40 °C to afford 1.15 g (72%) of the title
compound as a brown oil. MS (ES): m/z 208 (M+1); 1H NMR (CDCl3): δ 7.03 (m,
1H), 5.48 (s, 2H), 3.11 (s, 3H), 2.50 (d, 3H, J=0.9 Hz).
Preparation 35
Methanesulfonic acid 2-chloro-thiazol-4-ylmethyl ester

Prepare the title compound by essentially following the procedures as
described in Preparation 31, using (2-chloro-thiazol-4-yl)-methanol (Preparation 29)
to afford the title compound as a colorless oil. 1H NMR (CDCl3): 8 7.39 (s, 1H),
5.27 (d, 2H, J=0.9 Hz), 3.10 (s, 3H).
Preparation 36
2-Bromomethyl-thiazole

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Prepare the title compound according to literature procedures (Yang, L., et
al., Bioorg. Med. Chenu Lett. (1999) 9, 1761-1766).
Preparation 37
2-Bromomethyl-5-chloro-thiophene

Cool (5-chloro-thiophen-2-yl)-methanol (Preparation 30) (330 mg, 2.22
mmol) to 0 °C and add acetyl bromide (709 mg, 430 µL, 5.76 mmol). Allow to
warm to room temperature over 18 h, dilute with EtOAc (10 mL), and cautiously
add saturated aqueous NaHCO3 (3 mL). When the carbon dioxide evolution stops,
load the mixture onto a Varian Chem Elut CE1005 solid phase extraction cartridge
(Varian part number 12198006). Elute with EtOAc, collect, and concentrate about
50 mL to obtain the crude product. Purify on silica gel (12 g) using 0-15%
EtOAc/hexanes to afford 250 mg (53%) of the title compound as a yellow oil. MS
(EI): 210,212; 1H NMR (CDCl3): 5 6.92 (d, 1H, J=3.5 Hz), 6.78 (d, 1H, J=4.0 Hz),
4.66 (s, 2H).
Example 147
N-(6-Cyano-9-thiazol-4-ylmethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-
isobutyramide

Partition 4-chloromethyl-thiazole hydrochloride (199 mg, 1.17 mmol)
between Et2O (20 mL) and saturated aqueous NaHCO3 (20 mL). Separate the

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layers and dry the ether layer over MgSO4. Add DMF (3 mL) to the ether layer and
concentrate in vacuo to remove the ether. Add this solution to a slurry of N-(6-
cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 3) (300 mg,
1.07 mmol) and sodium hydride (60% suspension in mineral oil, 47 mg, 1.17 mmol)
in DMF (3 mL) which has stirred for 30 min at room temperature. Stir the reaction
at room temperature for 2 h, then add aqueous NaHCO3 (30 mL) and EtOAc (50
mL). Separate the layers and wash the organic portion with aqueous NaHCC>3 (2 x
30 mL). Dry the organic layer (MgSO4). Filter and concentrate in vacuo to obtain
487 mg crude yellow solid. Recrystallize the material from boiling toluene (10 mL)
to afford 296 mg (73%) of the title compound as a yellow solid. MS (ES): m/z 379
(M+1), 377 (M-1); 1H NMR (DMSO4): 8 9.01 (d, 1H, J=1.8 Hz), 7.90 (d, 1H,
J=1.3 Hz), 7.84 (d, 1H, J=7.9 Hz), 7.69 (d, 1H, J=8.4 Hz), 7.56 (d, 1H, J=1.8 Hz),
7.40 (dd, 1H, J=8.6,1.5 Hz), 5.47 (s, 2H), 3.99 (m, 1H), 3.03-2.81 (m, 3H), 2.49
(m, 1H), 2.37 (m, 1H), 1.98 (m, 1H), 1.80 (m, 1H), 0.99 (d, 6H, J=7.0 Hz); HPLC
(Method A): R, = 1.93 min, (97%).
Example 148
N-[9-(5-Chloro-thiophen-2-ylmethyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide

Prepare the title compound by essentially following the procedures as
described in Example 147, using 2-bromomethyl-5-chloro-thiophene (Preparation
37). Purify by silica gel chromatography (50-90% EtOAc/hexanes) to give the
product in 24% yield as a yellow solid. MS (ES): m/z 412 (M+1), 410 (M-1);
HPLC (Method A): Rt = 2.86 min, (92%).

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Example 149
N-(6-Cyano-9-thiazol-2-ylmethyI-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-
isobutyramide

Prepare the title compound by essentially following the procedures as
described in Example 147, using 2-bromomethyl-thiazole (Preparation 36). Purify
by silica gel chromatography (80 -100% EtOAc/Hexanes) to give the product in
55% yield as a white solid. MS (ES): m/z 379 (M+1), 377 (M-1); HPLC (Method
A):Rt=1.88min,(100%).
Example 150
N-[6-Cyano-9-(2-methyl-thiazol-4-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Prepare the title compound by essentially following the procedures as
described in Example 147, using 4-chloromethyl-2-methylthiazole hydrochloride.
Purify the crude material by recrystillizing from boiling toluene to provide the
product in 75% yield. MS (ES): m/z 393 (M+1), 391 (M-1); HPLC (Method A):
2.14 min, (100%).
Example 151

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(R)-N-[6-cyano-9-(2-methyl-thiazol-4-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide

Prepare the title compound by preparative chiral chromatography from
racemic N-[6-cyano-9-(2-methyl-thiazol-4-ylmethyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-isobutyramide (Example 150) in 97.7% ee using the following
conditions: Chiralpak AD (8 x 30cm), 75:15:10 heptane:EtOH:MeOH (350
mL/min), 240 nm detection. The title compound elutes first and the other
enantiomer (Example 152) elutes second. MS (ES): m/z 393 (M+1), 391 (M-1); 1H
NMR (CDCl3): 5 7.95 (d, 1H, J=1.1 Hz), 7.88 (d, 1H, J=7.7 Hz), 7.72 (d, 1H, J=8.4
Hz), 7.44 (dd, 1H, J=8.6,1.5 Hz), 5.40 (s, 2H), 4.04 (m, 1H), 2.95 (m, 3H), 3.05-
2.85 (m, 3H), 2.59 (s, 3H), 2.56 (m, 1H), 2.41 (m, 1H), 2.02 (m, 1H), 1.85 (m, 1H),
1.03 (d,6H, J=6.8 Hz).
Example 152
(5)-N-[6-cyano-9-(2-methy]-thiazol-4-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazo]-3-
yl]-isobutyramide

Prepare the title compound by preparative chiral chromatography from
racemic N-[6-cyano-9-(2-methyl-thiazol-4-ylmethyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-isobutyramide (Example 154) in 93.6% ee using the following

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conditions: Chiralpak AD (8 x 30cm), 75:15:10 heptane:EtOH:MeOH (350
mL/min), 240 nm detection. The title compound is the second of the two
enantiomers to elute. MS (ES): m/z 393 (M+1), 391 (M-1).
Example 153
N-[9-(2-Chloro-thiazol-4-ylmethyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Prepare the title compound by essentially following the procedures as
described in Example 143, using methanesulfonic acid 2-chloro-thiazol-4-ylmethyl
ester (Preparation 35) (190 mg, 1.0 mmol) and N-(6-cyano-2,3,4,9-tetrahydro-1H-
carbazol-3-yl)isobutyramide (Preparation 4) to give the product as a white solid
(21%). MS (ES): m/z 413 (M+1), 411 (M-1); HPLC (Method B): Rt = 4.66 min,
(96%).
Preparation 38
(R)-N-(6-Cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide

Dissolve (R)-N-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-
isobutyramide (Preparation 21) (1.00 g, 2.98 mmol) in 1-methyl-2-pyrolidinone (30
mL). Sparge the resulting solution with nitrogen for 15 min. Add copper(I) cyanide
(801 mg, 8.95 mmol) and copper(I) iodide (1.70 g, 8.95 mmol). Heat to 130 °C for
three days, then cool to room temperature. Dilute the reaction mixture with water
(100 mL), EtOAc (250 mL), and enough ethylene diamine to dissolve the copper

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143
solids (about 70 mL). Separate the layers, then wash the organic layer with water (2
x 50 mL). Dry the organic portion over MgSO4. Filter, concentrate, and purify on
silica gel (80 g) using 50 - 80% EtOAc/hexanes to afford 530 mg (63%) of the title
compound as a white solid. MS (ES): 282 (M+1), 280 (M-1); 1H NMR (CDCl3):
8 8.44 (s, 1H), 7.76 (s, 1H), 7.40 (dd, 1H, J=8.4,1.3 Hz), 7.37 (d, 1H, J=8.5 Hz),
5.64 (d, 1H, J=7.5 Hz), 4.42 (m, 1H), 3.11 (dd, 1H, J=15.2,5.1 Hz), 2.98-2.80 (m,
2H), 2.59 (dd, 1H, J=15.4,7.5 Hz), 2.38 (m, 1H), 2.17 (m, 1H), 2.02 (m, 1H), 1.21
(d, 6H, J=7.0 Hz); Chiral HPLC: Chiralcel OD-H 0.46 x 15 cm column, 15:85
EtOH/Heptane, 1.0 mL/min, 225 nm detection; Rt = 7.37 min; > 99%ee.
Example 154
(R)-N-[9-(2-Chloro-thiazol-4-ylmethyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide

Prepare the title compound by essentially following the procedures as
described in Example 147, using (R)-N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)-isobutyramide (Preparation 38) and methanesulfonic acid 2-chloro-thiazol-4-
ylmethyl ester (Preparation 35) to provide the product in 49% yield as a light yellow
solid. MS (ES): m/z 413 (M+1), 411 (M-1); 'H-NMR (CDCl3): δ 7.82 (d, 1H,
J=0.9 Hz), 7.43 (dd, 1H, J=8.6,1.5 Hz), 7.34 (d, 1H, J=8.4 Hz), 6.59 (s, 1H), 5.59
(d, 1H, J=7.9 Hz), 5.32 (s, 2H), 4.44 (m, 1H), 3.16 (dd, 1H, J=15.4,4.8 Hz), 2.89 (t,
2H, J=5.9 Hz), 2.64 (dd, 1H, J=15.6,7.3 Hz), 2.38 (m, 1H), 2.20 (m, 1H), 2.06 (m,
1H), 1.20 (d,6H, J=7.0 Hz).
Preparation 39
(2-Chloro-thiazol-5-yl)-methanol

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Treat an EtOH solution (10 mL) of 2-chloro-5-thiazolecarboxaldehyde (350
mg, 2.4 mmol) with sodium borohydride (60 mg, 1.6 mmol). After 1 h, carefully
quench with saturated ammonium chloride solution and remove the EtOH under
reduced pressure. Partition the reaction between EtOAc/water. Dry the organic
portion (Na2SO4), filter, and concentrate to give 296 mg (82%) of the title
compound as a colorless oil. MS (ES): m/z 150 (M+1); HPLC (Method B): Rt =
1.86 min (98%).
Preparation 40
Methanesulfonic acid 2-chloro-thiazol-5-ylmethyl ester

Prepare the title compound by essentially following the procedures as
described in Preparation 34, using (2-chloro-thiazol-5-yl)-methanol (200 mg, 1.3
mmol) to provide 277 mg (93%) of the title compound. Use without further
purification. 1H NMR (CDCl3): 8 7.62 (s.1H), 5.38 (s,2H), 3.05 (s,3H).
Example 155
N-[9-(2-Chloro-thiazol-5-ylmethyl)-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Prepare the title compound by essentially following the procedures as
essentially described in Example 143, using methanesulfonic acid 2-chloro-thiazol-
5-ylmethyl ester (Preparation 40) (1.3 mmol) and N-(6-cyano-2,3,4,9-tetrahydro-

WO 2007/002181 PCT/US2006/024122
1H-carbazol-3-yl)isobutyramide (Preparation 4) (281mg, 1.0 mmol) to give the
product as a white solid (10%). MS (ES): m/z 413 (M+1), 411 (M-1); HPLC
(Method B): Rt = 3.99 min, (95%).
Example 156
(R)-N-[6-Cyano-9-(4-methyl-thiazol-2-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide

Prepare the title compound by essentially following the procedures as
described in Example 147, using (R)-N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)-isobutyramide (Preparation 38) and methanesulfonic acid 4-methyl-thiazol-2-
ylmethyl ester (Preparation 34) to provide the product in 54% yield as a white solid
MS (ES): m/z 393 (M+1), 391 (M-1); 1H-NMR (CDCl3): δ 7.83 (d, 1H, J=0.9 Hz),
7.45 (dd, 1H, J=8.6,1.5 Hz), 7.41 (d, 1H, J=7.9 Hz), 6.82 (d, 1H, J=0.9 Hz), 5.56
(d, 1H, J=7.9 Hz), 5.53 (s, 2H), 4.45 (m, 1H), 3.16 (dd, 1H, J=15.2,5.1 Hz), 2.98-
2.82 (m, 2H), 2.64 (dd, 1H, J=15.9,7.0 Hz), 2.47 (d, 3H, J=0.9 Hz), 2.36 (m, 1H),
2.20 (m, 1H), 2.08 (m, 1H), 1.19 (dd, 6H, J=7.0,1.8 Hz).
Example 157
N-(6-Cyano-9-thiophen-3-ylmethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-
isobutyramide


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Add sequentially to a slurry of N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-
3-yl)-isobutyramide (Preparation 3) (100mg, 0.36 mmol) in THF (2 mL) at 0 °C:
trimethylphosphine (1.0 M in toluene, 530 µL, 0.53 mmol), 3-thiophenemethanol
(61 mg, 50 |iL, 0.53 mmol), and 1,1-(azodicarbonyl)-dipiperidine (ADDP, 134 mg,
0.53 mmol). Warm up to room temperature and stir in a sealed vial for 18 h.
Evaporate the reaction solvent and dissolve the residue in EtOAc (5 mL). Add
water (2 mL) and load onto a Varian Chem Elut CE1005 solid-phase extraction
cartridge (Varian part number 12198006). Elute with EtOAc, collect, and
concentrate (about 50 mL). Purify the crude product on silica gel (1 2g) eluting
with 30-90% EtOAc/hexanes to give the title compound in 11% yield as a colorless
oil. MS (ES): m/z 378 (M+1), 376 (M-1); 1H NMR (CDCl3): 5 7.81 (s, 1H), 7.40
(dd, m, J=8.4, 1.2 Hz), 7.33 (d, 1H, J=8.4 Hz), 7.30 (m, 1H), 6.86-6.81 (m, 2H),
5.60 (d, 1H, J=7.5 Hz), 5.29 (s, 2H), 4.41 (m, 1H), 3.16 (dd, 1H, J=15.2, 5.1 Hz),
2.90-2.72 (m, 2H), 2.63 (dd, 1H, J=15.4, 7.5 Hz), 2.36 (m, 1H), 2.16 (m, 1H), 2.02
(m, 1H), 1.18 (dd, 7H, J=6.8,3.7 Hz), 1.18 (dd, 6H, J=6.8, 3.7 Hz).
Example 158
N-(6-Cyano-9-thiophen-2-ylmethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-
isobutyramide

Prepare the title compound by essentially following the procedures as
described in Example 157, using 2-thiophenemethanol to give the product in 15%
yield as a white solid. MS (ES): m/z 378 (M+1), 376 (M-1); HPLC (Method A): Rt
= 2.34 min, (99%).
Example 159

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N-(6-Cyano-9-thiazol-5-ylmethyl-2,3,49-tetrahydro-1H-carbazol-3-yl)-
isobutyramide

Add potassium hydride (30% w/w in mineral oil, 129 mg, 0.97 mmol) to a
slurry of cyanomethyl-trimethyl-phosphonium chloride (prepare according to the
procedure essentially as described in Tsunoda, TV, et al., Tetrahedron Lett. (1996)
37,2459-2462) (166 mg, 1.10 mmol) at 0 °C under nitrogen. Allow the reaction
mixture to warm to room temperature and stir for 3 h. Add a solution of thiazol-5-
ylmethanol (100 mg, 0.87 mmol) in THF (2 mL), then add jV-(6-cyano-2,3,4,9-
tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 5) (122 mg, 0.44 mmol)
and heat at 70 °C for 18 h. Cool to room temperature and dilute with water (40
mL). Extract into EtOAc (3 x 50mL) and dry the organic portion (MgSO*). Filter
and concentrate to afford the crude product, (340 mg) as a yellow oil. Purify on
silica gel (24 g) using 5% (2M NH3/MeOH)/CH2Cl2, and then re-purify on silica gel
(40 g) using 80:18:2 EtOAc:hexanes:(2M NH3/MeOH) to afford 70 mg (42%) of
the title compound as an orange solid. MS (ES): m/z 379 (M+1), 377 (M-1); 1H-
NMR (CDCl3): 5 8.78 (s, 1H), 7.83 (d, 1H, J=1.3 Hz), 7.74 (s, 1H), 7.47 (dd, 1H,
J=8.6,1.5 Hz), 7.38 (d, 1H, J=8.4 Hz), 5.53 (d, 1H, J=7.9 Hz), 5.50 (s, 2H), 4.42
(m, 1H), 3.16 (dd, 1H, J=15.4,5.3 Hz), 2.97-2.80 (m, 2H), 2.62 (dd, 1H, J=15.4,
7.5 Hz), 2.37 (m, 1H), 2.21 (m, 1H), 2.05 (m, 1H), 1.20 (dd, 6H, J=7.0,1.8 Hz).
Preparation 41
trans-(4-Hydroxy-cyclohexyl)-carbarnic acid benzyl ester


WO 2007/002181 PCT/US2006/024122
Following procedures essentially as described in the literature (Janda, K. D.;
Ashley, J. A. Synth. Convn. 1990,20, 1073-1082) with the exception that the
organic layer is repeatedly concentrated under reduced pressure and the resulting
precipitate filtered. The reaction mixture is not concentrated to dryness, but only to
the point where a significant amount of precipitate has formed. Using this modified
protocol, an 80% yield is obtained on a 35.00 g scale.
Preparation 42
(4-Oxo-cyclohexyl)-carbamic acid benzyl ester

Dissolve oxalyl chloride (18.4 mL, 211 mmol) in CH2Cl2 (1000 mL), cool
below -70 °C, and add DMSO (18.0 mL, 253 mmol) via syringe pump over 30 min.
Stir for 45 min, and then add portionwise a suspension of tarns-(4-hydroxy-
cyclohexyl)-carbamic acid benzyl ester (35.00 g, 140 mmol) in CH2Cl2 (1000 mL),
while maintaining the temperature below -70 oC. Add the suspension by removing
a stopper from the reaction flask and quickly pouring in as much of the suspension
as possible while keeping the temperature below -70 °C, resulting in a slightly
turbid solution upon complete addition. Stir the reaction for 90 min, then add
triethylamine (97.8 mL, 702 mmol) slowly via syringe. Stir for another hour, and
allow the reaction to slowly warm to room temperature overnight. Wash
sequentially with water (1500 mL), brine (2 x 1500 mL), and saturated aqueous
NaHCO3 (2 x 1500 mL). Separate the organic portion and dry (MgSO4), filter, and
concentrate under reduced pressure. Triturate the crude residue twice with 4:1
Hexane/EtOAc (500 mL, then 250 mL). (Alternatively, triturate with 15%
EtOAc/Hexane. Then only one trituration is required.) Filter and collect the solids
and dry at 35 °C in a vacuum oven to obtain 26.44 g of the product. Combine the
filtrates of the triturations and concentrate under reduced pressure, followed by
trituration of the residue in 9:1 hexane/EtOAc (100 mL) to afford a second crop of
5.70 g, for a combined yield of 32.14 g (93%). ESI MS: m/z 248 [C14H17NO3 +

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H]+; 1H NMR (300 MHz, CDCl3): δ1.63-1.78 (m, 2H), 2.22-2.27 (m, 2H), 2.32-
2.49 (m, 4H), 3.95-4.04 (m, 1H), 4.75 (br s, 1H), 5.11 (s, 2H), 7.29-7.42 (m, 5H)
Preparation 43
(6-Trifluoromethoxy-2,3,4,9-tetrahydro- 1H-carbazol-3-yl)-carbamic acid benzyl
ester

Combine 4-(trifluoromethyl)phenylhydrazine hydrochloride (31.9 g, 140
mraol) and (4-oxo-cyclohexyl)-carbamic acid benzyl ester (Preparation 42) (34.6 g,
140 mmol) and add acetic acid (700 mL). Heat the reaction to 90 °C overnight,
cool to room temperature, and concentrate under reduced pressure. Purify the
residue by flash chromatography (silica gel, 9:1 chloroform:acetone), and trituration
(9:1 hexanes:dichloromethane) to provide 50.9 g (90%) of the title compound as a
tan solid, mp 123-126°C. MS (ES): m/z 403 (M-1); 1H NMR (CDCI3): 8 7.86 (s,
1H), 7.28-7.36 (m, 5H), 7.26 (m, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.99 (dd, J = 1.3,
8.7 Hz, 1H), 5.11 (s, 2H), 4.90-4.92 (m, 1H), 4.18 (m, 1H), 3.08 (dd, J = 4.9,15.4
Hz, 1H), 2.76-2.89 (m, 2H), 2.59 (dd, J= 6.8,15.3 Hz, 1H), 2.08-2.16 (m, 1H),
1.93-2.04 (m, 1H).
Preparation 44
2-Bromomethyl-6-fluoro-pyridine

Combine 2-metbyl-6-fluoro-pyridine (19.6 g, 176 mmol), 1.1'-azobis-
(cyclohexane-carbonitrile) (0.431 g, 1.77 mmol), and freshly recystallized N-
bromo-succinimide (32.96 g, 185 mmol) in carbon tetrachloride (200 mL) and stir
in a 1000 mL flask while radiating with UV light for 18 h. Allow to cool, then filter
to remove succinimide and wash with dilute Na2S2O3 solution. Dry over Na2SO4,

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filter and evaporate to give an amber oil. Purify by silica gel chromatography,
eluting with 0-30% EtOAc/hexanes to obtain 12.3 g (37%) of a clear oil. MS 100%
(m/e) 190 (EI); 1H NMR (DMSO, 400 MHz): 8 8.03-7.95 (m, 1H), 8.03-7.95 (m,
1H), 7.48 (dd, 1H, J=7.5,2.6 Hz), 7.11 (dd, 1H, J=7.9,2.6 Hz), 4.63 (s, 2H).
Preparation 45
[9-(6-Fluoro-pyridin-2-ylmethyl)-6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-carbamic acid benzyl ester

Add CS2CO3 (6.44 g, 19.8 mmol) to a solution of (6-trifluoromethoxy-
2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid benzyl ester (Preparation 43)
(4.00 g, 9.88 mmol) and 2-bromomethyl-6-fluoropyridine (Preparation 44) (3.11 g,
13.8 mmol) in DMF (40 mL). Heat the resulting mixture to 50 °C for 18 h and then
dilute with EtOAc (120 mL). Wash the organics with water (3 x 40 mL), dry
(MgSO4), filter, and concentrate to give the crude product (5.40 g) as a brown oil.
Purify the crude product on silica gel (120 g) eluting with 25-45% EtOAc/hexanes
to afford 2.85 g (56%) of the title compound as a tan oil. MS (ES): m/z 514 (M+1);
HPLC (Method A): Rt = 4.54 min (95%).
Preparation 46
[9-(3-Fluorobenzyl)-6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
carbamic acid benzyl ester

WO 2007/002181 PCT/US2006/024122

Prepare the title compound by essentially following the procedures as
described in Preparation 45, using 3-fluorobenzyl bromide to give 6.15 g (95%) as a
pale yellow oil. Purify on silica gel (10-60% EtOAc/hexanes) to give the title
compound in 95% yield. MS (ES): m/z 513 (M+1), 513 (M-1); HPLC (Method A):
Rt = 6.23min(97%).
Example 160
(R)-N-(6-Cyano-9-pyrazin-2-ylmethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-
isobutyramide

Prepare the title compound by essentially following the procedures as
described in Preparation 45, using (R)-N-(6-yano-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)-isobutyramide (Preparation 38) and 2-chloromethylpyrazine (prepare according
to literature procedure essentially as described in Newkome, G. R.; et. al. Synthesis
1984,8, 676-679). Purify on silica gel (EtOAc) to afford the title compound as a
light yellow solid. MS (ES): m/z 374 (M+1), 372 (M-1); HPLC (Method B): R, =
2.34 min (98%).

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Example 161
(R)-N-(6-cyano-9-pyridin-2-yImethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yI)-
isobutyramide

Prepare the title compound by essentially following the procedures as
described in Preparation 45, using (R)-N-(6-yano-2,3,4,9-tetrahydro-1H-carbazol-3-
y])-isobutyramide (Preparation 35) and 2-chloromethylpyidine-HCl to afford the
title compound as a white solid. MS (ES): m/z 373 (M+1); HPLC (Method B): Rt =
2.79 min (100%).
Preparation 47
9-(6-Fluoropyridin-2-ylmethyl)-6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-carbazol-
3-ylamine

Dissolve [9-(6-fluoro-pyridin-2-ylmethyl)-6-trifluoromethoxy-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]-carbamic acid benzyl ester (Preparation 45) (2.73 g,
5.32. mmol) in EtOH (100 mL) and THF (50 mL). Add 10% Pd/C (200 mg) and
stir at room temperature under a balloon of hydrogen for 18 h. Filter the reaction
through a pad of Celite®, rinse the pad with THF (50 mL), and concentrate the
filtrate in vacuo to afford 2.37 g (90%) of the title compound as a dark brown oil.
MS (ES): m/z 380 (M+1); HPLC (Method A): R, = 1.76 min (89%).

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Preparation 48
9-(3-Fluorobenzyl)-6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-carbazol-3-y]amine

Prepare the title compound by essentially following the procedures as
described in Preparation 47 using [9-(3-fluorobenzyl)-6-trifluoromethoxy-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]-carbamic acid benzyl ester (Preparation 46) to give
4.08 g (92%) of the title compound as a brown oil. MS (ES): m/z 379 (M+1) weak,
362 (M+1-NH3); HPLC (Method A): Rt = 1.83 min (89%).
Example 162
N-[9-(6-fluoro-pyridin-2-ylmethyl)-6-trifluoromethoxy-2,3,4,9-tetrahydro-licf-
carbazol-3-yl]-isobutyramide

Dissolve 9-(6-fluoro-pyridin-2-ylmethyl)-6-trifluoromethoxy-2,3,4,9-
tetrahydro-1H-carbazol-3-ylamine (Preparation 47) (580 mg, 1.53 mmol) and
triethylamine (201 mg, 277 µL, 1.99 mmol) in CH2Cl2 (20 mL). Slowly add
isobutyryl chloride (212 mg, 208 µL, 1.99 mmol) and stir at room temperature for
18 h. Dilute the reaction with dilute HCl (10 mL), then load the reaction onto a
Varian ChemElut CE1020 solid-phase extraction cartridge (Varian part number
12198008). Elute, collect, and concentrate 125 mL CH2Cl2 to give the crude
product (794 mg) as a brown oil. Purify the crude product on silica gel (40 g),

WO 2007/002181 PCT/US2006/024122
eluting with 35-65% EtOAc/hexanes to afford 358 mg (52%) of the title compound
as a yellow foam. MS (ES): m/z 450 (M+1), 448 (M-1); HPLC (Method B): Rt =
8.21 min (100%).
Examples 163 to 165, in the table below, are prepared essentially as
described in Example 162, above, using the following chloroacyl reagents
respectively: cyclopropanecarbonyl chloride, methyl chloroformate, and
dimethylcarbamylchloride.

Examples 166 to 169, in the table below, are prepared essentially as
described in Example 162, above, using 9-(3-fluorobenzyl)-6-trifluoromethoxy-
2,3,4,9-tetrahydro-1H-carbazol-3-ylamine (Preparation 45) and the following
chloroacyl reagents respectively: isobutyryl chloride, cyclopropanecarbonyl
chloride, methyl chloroformate, and dimethylcarbamylchloride.


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Preparation 49
6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid tert-butyl ester

Follow the procedures essentially as described in Preparation 3 (Method 1).
Mix p-bromophenylhydrazine hydrochloride (1.99 g, 8.9 mmol) and (4-oxo-
cyclohexyl)-carbamic acid tert-butyl ester (1.9 g, 8.9 mmol) in ethanol (50 mL) to
give 780 mg (25%) of the title compound after recrystallization from toluene. MS
(ES): 363,365 (M-1); HPLC: R, = 3.39 min, (94%).
Preparation 50
[6-Bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbamicacid
tert-butyl ester

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Prepare the title compound by essentially following procedures as described
in Example 96, using 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid
tert-butyl ester (6.0 g, 16.4 mmol), m-fluorobenzyl bromide (2.2 mL, 18 mmol) and
sodium hydride (720 mg of 60%, 18 mmol). Purify by column chromatography
using hexane/EtOAc to give 5.95 g (77%). MS (ES): m/z 473,475 (M+1); HPLC:
Rt = 7.24min,(97%).
Preparation 51
6-Bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1 H-carbazol-3-ylamine
hydrochloric salt

To remove the -BOC protecting group, dissolve [6-bromo-9-(3-fluoro-
benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbarnic acid tert-butyl ester (6.0 mg,
12.7 mmol) in 4N HC1 in dioxane (100 mL). Stir for 10 min and then add more
dioxane (50 mL) to aid in stirring the thick white solid. Collect the solid and wash
with diethyl ether to give 5.2 g (99%) 6-bromo-9-(3-fluoro-benzyl)-2,3,4,9-
tetrahydro-1H-carbazol-3-ylamine as the HC1 salt MS (ES): m/z 356,358 (M+1);
HPLC::Rt=1.84 min,(96%).

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Example 170
Cyclopropanecarboxylic acid[6-bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-amide

Mix 6-bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylamine
hydrochloride (195 mg, 0.48 mmol), triethylamine (210 µL, 1.5mmol),
cyclopropanecarbonyl chloride chloride (55 µL, 0.6 mmol) in dichloromethane (10
mL) and stir at room temperature for 18 h. Shake the reaction with dilute
HCl/water/EtOAc. Dry (MgSO4) the organic layer and concentrate to give 120 mg
crude product. Recrystallize (EtOH) to give 50 mg (24%) of the title compound.
MS (ES): m/z 441,443 (M+1); 1H NMR (CDCl3): 5 7.63 (s, 1H), 7.27 (m 2H), 7.08
(d,lH), 6.92 (t, 1H), 6.75 (d, 1H), 6.63 (d, 1H), 5.58 (br d, 1H), 5.23 (s, 2H), 4.44
(br m, 1H), 3.13 (dd, 1H), 2.74 (m, 2H), 2.64 (dd,lH), 2.23 (m,2H), 2.16 (m,lH),
2.02 (m,lH), 1.09 (m,4H); HPLC: R, = 3.55 min, (95%).
Examples 171 to 175, in the table below, are prepared following procedures
essentially as described in Example 170.


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Example 176
3-[6-Bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-1,1 -dimethyl-
urea

Mix 6-bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
ylamine-HCl (Preparation 51) (20 0mg, 0.49 mmol), N,N-dimethylcarbamoyl
chloride (54 µL, 63 mg, 0.59 mmol), triethylamine (205 µL, 149 mg, 1.47 mmol),
CH2Cl2 (6 mL), and N-methylpyrrolidinone (2 mL). Stir at room temperature for 18
h, then add more N,N-dimethylcarbamoyl chloride (54 |xL, 63 mg, 0.59 mmol). Stir
at room temperature for 60 h, then evaporate the solvents. Dilute the residue with

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EtOAc (80 mL) and wash the organic solution with HC1 ( aqueous NaHC03. Dry (MgSO4), filter, and concentrate the organic portion to
obtain 308 mg crude product as a brown oil. Purity on silica gel (12 g), eluting with
80-100% EtOAc/hexanes to afford 164 mg (75%) of the title compound as a white
foam. MS (ES): 444,446 (M+1); HPLC: Rt = 3.27 min, (92%).
Preparation 52
6-Cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid tert-butyl ester

As described in C Chen et al, J. Org. Chem. (1997) 62,2676-2677, mix 3-
iodo-4-aminobenzonitrile (T. H. Jonckers, et al, J. Med. Chem. 45 (16) 3497-3508
(2002)) (1.3 g, 5.3 mmol) and (4-oxo-cyclohexyl)-carbamic acid ferf-butyl ester (3.4
g, 16 mmol) l,4-diazobicyclo[2.2.2]octane (DABCO)(1.8 g, 16 mmol), magnesium
sulfate (960 mg, 8 mmol) and DMF (30 mL). Sparge the stirred mixture with
nitrogen for 10 min and add palladium(II) acetate (58 mg, 0.26 mmol) and place in
a 105 °C pre-heated oil bath. After 18 h, cool and dilute with EtOAc. Gravity filter
the reaction into a separatory funnel and shake with water/EtOAc. Dry the organic
layer (MgSCO4) and concentrate to give a dark brown oil. Triturate with hexane
(insoluble material is starting ketone). Concentrate the hexane solution and purify
by silica gel chromatography (120 g), eluting with methylene chloride (0-40 min),
then 10% EtOAc/methylene chloride (40-70 min) to give 550 mg (33%) of an off-
white foam. MS (ES): m/z 312 (M+1), 310 (M-1); HPLC: Rt = 2.30 min, (97%).
Preparation 53
[6-Cyano-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbamicacid
tert-butyl ester

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Follow procedures as essentially described in Example 96, using 6-cyano-
2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid tert-butyl ester (2.0 g, 6.4
mmol), m-fluorobenzyl bromide (0.982 mL, 8 mmol) and 60% NaH (435 mg, 10.9
mmol) in DMF (70 mL) to give 1.41 g (53%) of the title compound after
purification by flash chromotagraphy using EtOAc/hexane. MS (ES): m/z 420
(weak) (M+1), 418 (weak) (M-1); HPLC: Rt = 3.86 min, (100%).
Preparation 54
6-Amino-9-(3-fluoro-benzyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile,
hydrochloride

Prepare the title compound by essentially following procedures as described
in Preparation 48, starting with [6-cyano-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-carbamic acid tert-butyl ester (1.38 g, 3.28 mmol) and 4N HC1
dioxane (10 mL) to yield 1.02 g (87%). MS (ES): m/z 320 (weak) (M+1); HPLC:
Rt= 1.64 min, (92%).
Example 177
Cyclopropanesulfonic acid [6-cyano-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro- \H-
carbazol-3-yl)-amide

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Combine 6-amino-9-(3-fluoro-benzyl)-6,7,8.9-tetrahydro-5H-carbazole-3-
carbonitrile, hydrochloride salt (Preparation 54) (125 mg, 0.35 mmol) and
triethylamine (0.195 mL, 1.4 mmol) in dichloromethane (3 mL) under nitrogen.
Add cyclopropylsulfonylchloride (51 mg, 0.36 mmol) in dichloromethane (1 mL).
Stir for 18 h at room temperature. Purify the reaction solution directly by flash
chromatography, eluting with 20% ethyl acetate/hexane and then a gradient up to
50% ethyl acetate/hexane to obtain 80 mg. Triturate in diethyl ether to obtain 61
mg (41%) of a tan solid. MS (ES): m/z 424 (M+1), 422 (M-1); 1H NMR(DMSO-
d6): δ7.98 (d, 1H, J= 1.3 Hz), 7.56 (d, 1H, J= 8.4 Hz), 7.41 (dd, 1H, J= 8.4,1.3
Hz), 7.36-7.30 (m, 2H), 7.07 (dt, 1H, J = 8.7,2.5 Hz); 6.88 (d, 1H, J = 9.7 Hz),
6.83 (d, 1H, J = 7.9 Hz), 5.42 (d, 2H, J= 5.3 Hz), 3.68 (m, 1H), 3.10 (dd, 1H, J=
15.4,5.3 Hz), 2.90-2.81 (m, 1H), 2.79-2.61 (m, 3H), 2.13 (m, 1H), 1.86 (m, 1H),
0.98-0.91 (m, 4H).
Example 178
3-[6-Cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-liir-carbazol-3-yl]-l,l-
dimethylurea

Prepare the title compound by essentially following the procedures as
described in Example 162, using 6-amino-9-(3-fluoro-benzyl)-6,7,8,9-tetrahydro-

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5H-carbazole-3-carbonitrile hydrochloride (Preparation 54) and dimethylcarbamyl
chloride. Purify by silica gel chromatography (30-70% (4% (2M
NH3/MeOH)/CH2Cl2)/hexanes) to give the title compound in 69% yield as a white
solid. MS (ES): m/z 391 (M+1), 389 (M-1); HPLC (Method B): R, = 4.11 min
(99%).
Preparation 55
[6-Cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbamicacid 4-
nitrophenyl ester

Prepare the title compound by essentially following the procedures as
described in Example 162, using 6-amino-9-(3-fluoro-benzyl)-6,7,8,9-tetrahydro-
5H-carbazole-3-carbonitrile hydrochloride (Preparation 51)and 4-nitrophenyl
chloroformate. Purify by silica gel chromatography (50% (4% (2M
NH3/MeOH)/CH2Cl2)/hexanes) to give the title compound in 33% yield as a white
solid. MS (ES): m/z 346 (M - p-nitrophenolate); HPLC (Method B): Rt = 2.23 min
(86%).
Example 179
l-[6-Cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-3-methyl-urea


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Combine [6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
carbamic acid 4-nitrophenyl ester (Preparation 55) (306 mg, 0.63 mmol),
methylamine hydrochloride (426 mg, 6.30 mmol), triethylamine (1.40 g, 1.93 mL,
13.9 mmol), and THF (30 mL). Stir the reaction mixture at room temperature for
18 h, then dilute with water (100 mL). Extract into EtOAc (3 x 65 mL), dry the
combined organic portions (MgSO4), filter, and concentrate to give the crude
product (310 mg) as a yellow oil. Purify the crude product on 40 g silica gel (50-
100% (4% (2M NH3/MeOH)/CH2Cl2)/hexanes) to give 58 mg (24%) of the title
compound as a yellow solid. MS (ES): m/z 377 (M+1); HPLC (Method B): R, =
3.22min(98%).
Example 180
3-[6-Cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-l-methoxy-l-
methyl-urea

Prepare the title compound by essentially following the procedures as described in
Example 179, using N,0-dimethylhydroxylamine hydrochloride. Purify on silica
gel (10-30% (2% (2M NH3/MeOH)/CH2Cl2)/hexanes) to give 11 mg (13%) of the
title compound as a colorless oil. MS (ES): m/z 407 (M+1), 405 (M-1); HPLC
(Method B): R, = 5.42 min (88%).
Preparation 56
(5-Fluoro-pyridin-2-yl)-methanol


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Add butyllithium (10.9 mL, 27.22 mmol, 2.5 M solution in hexanes) to a -
78 °C solution of 2-bromo-5-fluoro-pyridine (3.99 g, 22.68 mmol) in toluene (200
mL). Stir the reaction at-78 °C for 90 min and then add N.N-dimethylformamide
(2.3 mL, 29.71 mmol) via syringe. Stir the reaction for an additional 2 h at -78 °C
and then add sodium borohydride (1.72 g, 45.36 mmol) and allow the reaction to
warm to room temperature over a 12 h period. Quench the reaction with saturated
aqueous sodium bicarbonate (20 mL) and dilute with ethyl acetate (100 mL).
Separate the organic phase and dry (magnesium sulfate), filter and concentrate in
vacuo to give a yellow oil. Purify the oil by column chromatography (silica gel;
10% to 50% ethyl acetate in hexanes) to give 1.30 g (45%) as a clear colorless oil.
1H NMR (300 MHz, CDCl3): 8 8.4Js, 1H), 7.46-7.37 (m, 1H), 7.32-7.27 (m, 1H),
4.75 (s,2H), 3.64 (br s.1H).
Preparation 57
2-Chloromethyl-5-fluoro-pyridine hydrochloride salt

Add thionyl chloride (320 uL, 4.30 mmol) slowly to a 0 °C solution of (5-
fluoro-pyridin-2-yl)-methanol (420 mg, 3.31 mmol) in methylene chloride (15 mL).
Stir the reaction at 0 °C for 3 h and quench with isopropyl alcohol. Dilute the
reaction contents with methylene chloride (50 mL) and then saturated aqueous
sodium bicarbonate (20 mL). Separate the organic phase, dry(magnesium sulfate),
filter and concentrate in vacuo to give an oil. The oil is treated with hydrochloric
acid (10 mL, 3 M solution in dioxane) at room temperature for 30 min. The
resultant solid is collected by filtration and washed with a minimal amount of cold
diethyl ether to give 200 mg (33%) as a yellow solid. MS (APCT): m/z 146
[C6H5CIFN + H]+; 1H NMR (300 MHz, CDCl3): δ 8.42. (s, 1H), 7.56-7.37 (m, 2H),
4.67 (s,2H).

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Example 181
N-[6-Cyano-9-(5-fluoro-pyridin-2-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Suspend sodium hydride (60% in oil, 80 mg, 1.99 mraol) in DMF (2 mL)
and chill to 0 °C. Add a solution of N-(6-cyano-2,3>4,9-tetrahydro-1H-carbazol-3-
yl)-isobutyramide (253 mg, 0.90 mmol) in DMF (2 mL) slowly via syringe, and
allow to stir 30 min before wanning to ambient temperature for 60 min. Add 2-
chloromethyl-5-fluoro-pyridine hydrochloride salt (180 mg, 0.99 mmol) and stir the
reaction for about 12 h. Quench the reaction with saturated aqueous ammonium
chloride (5 mL). Add ethyl acetate (50 mL) and wash the solution with water (50
mL), then brine (2 x 50 mL). Separate the organic phase and dry over magnesium
sulfate, filter, and evaporate under reduced pressure. Titurate the resulting residue
with diethyl ether (10 mL) for 5 min and then filter to afford 187 mg (53%) of the
title compound as a light yellow solid, mp 235-238 °C (dec); MS (ESI): m/z [391
C23H23FN4O + H]+; 1H NMR (300 MHz, CDCI3): $ 8.4?s, 1H), 7.78 (s, 1H), 7.38-
7.25 (m, 3H), 6.67 (dd, J= 8.6,4.2 Hz, 1H), 5.58 (d, J= 7.8 Hz, 1H), 5.35 (s, 2H),
4.40 (br s, 1H), 3.14 (dd, 7 = 15.4,5.0 Hz, 1H), 2.79 (br s, 2H), 2.60 (dd, 7 = 15.4,
7.6 Hz, 1H), 2.34 (pentet, J= 6.8 Hz, 1H), 2.15 (br s, 1H), 2.02-1.95 (m, 1H), 1.16
(d,J=6.9 Hz,6H).
Preparation 58
(6-Bromo-3-fluoro-pyridin-2-yl)-methanol

Slowly add n-Butyllithium (2.5 M in hexanes, 9.40 mL, 23.3 mmol) to a -78
°C solution of 2-bromo-5-fluoro-pyridine (3.42 g, 19.4 mmol) and diethyl ether

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(200 mL). Stir the reaction at -78 °C for 1 h, then add dimethylformamide (2.00
mL, 25.5 mmol) and continue stirring for an additional hour. Warm the reaction to
room temperature and remove the solvent under vacuum. Dissolve the crude
material in methanol (50 mL) and cool to 0 °C. Add sodium borohydride (1.47 g,
38.9 mmol) and allow the reaction is to slowly warm to room temperature over 12
h. Quench the reaction with saturated aqueous sodium bicarbonate (20 mL) then
add ethyl acetate (100 mL). Separate the layers and dry the resultant organic layer
with magnesium sulfate, filter, and concentrate under vacuum to give a yellow
solid. Purify the crude solid by column chromatography (silica gel; 10% to 50%
ethyl acetate in hexanes) to give 1.66 g (42%) of the title compound as a yellow
solid. 1H NMR (300 MHz, CDCl3): 5 7.50-7.49m, 1H), 7.35-7.25 (m, 1H), 4.80 (s,
2H),3.30(s,lH).
Preparation 59
(3 -Fluoro-pyridin-2-yl)-methanol

Dissolve (6-bromo-3-fluoro-pyridin-2-yl)-methanol (850 mg, 4.13 mmol) in
methanol (40 mL) then purge the solution with nitrogen. Add palladium on carbon
(200 mg of 5% wet) and stir the mixture under a hydrogen atmosphere (2 balloons)
for 20 h. Filter the mixture through Celite® and wash the filter cake with methanol.
Concentrate the filtrate under reduced pressure and dissolve the resulting residue in
chloroform (150 mL). Wash the organics with saturated aqueous sodium
bicarbonate (75 mL), dry over magnesium sulfate, filter, and concentrate to give 433
mg (82%) of the title compound which is used without further purification. JH
NMR (300 MHz, CDCI3): 8 8.40 (m, 1H), 7.42-7.36 (m, 1H), 7.29-7.23 (m, 1H),
4.84 (s, 2H), 3.97 (br s, 1H); MS (APCT): m/z 110 [C6H6FNO - H2O + H]+.
Preparation 60
2-Chloromethyl-3-fluoro-pyridine

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Dissolve (3-fluoro-pyridin-2-yl)-methanol (215 mg, 1.69 mmol) in
dichloromethane (10 mL) and cool to 0 °C. Add thionyl chloride (160 jiL, 2.20
mmol) and stir the reaction for one hour. Add dichloromethane (50 mL) and stir the
reaction with saturated aqueous sodium bicarbonate (2 x 40 mL) and brine (2 x 40
mL). Separate and dry the organic portion over magnesium sulfate, filter, and
concentrate under reduced pressure to provide 198 mg (80%) of product, which is
used without further purification. MS: m/z 146,148 [C6H5ClFN +1]+; 1H NMR
(300 MHz, CDCl3): 8 8.41-8.44 (m, 1H), 7.41-7.47 (m, 1H), 7.28-7.34 (m, 1H),
4.75 (d, J = 2.0 Hz, 2H); 19F NMR (282 MHz, CDCl3): 5 -123.8.
Example 182
N-[6-Cyano-9-(3-fluoro-pyridin-2-ylmemyl)-2,3,4,94etrahydro-1H-carbazol-3-yl3-
isobutyramide

Suspend sodium hydride (60% suspension in mineral oil, 114 mg, 1.64
mmol) in dimethylformamide (7 mL) and cool to 0 °C. Add a solution of N-(6-
cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 3) (385 mg,
1.37 mmol) in dimethylformamide (3.5 mL). After several minutes, warm the
reaction to room temperature, and stir for 30 min, after which time add 2-
chloromethyl-3-fluoro-pyridine (Preparation 60). Stir the reaction overnight and
then dilute with ethyl acetate (100 mL). Wash the reaction mixture sequentially
with brine (3 x 75 mL), water (75 mL), and brine (75 mL). Separate the organic
layer, dry over magnesium sulfate, filter, and concentrate under reduced pressure.
Purify using flash chromatography [silica gel, gradient from 0:100 to 20:80 (90:10:1

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dichloromethane:methano]:concentrated ammonium hydroxide):dichloromethane]
to provide 184 mg (38%) of the title compound as an off-white solid, m.p. = 213-
216 °C; MS: m/z 391 [C23H23FN4O + 1]+; 1H NMR (300 MHz, DMSO-d6): δ 8.29-
8.31 (m, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.71-7.78 (m, 1H),
7.58 (d, 7 = 8.5 Hz, 1H), 7.38-7.44 (m, 2H), 5.56 (s, 2H), 3.99-4.04 (m, 1H), 2.73-
3.00 (m, 3H), 2.49-2.55 (m, 1H), 2.37 (septet, 7 = 6.8 Hz, 1H), 1.96-2.00 (m, 1H),
1.76-1.83 (m, 1H), 1.01 (d, 7 = 6.8 Hz, 6H).
Example 183
(R)-N-[6-Cyano-9-(6-fluoro-pyridin-2-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide

Prepare the title compound by essentially following the procedures as
described in Example 147, using N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3~yl)-
isobutyramide (Preparation 35) (0.7 mmol, 200 mg), anhydrous dimethylformamide
(10 mL), sodium hydride (60% mineral oil suspension, 1.2 eq., 0.85 mmol, 34 mg),
and 2-bromomethyl-6-fluoro-pyridine (Preparation 41) (0.85 mmol., 162 mg) as a
solution in 1 mL anhydrous DMF. Stir the resulting mixture for 30 min at room
temperature and then quench the reaction slowly with water (40 mL) to precipitate
white solids. Collect the product via filtration and wash the cake with hexanes.
Dissolve the filter cake in ethyl acetate and dichloromethane; dry the resulting
solution with magnesium sulfate and strip to dryness. Crystallize the product from
dichloromethane/hexanes and dry under vacuum at 40 °C to provide 242 mg (87%)
white solids. LCMS 100% (m/z) 391 (M+1, APES-pos); lH NMR (DMSO, 400
MHz): δ 7.94 (d, 1H, J=1.3 Hz), 7.90 (dd, 1H, J=15.9,8.4 Hz), 7.82 (d, 1H, J=7.5
Hz), 7.58 (d, 1H, J=8.4 Hz), 7.40 (dd, 1H, J=8.4,1.8 Hz), 7.05 (dd, 1H, J=8.1,2.4
Hz), 6.92 (dd, 1H, J=7.3,2.4 Hz), 5.44 (s, 2H), 4.06-3.95 (m, 1H), 2.97 (dd, 1H,

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J=15.2,5.1 Hz), 2.97 (dd, 1H, J=15.2,5.1 Hz), 2.88-2.68 (m, 2H), 2.52 (dd, 1H,
J=14.9,8.1 Hz), 2.42-2.31 (m, 1H), 2.00-1.91 (m, 1H), 1.86-1.74 (ra, 1H), 0.99 (d,
3H, J=3.1 Hz), 0.98 (d, 3H, J=2.6 Hz)
Preparation 61
(6-Cyano-2,3,4,9-tetrahydro-li/-carbazol-3-yl)-carbamic acid benzyl ester

Combine 4-cyanophenylhydrazine hydrochloride (27.4 g, 162 mmol) and (4-
oxo-cyclohexyl)-carbamic acid benzyl ester (Preparation 42) (40.0 g, 162 mmol) in
acetic acid (800 mL). Heat the reaction to 90 °C overnight, then cool to room
temperature and concentrate under reduced pressure. Triturate the residue in
dichloromethane and discard the filter cake. Concentrate the filtrate under reduced
pressure. Purify the resulting residue by flash chromatography (silica gel, 9:1
chlorofornr.acetone). Recrystillize the resulting material from benzene to provide
38.8 g (69%) of the title compound. m.p. = 141-143 °C; mass spectrum (m/e): 344
[C21H19N3O2 - 1]; 1H NMR (300 MHz, CDCl3): δ 8.15 (s, 1H), 7.73 (s, 1H), 7.29-
7.38 (m, 7H), 5.12 (s, 2H), 4.89-4.92 (m, 1H), 4.18 (m, 1H), 3.09 (dd, J= 5.0,15.5
Hz, 1H), 2.78-2.91 (m, 2H), 2.59 (dd, J= 7.0,15.5 Hz, 1H),
2.07-2.17 (m, 1H), 1.93-2.05 (m, 1H).
Preparation 62
(R)-(6-Cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid benzyl ester


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170
Ressolveracemic(6-cyano-2,3,4,9-tetrahydro-1H-carba2ol-3-yl)-carbamic
acid benzyl ester (Preparation 61) (43.28 g) using preparative HPLC under the
following conditions: Chiralcel OD column (8 x 35 cm), MeOH/0.2%
dimethylethyl amine (DMEA) mobile phase at 350 ml/min flow rate with UV
detection at 240 nM. Use 20 mL (666 mg) injections in 1:3 CHCl3/MeOH diluent
with a runtime of 18.2 min and a stacked recycle injection (2 passes through the
column to completetly remove both isomers). First isomer to elute is is S isomer
(21.34 g) with 98.2% ee. Second isomer to elute is R isomer (20.45 g) with 95.0%
ee to give the title compound.
Preparation 63
(R)-6-Amino-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile

Combine (R)-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid
benzyl ester (Preparation 62) (7.1 mmol, 2.44 g) in anhydrous ethanol (100 mL).
To the stirred solution add 5% palladium/carbon (600 mg). Purge and fill the
reaction vessel with hydrogen (3x) and stir the reaction mixture under hydrogen at
atmospheric pressure for about 18 h. Filter the reaction mixture through a Celite®
and wash the cake with methanol. Strip the filtrate to dryness and isolate the first
crop via crystallization from ethyl acetate/methanol/hexanes to yield 720 mg of pure
product. Strip the crystallization mother liquors to dryness, purify and isolate
additional product via flash chromatography (25% methanol/dichloromethane
isocratic) for a total yield of 1.17 g (78%). LCMS 100% (m/e) 212 (M+l, APES-
pos), 210 (M-1, APES-neg); 1H NMR (DMSO, 400 MHz): δ 11.29 (s, 1H), 7.81 (d,
1H, J=0.9 Hz), 7.36 (dd, 1H, J=8.4,0.9 Hz), 7.30 (dd, 1H, J=8.4,1.8 Hz), 3.11-3.02
(m, 1H), 2.87 (dd, 1H, J=15.4,4.8 Hz), 2.79-2.70 (m, 2H), 2.28 (dd, 1H, J=15.4,
8.4 Hz), 1.97-1.89 (m, 1H), 1.78 (s, 2H), 1.66-1.54 (m, 1H)
Preparation 64

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6-Amino-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile

Combine (4-oxocyclohexyl)carbamic acid tert-butyl ester (40.9 g, 192
mmol) and 4-cyanophenylhydrazine hydrochloride (25.0 g, 147 mmol) in
concentrated hydrochloric acid (100 mL) and water (200 mL) and heat at reflux for
18 h. Allow to cool and collect the precipitate. Wash with Na2CO3 solution and
azetrope with CHCl3, absolute EtOH, and CHCI3 again to obtain 25.5 g of a white
solid (82%). MS (ES): m/z 212 (M+1).
Preparation 65
(R)-(6-Cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid methyl ester

Combine 6-amino-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile (2.4
mmol, 0.5 g) and triethylamine (4.7 mmol, 0.66 mL) in DMSO (10 mL) with
stirring. Add methyl chloroformate (3.6 mmol, 275 µL) and stir the resulting
mixture at room temperature for 5-10 min. Quench with water (35 mL) and dilute
the reaction mixture with ethyl acetate (200 mL). Separate the layers and wash the
organic layer with with brine (100 mL). Back wash the brine layer with ethyl
acetate (2 x 100 mL) and dry the combined organic layers with magnesium sulfate.
Filter and concentrate in vacuo to provide crude product that is used without further
purification. LCMS of the reaction mixture prior to workup gave masses 270.0
(APCI-pos) and 268.0 (APCI-neg) for the desired product.
Preparation 66
(6-Cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid methyl ester

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Prepare the title compound by essentially following procedures as described
in Preparation 65, using 6-amino-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile
(Preparation 64) (500 mg, 2.37 mmol), triethyl amine (660 µl, 4.73 mmol) and
methyl chloroformate (275 µl, 3.55 mmol) to obtain 460 mg (75%) white solids. 1H .
NMR (DMSO, 400 MHz): δ11.35 (s, 1H), 7.85 (s, 1H), 7.31-7.39 (m, 3H), 3.72-
3.82 (m, 1H), 3.53 (s, 3H), 2.93 (dd, J = 4.8,14.8 Hz, 1H), 2.80-2.82 (m, 2H), 2.45-
2.52 (m, 1H), 1.97-2.02 (m, 1H), 1.72-1.79 (m, 1H).
Example 184
[6-Cyano-9-(3-fiuoro-benzyl)-2,3,4,9-tetrahydro-1 H-carbazol-3-yl] -carbamic acid
methyl ester

Combine (6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid
methyl ester (460 mg, 1.7 mmol) and anhydrous dimethylformamide (15 mL) under
nitrogen. Chill the mixture to 0 °C and add potassium bis(trimethylsilyl)amide
(0.5M toluene solution, 3.4 mL, 1.7 mmol). Stir the resulting mixture for 30
minutes, then add 3-fluorobenzyl bromide (210 µL, 1.7 mmol) and stir the reaction
mixture for 4 h allowing slow warming to room temperature. Quench the reaction
with water (50 mL) and extract the product with ethyl acetate (2 x 50 mL). Dry the
combined extracts with magnesium sulfate and concentrate in vacuo. Purify the
product via flash chromatography (25% ethyl acetate/hexanes isocratic) to afford
475 mg (74%) of a white solid. LCMS (Method E): 100% (m/z) 378 (M+1, APCI-
pos); 1H NMR (DMSO, 400 MHz):. δ 11.33 (s, 1H), 7.85 (s, 1H), 7.46 (d, 1H,

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J=7.9 Hz), 7.39-7.27 (m, 7H), 5.03 (q, 2H, J=8.8 Hz), 3.87-3.75 (m, 1H), 3.87-3.75
(m, 1H), 2.96 (dd, 1H, J=15.2,5.1 Hz), 2.85-2.77 (m, 2H), 2.55-2.49 (m, 1H), 2.07-
1.97 (m,lH), 1.85-1.71 (m, 1H).
Example 185
(6(R)-Cyano-9-pyridin-2-ylmethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic
acid methyl ester

Combine (6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid
methyl ester (1.4 mmol, 370 mg), anhydrous dimethylformamide (15 mL), cesium
carbonate (4.1 mmol, 1.34 g), and 2-chIoromethylpyridine hydrochloride (1.8 mmol,
295 mg). Stir the resulting slurry under nitrogen at 50 °C for 24 h. Quench the
reaction with slow addition of water (about 50 mL) to allow for base dissolution and
product precipitation. Collect the product via filtration and wash the cake with
hexanes. Dry the product at 40 °C under vacuum overnight to yield 385 mg (78%).
LCMS 93% (m/e) 361 (M+1, APES-pos); 1H NMR (DMSO, 400 MHz); 8 8.48
(ddd, 1H, J=4.8,1.8,0.9 Hz), 7.92 (d, 1H, J=1.3 Hz), 7.70 (td, 1H, J=10.9,3.9 Hz),
7.56 (d, 1H, J=8.4 Hz), 7.33 (d, 1H, J=7.5 Hz), 7.25 (ddd, 1H, J=7.5,4.8,0.9 Hz),
7.00 (d, 1H, J=7.9 Hz), 5.45 (q, 2H, J=12.4 Hz), 3.82-3.69 (m, 1H), 3.53 (s, 3H),
2.98 (dd, 1H, J=15.6,5.1 Hz), 2.93-2.84 (m, 1H), 2.80-2.68 (m, 1H), 2.53 (dd, 1H,
J=15.4,9.7 Hz), 2.06-1.97 (m, 1H), 1.82-1.69 (m, 1H).
Example 186
(R)-[6-Cyano-9-(6-fluoro-pyridin-2-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
carbamic acid methyl ester

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Prepare the title compound by essentially following the procedures as
described in Example 147 using (6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-
carbamic acid methyl ester (700 mg, 2.6 mmol), anhydrous dimethylformamide (30
mL), sodium hydride (60% mineral oil suspension, 12.5 mg, 3.1 mmol), and 2-
bromomethyl-6-fluoro-pyridine (Preparation 41) (594 mg, 3.1 mmol) as a solution
in 1 mL anhydrous DMF. Stir the resulting mixture for 30 min at room
temperature, and then quench the reaction slowly with water (100 mL). Extract the
crude product with ethyl acetate (2 x 100 mL) and wash the combined organic
extracts with brine. Dry with magnesium sulfate, filter and concentrate in vacuo.
Purify the product via flash chromatography (5% MTBE/dichloromethane for 15
min, step gradient to 10% MTBE). Combine the product fractions and concentrate
until solids start crystallizing. Add hexanes as anti-solvent, collect the product via
filtration, and wash the cake with hexanes to afford the first crop. Strip the mother
liquors and purify additional product as above to afford a total yield of 502 mg
(51%) of a white solid. LCMS 100% (m/e) 379 (M+l, APES-pos); 1H NMR
(DMSO, 400 MHz); δ 7.94-7.87 (m, 2H), 7.57 (d, 1H, J=8.4 Hz), 7.39 (dd, 1H,
J=8.4,1.3 Hz), 7.33 (d, 1H, J=7.5 Hz), 7.05 (dd, 1H, J=8.1,2.4 Hz), 6.91 (dd, 1H,
J=7.5,2.2 Hz), 5.43 (q, 2H, J=12.9 Hz), 3.82-3.70 (m, 1H), 3.53 (s, 3H), 3.53 (s,
3H), 2.99 (dd, 1H, J=15.2,5.1 Hz), 2.92-2.82 (m, 1H), 2.79-2.67 (m, 1H), 2.53 (dd,
1H, J=15.2,9.0 Hz), 2.53 (dd, 1H, J=15.2,9.0 Hz), 2.07-1.98 (m, 1H), 1.83-1.70
(m,1H).
Example 187
(R)-9-(3-fluorobenzyl)-6-isobutyrylamino-6,7,8,9-tetrahydro-5H-carbazole-3-
carboxylic acid methyl ester

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Combine (R)-N-(9-benzyl-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)isoburtyramide (Example 122) (4.00 g, 9.02 mmol), sodium acetate (2.96 g, 36
mmol), and dichloro[1,1'-bis(diphenyl-phosphino)ferrocene]paIladium (II)
dichloromethane adduct.(0.368 g, 0.45 mmol) in methanol (36 mL) in a Pan-
reactor. Charge with carbon monoxide (55 psi) and heat at 95 °C for 20 h.
Concentrate and chromatograph over silica eluting with 5-20% EtOAc/CHCl3 to
give 3.3 g (87%) of a white cottony solid that is slurried in diethyl ether for
collection by filtration. MS (ES): m/z 423 (M+1); HPLC: Rt = 1.93 min (100%).
Example 188
(R)-N-(9-Benzyl-6-isobutyrylamino-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic
acid

Add (R)-9-(3-fluorobenzyl)-6-isobutyrylamino-6,7,8,9-tetrahydro-5H-
carbazole-3-carboxylic acid methyl ester (2.54 g, 6.01 mmol) to a solution of excess
LiOH in raethanol/water/THF (33:33:33) and stir for 24 h at 70 °C. Concentrate in
vacuo, partition between water and EtOAc/Et2O. Make the aqueous layer acidic

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with aqueous HC1 and extract with EtOAc. Wash with brine, filter the solids from
the EtOAc layer and slurry in hot EtOAc. Collect by filtration and dry to give 2.35
g (96%) of a white solid. MS (ES): m/z 409 (M+1), HPLC: Rt = 1.93 (100%).
Example 189
(R)-[9-(3-Fluoro-benzyl)-6-isobutyrylamino-6,7,8,9-tetrahydro-5H-carbazol-3-yl]-
carbamic acid ethyl ester

Combine (R)-N-(9-(3-fluorobenzyl)-6-isobutyrylamino-6,7,8,9-tetrahydro-
5H-carbazole-3-carboxylic acid (Example 188) (0.281 g, 0.67 mmol) with
diphenylphosphorylazide (1.3 ml, 0.67 mmol), and triethylamine (0.73 mL, 0.67
mmol) in benzene (3 mL) and heat at reflux for 18 h. Add absolute ethanol and heat
for 4 h longer. Concentrate in vacuo, and partition the resulting residue between
EtOAc and water. Separate and dry the EtOAc layer over sodium sulfate. Filter
and concentrate in vacuo. Redissolve the resulting residue in a minimal amount of
EtOAc and pass through a pad of silica to afford 0.248 g (83%) of the title
compound, mp: 169-171°C; MS (ES): m/z 452 (M+1), HPLC: Rt = 2.2 min (89%).
Example 190
(R)-[9-(3-Huoro-benzyl)-6-isobutyrylamino-6,7,8,9-tetrahydro-5H-carbazol-3-yl]-
carbamic acid methyl ester

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Prepare the title compound from (R)-N-(9-(3-fluorobenzyl)-6-
isobutyrylamino-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid (Example 188)
(1.00 g, 2.4 mmol) by essentially following procedures as described in Example
189. Purify by silica gel chromatography, eluting with 20-80% EtOAc/hexanes
gradient to give 0.35 g (34%) of product, mp: 111-115 °C; MS (ES): m/z 438
(M+1).
Example 191
(R)-N-[6-Acetyl-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Treat (R)-N-[6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]isobutyramide (Example 123) (2.07 g, 5.32 mmol) with methyl magnesium
bromide (9 mL) in refluxing tetrahydrofuran for 18 h. Quench with MeOH, filter to
remove the solids, and concentrate in vacuo. Treat the residue with IN HCl/THF
and reflux for 2 h. Add ethyl acetate, filter to remove insoluable precipitate, and
concentrate the filtrate in vacuo to give 2.7g (74%) of a yellow solid. MS (ES): m/z
407 (M+1); HPLC: Rt = 2.3 min (97%).

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Example 192
(R)-N-[9-(3-Fluoro-benzyl)-6-isoxazol-5-yl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Combine (R)-N-[6-Acetyl-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-isobutyramide (Example 191) (0.055 g, 0.14 mmol) and
dimediylformamide dimethylacetal (0.81 g, 6.8 mmol) and heat at 100 °C for 82 h.
Concentrate in vacuo and treat the resulting residue with hydroxylamine
hydrochloride (0.012 g, 0.18 mmol) in dioxane at 23 °C for 1 h before warming to
40 °C briefly. Dilute with water and collect 0.029 g of a solid by filtration.
Recrystallize from EtOAc/hexanes to yield a light yellow solid, mp: 238-241 °C;
MS (ES): m/z 432 (M+1); HPLC: Rt = 2.59 (85%).
Preparation 67
Cyclopropanecarboxylic acid (4-hydroxycyclohexyl)amide

Add cyclopropylcarbonyl chloride (200 g, 1.74 mol) dropwise to trans 4-
aminocyclopropylhexanol (272 g, 2.60 mol) and potassium carbonate (360 g, 2.60
mol) in methanol (6.9 liters) in a twelve liter mechanically stirred flask. Stir at
room temperature under nitrogen for 18 h. Concentrate in vacuo, re-suspend the
residue in MeOH (1 liter) and methylene chloride (3 liters) and filter. Concentrate
the filtrate in vacuo, re-suspend in iso-propanol, filter and evaporate again to give
311 g (66%) of an off-white solid, mp: 220-222 °C; MS (ES): m/z 184 (M+1).

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Preparation 68
Cyclopropanecarboxylic acid (4-oxocyclohexyl)amide

Prepare the title compound from cyclopropanecarboxylic acid (4-
hydroxycyclo-hexyl)amide (379 g, 2.07 mmol) by essentially following procedures
as described in Preparation 2 to obtain 141 g (38%) of white crystals, mp: 155-157
°C; MS (ES): m/z 182 (M+1).
Preparation 69
Cyclopropanecarboxylic acid (6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-amide

Prepare the title compound from cyclopropanecarboxylic acid (4-
oxocyclohexyl)amide (51.3 g, 283 mmol) and 4-cyanophenylhydrazine
hydrochloride (48.0 g, 283 mmol) by essentially following procedures as described
in Preparation 3 to obtain 57.0 g (72%) of a pale yellow solid, mp: 231-233 °C; MS
(ES): m/z 280 (M+1).
Example 193
Cyclopropanecarboxylic acid [6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]amide

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Prepare the title compound from cyclopropanecarboxylic acid (6-cyano-
2,3,4,9-tetrahydro-1H-carbazol-3-yl)amide (3.00 g, 10.7 mmol) and 3-fluorobenzyl
bromide (2.2 g, 11.8 mmol) by essentially following procedures as described in
Example 1 to obtain 1.4 g (34%) of a beige solid, mp: 207-209 °C; MS (ES): m/z
388 (M+1); HPLC: Rt = 2.28 min (100%).
Example 194
(R)-Cyclopropanecarboxylic acid[6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-
1H-carbazol-3-yl]amide

Cyclopropanecarboxylic acid [6-cyano-9-(3-fluorobenzyl)-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]amide is resolved into its enantiomers via chiral
chromatography as described for Example 123, using iPrOH/MeOH/heptanes as
eluent. First to elute is Isomer 1 (R), as the title compound with e.e. >99.8% mp:
208-210 °C; MS (ES): m/z 389 (M+1).
Example 195
Cyclopropanecarboxylic acid [6-cyano-9-(6-fluoro-pyridin-2-ylmethyl)-2,3,4,9-
tetrahydro-1H-carbazol-3-yl3-amide

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Prepare the title compound from cyclopropanecarboxylic acid (6-cyano-
2,3,4,9-tetrahydro-1H-carbazol-3-yl)amide (Preparation 69) (10.0 g, 35.8mmol) and
2-bromomethyl-6-fluoro-pyridine (Preparation 44) (7.49 g, 39.4 mmol) by
essentially following procedures as described in Preparation 45 to obtain 4.30 g
(31%) of a salmon colored solid. Resolve the enantiomers using chiral
chromatography essentially as described for Example 194, but using 0.2%
DMEA/EtOH eluent. (R)-Isomer is first to elute. Slurry the solid in EtOAc and
filter to give the title compound. m.p. = 243-245 °C; MS (ES): m/z 389 (M+1).
Example 196
Cyclopropanecarboxylic acid [6-cyano-9-(pyridin-2-ylmethyl)-2,3,4,9-tetrahydro-
1H-carbazol-3-yl]-amide

Prepare the title compound from cyclopropanecarboxylic acid (6-cyano-
2,3,4,9-tetrahydro-1H-carbazol-3-yl)amide (Preparation 69) (19.0 g, 68.0 mmol), 2-
bromomethyl-6-pyridine hydrobromide (22.4 g, 88.4 mmol), and cesium carbonate
(57.5 g, 177 mmol) by essentially following procedures as described in Preparation
45. Resolve a portion of the racemic product by essentially following procedures as

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described in Example 195, but using 100% EtOH as eluent to obtain the R-isomer
as 8.56 g of yellow solid, e.e = 100%; mp: 239-241 °C; MS (ES): m/z 371 (M+1).
Example 197
N-[9-(3-Fluoro-benzyl)-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Mix N-(6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)isobutyramide (Preparation 3) (8.1 g, 20.8 mmol), Al-Ni catalyst (15.0 g, 231
mmol) in 90% formic acid (125 mL). Heat at reflux for 3 h, then dilute with MeOH
and filter hot. Concentrate and partition the residue between aqueous
NaHCO3/EtOAc. Dry the organic layer (MgSO4) and concentrate to give 5.9 g
yellow semi-solid. Purify using silica gel chromotagraphy, eluting with 30-75%
EtOAc in hexane to give 3.3 g (40%) as a white solid. MS (ES): m/z 393 (M+1),
391 (M-1); HPLC (Method B): Rt = 4.41 (100%).
Example 198
N-[6-Difluoromethyl-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide


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Following procedures as described by Lal, G. S., et. al. (7. Org. Chem
(1999) 64,7048) combine N-[9-(3-fluoro-benzyl)-6-formyl-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-isobutyramide (1.29 mmol, 506 mg) and bis(2-methoxyethyl)amine
sulfur trifluoride (21.9 mmol, 485 mg) in dichloromethane (8 mL). Reflux the
stirred reaction mixture under nitrogen for 7 h. Quench the reaction with saturated
aqueous sodium bicarbonate and dilute the mixture with ethyl acetate. Separate the
layers and wash the organic layer with water, dilute aqueous hydrochloric acid, and
water (3x). Dry the organics with sodium sulfate and strip to dryness. Purify the
product via flash chromatography (5% ethyl acetate/dichloromethane -25 min., step
gradient to 10% ethyl acetate) to yield 175 mg (33%). LCMS 100% (m/e) 415
(M+1, APES-pos); 1H NMR (DMSO, 400 MHz); δ 7.64 (s, 1H), 7.31-7.20 (m, 4H),
6.93 (td, 1H, J=11.9,4.2 Hz), 6.76-6.72 (m, 1H), 6.64-6.59 (m, 1H), 5.50 (d, 1H,
J=7.9 Hz), 5.26 (s, 2H), 4.46-4.36 (m, 1H), 3.16 (dd, 1H, J=15.4, 5.3 Hz), 2.81-2.71
(m, 1H), 2.70-2.61 (m, 2H), 2.36-2.25 (m, 1H), 2.15-1.97 (m, 2H), 0.00 (s, 2H),
1.62 (s, 2H), 1.14 (d, 3H, J=5.3 Hz), 1.13 (d, 3H, J=4.8 Hz).
Example 199
N-[9-(3-Fluoro-benzyl)-6-(methoxyimino-methyl)-2,3,4,9-tetrahydro-1H-carbazol-
3-yl]-isobutyramide

Add N-[9-(3-fluoro-benzyl)-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide (Example 197) (crude, 506 mg, 1.29 mmol) to a suspension of
methoxyamine hydrochloride salt (140 mg, 1.48 mmol) and pyridine (10 mL). Stir
the reaction at ambient temperature for 12 h. Remove the pyridine under vacuum
and dissolve the resultant residue in ethyl acetate (100 mL). Wash with saturated
aqueous copper sulfate (2 x 50 mL) and water (2 x 50 mL). Separate the organic

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layer and dry over magnesium sulfate, filter, and concentrate under vacuum to give
a greasy yellow solid. The solid was purified with column chromatography (silica
gel; 10% to 50% ethyl acetate in hexanes) to give 183 mg (34%) of the title
compound as a white solid, mp: 180-182 °C; ESI MS m/z 422 [C25H28FN3O2 +
H]+; 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.79 (s, 1H), 7.45 (d, 7 = 7.9 Hz,
1H), 7.26-7.17 (m, 2H), 6.93 (t, J= 7.1 Hz, 1H), 6.75 (d, 7 = 7.6 Hz, 1H), 6.62 (d,
J= 9.1 Hz, 1H), 5.49 (br d, J= 7.0 Hz, 1H), 5.24 (s, 2H), 4.40 (br s, 1H), 3.97 (s,
3H), 3.15 (dd, J= 15.8,4.7 Hz, 1H), 2.71-2.61 (m, 3H), 2.28 (septet, 7 = 6.8 Hz,
1H), 2.07-2.00 (m, 2H), 1.14 (d, 7 = 6.7 Hz, 3H), 1.12 (d, 7 = 6.7 Hz, 3H).
Example 200
(R)-N-[9-(3-Fluorobenzyl)-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide

Add Al-Ni catalyst [12635-27-7] (3.0 g) to a solution of (R)-N-(6-cyano-9-
(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Example 123)
(2.50 g, 6.42 mmol) in formic acid (96%, 40 mL) and water (5 mL). Heat the
reaction mixture to 90 °C for 18 h, then add 2 g fresh Al-Ni catalyst. Heat to reflux
for 18 h, cool to 60 °C, dilute with MeOH (30 mL), and resume heating. When
reflux has begun, filter the reaction mixture while hot through filter paper.
Concentrate the filtrate in-vacuo. Dilute the residue with water (30 mL) and
saturated aqueous NaHCO3 (30 mL), then extract into EtOAc (3 x 150 mL). Dry
the organics (MgSCO4), filter, and concentrate to give 2.25g (89%) of the title
compound as a brown solid. MS (ES): m/z 393 (M+1); HPLC (Method B): Rt =
4.57min(91%).

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Example 201
(R)-N-[9-(3-Fluorobenzyl)-6-(methoxyimino-methyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-isobutyramide

Add methoxyamine hydrochloride (613 mg, 7.34 mmol) to a solution of (R)-
N-[9-(3-fluorobenzyl)-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide
(Example 200) (2.40 g, 6.11 mmol) in pyridine (40 mL). Stir the reaction mixture
at room temperature for 18 h. Concentrate the reaction in-vacuo and dilute with
EtOAc (175 mL). Wash the organics with water (3 x 75 mL), dry (MgSO4), filter,
and concentrate to give the crude product (2.22 g) as a brown foam. Purify the
crude product on 40 g silica gel (15-80% EtOAc/hexanes) to give 261 mg (10%) of
the title compound as a yellow flaky solid. Re-purify the impure fractions on 40 g
silica gel (50-80% (1% (2M NH3/MeOH)/CH2Cl2)/hexanes) and combine the
purified materials to give 673 mg (26%) of the title compound as a yellow flaky
solid. MS (ES): m/z 422 (M+1), 420 (M-1); HPLC (Method B): Rt = 7.98 min
(99%).
Preparation 70
Cyclopropanecarboxylic acid [9-(3-fluorobenzyl)-6-formyl-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-amide

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Prepare the title compound by essentially following procedures as described
in Example 200, by using cyclopropanecarboxylic acid [6-cyano-9-(3-
fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amide (Example 193) (0.500 g,
1.29 mmol) and aluminum-nickel catalyst (1.3 g) in 90% formic acid (10 ml) to
obtain 0.32 g (64%) of a light brown solid. MS (ES): m/z 391 (M+1); 1H NMR
(DMSO-d6): δ 9.90 (s, 1H), 8.19 (d, 1H), 8.04 (s, 1H), 7.61 (d, 1H), 7.57 (d, 1H),
7.37 (dd, 1H), 7.15 (m, 1H), 6.81-6.92 (m, 2H), 5.44 (s, 2H), 4.08 (m, 1H), 3.03
(dd, 1H), 2.57 - 2.82 (m, 4H), 2.00 (m, 1H), 1.59 (m, 1H), 1.82 (m, 1H), 0.65 (m,
4H).
Example 202
Cyclopropanecarboxylic acid [9-(3-fluorobenzyl)-6-(methoxyimino-methyl)-
2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide

Combine cyclopropanecarboxylic acid [9-(3-fluoro-benzyl)-6-formyl-
2,3,4,9-tetrahydro-1H-carbazol-3-ylJ-amide (Preparation 70) (0.32 g, 0.82 mmol),
methoxylamine (0.21 g, 2.4 mmol), and sodium hydroxide (0.049 g, 1.3 mmol) in
EtOH (15 mL). Add enough water to dissolve the sodium hydroxide and stir for 18
h. Dilute with water and extract with EtOAc. Dry EtOAc extracts over Na2SO4 and

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filter twice through a pad of silica to give 0.21 g (61%) of an off-white solid. MS
(ES):m/z420(M+1).
Preparation 71
(R)-Cyclopropanecarboxylic acid [9-(3-fluorobenzyl)-6-formyl-2,3,4,9-tetrahydro-
1H-carbazol-3-yl]-amide

Combine (R)-cyclopropanecarboxylic acid [6-cyano-9-(3-fluorobenzyl)-
2,3,4,9-tetrahydro-1H-carbazol-3-yl]amide (Example 194) (3.70 g, 9.55 mmol) and
nickel -aluminum catalyst (10.0 g) in 90% formic acid and heat at 90-100°C for 18
h. Dilute with methanol, filter to remove catalyst, and concentrate the filtrate in
vacuo. Neutralize the filtrate by addition of solid NaHCC>3 after taking up in ethyl
acetate/water. Dry the ethyl acetate portion over Na2SO4, filter, and evaporate to
give 3.53 g (95%) of the title compound as a foam. MS (ES): m/z 391 (M+1); 1H
NMR(DMSO-d6): δ 9.90 (s, 1H), 8.19 (d, 1H), 8.04 (s, 1H), 7.61 (d, 1H), 7.57 (d,
1H), 7.37 (dd, 1H), 7.15 (m, 1H), 6.81-6.92 (m, 2H), 5.44 (s, 2H), 4.08 (m, 1H),
3.03 (dd, 1H), 2.57 - 2.82 (m, 4H), 2.00 (m, 1H), 1,82 (m, 1H), 1.59 (m, 1H), 0.65
(m,4H).
Example 203
(R)-Cyclopropanecarboxylic acid [9-(3-fluoro-benzyl)-6-(hydroxyimino-methyl)-
2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide

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Combine (R)-cyclopropanecarboxylic acid [9-(3-fluorobenzyl)-6-formyl-
2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide (Preparation 71) (1.50 g, 3.82 mmol),
hydroxylamine hydrochloride (0.801 g, 11.5 mmol), and sodium hydroxide (0.23 g,
5.76 mmol) and stir under nitrogen for 1.5 h. Dilute with water and extract with
EtOAc. Pass the dark residue through a pad of silica eluting with 50%
EtOAc/hexanes to give 1.27 g (82%) of the title compound. MS (ES): m/z 406
(M+1).
Example 204
(R)-Cyclopropanecarboxylicacid[9-(3-fluoro-benzyl)-6-(5-methyl-isoxazol-3-yl)-
2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide

Bubble propyne gas through a solution of (R)-cyclopropanecarboxylic acid
[9-(3-fluoro-benzyl)-6-(hydroxyirnino-methyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-amide (Example 203) (0.065 g, 0.16 mmol) in methylene chloride and NaOCl
solution maintained in a sealed tube. Cap the tube and stir at 23 °C for 16 h.
Partition the reaction between methylene chloride and water. Separate and dry the
organic portion over Na2SO4 to give 0.045 g of a tan solid. Purify by silca gel

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chromatography, eluting with 20-80% EtOAc/gradient to give an 0.030g (42%) of
an off-white solid, mp: 190-192 °C; MS (ES): m/z 444 (M+1).
Example 205
(R)- Cyclopropanecarboxylic acid [9-(3-fluoro-benzyl)-6-(l-methoxyimino-methyl)-
2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide

Prepare the title compound from (R)-cyclopropanecarboxylic acid [9-(3-
fluorobenzyl)-6-fonnyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide (Preparation
71) (3.10 g, 7.94 mmol), methoxylamine hydrochloride (1.99 g, 23.8 mmol), and
sodium hydroxide (0.48 g, 11.9 mmol) by essentially following procedures as
described in Example 204. Purify using silica gel chromatography eluting with
10% EtOAc/CH2Cl2 to provide 1.94 g (58%) of product, mp: 200-203 °C; MS (ES)
m/z 420 (M+1).
Example 206
Cyclopropanecarboxylic acid [9-(3-fluorobenzyl)-6-formyl-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-amide


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190
Prepare the title compound from cyclopropanecarboxylic acid [6-cyano-9-
(pyridin-2-y]methyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide (Example 196)
(1.00 g, 2.70 mmol) and Al-Ni catalyst (3.0 g) by essentially following procedures
as described in Example 200 to obtain 0.78 g (77%) of a tan solid. MS (ES): m/z
374 (M+1).
Example 207
Cyclopropanecarboxylic acid [6-(1-methoxyimino-methyl)-9-pyridin-2-ylmethyl-
2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide

Prepare the title compound from cyclopropanecarboxylic acid [9-(3-
fluorobenzy])-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide (Example 206)
(0.62 g, 1.66 mmol), methoxylamine hydrochloride (0.416 g, 4.98 mmol), and
sodium hydroxide (0.100 g, 2.5 mmol) by essentially following procedures as
described in Example 204 to give 0.54 g (81%) of a tan solid, mp: 88-92 °C; MS
(ES): m/z 403 (M+1).
Example 208
(R)-Cyclopropanecarboxylic acid [6-(l-methoxyimino-methyl)-9-pyridin-2-
ylmethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide

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Resolve cyclopropanecarboxylic acid [6-(1-methoxyimino-ethyl)-9-pyridin-
2-ylmethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide using chiral
chromatography on a Chiralcel OD-H column similarly as described for Example
194, but using 0.2% DMEA/MeOH as eluent. (R)-Isomer is first to elute.
Concentrate the eluent and slurry the residue in EtOAc. Collect by filtration to give
the title compound, mp: 215-217 °C; MS (ES): m/z 403 (M+1).
Preparation 72
Cyclopropanecarboxylic acid (6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-amide

Prepare the title compound from cyclopropanecarboxylic acid (6-cyano-
2,3,4,9-tetrahydro-1H-carbazol-3-yl)-amide (10.2 g, 36.5 mmol) and AI-Ni catalyst
(20.0 g) by essentially following procedures as described by in Example 205 to
obtain 6.80 g (66%) of a yellow-orange solid. MS (ES): m/z 283 (M+1).
Preparation 73
Cyclopropanecarboxylic acid [6-(methoxyimino-methyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-amide

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Prepare the title compound from cyclopropanecarboxylic acid (6-formyl-
2,3,4,9-tetrahydro-1H-carbazol-3-yl)-amide (Preparation 72) (6.50g, 57.3 mmol)
methoxylamine hydrochloride (4.81 g, 57.6 mmol) and sodium hydroxide (1.84 g,
46.0 mmol), by essentially following procedures as described in Example 202 to
obtain 6.00 g (84%) of product. MS (ES): m/z 312 (M+1).
Example 209
(R)- Cyclopropanecarboxylic acid [6-(l-methoxyimino-methyl)-9-pyridin-2-
ylmethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide

Prepare the title compound from cyclopropanecarboxylic acid [6-
(methoxyimino-methyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide (Preparation
73) (6.00 g, 19.3 mmol) and 2-bromomethyl-6-fluoro-pyridine (Preparation 44)
(4.03 g, 21.2 mmol) by essentially following procedures in Example 1 to obtain 9.2
g of an orange-brown foam. Purify the material by silica gel chromatography,
eluting with 20-80% EtOAc/hexanes to give 2.65 g of a yellow solid. Resolve the
enantiomers by chiral chromatography on a Chiralcel OD-H column similarly as
described for Example 194, but using 0.2% DMEA/MeOH as eluent. (R)-Isomer is
first to elute. Concentrate the eluent and slurry the residue in EtOAc. Collect by
filtration to give the title compound, mp: 223-225 °C; MS (ES): m/z 421 (M+1).

WO 2007/002181 PCT/US2006/024122
Preparation 74
N-[6-(2,2,2-Trifluoro-acetyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide

Mix 4-trifIuoroacetylphenylhydrazine (prepare essentially as described by
Tschirret-Guth, R. A., et. al., J. Am. Chem. Soc. (1999) 121,4731) (2.6 g, 12.7
mmol) and N-(4-oxocyclohexyl)isobutyramide (2.2 g, 12 mmol) in EtOH (100 mL)
containing concentrated HC1 (20 mL). Reflux the reaction for 18 h, cool to ambient
temperature and remove the EtOH under vacuum. Extract the product into EtOAc,
dry (MgSO4), filter and concentrate to give 2.0 g yellow semi-solid. Purify by silica
gel chromotagraphy (ISCO (120 g) using 50% to 100% EtOAc in hexane over 60
min). Obtain 590 mg (14%) N-[6-(2,2,2-trifluoro-acetyl)-2,3,4,9-tetrahydro-1H-
carbazoI-3-yl]-isobutyramide as a yellow solid. MS (ES) m/z 353 (M+1), 351 (M-
1); HPLC (Method B): Rt= 3.69 min (98%).
Example 210
N-[9-(3-Huoro-benzyl)^-(2,2,2-trifluoro-acetyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide

Mix N-[6-(2,2,2-trifluoro-acetyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide (Preparation 74) (428 mg, 0.93 mmol), m-fluorobenzyl bromide (216
mg, 1.11 mmol), CS2CO3 (650 mg, 2 mmol) and DMF (10 mL). Warm the reaction
at 50 °C for 18 h, cool and partition between water/brine/EtOAc. Separate and dry
the organic layer (MgSO4), filter and concentrate to give 590 mg of crude product.
Purify by silica gel chromatography, using 10% to 60% EtOAc/hexane to obtain 68

WO 2007/002181 PCT/US2006/024122
mg (16%) of the title compound as a pale yellow solid. MS (ES) m/z 461 (M+1);
HPLC:R, = 3.43min(95%).
Example 211
(R)-N-[6-Formyl-9-(2-methyl-thiazol-4-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-
yl]-isobutyramide

Follow the procedures essentially as described in Example 200, using (R)-N-
[6-cyano-9-(2-methyl-thiazol-4-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-
isobutyramide (Example 151) (134 mg, 0.34 mmol). Purify the crude product on 12
g silica gel {30-70% [4% (2 M NH4/MeOH)CHCl2/hexanes} to afford 58 mg
(43%) of the title compound as a white solid. MS (ES): m/z 396 (M+1), 394 (M-1);
1H-NMR (CDCl3): δ 10.01 (s, 1H), 8.01 (d, 1H, J=1.3 Hz), 7.72 (dd, 1H, J=8.4,1.8
Hz), 7.35 (d, 1H, J=8.4 Hz), 6.47 (s, 1H), 5.57 (d, 1H, J=7.9 Hz), 5.37 (d, 2H, J=2.6
Hz), 4.43 (m, 1H), 3.18 (dd, 1H, J=15.9,5.3 Hz), 2.86 (t, 2H, J=6.4 Hz), 2.73 (s,
3H), 2.66 (m, 1H), 2.34 (m, 1H), 2.15 (m, 1H), 2.03 (m, 1H), 1.16 (d, 6H, J=7.0
Hz).
Example 212
(R)-N-[6-(Methoxyimino-methyl)-9-(2-methyl-thiazol-4-ylmethyl)-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]-isobutyramide

WO 2007/002181 PCT/US2006/024122
I
Dissolve (R)-N[6-formyl-9-(2-methyl-thiazol-4-ylmethyl)-2,3,4,9-
tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 211) (53 mg, 0.13 mmol)
and methoxyamine-HCl (22 mg, 0.27 mmol) in pyridine (1 mL). Stir the reaction
mixture for 18 h at 25 °C. Dilute the reaction mixture with water (2 mL), IN HC1
(1 mL), and EtOAc (10 mL). Load the mixture onto a Varian ChemElut CE1005
solid-phase extraction cartridge (Varian part number 12198006), then elute, collect,
and concentrate 50 mL EtOAc to give the crude product (59 mg) as a white solid.
Purify on 8 g silica gel (50-60% EtOAc/hexanes) to afford 34 mg (62%) of the title
compound as a white solid. MS (ES): m/z 425 (M+1), 469 (M+HCO2); 1H NMR
(CDCl3): δ 8.16 (s, 1H), 7.63 (d, 1H, J=1.3 Hz), 7.44 (dd, 1H, J=8.6,1.5 Hz), 7.24
(d, 1H, J=8.5 Hz), 6.36 (s, 1H), 5.55 (d, 1H, J=7.9 Hz), 5.29 (td, 2H, J=24.7, 9.0
Hz), 4.41 (m, 1H), 3.96 (s, 3H), 3.13 (dd, 1H, J=15.4,4.8 Hz), 2.80 (m, 2H), 2.68
(s, 3H), 2.62 (dd, 1H, J=15.6,6.8 Hz), 2.30 (m, 1H), 2.14-1.97 (m, 2H), 1.14 (d,
6H, J=6.6 Hz).
Preparation 75
[6-Cyano-9-(3-fluoro-benzyI)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbamicacid
benzyl ester


WO 2007/002181 PCT/US2006/024122
Prepare the title compound by essentially following procedures as described
in Example 184 using (6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid
benzyl ester (Preparation 61) and 3-fluorobenzyl bromide to obtain 1.34 g (51%) of
product. LCMS 100% (m/e) 454 (M+l, APCI-pos).
Preparation 76
6-Arnino-9-(3-fluoro-benzyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile

Prepare the title compound by essentially following procedures as described
in Preparation 63 using [6-cyano-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]-carbamic acid benzyl ester to obtain crude product. Purify the
product via flash chromatography (10 to 25% methanol/dichloromethane) to obtain
a thick oil containing ~25% of a co-eluting impurity. Crystallize the product from
dichloromethane/hexanes to obtain a small amount (40 mg, 35%) for analysis.
LCMS 75% (m/z) 320 (M+1, APCI-pos)
Example 213
N-[6-Cyano-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-N'.N'-
dimethylmethanesulfamide

Mix 6-amino-9-(3-fluoro-benzyl)-6,7,8,9-tetrahydro-5H-carbazole-3-
carbonitrile (Preparation 76) (900 mg, 2.8 mmol), triethylamine (600 µL, 4.2 mmol)
in methylene chloride (15 mL). Add dimethylsulfamoyl chloride (391 µL, 3.64

WO 2007/002181 PCT/US2006/024122
197
mmol) and stir overnight at ambient temperature. Shake the reaction with
water/methylene chloride and dry the organic layer (Na2SO4). Concentrate to give
1.44 g tan oil. Purify by silica gel chromatography, using 10% to 60% EtOAc in
hexane to give 630 mg (53%) of the title compound as a white solid. MS (ES): m/z
427 (M+1), 425 (M-1); HPLC (Method B): Rt = 6.14 min (100%).
Preparation 77
Cyclopropanecarboxylic acid (2,2-difluoro-6,7,8,9-tetrahydro-5H-l ,3-dioxa-9-aza-
cycIopenta[6]fluoren-6-yl)-amide

Prepare the title compound by essentially following the procedures as
described in Preparation 3, using (2,2-difluoro-benzo[l,3]dioxol-5-yl)-hydrazine
hydrochloride salt (Preparation 10) and cyclopropanecarboxylic acid (4-
oxocyclohexyl)amide (Preparation 68) to provide 7.12 g (80%) of product.
Example 214
Cyclopropanecarboxylic acid (2,2-difluoro-9-pyridin-2-ylmethyl-6,7,8,9-tetrahydro-
5H-1,3-dioxa-9-aza-cyclopenta[b]fluoren-6-yl)-amide

Prepare the title compound by essentially following the procedures as
described in Example 1, using cyclopropanecarboxylic acid (2,2-difluoro-6,7,8,9-
tetrahydro-5H-l,3-dioxa-9-aza-cyclopenta[b]fluoren-6-yl)-amide and 2-
bromomethylpyridine hydrobromide. Purify the crude material by silica gel

WO 2007/002181 PCT/US2006/024122
chromatography eluting with 0-100% EtOAc/dichloromethane. Run a second
chromatography eluting with 5-40% EtOAc/dichloromethane to provide 0.42 g
(4.7%) of a white solid. MS (ES): m/z 426 (M+1).
Example 215
Cyclopropanecarboxylicacid[2,2-difluoro-9-(6-fluoro-pyridin-2-ylmethyl)-6,7,8.9-
tetrahydro-5H-1,3-dioxa-9-aza-cyclopenta[b]fluoren-6-yl]-amide

Prepare the title compound by essentially following the procedures as
described in Example 1, using cyclopropanecarboxylic acid (2,2-difluoro-6,7,8,9-
tetrahydro-5H-1,3-dioxa-9-aza-cyclopenta[b]fluoren-6-yl)-amide and 2-
bromomethyl-6-fluoro-pyridine (Preparation 44). Purify the crude material by silica
gel chromatography eluting with 5-50% EtOAc/dichloromethane to provide 0.29 g
(46%) of a white solid. MS (ES): m/z 444 (M+1).
Biological Data












WO 2007/002181 PCT/US2006/024122

"Ex" = Example Number
"nd" = not determined
"n" = number of trials used to calculate average values
*AREC50 n = l
In vivo data of select examples:

WO 2007/002181 PCT/US2006/024122

Seminal vesicle and/or prostate showed no statistical significant weight
change compared to castrated vehicle-only control group for the Examples listed in
Table IL

WO 2007/002181 PCT/US2006/024122
X-16663 Sequence Listing.ST25.txt
SEQUENCE LISTING
Eli Lilly and company
Tetrahydrocarbazole Derivatives Useful AS Androgen Receptor
Modulators
x-16663
3
Patentln version 3.3
1
15
DNA
Artificial

synthetic construct
1
ggttcttgga gtact 15
2
15
DNA
Artificial

Synthetic Construct
2
tgtacaggat gttct 15
3
15
DNA
Artificial

synthetic Construct
3
tgtacaggat gttct 15
Page 1

X-16663 OUS
We claim:
1. A compound of the formula:
wherein,
R1 represents hydrogen, hydroxy, cyano, halo, nito, (C1-C4)alkyl, halo(C1-
C4)alkyl, halo(C1-C4)alkoxy, SCH3, C( =S)NH2, CH=NOCH3, CH=NOCH2CH3,
C(NOCH3)CH3, C(NOCH2CH3)CH3, CIMMOH, CORla, ORlb, SO2Rlc, NHCORld,
or a 5 to 6 membered heteroaryl group optionally substituted with 1 or 2
substituents selected from the group consisting of amino, cyano, (C1-C4)alkyl, (C1-
C4)alkoxy, halo, halo(C1-C4)alkyl, or halo(C1-C4)alkoxy;
Rla represents hydrogen, amino, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, or
halo(C1-C4)alkyl;
Rlb represents (C1-C4)alkyl, cyclopropyl, or cyclopropylmethyl;
Rlc represents amino or (C1-C4)alkyl;
Rld represents (C1-C4)alkoxy;
R~ represents hydrogen, halo, (C1-C4)alkyl, or (C1-C4)alkoxy, or R1 and R2
together form a group of the formula

R3 represents NHCOR3a or Nl ISO2R3b;
R3a and R3b each independently represent at each occurrence (C1-C(,)alkyl,
halo(C1-C4)alkyl, (C1-C4)alkoxy, cyclopropyl, cyclobutyl, NH-(C1-C4)alkylaminc.
N,N-(C1-C6)dialkylamine, orN(CH3)OCH3; and

X-16663 OUS
R represents a phenyl group optionally substituted with 1 or 2 substitucnts
independently selected from the group consisting of amino, hydroxy, cyano, halo,
nitro, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, NH-(C1-
C4)alkylamine, N,N-(C1-C6)dialkylaminc, NHSO2CH3, or COOCH3; or a 5 to 6
memebered heteroaryl group optionally substituted with 1 or 2 substituents
independently selected from the group consisting of amino, (C1-C4)alkyl, halo, or
hydroxy,
or a pharmaceutically acceptable salt thereof.
2. The compound or salt according to Claim 1 wherein R1 represents
cyano, halo, (C1-C4)alkyl, CF3, OCF3, CMF2, OCHF2, CH=NOCH3,
CH=NOCH2CH3, C(NOCH3)CH3, C(NOCH2CH3)CH3.COR1a, OR1b, SO2R1c,
NHCOR1d, or a 5 to 6 membered heteroaryl group optionally substituted with 1 or 2
substituents independently selected from the group consisting of amino, cyano, (C1-
C4)alkyl, (C1-C4)alkoxy, halo, halo(C1-C4)alkyl, or halo(C1-C4)alkoxy.
3. The compound or salt according to Claim 2 wherein R1 represents
cyano, halo, (C1-C4)alkyl, CF3, OCF3, CHF2, OCHF2, CH=NOCH3,
CH=NOCH2CH3, C(NOCH3)CH3, C(NOCH2CH3)CH3. COR1a wherein R1a
represents hydrogen, hydroxyl, methyl, mcthoxy, ethoxy, amino, or trifluoromethyl;
OR1 wherein R1b represents methyl, ethyl, propyl, isopropyl, cyclopropyl. or
cyclopropylmethyl; SO2R|C wherein Rlc represents methyl or ethyl; Nl ICOR1d
wherein R1 represents methoxy or ethoxy: or a 5 to 6 membered heteroaryl group
selected from the group consisting of furanyl, thiophenyl, pyrrolyl, tetrazolyl,
thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, oxazolyl, isoxazolyl.
imidazolyl, pyrazolyl, pyridinyl, pyradazinyl, pyrimidinyl, pyrazinlyl, and triazinyl,
each optionally substituted with 1 or 2 substituents independently selected from the
group consisting of amino, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, halo, halo(C1-
C4)alkyl, or halo(C1-C4)alkoxy.
4. The compound or salt according to Claim 3 wherein R1 represents
cyano, bromo, chloro, fluoro, methyl, CF3, OCF3, CHF2, OCHF2. CH=NOCH3,

X-16663 OUS
CH=NOCH2CH3, C(NOCH3)CH3, C(NOCH2CH3)CH3, COR1a wherein R1a
represents hydrogen, hydroxyl, methyl, methoxy, ethoxy, amino, or trifluoromethyl;
OR1b wherein R1b represents methyl, ethyl, propyl, isopropyl, cyclopropyl, or
cyclopropylmcthyl; SO2R1c wherein R1c represents methyl or ethyl; NHCOR1d
wherein Rld represents methoxy or ethoxy; or a 5 to 6 membered heteroaryl group
selected from the group consisting of thiazolyl, thiadiazolyl, isoxazolyl, pyridinyl.
pyradazinyl, pyrimidinyl, each optionally substituted with a first substituent selected
from the group consisting of cyano, amino, (C1-C4)alkyl, or halo and a second
substituent that is (C1-C4)alkyl.
5. A compound or salt according to any one of Claims 1-4 wherein R2
represents hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoro,
bromo, chloro, or or R1 and R2 together form a group of the formula:

6. A compound or salt according to any one of Claims 1-5 wherein R3
represents NHCOR3a wherein R3a represents at each occurrence methyl, ethyl,
isopropyl, CH(C2H5)2, CH(CH3)CH2CH3, CF3, methoxy, ethoxy, cyclopropyl,
cyclobutyl, NH(CH3), or N(CH3)2; or R3 represents NHSO2R3b, wherein R1b
represents at each occurrence cyclopropyl, NH(CH3), N(CH3)2, or N(CH3)OCH3.
7. The compound or salt according to Claim 6 wherein R3 represents
NHCOR3a wherein R3a represents isopropyl.
8. A compound or salt according to any one of Claims 1-7 wherein R4
represents a phenyl group optionally substituted with 1 or 2 substitucnts
independently selected from the group consisting of amino, hydroxy, cyano, halo,
nitro, methyl, methoxy, CF3, OCF3, CHF2, OCHF2, NH(CH3), NH(C2H5), N(CH3)2,
NHSO2CH3, or COOCH3; or a 5 to 6 membered heteroaryl group selected from the
group consisting of furanyl, thiophenyl, pyrrolyl, tetrazolyl, thiazolyl, isothiazolyl.

X-16663 OUS
oxadiazolyl, triazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl,
pyridinyl, pyradazinyl, pyrimidinyl, pyrazinlyl, and triazinyl, optionally substituted
with one or two substituents independently selected from the group consisting of
amino, (C1-C4)alkyl, or halo.
9. The compound or salt according to Claim 8 wherein R4 represents a
phenyl group optionally substituted with 1 or 2 substituents independently selected
from the group consisting of amino, hydroxy, cyano, halo, nitro, methyl, methoxy.
CF3, OCF3, CHF2, OCHF2, NH(CH3), NH(C2H5), N(CH3)2, NHSO2CH3, or
COOCH3; or a 5 to 6 membered heteroaryl group selected from the group consisting
of thiophenyl, thiazolyl, pyridinyl, or pyra/.inyl, each optionally substituted with one
or two substituents independently selected from the group consisting of amino, (C1-
C4)alkyl, or halo.
10. The compound or salt according to Claim 9 wherein R4 represents a
phenyl group optionally substituted with 1 or 2 substituents selected from the group
consisting of amino, hydroxy, cyano, halo, nitro, methyl, methoxy, CF3, OCF3,
CHF2, OCHF2, NH(CH3), NH(C2H5). N(CH3)2, NHSO2CH3. or COOCH3; or a 5 to
6 membered heteroaryl group selected from the group consisting of thiophenyl.
thiazolyl, pyridinyl, or pyrazinyl, each optionally substituted with a substitucnt
selected from the group consisting of amino, methyl, fluoro, or chloro.
11. A compound of the formula

wherein,

X-16663 OUS
R1 represents cyano, halo, (C1-C4)alkoxy, halo(C1-C4)alkoxy, CH=NOCH3,
CH=NOCH2CH3, C(NOCH3)CH3, C(NOCH2CH3)CH3, or COH;
R3 represents NHCOR3a;
R3a represents (C1-C6)alkyl, (C1-C6)alkoxy, cyclopropyl, cyclobutyl, NH-
(C1-C4)alkylamine, or N,N-(C1-C6)dialkylamine; and
R represents a 5 to 6 membercd hetcroaryl group optionally substituted with
1 or 2 substituents independently selected from the group consisting of amino, (C1-
C4)alkyl, or halo, or a pharmaceutically acceptable salt thereof.
12. A compound or salt according to Claim 11 wherein R1 represents
cyano, fluoro, bromo, chloro, methoxy. OCF3, OCHF2, CH==NOCH3,
CH=NOCH2CH3, C(NOCH3)CI I3, C(NOCH2CH3)CH3, or COM.
13. The compound or salt according to Claim 12 wherein R1 represents
cyano, fluoro, bromo, chloro, methoxy, OCF3, CH=NOCH3, or COH.
14. A compound or salt according to anyone of Claims 11-13 wherein
R3 represents NHCOR3a, wherein R3a represents isopropyl, methoxy, cyclopropyl.
or N(CH3)2.
15. The compound or salt according to Claim 14 wherein R3 represents
NHCOR3a and wherein R3a represents isopropyl.
16. A compound or salt according to anyone of Claims 11-15 wherein
R4 represents a 5 to 6 membered hetcroaryl group seleceted from the group
consisting of thiophenyl, thiazolyl, pyridinyl, or pyrazinyl each optionally
substituted with 1 or 2 substituents independently selected from the group
consisting of amino, (C1-C4)alkyl, or halo.
17. The compound or salt according to Claim 16 wherein R4 represents a
5 to 6 membercd hetcroaryl group seleceted from the group consisting of

X-16663 OUS
thiophenyl, thiazolyl, pyridinyl, or pyrazinyl, each optionally substituted with a
substituent selected from the group consisting of amino, methyl, chloro, or fluoro;
18. A compound of the formula

CH2
R4
formula 1(b)
wherein.
R1 represents hydrogen, hydroxy, cyano, halo, nitro, (C1-C4)alkyl,
halo(C1-C4)alkyl, halo(C1-C4)alkoxy, C( = S)NH2, CH=NOCH3, CH-NOH. COR1a
OR1b, SO2R1c,NHCOR1d;
R a represents hydrogen, amino, hydroxy. (C1-C4) alkyl. (C1-
C4)alkoxy, or halo(C1-C4)alkyl;
R1b represents (C1-C4)alkyl. cyclopropyl, or cyclopropylmcthyl:
R1c represents (C1-C4)alkyl:
R1d represents (C1-C4)alkoxy;
R2 represents hydrogen halo, (C1-C4)alkyl, or (C1-C4)alkoxy, or R1
and R2 together represent a group of the formula

R3 represents NHCOR3a or NHSO2R3b;
R3n and R3b each independently represent at each occurrence (C1-
C6)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, cyclopropyl, cyclobutyl, NH-(C1-
C4)alkylamine, N,N-(C1-C6)dialkylaminc, or N(CH3)OCH3; and
R4 represents a phenyl group optionally substituted with 1 or 2
substituents independently selected from the group consisting of amino, hydroxy.
cyano, halo, nitro, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-

X-16663 OUS
C4)alkoxy, NH-(C1-C4)alkylaminc, N,N-(C1-C6)dialkylamine, NHSO2CH3, or
COOCH3, or a pharmaceutically acceptable salt thereof.
19. The compound or salt according to Claim 18 wherein R1 represents
hydroxy, cyano, fluoro, chloro, bromo. nitro, methyl, CF3, CHF2. OCF3. OCHF2.
CH=NOCH3, CH-NOCH2CH3, C(NOCH3)CH3, C(NOCH2CH3)CH3, COR1a. OR1h.
SO2R1c, orNHCOR1d.
20. The compound or salt according to Claim 19 wherein R1 represents
cyano, fluoro, chloro. bromo, methyl. CF3, CHF2, OCF3, OCHF2. CH-NOCH3.
CH-NOCH2CH3. C(NOCH3)CH3, C(NOCl2CH3)CH3. CORla wherein R1a
represents hydrogen, hydroxyl, amino, methyl, methoxy, ethoxy. or CF3: OR1b
wherein Rlb represents methyl, ethyl, propyl, isopropyl, cyclopropyl, or
cyclopropylmethyl; SO2R1C wherein R1c represents methyl; or NHCORld wherein
R represents methoxy or ethoxy.
21. A compound or salt according to any one of Claims 18-20 wherein
R2 represents hydrogen bromo, chloro. fluoro, methyl, or methoxy, or R and R"
together represent a group of the formula

22. A compound or salt according to any one of Claims 18-21 wherein
R represents NHCOR3a wherein R3a represents at each occurrence methyl, ethyl.
isopropyl. CH(C2H5)O2, CH(CH3)CH2CH3. CF3, methoxy, ethoxy, cyclopropyl.
cyclobutyl, NH(CH3), or N(CH3)2; or R3 represents NHSO2R3b, wherein R1b
represents at each occurrence cyclopropyl. NH(CH3). N(CH3)2. or N(CH3)OCH3.
23. The compound or salt according to Claim 22 wherein R3 represents
NHCOR3a wherein R3a represents isopropyl.

X-16663 OUS
214
24. A compound or sail according to any one of Claims 18-23 wherein
R' represents a phenyl group optionally substituted with a first subsitutcnt selected
from the group consisting of amino, hydroxy, cyano, bromo. chloro. fluoro, nitro.
methyl, mcthoxy. CF3, CIH2, OCF3. OCHF2, NH(C2H2) N(CH)2. NHSO2CH3, or
COOCH3 and a second subsitutcnt selected from the group consisting of bromo.
chloro, fluoro. or methyl.
25. The compound or salt according to Claim 24 wherein R1 represents a
phenyl group optionally substituted with a subsitutcnt selected from the group
consisting of cyano, bromo, chloro, lluoro. methyl, or mcthoxy.
26. A compound of the formula

wherein.
R1 represents a 5 to 6 membered hcteroaryl group optionally
substituted with 1 or 2 substituents independently selected from the group
consisting of amino, cyano, (C1-C4)alkyl. (C1-C4)alkoxy, halo. CF3, CHF2. OCF3, or
OCHF2;
R3a represents a (C1-C6)alkyl. halo(C1-C4)alkyl, (C1-C4)alkoxy,
cyclopropyl, cyclobutyl, NFI-(C1-C4)alkylaminc, N,N-(C1-C4)dialkylaminc, or
N(CH3)OCH3; and
R4 represents a phenyl group optionally substituted with 1 or 2
substituents independently selected from the group consisting of amino, hydroxy,
cyano, halo, nitro, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-

X-16663 OUS
C4)alkoxy, NH-(C1-C4)alkylaminc, N,N-(C1-C6)dialkylaminc, NHSO2CH3, or
COOCH3;
or a pharmaccutically acceptable sail thereof.
27. The compound or salt according to Claim 26 wherein R1 represents a
5 to 6 membered hetcroaryl selected from the group consisting of thiazolyl,
thiadiazolyl, isoxazolyl, pyridinyl, pyrada/inyl, pyrimidinyl, each optionally
substituted a first substituent selected from the group consisting of amino, methyl.
or fluoro, and a second substitutcnt that is methyl.
28. A compound or salt according to any one of Claims 26-27 wherein
R3a represents methyl, ethyl, propyl, isopropyl. cyclopropyl, or cyclobutyl.
29. A compound or salt according to any one of Claims 26-28 wherein
R4 represents a phenyl group optionally substituted with 1 or 2 substitucnts
independently selected from the group consisting of amino, hydroxy, cyano, halo.
nitro, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyI, halo(C1-C4)alkoxy, NH-(C1-
C4)alkylamine. N,N-(C1-C6)dialkylamine. NHSO2CH3, or COOCH,.
30. The compound or salt according to Claim 29 wherein R represents
a phenyl group optionally substituted with 1 or 2 substitucnts independently
selected from the group consisting of cyano. halo. (C1-C4)alkyl. or ((C1-C4)alkoxy.
31. The compound or salt according to Claim 30 whrein R1 represents a
phenyl group optionally substituted with a substituent selected from the group
consisting of cyano. fluoro, methyl, or methoxy.
32. A compound selected from the group consisting of (S)-N-(6-Cyano-
9-(3-fluorobcnzyl)-2,3,4,9-tctrahydro-1H-earbazol-3-yl)isobutyramidc:
Cyclopropanecarboxylic acid 16-cyano-9-(6-fiuoro-pyridin-2-ylmethyl)-2.3.4.9-
tetrahydro-1H-carbazol-3-yl]-amidc; (R)-Cyclopropanecarboxylic acid |6-( 1 -
methoxyimino-mcthyl)-9-pyridin-2-ylmethyl-2,3,4,9-tctrahydro-1H-carbazol-3-yl |-

X-16663 OUS
amide, or Cyclopropanecarboxylic acid [(R)-9-(6-fluoro-pyridin-2-ylmethyl)-6-
(methoxyimino-methyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide, or a
pharmaceutically acceptable salt thereof.
33. A pharmaceutical composition comprising as an active ingredient a
compound or salt according to any one of Claims 1-32 in combination with a
pharmaceutically acceptable carrier, diluent or excipient.
34. The use of a compound or salt according to any one of Claims 1-32
for the manufacture of a medicament for the treatment of reduced muscle mass or
strength, frailty, hypogonadism, osteoporosis, osteopenia, reduced bone mass or
density, bone fractures, sarcopenia, age related functional decline, reduced libido,
male or female sexual dysfunction, erectile dysfunction, depression, prostate cancer,
decreased cognitive ability, or lethargy.
35. A compound or salt according to Claim 1 for use in therapy.
36. A compound of formula (I) and/or a pharmaceutical composition
and/or the use of a compound substantially as herein described with reference and
examples.
Dated this 30th day of November 2007.

The present invention provides a compound of the formula : Formula (I) or a
pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising an
effective amount of a compound of Formula (1) in combination with a suitable carrier,
diluent, or excipient; and methods for treating physiological disorders, particularly frailty,
osteoporosis, osteopenia, and male and female sexual dysfunction comprising administering
to a patient in need thereof an effective amount of a compound of Formula (I).s

Documents:

04710-kolnp-2007-abstract.pdf

04710-kolnp-2007-claims.pdf

04710-kolnp-2007-correspondence others.pdf

04710-kolnp-2007-description complete.pdf

04710-kolnp-2007-form 1.pdf

04710-kolnp-2007-form 2.pdf

04710-kolnp-2007-form 3.pdf

04710-kolnp-2007-form 5.pdf

04710-kolnp-2007-international publication.pdf

04710-kolnp-2007-international search report.pdf

04710-kolnp-2007-pct priority document notification.pdf

04710-kolnp-2007-pct request form.pdf

04710-kolnp-2007-sequence listing.pdf

4710-KOLNP-2007-(11-01-2012)-CORRESPONDENCE.pdf

4710-KOLNP-2007-(11-01-2012)-FORM-27.pdf

4710-KOLNP-2007-ABSTRACT 1.1.pdf

4710-KOLNP-2007-ASSIGNMENT.pdf

4710-KOLNP-2007-CANCELLED PAGES.pdf

4710-KOLNP-2007-CLAIMS 1.1.pdf

4710-KOLNP-2007-CORRESPONDENCE OTHERS 1.1.pdf

4710-KOLNP-2007-CORRESPONDENCE OTHERS 1.2.pdf

4710-kolnp-2007-correspondence.pdf

4710-KOLNP-2007-DESCRIPTION (COMPLETE) 1.1.pdf

4710-KOLNP-2007-FORM 1.1.1.pdf

4710-KOLNP-2007-FORM 13.pdf

4710-KOLNP-2007-FORM 18.pdf

4710-KOLNP-2007-FORM 2.1.1.pdf

4710-kolnp-2007-form 27.pdf

4710-KOLNP-2007-FORM 3.1.1.pdf

4710-KOLNP-2007-PA.pdf

4710-KOLNP-2007-PETITION UNDER RULE 137.pdf

4710-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

abstract-04710-kolnp-2007.jpg


Patent Number 244647
Indian Patent Application Number 4710/KOLNP/2007
PG Journal Number 52/2010
Publication Date 24-Dec-2010
Grant Date 14-Dec-2010
Date of Filing 05-Dec-2007
Name of Patentee ELI LILLY AND COMPANY
Applicant Address LILLY CORPORATE CENTER, CITY OF INDIANAPOLIS, STATE OF INDIANA
Inventors:
# Inventor's Name Inventor's Address
1 GREEN, JONATHAN, EDWARD 7464 GLENDALE DRIVE, AVON, INDIANA 46123
2 FALES, KEVIN, ROBERT 6384 GRANNY SMITH LANE, AVON, INDIANA 46123
3 JADHAV, PRABHAKAR, KONDAJI 7422 FOX HOLLOW RIDGE, ZIONSVILLE, INDIANA 46077
4 MATTHEWS, DONALD, PAUL 7736 WAWASEE DRIVE, INDIANAPOLIS, INDIANA 46250
5 NEEL, DAVID, ANDREW 980 WILLIAMSBURG LANE, ZIONSVILLE, INDIANA 46077
6 SMITH, EDWARD, C R 9969 PARKWAY DRIVE, FISHERS, INDIANA 46037
PCT International Classification Number C07D 209/88
PCT International Application Number PCT/US2006/024122
PCT International Filing date 2006-06-21
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/693,604 2005-06-24 U.S.A.